Inadequate Empiric Antibiotic Therapy - T-Space - University of

78 Pages·2008·0.42 MB·English

by  Bassem Hamandi

Inadequate Empiric Antibiotic Therapy among Canadian
Hospitalized Solid-Organ Transplant Patients:
Incidence and Impact on Hospital Mortality

by

Bassem Hamandi

A thesis submitted in conformity with the requirements
for the degree of Master of Science
Graduate Department of Pharmaceutical Sciences
University of Toronto

© Copyright by Bassem Hamandi (2008)
Inadequate Empiric Antibiotic Therapy among Canadian
Hospitalized Solid-Organ Transplant Patients:
Incidence and Impact on Hospital Mortality

Master of Science (2008)

Bassem Hamandi

Graduate Department of Pharmaceutical Sciences, University of Toronto

ABSTRACT

Background: The incidence of inadequate empiric antibiotic therapy (IET) and its clinical
importance as a risk factor for hospital mortality in Canadian solid-organ transplant patients
remains unknown.
Methods: This retrospective cohort study evaluated all patients admitted to a transplant unit
from May/2002-April/2004. Therapy was considered adequate when the organism cultured was
found to be susceptible to an antibiotic administered within 24 hours of the index sample
collection time. Univariate and multivariate regression analyses were conducted to determine
associations between potential determinants, IET, and mortality.
Results: IET was administered in 169/312 (54%) transplant patients. Regression analysis
demonstrated that an increasing duration of IET (adjusted OR at 24h, 1.33; p < 0.001), ICU-
associated infections (adjusted OR, 6.27; p < 0.001), prior antibiotic use (adjusted OR, 3.56; p =
0.004), and increasing APACHE-II scores (adjusted OR, 1.26; p < 0.001), were independent
determinants of hospital mortality.
Conclusions: IET is common and appears to be an important determinant of hospital mortality in
the Canadian transplant population.
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ACKNOWLEDGEMENTS

I would like to thank my supervisor, Dr. Anne Holbrook for her support and guidance during my
graduate studies. Her constructive criticism and comments from the initial conception to the end
of this work were highly appreciated. Thank you to my committee members, Dr. James Brunton
and Dr. Manny Papadimitropoulos for their expert opinions, advice, and invaluable feedback at
our meetings. Dr. Michael Gardam’s expertise and feedback were much appreciated. I would
also like to thank Dr. Lehana Thabane for his statistical insight and advice. A special thanks to
Dr. Atul Humar for his unique expertise in transplant infectious diseases.

I am indebted to Mr. Gary Wong for his support, suggestions, and feedback during the early
planning and throughout the implementation of the study. I would also like to thank my
colleagues in the Pharmacy Department at The University Health Network for their help and
support.

Finally, I would like to thank my family and friends for their encouragement and support
throughout my studies.
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TABLE OF CONTENTS

ABSTRACT................................................................................................................................................................II
ACKNOWLEDGEMENTS.....................................................................................................................................III
LIST OF ABBREVIATIONS..................................................................................................................................VI
LIST OF TABLES...................................................................................................................................................VII
LIST OF FIGURES...............................................................................................................................................VIII
LIST OF APPENDICES..........................................................................................................................................IX
1.0 INTRODUCTION........................................................................................................................................1
1.1 STATEMENT OF THE PROBLEM.....................................................................................................................2
1.1.1 Infection after Solid-Organ Transplantation.............................................................................................2
1.1.2 Antibiotic Resistance.................................................................................................................................3
1.1.3 Inadequate Empiric Antibiotic Therapy....................................................................................................5
1.2 PURPOSE......................................................................................................................................................7
1.2.1 Objective 1.................................................................................................................................................7
1.2.2 Objective 2.................................................................................................................................................7
1.3 STATEMENT OF RESEARCH HYPOTHESIS.....................................................................................................7
1.4 RATIONALE FOR HYPOTHESIS.....................................................................................................................8
1.5 REVIEW OF THE LITERATURE......................................................................................................................8
2.0 METHODS.................................................................................................................................................25
2.1 STUDY LOCATION AND POPULATION.........................................................................................................25
2.1.1 Inclusion Criteria....................................................................................................................................25
2.1.2 Exclusion Criteria...................................................................................................................................25
2.2 STUDY DESIGN..........................................................................................................................................25
2.3 MICROBIOLOGY.........................................................................................................................................26
2.4 DEFINITIONS..............................................................................................................................................27
2.4.1 Infection vs. Contamination vs. Colonization..........................................................................................27
2.4.2 Infectious Episodes..................................................................................................................................28
2.4.3 Healthcare vs. ICU vs. Community Associated Infections.......................................................................28
2.4.4 Primary Site of Infection..........................................................................................................................28
2.4.5 Empiric Antibiotic Therapy.....................................................................................................................29
2.4.6 Adequate vs. Inadequate Empiric Antibiotic Therapy.............................................................................29
2.4.7 Previous Antibiotic Therapy....................................................................................................................30
2.4.8 Previous Graft Rejection and Immunosuppressant Use..........................................................................30
2.4.9 Multi-Drug Resistance.............................................................................................................................31
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2.5 OUTCOMES................................................................................................................................................31
2.6 STATISTICAL ANALYSIS............................................................................................................................31
3.0 RESULTS....................................................................................................................................................33
3.1 PATIENTS..................................................................................................................................................33
3.2 INADEQUATE EMPIRIC ANTIBIOTIC THERAPY...........................................................................................33
3.3 CHARACTERISTICS RELATED TO HOSPITAL MORTALITY...........................................................................40
3.4 LOGISTIC REGRESSION ANALYSIS.............................................................................................................43
3.5 SECONDARY OUTCOMES...........................................................................................................................44
4.0 DISCUSSION.............................................................................................................................................45
4.1 STUDY LIMITATIONS.................................................................................................................................48
4.2 IMPLICATIONS OF INADEQUATE EMPIRIC THERAPY...................................................................................49
5.0 CONCLUSIONS.........................................................................................................................................51
6.0 REFERENCES...........................................................................................................................................52
7.0 PUBLICATIONS AND ABSTRACTS TO DATE..................................................................................58
8.0 APPENDICES............................................................................................................................................59
APPENDIX I – LITERATURE REVIEW SEARCH STRATEGY.........................................................................................59
APPENDIX II – RAW DATA.......................................................................................................................................60
APPENDIX III – MULTIVARIATE LOGISTIC REGRESSION MODELLING......................................................................66
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LIST OF ABBREVIATIONS

AET Adequate empiric antibiotic therapy
APACHE Acute Physiology and Chronic Health Evaluation
ATG Anti-thymocyte globulin
BAL Bronchoalveolar lavage
CDC Centers for Disease Control
CLSI Clinical and Laboratory Standards Institute
CMV Cytomegalovirus
CNS Coagulase-negative staphylococci
CVC Central venous catheter
HAI Healthcare-associated infections
ICU Intensive care unit
IET Inadequate empiric antibiotic therapy
IL-2 Interleukin-2
MDR Multi-drug resistant
MIC Minimum inhibitory concentration
MOT Multi-organ transplant
MRSA Methicillin-resistant Staphylococcus aureus
NNIS National Nosocomial Infections Surveillance
OR Odds ratio
RR Relative risk
SOT Solid-organ transplant
UTI Urinary tract infection
VAP Ventilator-associated pneumonia
VRE Vancomycin-resistant enterococci
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LIST OF TABLES

TABLE 1. A SUMMARY OF 22 NON-RANDOMIZED COMPARATIVE COHORT STUDIES ASSESSING THE ASSOCIATION
BETWEEN IET AND MORTALITY..........................................................................................................................11
TABLE 2. CHARACTERISTICS OF PATIENTS RECEIVING ADEQUATE OR INADEQUATE EMPIRIC ANTIBIOTIC THERAPY.....34
TABLE 3. CHARACTERISTICS OF TRUE INFECTIOUS EPISODES TREATED WITH ADEQUATE OR INADEQUATE EMPIRIC
ANTIBIOTIC THERAPY..........................................................................................................................................36
TABLE 4. ORGANISMS CULTURED FROM PATIENTS WITH INADEQUATELY TREATED INFECTIOUS EPISODES..................38
TABLE 5. MULTI-DRUG RESISTANT ORGANISMS CULTURED AMONG PATIENTS RECEIVING ADEQUATE OR INADEQUATE
EMPIRIC ANTIBIOTIC THERAPY............................................................................................................................39
TABLE 6. INTRA-ABDOMINAL ORGANISMS CULTURED AMONG 17 PATIENTS RECEIVING ADEQUATE AND 30 PATIENTS
RECEIVING INADEQUATE EMPIRIC ANTIBIOTIC THERAPY.....................................................................................39
TABLE 7. REASONS FOR ADMINISTRATION OF INADEQUATE EMPIRIC THERAPY............................................................40
TABLE 8. PATIENT CHARACTERISTICS AMONG HOSPITAL SURVIVORS AND NONSURVIVORS.........................................41
TABLE 9. CULTURE CHARACTERISTICS AMONG HOSPITAL SURVIVORS AND NONSURVIVORS........................................42
TABLE 10. MOST COMMONLY CULTURED ORGANISMS AND THEIR ASSOCIATED MORTALITY AMONG PATIENTS
RECEIVING ADEQUATE OR INADEQUATE EMPIRIC ANTIBIOTIC THERAPY..............................................................42
TABLE 11. LOGISTIC REGRESSION ANALYSIS PREDICTING HOSPITAL MORTALITY.........................................................44
TABLE 12. OUTCOMES OF PATIENTS RECEIVING ADEQUATE VS. INADEQUATE EMPIRIC ANTIBIOTIC THERAPY..............44
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LIST OF FIGURES

FIGURE 1. INDIVIDUAL MULTIVARIABLE REGRESSION ANALYSIS OR (95% CI) OF 20 NON-RANDOMIZED COMPARATIVE
STUDIES ILLUSTRATING THE ASSOCIATION BETWEEN INADEQUATE ANTIBIOTIC THERAPY AND MORTALITY AT
END OF FOLLOW-UP. STUDIES CONDUCTED IN CRITICALLY ILL UNITS ARE SHOWN SEPARATELY NEAR THE
BOTTOM..............................................................................................................................................................13
FIGURE 2. AN ILLUSTRATION DEPICTING THE TIMELINE FOR DETERMINING INADEQUATE EMPIRIC ANTIBIOTIC
THERAPY. THERAPY WAS CONSIDERED ADEQUATE WHEN, FOR A GIVEN INFECTIOUS EPISODE, THE ORGANISM
CULTURED WAS SUBSEQUENTLY FOUND TO BE SUSCEPTIBLE TO AN ANTIBIOTIC THAT WAS ADMINISTERED
WITHIN 24 HOURS OF THE SAMPLE COLLECTION TIME.........................................................................................30
FIGURE 3. INCIDENCE AND RELATIVE RISK OF MORTALITY FOR INADEQUATE VERSUS ADEQUATE EMPIRIC ANTIBIOTIC
THERAPY AMONG HOSPITALIZED SOLID-ORGAN TRANSPLANT RECIPIENTS..........................................................34
FIGURE 4. DELAY IN ADMINISTRATION OF ADEQUATE EMPIRIC ANTIBIOTIC THERAPY AND ASSOCIATED MORTALITY
RATES.................................................................................................................................................................43
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LIST OF APPENDICES

APPENDIX I – LITERATURE REVIEW SEARCH STRATEGY.........................................................................................59
APPENDIX II – RAW DATA.......................................................................................................................................60
APPENDIX III – MULTIVARIATE LOGISTIC REGRESSION MODELLING......................................................................66
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1
1.0 INTRODUCTION

Healthcare–associated infections (HAIs) are infections that patients acquire in a healthcare
setting, during the course of receiving treatment for another condition (1). HAIs have imposed
significant burdens on our healthcare system, leading to increased morbidity, mortality, and
healthcare costs (2-4). As a result, the optimal management of HAIs has become an important
healthcare concern. HAIs typically affect patients who are immunocompromised, either because
of their age, underlying disease, or as a result of medical or surgical treatments (2). Along with
an aging population, the growing use of medical and surgical interventions, including invasive
devices and organ transplantation, have resulted in patients who are quite susceptible. The
pathogens involved and the body sites of infection are often related to the treatments and devices
used in intensive care units (ICUs). As a result, the highest infection rates are found among ICU
patients, who experience approximately three times higher rates than patients found elsewhere in
the hospital (2).

Upon clinical suspicion of infection, antibiotic therapy is often started early and empirically,
before pathogen identification, and before antibiotic susceptibilities are known. Deciding on the
use of an antibiotic requires a balance between the benefits of more potent broad-spectrum
antibiotics against their costs, including the potential for increased antibiotic resistance rates
caused by their overuse. Once the decision to initiate antibiotic therapy has been made, it should
ideally be directed at the most likely causative pathogens, taking into account local antibiotic
susceptibility patterns. As antibiotic resistance rates continue to increase, it appears that the
likelihood of administrating inadequate empiric antibiotic therapy (IET) also increases (5;6).
Most clinicians consider therapy to be inadequate when the antibiotic agent initiated