THE EPIDEMIOLOGY OF CUTANEOUS INJECTION‐RELATED INFECTIONS AMONG INJECTION DRUG USERS AT A SUPERVISED INJECTION FACILITY by ELISA LLOYD‐SMITH BSc, Queen’s University, Canada, 2003 BAH, Queen’s University, Canada, 2004 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Health Care and Epidemiology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) September 2009 © Elisa Lloyd‐Smith, 2009 ABSTRACT Background: To date, there is limited understanding of the epidemiology of cutaneous injection‐related infections (CIRI), including abscesses and cellulitis, among persons who inject drugs (IDU). The objectives of this thesis were to: describe the microbiology of wounds among IDU; examine the correlates of developing a CIRI; investigate determinants of CIRI care at a supervised injection facility (SIF); model predictors of Emergency Department (ED) visits for CIRI; and explore predictors of hospitalization for CIRI or related infectious complications. Methods: Quantitative data was derived from a prospective cohort study established to evaluate a SIF in Vancouver, Canada. A random sample of 1083 IDU attending the SIF were asked to complete an interview‐administered questionnaire, undergo semi‐annual HIV and hepatitis C virus testing and to consent to hospital database linkage. Results: Nearly 25% participants with a wound had a culture positive for community‐associated methicillin‐resistant Staphylococcus aureus (CA‐MRSA). Female sex, living in unstable housing, borrowing a used syringe, requiring assistance with injection and cocaine injection at least daily were associated with developing a CIRI. Female sex, living in unstable housing and heroin injection daily or more frequently were associated with receiving CIRI care by nurses at the SIF. Being referred to hospital by a nurse at the SIF was predictive of ED use for CIRI. Among females, residing in Vancouver’s Downtown Eastside was associated with an increased likelihood of ED use for CIRI, whereas among men, requiring assistance with injecting and being HIV positive were associated this outcome. Participants were more likely to be hospitalized for a CIRI or related infectious complication if they were HIV positive and referred to hospital by a nurse at the SIF. Importantly, length of stay in hospital was significantly shorter and less expensive among participants referred to hospital by a nurse at the SIF. Conclusions: CIRI are common among IDU in our setting and are associated with a number of individual harm and environmental factors. Our findings support the need for prevention and treatment efforts to reduce the burden of CIRI. Additional improvements in treatment protocols, such as wound management clinics within harm reduction services, are urgently needed. ii TABLE OF CONTENTS ABSTRACT.................................................................................................................................. ii TABLE OF CONTENTS ...........................................................................................................iii LIST OF TABLES......................................................................................................................vii LIST OF FIGURES..................................................................................................................... ix ACKNOWLEDGEMENTS.........................................................................................................x DEDICATION............................................................................................................................ xi CO‐AUTHORSHIP STATEMENT........................................................................................ xii CHAPTER 1: BACKGROUND, RATIONALE AND OBJECTIVES..................................1 1.1 INTRODUCTION .........................................................................................................................1 1.2 INJECTION DRUG USE...............................................................................................................1 1.3 CUTANEOUS INJECTION‐RELATED INFECTIONS ............................................................5 1.4 HOST, AGENT, ENVIRONMENT INTERACTION ................................................................5 1.5 STUDY SETTING ..........................................................................................................................9 1.6 STUDY SAMPLE .........................................................................................................................11 1.7 RATIONALE................................................................................................................................13 1.8 OBJECTIVES ................................................................................................................................14 1.9 SUMMARY ..................................................................................................................................19 1.10 REFERENCES...............................................................................................................................20 CHAPTER 2: CUTANEOUS INJECTION‐RELATED INFECTIONS AMONG INJECTION DRUG USERS: A REVIEW ..............................................................................32 2.1 INTRODUCTION ..........................................................................................................................32 2.1.1 Search strategy .......................................................................................................................33 2.2 EPIDEMIOLOGY ...........................................................................................................................33 2.3 MICROBIOLOGY ..........................................................................................................................36 2.4 RISK FACTORS..............................................................................................................................39 2.5 COMPLICATIONS ........................................................................................................................43 iii 2.6 TREATMENT .................................................................................................................................44 2.7 DISCUSSION..................................................................................................................................48 2.8 REFERENCES ............................................................................................................................................ 54 CHAPTER 3: COMMUNITY‐ASSOCIATED METHICILLIN‐RESISTANT STAPHYLOCOCCUS AUREUS IS PREVALENT IN WOUNDS OF INJECTION DRUG USERS ............................................................................................................................65 3.1 BACKGROUND.............................................................................................................................65 3.2 METHODS ......................................................................................................................................66 3.3 RESULTS .........................................................................................................................................68 3.4 DISCUSSION..................................................................................................................................70 3.5 REFERENCES.................................................................................................................................76 CHAPTER 4: RISK FACTORS FOR DEVELOPING A CUTANEOUS INJECTION‐RELATED INFECTION AMONG INJECTION DRUG USERS: A COHORT STUDY......................................................................................................................81 4.1 BACKGROUND.............................................................................................................................81 4.2 METHODS .....................................................................................................................................83 4.2.1 Data source: Scientific Evaluation of Supervised Injection ..............................................83 4.2.2 Outcome measure and explanatory variables ...................................................................84 4.2.3 Statistical analysis..................................................................................................................85 4.3 RESULTS .........................................................................................................................................86 4.4 DISCUSSION..................................................................................................................................87 4.5 CONLCUSION...............................................................................................................................92 4.6 REFERENCES.................................................................................................................................96 CHAPTER 5: DETERMINANTS OF CUTANEOUS INJECTION‐RELATED INFECTION CARE AT A SUPERVISED INJECTION FACILITY................................101 5.1 INTRODUCTION ........................................................................................................................101 5.2 METHODS ...................................................................................................................................103 5.2.1 Study sample.........................................................................................................................103 5.2.2 Study outcome .....................................................................................................................104 5.2.3 Statistical analysis................................................................................................................105 iv 5.3 RESULTS ......................................................................................................................................107 5.4 DISCUSSION ...............................................................................................................................110 5.5 REFERENCES...............................................................................................................................117 CHAPTER 6: DETERMINANTS OF CUTANEOUS INJECTION‐RELATED INFECTIONS AMONG INJECTION DRUG USERS AT AN EMERGENCY DEPARTMENT ........................................................................................................................123 6.1 INTRODUCTION .......................................................................................................................123 6.2 METHODS ....................................................................................................................................124 6.2.1 Study setting.........................................................................................................................124 6.2.2 Study sample........................................................................................................................125 6.2.3 Data collection and measures ............................................................................................125 6.2.4 Statistical analysis................................................................................................................126 6.3 RESULTS .......................................................................................................................................128 6.4 DISCUSSION ...............................................................................................................................130 6.5 REFERENCES..............................................................................................................................139 CHAPTER 7: DETERMINANTS OF HOSPITALIZATION FOR CUTANEOUS INJECTION‐ RELATED INFECTIONS AMONG INJECTION DRUG USERS.........144 7.1 BACKGROUND...........................................................................................................................144 7.2 METHODS ...................................................................................................................................145 7.2.1 Design and participants......................................................................................................145 7.2.2 Measurements ......................................................................................................................146 7.3 RESULTS ......................................................................................................................................149 7.4 DISCUSSION ...............................................................................................................................151 7.5 CONCLUSION.............................................................................................................................154 7.5 REFERENCES..............................................................................................................................157 CHAPTER 8: SUMMARY, CONTRIBUTIONS, RECOMMENDATIONS, FUTURE RESEARCH AND CONCLUSIONS ....................................................................................161 8.1 SUMMARY OF OBJECTIVES ....................................................................................................161 8.2 SUMMARY OF FINDINGS ........................................................................................................161 8.2.1 Microbiology .........................................................................................................................162 8.2.2 Risk factors ............................................................................................................................164 v 8.2.3 Nurse care at supervised injection facility ........................................................................165 8.2.4 Emergency Department treatment.....................................................................................166 8.2.5 Hospitalization ................................................................................................................................ 167 8.3 SUMMARY OF RISK ENVIRONMENT FRAMEWORK……………...…………………… 168 8.3.1 Host, agent, environment interaction ................................................................................170 8.3.2 Summary of “illness path” .................................................................................................171 8.4 CONTRIBUTIONS TO RESEARCH..........................................................................................172 8.5 UNIQUE CONTRIBUTIONS .....................................................................................................173 8.6 LIMITATIONS..............................................................................................................................176 8.7 RECOMMENDATIONS .............................................................................................................178 8.8 FUTURE RESEARCH..................................................................................................................180 8.9 CONCLUSION.............................................................................................................................182 8.10 REFERENCES.............................................................................................................................183 APPENDIX 1: HUMAN ETHICS APPROVAL CERTIFICATE…………….…………………......187 APPENDIX 2: Chapter 3….………………...........................................................................................190 APPENDIX 3: Chapter 5….………………...........................................................................................194 APPENDIX 4: Chapter 6….…………………………………………………………………………...200 APPENDIX 5: Chapter 7….………………...........................................................................................203 vi LIST OF TABLES Table 2.1: Summary of research on risk factors of cutaneous injection‐related infections………………………………………………………………………………….........51 Table 2.2: Antimicrobial agents for cutaneous injection‐related infections……..........53 Table 3.1: Antimicrobial susceptibility patterns of Staphylococcus aureus isolates from wound cultures according to pulsed‐field type……………………………….........75 Table 4.1: Univariate and multivariate analysis of developing a cutaneous injection‐related infection among Scientific Evaluation of Supervised Injection participants (n = 1065) ...............................................................................................................94 Table 5.1: Baseline profile of Scientific Evaluation of Supervised Injection participants receiving cutaneous injection‐related infection care at a supervised injection facility (n = 1080) ...................................................................................................115 Table 5.2: Univariate and multivariate Cox proportional hazard analyses of receiving cutaneous injection‐related infection care among Scientific Evaluation of Supervised Injection participants (n = 1065)..................................................................116 Table 6.1: Baseline characteristics, stratified by sex, among injection drug users at a supervised injection facility (n = 1083).........................................................................136 Table 6.2: Univariate and multivariate Cox proportional hazard analyses of time to Emergency Department use for a cutaneous injection‐related infection among 306 female injection drug users ............................................................................................137 Table 6.3: Univariate and multivariate Cox proportional hazard analyses of time to Emergency Department use for a cutaneous injection‐related infection among 762 male injection drug users ................................................................................................138 Table 7.1: Description of diagnosis for hospitalization events among Scientific Evaluation of Supervised Injection participants...............................................................155 Table 7.2: Univariate and multivariate Cox proportional hazard analyses of hospitalization for a cutaneous injection‐related infection or related infectious complication among injection drug users...........................................................................156 Table 3.2 Baseline characteristics of a sub‐sample of Scientific Evaluation of Supervised Injecting cohort, stratified by presence or not of a wound………………190 Table 3.3 Baseline characteristics among sub‐sample of Scientific Evaluation of Supervised Injecting cohort, stratified by the presence or not of a wound vii community‐associated methicillin resistant Staphylococcus aureus (CA‐MRSA) culture positive……………………………………………………………………………….191 Table 3.4 Frequency of wound locations among a sub‐sample of Scientific Evaluation of Supervised Injection cohort……………………………………………….193 Table 5.3 Frequency of reason for nurse treatment among Scientific Evaluation for Supervised Injection participants at the supervised injection facility………………194 Table 5.4 Frequency of reason for nurse visit among Scientific Evaluation for Supervised Injection participants at the supervised injection facility ……..……… 195 Table 5.5 Baseline profile of Scientific Evaluation of Supervised Injection participants receiving cutaneous injection‐related infection care at a supervised injection facility (n = 1080)……………………...…………………………………………..197 Table 5.6 Univariate and multivariate Cox proportional hazard analyses of receiving cutaneous injection‐related infection care among Scientific Evaluation of Supervised Injection participants: a model with the variable homelessness in place of unstable housing …………………..………………………....199 Table 6.4: Univariate and multivariate Cox proportional hazard analyses of time to Emergency Department use for a cutaneous injection‐related infection among injection drug users……………………….............................................201 Table 6.5 Number of Emergency Department visits among Scientific Evaluation of Supervised Injection cohort……………………………………………….202 Table 7.3 Overlap in diagnoses of cutaneous injection‐related infections or related infectious complications among Scientific Evaluation of Supervised Injection participants………………………………………………………………………..203 Table 7.4 Frequency of diagnoses of cutaneous injection‐related infections or related infectious complications among Scientific Evaluation of Supervised Injection participants………………………………………………………………………..204 Table 7.5: Baseline characteristics among injection drug users at a supervised injection facility who were hospitalized for a cutaneous injection‐related infection or related infectious complication……………………………………………..206 viii LIST OF FIGURES Figure 1.1: Modified agent, host and environment triad of infectious disease to incorporate risk environment framework...………………………………….……………. 9 Figure 1.2: Incorporation of chapter themes into an illness path of cutaneous injection‐related infections of injection drug users………………………………………18 Figure 3.1: Microbiology distribution of wounds among injection drug users............74 Figure 4.1: Proportion of Scientific Evaluation of Supervised Injection participants reporting a cutaneous injection‐related infection (January 1, 2004 – December 31, 2005, n = 1065)....................................................................................................93 Figure 5.1: Incidence of cutaneous injection‐related infection (CIRI) care among Scientific Evaluation of Supervised Injection participants, stratified by sex (n = 1080); log rank p‐value < 0.001 .......................................................................................114 ix ACKNOWLEDGEMENTS Sincere gratitude to my co‐supervisors, Drs. Samuel Sheps and Robert Hogg and my committee members, Drs. Thomas Kerr and Mark Tyndall, for their continued guidance and support. Also, to Dr. Evan Wood who provided inspiration and direction. To Drs. Mark Hull and Marc Romney, thank you for providing me with insight into microbiology. My work would not be possible without SEOSI participants, from whom I have learned. In addition to staff of Insite and VCH, I thank past and present staff at SEOSI and VIDUS‐in particular Steve Kain, Peter Vann, Deborah Graham, Calvin Lai, Kathy Li, Ruth Zhang and staff at the microbiology laboratory. I thank the Michael Smith Foundation, Canadian Institutes of Health Research and BC Centre for Excellence in HIV/AIDS for their generous support. My graduate study experience has been enriched by my peers: Angela Kaida, M‐J Milloy, Brandon Marshall, Viviane Dias Lima, Karissa Johnston, Kora DeBeck, Will Small, Beth Rachlis, Kate Shannon, Melanie Rusch, Sarah Fielden, Helen Hsu, Carmen Ng, Meghan Winters, Kristy Armstrong, Megan Alley and Margot Kuo. Taylor Stokes, Cobie Smulders, Erin Taylor‐Mitchell, Natania Tobias, Leah Kassautzki, Danya Fast, Emily Holmes, Susie Knight, and Laura Low Ah Kee thank you for keeping me even‐keeled. x DEDICATION Rob Lloyd‐Smith, Elizabeth MacKenzie, Alexandra Lloyd‐Smith, Patrick Lloyd‐Smith, Georgia Lloyd‐Smith xi CO‐AUTHORSHIP STATEMENT This is to certify that the work presented in this thesis was conceived, instrumented, written and disseminated by the PhD candidate. The co‐authors of the manuscripts that make up part of this thesis made contributions only as was commensurate with committee or collegial duties. The co‐authors reviewed each manuscript prior to submission for publication and offered critical evaluations; however, the student was responsible for overseeing and conducting data analyses, preparing the initial drafts of all manuscripts. In addition, the candidate was responsible for revising the manuscripts based on the suggestions of the co‐authors, submitting manuscripts for publication and preparing final revisions based on the comments of the journal editors and external peer reviewers. xii CHAPTER 1: BACKGROUND, RATIONALE AND OBJECTIVES 1.1 INTRODUCTION People who inject drugs (IDU) are an often stigmatized and marginalized subpopulation that frequently experiences barriers to receiving appropriate health care. IDU are susceptible to a myriad of health issues. A primary reason for hospital visits by IDU is cutaneous injection‐related infections (CIRI), which include abscesses and cellulitis. CIRI can result in serious morbidity and can lead to mortality. Existing research on this issue is scarce. Using an infectious disease epidemiological framework, this research project quantifies CIRI and examines risk factors for CIRI and determinants of treatment for CIRI at different locations. A more in‐depth understanding of CIRI facilitates optimal prevention and medical management, ideally reducing morbidity and mortality in this vulnerable population. 1.2 INJECTION DRUG USE Injection drug use is an international public health concern. Recent United Nation estimates suggest that worldwide there are 13.2 million IDU in 1 130 different countries or territories [1, 2]. IDU make up a highly marginalized subpopulation that experiences a higher level of morbidity and mortality than the general population [3, 4]. Rates of Emergency Department (ED) use and hospitalization are also elevated among IDU populations [5]. Mortality estimates among IDU are reported to be 13 times greater than in non‐drug using populations [6, 7]. Among HIV positive individuals in British Columbia, Canada, life expectancy among IDU is substantially lower than among individuals who are HIV positive but not IDU regardless of whether or not an individual is on Highly Active Antiretroviral Therapy (HAART) [8]. The focus of infectious disease epidemiology within the IDU population has been on HIV and HCV infections [1, 9]. Among 78 countries that have documented HIV prevalence among IDU, 25 countries report HIV to be greater than 20% in at least one site [2]. HCV infection among IDU has been reported in 57 countries or territories and 49 have reported a prevalence of greater than 50% in at least one site [10]. Co‐infection of HIV and HCV among IDU has been documented in 16 countries [10]. Sharing of injection paraphernalia, most notably sharing of used syringes, is considered a direct mode of blood‐borne viral transmission [3, 9]. Eastern Europe and Central Asia have reported that 2 two out of every three new HIV infections among IDU were related to a failure to use sterile injecting paraphernalia, such as a new syringe for each injection [9]. In several North American settings, declining HIV incidence among IDU has been attributed to the widespread implementation of harm reduction measures and addiction treatment. Recent estimates in New York City show a reduction of HIV incidence to below 2 per 100 person‐years [11] and, in Baltimore, following an increase in incidence in 2003 to 2.59 per 100 person‐ years, incidence among IDU declined to 0 in 2004 [12]. In Vancouver, the high incidence of 18 per 100 person‐years observed during 1997 [13] among local IDU has decreased substantially [14]. However, in Eastern Canada between 1995 and 2000, HIV incidence among IDU was transiently very high reflecting outbreak situations, at 6 per 100 person years in Montreal, 3.2 per 100 person years in Quebec City, and 7 per 100 person years in Ottawa [15]. Further, increases in HIV incidence have been observed in some settings among specific populations of IDU. In England, increases in HIV incidence among IDU have recently been observed following years of continual decline [16]. IDU are vulnerable to a wide range of infections including but not limited to: HIV, hepatitis B and HCV [17], tuberculosis, nectrotizing faciitis, tetanus, 3 wound botulism, abscesses, cellulitis, endocarditis, osteomyelitis, and septecaemia [18]. Some infections among IDU (e.g., abscesses) have methicillin‐resistant Staphylococcus aureus (MRSA) as the causative agent [19]. A dramatic increase in MRSA has been described as a major public health problem in North America [20‐22]. In 2005, there were an estimated 94,360 MRSA infections in the United States, and these infections are believed to have been associated with more than 18,000 deaths [21]. A recent retrospective cohort study of HIV positive individuals reported a 6.2‐fold increase in community‐associated MRSA (CA‐ MRSA) from 2000‐2003 [23]. Injection drug use has now been identified as a major risk factor for acquisition of MRSA [24], prompting concerns that the IDU population could constitute a key source of CA‐MRSA [25]. The US Centers for Disease Control and Prevention has called for enhanced surveillance of CA‐ MRSA and studies of MRSA incidence as a means of informing the design of preventive interventions [26]. The CA‐MRSA strain is of particular concern as it is associated with greater morbidity, including clinical presentation of severe skin and soft tissue infections and elevated levels of mortality [27]. In the UK in the early 2000s, public health authorities were on high alert due to reported fatalities among IDU [28]. Mortality was suspected to be due to 4 injecting heroin that had been contaminated with Clostridia into the muscle [28]. Several Clostridial species have been associated with development of severe illness of soft tissue infection and septicaemia among IDU, including C. novyi [29‐ 32], C. periforins [33], C. sordelli [34] and C. histolyticum [35]. During the outbreak scare, a documented death related to Clostridium myonecrosis occurred in British Columbia, Canada [36]. Despite the severity in morbidity of bacterial infections among IDU, a paucity of research on this subject has been conducted to date. A search of the number of publications listed in the U.S. National Library of Medicine (PubMed) in the last 5 years (using the terms ‘viral infection IDU’ and ‘bacterial infection IDU’) revealed that while there were >400 publications focused on viral infections among IDU, there were only 34 publications on bacterial infections among IDU during this same period. 1.3 CUTANEOUS INJECTION‐RELATED INFECTIONS Bacterial infections, such as CIRI, have not been well researched among IDU. CIRI, which include abscesses and cellulitis, are a frequent cause of morbidity and can lead to mortality among IDU, despite known prevention and medical management [37]. The prevalence of CIRI among IDU has been reported 5 to be between 6‐35% [37‐41]. CIRI are a common diagnosis and primary reason for hospitalization among IDU who visit the ED [42, 43]. In a study from Bristol, England, dramatic increases in diagnosis of CIRI of the trunk (566%) or groin (469%) occurred from 1997‐1998 to 2003‐2004 [44]. In Vancouver, Canada, 17% of all ED visits among IDU and 18% of all hospitalizations were due to CIRI [43]. CIRI can lead to further infectious complications such as endocarditis, considered to be one of the most serious infections among IDU [45]. A lack of rigorous assessment of CIRI is evident. Much of the literature is in the form of case reports or case series [46‐52] and therefore vulnerable to low internal and external validity. In addition, many studies are descriptive [53, 54], utilize different clinical and epidemiologic definitions of CIRI [46, 47, 49], or are based solely on hospital administrative databases [42, 43]. Longitudinal analyses using a large sample of IDU would allow for a better assessment of the prevalence, incidence and determinants of CIRI. Previous literature has used the term ‘skin and soft tissue infections’ or ‘injection‐related infections’ to describe abscesses and cellulitis among injection drug users. The term CIRI has been used to incorporate aspects of both terms. The use of the term ‘skin and soft tissue infections’ does not specifically indicate that these infections are injection‐related infections whereas, the term ‘injection‐ 6 related infections’ does not capture the fact that these infections are cutaneous in nature. The inclusion of both abscesses and cellulitis in the definition of the outcome CIRI, as opposed to focusing on one only, is related to the often polymicrobial nature and potential for overlap in diagnosis of CIRI (e.g., both abscess and cellulitis present). Further, although International Classification of Diseases (ICD) 10 (Chapter 7) codes separate abscess and cellulitis diagnoses, ICD 9 codes (Chapter 6) combines the diagnoses into one code. Therefore, it would not have been possible to measure, for example, only abscesses using ICD 9 code data. 1.4 HOST, AGENT, ENVIRONMENT INTERACTION The interaction of agent, host and environment provides a framework to understand the spread of infectious disease in a population [55]. Briefly, the agent is the etiologic cause of the infection or illness. The agent is important to identify because it is linked to the nature of illness, the possible modes of transmission, as well as the potential appropriate methods of prevention and treatment. The host is a susceptible human infected by the agent. Host factors, such as age, sex, co‐morbidities, socioeconomic status and various behaviours (e.g., drug use, hygiene practices, health resource utilization) shape vulnerability 7 to infectious disease among individuals. The environment is the milieu where factors from both the natural environment and human contact impact on the host susceptibility, therefore facilitating infectious disease transmission. In other words, the environment enables the interface of host and agent. In this research project, as displayed in Figure 1.1, the concept of environment in the agent, host and environment triad has been expanded to include Rhodes and colleagues risk environment concept, whereby social factors and physical aspects of place produce or reduce drug‐related harm [56‐58]. The risk environment includes factors in four domains – physical, social, economic and policy – and at two levels – micro and macro – that determine drug‐related harms [58]. This expansion incorporates a broader definition of environment than is included in the infectious disease triad. Broadening this definition is critical to examining the complex dynamic of physical, social, economic and policy environmental conditions that shape individual IDU risk behaviour, which is in turn related to their risk of infectious disease transmission. 8 Agent Environment Host Physical Social Economic Policy Figure 1.1: Modified host, agent and environment interaction to incorporate risk environment framework 1.5 STUDY SETTING The chapters of this thesis are analyses that describe, quantify and assess the effects of microbiological, individual and environmental factors that impact the development of CIRI and treatment settings of CIRI. The studies draw on previous literature about CIRI as well as longitudinal epidemiologic data from 9 an existing prospective cohort of active IDU based in the Downtown Eastside (DTES) of Vancouver, Canada. Vancouver is considered to be one of the world’s most livable cities because of its natural beauty and dense downtown area. However, directly adjacent to the downtown core is the DTES. The 10 city block radius of this neighbourhood is an epicenter of unstable housing, open and intense drug use and explosive outbreaks of infectious disease (e.g., HIV and HCV). There are an estimated 5,000 IDU in this setting [13]. Pronounced poverty, measured in mean income, contributes to the DTES being classified as Canada’s poorest postal codes [59]. To date and because of the uniqueness of this open drug scene, many drug–related services are available and extensive research has been conducted in this neighbourhood [59]. The first investigation into injection drug use in the DTES was from the Point Project, a case‐control study of 288 IDU set up in 1995 to examine risk factors for HIV infection [60, 61]. This study was the prototype for the Vancouver Injection Drug Users Study (VIDUS), which has enrolled over 1,500 IDU in an ongoing open prospective study [13, 60]. Research from VIDUS has examined a variety of aspects of drug use from individual and environmental levels. In terms of infectious disease research, VIDUS has identified that, among 10 participants, approximately 30% are HIV positive and 90% are HCV positive [14, 62]. Although vulnerable to cohort effects, whereby a saturation of infectious disease transmission occurs over time in a defined population, the data derived from this cohort captures the extensive spread of blood‐borne viral infections among IDU in the DTES [14]. Furthermore, research on blood‐borne viral transmission has determined several factors to be independently and positively associated with transmission, including frequent cocaine injection [14], unstable housing [63] and requiring help injecting [64]. This research has highlighted the devastating effects and extensiveness of drug use in Vancouver. 1.6 STUDY SAMPLE Collective research, strong political leadership and activism on the part of community organizations (e.g., Vancouver Area Network of Drug Users or VANDU) and the City of Vancouver (in particular drug policy coordinator Donald McPherson) led to the “Four Pillars” approach in 2001. This policy approach, based on prevention, treatment, harm reduction and enforcement, is the foundation of a comprehensive strategy to address drug‐related harms in the city [65]. As a commitment to the pillar of harm reduction, North America’s first sanctioned supervised injection facility (SIF) opened as a pilot project in the 11 DTES in September 2003 [66]. The SIF, named Insite, has been described extensively [67]. In brief, there are 12 booths where IDU inject pre‐obtained illicit drugs in a hygienic environment with sterile injecting paraphernalia and under nurse supervision. The SIF has been evaluated for its effect on the prevalence of risk factors for infectious disease transmission (such as syringe sharing), as well as on referral into drug and alcohol treatment [66, 67]. This research project investigates CIRI among a cohort of IDU that use the SIF, known as the Scientific Evaluation of Supervised Injection (SEOSI) cohort. The SEOSI cohort is comprised of a random and representative sample of IDU from the SIF [67]. Recruitment involves the use of random number generation to select blocks of time during Insite’s hours of operation (between 10:00am and 4:00am, seven days a week) [67]. During these times, users of the SIF were invited by nurses and the staff to enroll in the SEOSI study. A nominal financial stipend ($20) was provided for their participation at the research site, located a block away from Insite [67]. Participants are known to be high‐risk IDU at an elevated risk of blood‐borne infectious disease transmission and non‐fatal overdoses [68]. In 2006, the seroprevalence of HIV was reported to be 17% among SEOSI participants [69]. Recent research from the SEOSI cohort has found that use of the SIF has been associated with a number of benefits [70], including reductions in the prevalence of risk behaviours for blood‐borne 12 infections, such as syringe sharing [71], and the successful response of over 1000 overdoses [72, 73]. Further, the SIF has not resulted in the initiation into injection drug use [70]. SEOSI as well as this particular research study (refer to Appendix 1) has been approved by the Providence Health Care/University of British Columbia’s Research Ethics Board. 1.7 RATIONALE This research project seeks to address the paucity of research on CIRI by conducting microbiological and epidemiological investigation of CIRI and risk factors of CIRI development in IDU, as well as determinants of accessing care or treatment at different locations. This work examines CIRI from the perspective of the agent (e.g., microbiology), the host (e.g., sex, age, etc.) and the environment (e.g., living conditions, etc.). It examines features that both contribute to the development of CIRI (factors prior to CIRI development) and predict the location of care or treatment for CIRI (factors after CIRI development). By quantifying CIRI, risk factors of CIRI and predictors of accessing care or treatment at different locations, findings from this research project have major implications, among them the development of relevant, efficient and streamlined treatment for CIRI. 13 1.8 OBJECTIVES This thesis is presented in eight chapters. Chapter 1 provides an introductory context for the analyses that follow, including the background on IDU, CIRI, the infectious disease triad, the rationale, the study setting and sample and objectives of the studies. This research project addresses the following objectives: 1) To conduct a review of the biomedical literature of CIRI. Chapter 2 is a literature review examining the epidemiology, risk factors, microbiology, complications and treatment of CIRI. 2) To assess the prevalence of community‐associated methicillin‐ resistant Staphylococcus aureus of wounds among a sub‐sample of SEOSI participants. Chapter 3 is a descriptive study of the microbiology of wounds among a sub‐sample of SEOSI participants. 3) To evaluate risk factors for developing a CIRI among SEOSI participants. Chapter 4 is a longitudinal analysis of the prevalence and correlates of CIRI among SEOSI participants. 4) To investigate the socio‐demographic and behavioural predictors of receiving CIRI care by a nurse at the SIF among SEOSI participants. 14 Chapter 5 examines determinants of CIRI care at the SIF among SEOSI participants. 5) To examine the socio‐demographic and behavioural predictors of ED use for a CIRI at St. Paul’s Hospital among SEOSI participants. Chapter 6 investigates determinants of ED use for CIRI among SEOSI participants. 6) To assess the socio‐demographic and behavioural predictors of hospitalization for a CIRI or related infectious complication at St. Paul’s Hospital among SEOSI participants. Chapter 7 evaluates determinants of hospitalization for a CIRI or related infectious complications among SEOSI participants. Chapter 8 synthesizes the research findings and suggests possible contributions of this thesis to evidence‐based public policies regarding treatment models; it also recommends avenues for future research. The definition of CIRI essentially is an abscess or cellulitis among an individual who injects drugs. However, this outcome differs across chapters. The fourth chapter uses the most specific definition of this term since the outcome is based on an abscess or sore “at the site of injection”. The use of the term CIRI in Chapter 5 is related to the provision of CIRI care by nurses at the 15 SIF and includes the use of the terms abscess, cellulitis, wound or relevant wound management materials including ‘combiderm’ and ‘mesalt’. In Chapters 6 and 7, CIRI are defined according to ICD 9 or 10 codes for abscesses and cellulitis among SEOSI participants. The following diagram (Figure 1.2) is an “illness path” of the progression from exposure of an agent, through the development of a CIRI, towards treatment and ultimately towards cure of a CIRI. The concept of the “illness path” has been derived from the illness trajectory framework applied to chronic disease, as described by Corbin and Strauss [74]. The movement through the illness trajectory relates to an individual’s ability to manage the illness [74]. This figure reflects the interrelationship of the various themes explored throughout the following chapters (i.e., microbiology – Chapter 3, risk factors – Chapter 4, and treatment Chapters 5, 6, 7) but has been expanded and developed to reflect an “illness path”. In addition, the “illness path” provides a structure for examining the role of the risk environment introduced in Figure 1.1. Data acquisition and analysis of this research project are presented under each theme (i.e., microbiology, risk factors and treatment). The location contained within the treatment theme includes treatment at the SIF, ED at St. Paul’s Hospital and hospitalization at St. Paul’s Hospital. This research project provides information 16 on individual risk variables (e.g., requiring help injecting and frequent injection of cocaine) that should be interpreted in the context of Rhodes’ risk environment framework. When considering an IDU with individual behaviours it is imperative to apply the factors of Rhodes framework (i.e., physical, social, economic, policy) to understand the context and to consider appropriate interventions. An individual’s risk environment conceptualized by Rhodes may impact the movement through this path ‐ from exposure to infection to responding to symptoms to treatment to cure. IDU may be in situational and structural circumstances of risk that facilitate progression through the earlier part of this path to the development of CIRI. For example, the unstable environment an IDU may reside in, such as a single room occupancy hotel with shared washroom facilities, may promote the transmission of bacterial infections [75], and subsequently, the development of CIRI. Continuing along the pathway, an IDU may be in an environment that facilitates progression to treatment, for example, if an IDU is in contact with a nurse at the SIF who is able to provide appropriate treatment of a CIRI or referral to hospital for more serious CIRI [76]. Therefore, the risk environment is a useful application to the “illness path” because it considers an individual behaviour in the context of physical, social, economic and policy environmental factors that interact and shape individual behaviour. 17 ENVIRONMENT exposure Microbiology: CA-MRSA {CHAPTER 3} Risk Factor: socio-demgraphic, drug use behaviour {CHAPTER 4} CIRI responding to symptoms Treatment: Supervised Injection Facility {CHAPTER 5} Emergency Department {CHAPTER 6}, Hospitalization {CHAPTER 7} adherent to treatment cure Figure 1.2: Incorporation of chapter themes into an illness path of cutaneous injection‐related infections of injection drug users 18 1.9 SUMMARY CIRI are a frequent cause of morbidity and can lead to mortality among IDU despite known prevention and medical management. Current CIRI research is scarce and predominantly descriptive in nature. This thesis aims to enhance the literature in this area through works presented in eight distinct chapters. 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The impact of unregulated single room occupancy hotels on the health status of illicit drug users in Vancouver. Int J Drug Policy 2006; 17: 107‐114. 76. Small W, Wood E, Lloyd‐Smith E, Tyndall M, Kerr T. Accessing care for injection‐related infections through a medically supervised injecting facility: a qualitative study. Drug Alcohol Depend 2008; 98: 159‐162. 31 CHAPTER 21: CUTANEOUS INJECTION‐RELATED INFECTIONS AMONG INJECTION DRUG USERS: A REVIEW 2.1 INTRODUCTION Injection drug use remains a common practice world‐wide, with an estimated 200 million people having used illicit drugs at least once within the last 12 months [1]. Use of injection drugs is associated with significant morbidity and healthcare utilization. Research on injection drug use‐related morbidity has focused primarily on blood‐borne infections such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV) [2], whereas common cutaneous injection‐related infections (CIRI), such as abscesses and cellulitis, have been less well systematically investigated [3]. However, these skin infections are an important contributor to morbidity among injection drug users (IDU) and the associated complications can be fatal [3]. The term cutaneous injection‐related infection (CIRI) is used to describe common skin infections experienced by IDU [4]. The term encompasses entities such as abscesses and cellulitis, but excludes the uncommon but severe necrotizing fasciitis. The mechanism by which CIRI are established in IDU 1 A version of this chapter has been submitted for publication. Lloyd‐Smith E, Hull, M: Cutaneous injection‐related infections among injection drug users: a review. 32 relates to tissue trauma, direct effect of drugs, tissue ischemia and inoculation of bacteria. The aim of this review is to examine the epidemiology, microbiology, risk factors, complications and treatment of CIRI. 2.1.1 Search strategy: To retrieve pertinent literature for this review, U.S. National Library of Medicine (PubMed) and Google Scholar were used to identify English language articles. No timeframe for published articles was applied to this review. Search terminology included “abscess”, “cellulitis”, “skin infection”, “skin and soft tissue infection”, “injection‐related infection” in combination with “injection drug user” or “injection drug use”. Citations from identified articles were also reviewed. No grey literature was included. 2.2 EPIDEMIOLOGY The prevalence of abscesses and/or cellulitis amongst IDU is reported to be between 6‐35% approximately [5‐9]. A cross‐sectional study of IDU in San Francisco found that 32% had an abscess, 4% had cellulitis and 14% had both; these results were confirmed by physical examination [9]. Recently, from a cross‐ sectional study of community recruited IDU from seven locations across 33 England, 36% participants reported having a CIRI in the past year [10]. In an Australian study that sampled IDU from six different needle and syringe exchange programs, it was found that 16% of IDU reported having an abscess in the past year [11]. From a cohort study of IDU in Vancouver, visually confirmed CIRI have been reported to range between 6% and 10% over a two year period [4]. The incidence of these infections, although difficult to estimate, has been reported as high as 33 per 100 person‐years according to a prospective study of IDU in Amsterdam [8]. In contrast, incidence of common skin and soft tissue infections amongst the general populations has been estimated at 2.5 per 100 person‐years [12]. Abscesses and cellulitis account for the most common diagnoses and the most common reason for hospitalization among IDU who visit Emergency Departments (ED) [13, 14]. In an urban hospital in Vancouver, Canada, 17% of all ED visits among IDU and 18% of all hospitalizations, were due to CIRI [13]. In a study examining hospital admissions for CIRI, dramatic increases in diagnosis of abscess and cellulitis (566%, 469%, respectively) occurred from 1997‐ 1998 to 2003‐2004 [15]. This study was conducted with an administrative dataset with limited capacity to examine the reason for this increase; therefore, the cause of this increase cannot be determined from the data but the choice of illicit drug was discussed as potentially being a contributing factor by authors [15]. 34 CIRI most frequently occur at injection sites, usually involving the extremities. In a retrospective review of 242 patients with CIRI, patients with cellulitis presented with involvement of either arm or leg, whereas patients with abscesses presented predominantly with infection of arm, deltoid or buttock [16]. Similarly, in a prospective study of antibiotic therapy for cutaneous abscesses, common sites included the arm, hand and shoulder [17]. This likely reflects commonly accessed injection sites. Further, geographical location of IDU may impact injection practices [18]. A lack of rigorous assessments of skin infections among IDU is evident. Much of the literature is in the form of case reports or case series, [19‐24] and, therefore, vulnerable to low internal and external validity. In addition, many studies are descriptive [25, 26], utilize different clinical and epidemiologic definitions of CIRI, or are based on hospital administrative databases. Hospital‐ based data requires an IDU to seek medical care. Community‐based epidemiological studies are able to capture self‐reported CIRI and can include IDU who do not seek medical care. Although useful for describing general patterns in specific populations, these data sources are limited due to being unable to provide specific details on circumstances of exposure, risk and severity of CIRI. 35 2.3 MICROBIOLOGY Although severe infections and death have been associated with Clostridial species, most CIRI are either predominantly due to an aerobic bacteria (such as Staphylococcus aureus [S. aureus] or Streptococcal species.) or are polymicrobial (a mix of aerobic bacteria including S. aureus and Streptococcal species and anaerobic bacteria) [3]. The microbiology of CIRI has not been well described and has mostly been derived from a small number of case series and studies regarding the treatment of CIRI [16, 17, 21, 27, 28]. CIRI are often caused when bacteria are introduced into deeper tissues, or sterile sites within the body; the microbiologic etiology of the infection may be influenced by factors associated with drug manufacture and injecting technique. Most commonly, gram‐positive bacteria such as S. aureus are present on the skin surface [29] and during the injection process can be directly inoculated into deeper tissues at the site of injection, resulting in infection [3]. Secondly, bacteria may contaminate injection drug use paraphernalia (e.g., cookers, filters, alcohol swabs, water, citric acid, needles and syringes), resulting in CIRI due to bacteria not commonly found as part of the host skin flora. For example, oral bacteria may contaminate drug preparation when the injection needle is licked or tablets are crushed between teeth before injection [5, 9]. Thirdly, the drug itself may contain bacteria that are 36 subsequently introduced into the body. For example, contamination during the drying process of black tar heroin, found commonly in San Francisco, has been associated with wound botulism from Clostridium botulinum and with tetanus from C. tetani [30]. The microbiology of CIRI is altered by drug preparation. Heroin requires heating to dissolve the drug into an injectable form. Heating decreases gram‐ negative bacterial contamination and, therefore, organisms causing CIRI are more likely to be gram‐positive skin flora, such as S. aureus [31]. However, not all heroin requires heating. Comparatively, other drugs such as pentazocine (Talwin), are soluble in water and do not need to be heated for the drug to dissolve before injection. Consequently, individuals who inject are more vulnerable to gram‐negative infections [30]. Diluents such as citric acid and lemon juice with a pH of 2.5 are used to dissolve heroin and can kill non‐spore‐ forming bacteria. Spore‐forming bacteria such as Clostridial species may preferentially survive and cause a CIRI [31]. S. aureus are the most commonly reported aerobic bacteria of CIRI [21, 29, 32]. Other organisms include Group A Streptococcus [33] and Streptococcus milleri [19]. Anaerobic bacteria contributing to CIRI include Fuscobacterium nucleatum [21, 34], Peptostreptococcus micros [34], Clostridium botulinum [30], C. 37 myonecrosis [23], C. sordellii [35], C. novyi [31], C. tetani [36], Actinomyces odontolyticus [37], Prevotella buccase [37], Prevotella melaninogenica [37]. Methicillin‐resistant S. aureus (MRSA) has been a focus of concern because of its resistance to many antibiotics. IDU have long been identified as being at increased risk for MRSA [38, 39]. MRSA in this setting was typically genotypically matched to strains endemic in hospital settings [40]. Recently however, there has been recognition of novel strains of MRSA arising predominantly in the community setting. Community‐associated MRSA (CA‐ MRSA) infections tend to be more severe in nature and are caused by a predominant strain (USA300), which is associated with production of novel virulence factors such as the Panton‐Valentine leukocidin (PVL) [41]. The USA300 strain has become the predominant cause of skin and soft tissue infections in many locales in North America. In prospective laboratory‐based surveillance of S. aureus associated skin and soft tissue infections presenting to an urban hospital in Atlanta, Georgia, 63% of S. aureus infections were CA‐MRSA and 99% of CA‐MRSA isolates tested belonged to the USA300 pulsed‐field group [42]. Similarly, surveillance of adults presenting with acute purulent skin and soft tissue infections to ED in 11 cities in the United States in 2004 found that S. aureus was the most common isolate identified (76% of all wounds) and that the majority of S. aureus was in fact MRSA (59% prevalence overall), with USA300 38 accounting for 97% of MRSA isolates [43]. The severity of the skin and soft tissue infections caused by CA‐MRSA strains is thought to be due in part to the elucidation of the PVL, which is capable of destroying leukocytes and leading severe tissue damage [44]. Injection drug use has been associated as a broad risk factor for CA‐MRSA infection [45] and microbiologic assessments of CIRI have shown an increase in MRSA prevalence, with MRSA comprising 5% of S.aureus cultures from upper arm abscesses in IDU 1999 and 82% in 2005 [32]. 2.4 RISK FACTORS Studies of IDU specific risk factors of CIRI are presented in Table 1. The most consistent risk factor for abscess development is ‘skin popping’ [29]. Skin popping has been defined as intramuscular or subcutaneous injection [9], whereas other studies only included subcutaneous injection and described intramuscular injection as ‘muscling’ [46]. Regardless, injecting into the skin or muscle creates a niche environment in which multiple types of organisms reside and flourish; this niche is removed when injection is restricted to the vein [47]. There are IDU that choose to inject intramuscularly or subcutaneously. However, some IDU inject intramuscular or subcutaneously because of sclerosed veins that are no longer accessible for direct injection. Intramuscularly or subcutaneous injection can also occur inadvertently [46]. 39 ‘Booting’, the practice of drawing blood into the syringe before injection to determine whether a vein has been accessed, has also been associated with a greater likelihood of developing a CIRI [5]. Other injection practices also influence the likelihood of developing a CIRI. Not cleaning the skin with an alcohol swab prior to injecting [5, 48], reusing needles [5] and sharing a filter [49] are all independently and positively associated with developing a CIRI. Frequency of injection has also been related to the development of a CIRI [6, 8]. Furthermore, repeated injection at one site, as opposed to rotating the location of injection, damages skin and soft tissue with local ischemia and necrosis and results in increased susceptibility to infection [26]. The drugs used by IDU vary in availability, purity and geographical setting. The risk of developing a CIRI also varies according to drug. Speedball (a combination of heroin and cocaine) injection has been associated with CIRI in several studies from San Francisco and Amsterdam [5, 8, 30], whereas cocaine injection has been associated with CIRI in Vancouver [6]. Injecting heroin four or more times per day was linked with developing CIRI in a study from Paisley, Scotland but, as stated above, the frequency of the drug injected may have also be related to development of a CIRI [49]. The injection of black tar heroin has been associated with developing a CIRI, particularly when skin‐popping is 40 employed, because devitalized tissue creates an anaerobic environment conducive to the growth of Clostridial species and subsequent toxin formation [36]. Different drugs are associated with varied effects on the skin and subcutaneous tissues [3]. More specifically, the chemical effects of certain drugs and dilutents may compound the tissue injury by causing vasospasm and thrombosis. Cocaine, in particular, has been associated with vasoconstriction [50]. Speedball injection has also been reported to induce soft tissue ischemia [30]. Heroin, which is not readily soluble in water, is often dissolved in lemon juice or citric acid and heated prior to injection. These diluents have an approximate pH of 2.5. Repetitive injection of acid and particulate debris ‐ commonly found in illicit drugs ‐ into muscle decreases muscle aerobicity and creates the conditions for the more favourable growth of anaerobes [36]. The number of years of injecting has been inconsistently associated with CIRI. Inexperience may heighten an individual’s likelihood to develop CIRI [29]. Alternatively, after many years of repeated injecting, veins become sclerosed, increasing the need to inject under the skin or muscle and placing this group at risk of developing a CIRI [29]. Although the relationship between common bacterial infections and HIV is uncertain [51], the association between HIV status and CIRI has been reported 41 [6, 8]. This may be related to reduced immune function [29, 51]. In addition, people living with HIV are more likely to develop complications from CIRI, such as endocarditis [8]. Female gender has been identified as another consistent risk factor for CIRI, even after adjusting for sex trade involvement [6, 8]. Biological differences between males and females, such as females having smaller, less easily accessible veins, may be associated with more frequent skin popping and, therefore, the likelihood of developing an abscess [5, 52]. Furthermore, females more often than males report requiring help in order to inject [52], which may place them at an elevated risk for a ‘missed hit,’ or an injection that misses the vein. Sex trade involvement has been independently and positively related to developing an abscess in several studies [6, 8]. Environmental conditions have been reported to be associated with the development of CIRI. According to Rhodes’ risk environment framework, a broad understanding of the environment, beyond the physical environment, is important to consider when assessing drug‐related harms, since physical, social, economic and policy environmental factors shape the context in which individual behaviour occurs [53]. Individuals who are homeless and those that reside in unstable housing have been reported to be at elevated risk for CIRI development [4]. Public injecting has also been associated with development of 42 infections [11]. Indeed, both living and injecting environments may structurally and situationally promote poor hygiene [54] or risky injecting environments conducive to injecting in a high‐risk location like the groin for a ‘quick fix’ [55]. 2.5 COMPLICATIONS CIRI can result in a myriad of complications, including bacteremia, sepsis and death [3, 29]. The anatomical site of the complication can be either local or distal [56]. Examples of local complications include contiguous spread of the infection to the surrounding connective tissue with resultant tenosyovitis [26], septic arthritis [26], osteomyelitis [57], suppurative thrombophlebitis [25, 58], arterial aneurysms [3] and mycotic aneurysms [25]. A local complication that may arise from an injection‐related abscess is a non‐healing ulcer [59], which arises on the basis of venous insufficiency from venous damage related to repeated injection. The vascular periphery of the ulcer can be used as an injection site, perpetuating the ulcer [59]. Reported distal complications of CIRI include endocarditis [60], osteomyelitis [57, 56], septic arthritis [26, 57], spinal abscess [26, 56] and intracranial abscess [56]. The most commonly reported and serious complication of CIRI is endocarditis, mostly of the tricuspid heart valve, caused by Staphylococci or gram‐negative bacteria [60, 61]. Incidence of endocarditis among 43 a cohort of injection drug users from Amsterdam has been reported to be 1.3/100 person‐years [8]. Distal infections of the skeletal system, typically caused by Serratia marcescens or Pseudomonas aeruginosa, present as septic arthritis of the sternoclavicular or sacroiliac joints or osteomyelitis of the spine originating from a discitis (disc space infection) [26, 57]. The potential for serious clinical outcomes following Clostridia species infections is high. Wound botulism, caused by Clostridium botulinum, can lead to paralysis of the arms, legs, trunk and respiratory system and death [9]. Tetanus, caused by Clostridium tetani, can lead to toxin induced respiratory failure and death [62]. Complications of CIRI vary in severity, mechanism of spread and location. Timely diagnosis and management of the complications of CIRI reduce morbidity and mortality [62]. 2.6 TREATMENT Self‐treatment for complications such as an abscess (i.e., incision and drainage) is common amongst IDU [16]. If an IDU seeks medical attention, treatment of CIRI largely occurs in the ED of hospitals, instead of within a 44 primary care setting. Treatment for CIRI often involves incision and drainage (for abscesses) and a course of antibiotics administered either intravenously or orally [16, 63]. There have been numerous reviews of antibiotic therapy for non‐ injection related soft tissue infections, but treatment options amongst IDU populations have been reported to be poorly described [64, 65]. The specific choice of antimicrobial agent is based on clinical features including the individual’s immune status and comorbid diseases, careful physical examination of the lesion or wound, severity of infection and local bacterial resistance patterns (e.g., prevalence of CA‐MRSA) [63]; these factors are often different among IDU. In general, antibiotic therapy for serious IDU‐related abscesses should involve a broad spectrum antibiotic as many infections are polymicrobial [3]. Therapy may also require a course of vancomycin, when MRSA is suspected, for severe infections [26]. Treatment of IDU is often complicated by concomitant diseases such as HIV and concerns for possible drug interactions with antiretroviral medications [63]. Further, IDU are known to resist protracted in‐hospital care, which is often required to optimally treat the infection or complication and prematurely leave against medical advice [66]. Since culturing of abscesses has not been standard practice, empiric antibiotic therapy is initiated and modified if there is poor response. However, due to rising rates of resistant bacteria such as CA‐MRSA, 45 routine cultures may become necessary [65, 67]. Antibiotics may prevent the spread of infection but often do not diminish the burden of microorganisms that reside within an abscess; therefore, surgical debridement is crucial [67]. In some reports, incision and drainage alone, without antibiotic prescription, has been considered adequate treatment for abscesses [26]. This is particularly true for CA‐MRSA infections, where the role of additional antibiotic therapy has been less well defined [69]. Hospital records from San Francisco General Hospital between the fiscal years 1996‐1997 and 1999‐2000, respectively, reported that ED discharges due to CIRI increased from 1 292 to 2 619 (103%) [24]. In a cohort study of IDU seeking treatment from a county hospital in Washington State, 55 of 135 (40%) IDU who sought ED treatment for a CIRI from May 2001 to May 2002 were admitted to the hospital [28]. Participants admitted were more likely to be living in a shelter and to report being hospitalized two or more times in the past year [28]. Interestingly, a delay in seeking care was not associated with hospital admission [17]. Most participants presented with abscesses (69%, n=101/155): 60% had their abscess incised and drained at the bedside; 23% were treated in the operating room and 3% required drainage in the operating room following initial bedside drainage. Among those with 46 abscesses, 10% had abscesses that had been drained previously, either spontaneously or by self‐incision and drainage [28]. Hospital treatment for CIRI is costly. In a study at a Detroit hospital from 1986, inpatient costs for CIRI were $6.9 million for 1 year which roughly equates to $13.6 million in 2009 using national inflation rates in the US [70]. In a chart review of HIV‐negative IDU at the Rhode Island Hospital in 1998, 49% of admissions were related to CIRI and an additional 24% were due to the biological effects of the injected drug [71]. In addition, admissions for CIRI were significantly more costly than other admissions of IDU ($13958 vs. $7906) [71]. Hospital records from San Francisco General Hospital reported that ED discharges due to CIRI resulted in treatment charges for in‐patients that averaged $9.9 million per fiscal year between 1996 and 2000 [24]. Ideally, CIRI should not become as severe as to require ED or hospital admission. Currently, however, IDU with a CIRI who do require a course of intravenous antibiotics usually must seek this treatment at the ED of a local hospital. There are, however, some examples of low‐threshold models that incorporate CIRI treatment and wound care management. In San Francisco, the Integrated Soft Tissue Infection Services (ISIS) Clinic has proven to be valuable and cost effective [14]. In the first year of operation, the clinic resulted in a 47% decrease in surgical service admissions, a 34% reduction 47 in ER visits and an estimated savings of over $8 million for costs related to CIRI [14]. It effectively changed a predominately inpatient model of care to an outpatient model that offers quality surgical interventions, counseling and social services for individuals with soft tissue infections [14]. The study found that IDU were as adherent to their medical regiment as non‐IDU, signifying that IDU are not inherently irresponsible for their health when services exist in a non‐ judgmental environment [14]. Another example of effective treatment for CIRI located outside the hospital is a wound management clinic operated in collaboration and conjunction with a syringe exchange program in Oakland, California [72]. The average cost per individual treated was $5, substantially lower than equivalent hospital costs, which are averaged to between $185 and $360, not including medication, and physician fees [72]. Note that this cost does not include overhead that should be taken into consideration when comparing to hospital costs. The impact of these services for CIRI on hospitalization rates are difficult to measure and have not been evaluated to date [72]. 2.7 DISCUSSION The microbiology of CIRI is diverse and is predominantly polymicrobial; however, S. aureus remains the single most common bacteria. 48 There are three main sources of the organisms that cause CIRI. Firstly, the IDU can self‐inoculate skin flora during drug injection. Secondly, injecting equipment contamination may occur during the process of preparing and using drugs, or when injecting equipment is reused. Thirdly, drug contamination during manufacturing (e.g., drying process), handling (e.g., when repackaging and adding bulking substances) or distribution of drugs can occur. Certain injection practices are known to increase or decrease the likelihood of developing an abscess and can improve vein health. For example, by reducing major risk factors such as skin popping or muscling and by cleaning the skin with alcohol before injection, IDU can reduce their risk of developing a CIRI. However, these practices will not ensure that infection risk is eliminated, such as when the source of the organism is from the drug itself (e.g., risk of C. botulinum infection from contaminated heroin). Nevertheless, early recognition and publicity about potentially ‘rogue’ batches of heroin and clinical awareness of the problem are important for infection control [36]. Excessive costs associated with CIRI are preventable and interventions aimed at increasing the receipt of timely and appropriate ambulatory care by IDU have been successful in reducing hospitalization and associated health care costs [73]. To improve access to care for CIRI among IDU, there should be a 49 better understanding of geographic locations where low threshold ambulatory services would be best located for effectiveness [73]. Since complications of CIRI can lead to serious medical emergencies, it would be ideal to treat these complications in a manner that is in close proximity to the areas frequented by IDU, such as within existing harm reduction services, community clinics, or other integrated care services [14, 70]. In summary, defining and treating CIRI remains a challenge. The microbiology of CIRI is diverse and is often polymicrobial. In addition, there is growing concern regarding the shifting microbiology of these infections, specifically with the advent of CA‐MRSA; CIRI are a primary reason for hospitalization and ED use among IDU. Complications of CIRI are severe and can lead to medical emergencies. Current approaches to treatment for CIRI often involve lengthy and expensive ED or hospital admission. Innovative ways to prevent and treat CIRI, such as combining harm reduction services with treatment services, are urgently needed among this marginalized population. 50 Table 2.1: Summary of research on risk factors of cutaneous injection‐related infections Study Design City/Country Measures of Findings Association 1.1 Case‐ control San Francisco/ U.S.A. Adjusted Odds Ratio (AOR) 1.2 Cohort San Francisco/ U.S.A. AOR 1.3 Descriptive & Case Report San Francisco/ U.S.A. N/A 1.4 Cohort Amsterdam/ Netherlands Adjusted Rate Ratio (RR) 1.5 Case‐control Paisley, Glasgow/ Scotland AOR 1.6 Cross‐ sectional Baltimore/ U.S.A. Percentage 1.7 Cross‐ sectional Montreal/ Canada Percentage/ t‐ test ‐ 6.13 (6.51 ‐ 10.70) Skin popping ‐ 1.56 (1.13 ‐ 2.14) Booting with skin‐popping ‐ 2.33 (1.46 ‐ 3.70) Booting without skin popping ‐ 3.45 (1.75 ‐ 6.82) Reuse needle ‐ 3.31 (1.37 ‐ 7.95) Speedball injection ‐ 0.48 (0.32 ‐ 0.74 ) Clean skin with alcohol before inject ‐ 4.9 (2.2 ‐ 11.4) Skin popping ‐ 0.3 (0.1 – 0.9) 30+ years duration injection ‐Skin popping ‐Reuse needle ‐ 1.55 (1.30 ‐ 1.84) HIV positive ‐ 1.27 (1.00 ‐ 1.60) Female, no prostitution ‐ 1.66 (1.34 ‐ 2.05) Female, prostitution ‐ 1.39 (1.09 ‐ 1.78) Speedball injection ‐ 1.45 (1.12 ‐ 1.88) Daily injection ‐ 2.30 (1.84 ‐ 2.89) > Once per day injection ‐ 4.64 (1.00 ‐ 21.80 Female ‐ > 30 years 5.44 (1.44 ‐ 20.63) ‐ 0.15 (0.03 ‐ 0.73) Cocaine injection ‐ 18.30 (3.99 ‐ 83.93) Skin popping ‐ 21.40 (3.95 ‐ 116.0) Share a filter most of the time ‐ 10.03 (1.68 ‐ 59.96) 0.2‐0.5g heroin injected ‐ Abscesses at the site of injection are common ‐ Clean skin before inject protective ‐no one reported intentionally skin popping ‐47.1% reported unplanned injections ‐13.1% subcutaneous, 3.8% intramuscular injections Reference Murphy, 2001 [5] Binswanger, 2000 [9] CDC, 2001 [24] Spijkerman, 1996 [8] Taylor, 2004 [49] Vlahov, 1992 [48] Hankins, 2000 [46] 51 Study Design City/Country Measures of Association Findings Reference 1.8 Cohort Vancouver/ Canada AOR ‐ 1.7 (1.4 ‐ 2.4) Female ‐ 1.5 (1.2 ‐ 2.0) Daily cocaine injection ‐1.7 (1.3 ‐ 2.2) Recent incarceration ‐ 1.5 (1.1 ‐ 2.1) Sex trade involvement ‐ 1.5 (1.2 ‐ 2.0) HIV serostatus Lloyd‐Smith, 2005 [6] 1.9 Cohort Vancouver/ Canada AOR ‐1.7 (1.2 ‐ 2.4) Female ‐1.4 (1.0 ‐ 2.0) Daily cocaine injection ‐1.5 (1.1 ‐ 2.0) Unstable housing ‐1.6 (1.0 ‐ 2.5) Borrowing syringes ‐1.4 (1.0 ‐ 1.9) Requiring help injecting Lloyd‐Smith, 2008 [4] 1.10 Cross‐ sectional 7 cities/ England AOR ‐1.7 (1.2 ‐ 2.4) Female Hope, 2008 [10] ‐1.7 (1.3 ‐ 2.4) Received prescription substitute drug ‐1.6 (1.0 ‐ 2.6) 25‐29 years; 2.0 (1.3‐3.2) 30‐34; 1.9 (1.2 ‐3.0) 35+ years ‐2.2 (1.6 ‐ 3.1) Inject leg; 1.4 (1.1 ‐ 1.9) groin; 1.9 (1.3 ‐ 2.6) hand ‐1.5 (1.1 ‐ 2.0) Reuse syringe ‐1.5 (1.0 ‐ 2.3) Crack injection ‐1.8 (1.2 ‐2.9) 14‐27 days injecting last 4 weeks; 1.5 (1.0 ‐2.3) 28 days ‐1.5 (1.1 ‐ 2.0) HCV serostatus 1.11 Cross‐ sectional Multiple cities/ Australia AOR ‐3.0 (1.7 ‐ 5.4) Injecting in sites other than arms ‐2.0 (1.1 ‐ 3.5) Unstable accommodation ‐4.3 (1.7 ‐ 10.6) 25 years or older ‐9.3 (2.1 ‐ 41.8) Not always washing hand before injection Dwyer, 2009 [11] 1.12 Cross‐ sectional Multiple cities/ Australia AOR ‐2.1 (1.6 ‐ 2.6) Female, 2.9 (1.7 ‐ 4.8) Bisexual ‐2.6 (1.7 ‐ 3.8) Daily or more often injection ‐2.2 (1.5 ‐ 3.2) Substitute injection; 1.7 (1.4 ‐ 2.6) Morphine injection ‐1.8 (1.1 ‐ 2.9) Greater than 3 years injecting ‐1.6 (1.3 ‐ 2.1) HCV serostatus Topp, 2008 [7] 52 Table 2.2: Antimicrobial agents for cutaneous injection‐related infections Clinical Presentation Common microbiologic etiology Antibiotic Therapy and management Cellulitis – mild Group A Steptococcus, S.aureus Group A Streptococcus, S.aureus Cephalexin, or clindamycin (if penicillin allergy) Cefazolin Oral Step‐down therapy Cephalexin when improvement Cellulitis – moderate Larger surface area Fever but no systemic features Underlying comorbidities Abscess Group A Streptococcus S. aureus Or Polymicrobial (gram negatives and anaerobes may be present) Abscess in locations with high Group A Streptococcus community‐associated MRSA MRSA prevalence (>15%) Severe infections Extensive skin and soft tissue disease Systemic features (hypotension,tachycardia, altered mental status) Sepsis MRSA and/or Polymicrobial infection Incision and drainage may be all that is required for small collections. 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Int J Drug Policy 2005; 16: 137‐138. 64 CHAPTER 32: COMMUNITY‐ASSOCIATED METHICILLIN‐RESISTANT STAPHYLOCOCCUS AUREUS IS PREVALENT IN WOUNDS OF INJECTION DRUG USERS 3.1 BACKGROUND The microbiological distribution of wounds is diverse. Recently, particular concern has emerged for community‐associated methicillin‐resistant Staphylococcus aureus (CA‐MRSA), particularly strain USA300, as it has been associated with the development of severe skin and soft tissue infections and even necrotizing fasciitis [1‐4]. CA‐MRSA strains are defined on a molecular basis by the presence of the Panton‐Valentine leukocidin (PVL) toxin, common pulsed‐field gel electrophoresis pattern and preserved susceptibility to non‐β‐ lactam antibiotics [5]. Individuals who inject illicit drugs are more likely to be positive for CA‐ MRSA [2, 3, 6, 7]. This is not surprising given the intrinsic host factors related to bacterial transmission and infection such as compromised skin integrity, as well as extrinsic factors such as poor personal hygiene or environmental conditions 2 A version of this chapter has been submitted for publication. Lloyd‐Smith E, Hull M, Tyndall M, Wood E, Kerr T, Romney M. Community‐associated methicillin‐resistant Staphylococcus aureus is prevalent in wounds of injection drug users. 65 such as crowding [2, 3, 8], residing in shelters or single room occupancy (SRO) hotels [9]. It is important to examine the prevalence of CA‐MRSA among injection drug users (IDU) because MRSA infections cause severe morbidity and likely a greater mortality compared to MSSA infection [10, 11]. Furthermore, CA‐MRSA remains susceptible to an increasingly limited number of antibiotics and inappropriate use of these antibiotics may promote development of resistance to these antibiotics [12]. The objective of this paper is to describe the microbiologic distribution and related antibiotic susceptibilities of wound cultures among a community‐ recruited cohort of IDU. 3.2 METHODS Vancouver’s supervised injection facility (SIF) has been evaluated through the Scientific Evaluation of Supervised Injection (SEOSI) cohort, which has been described in detail [13]. Briefly, the cohort was assembled through random recruitment of IDU from within the SIF [13]. From July to November 2008, a sub‐study was conducted among SEOSI participants who were recruited at visits to the SEOSI research office. All SEOSI participants were eligible for the sub‐study. A brief questionnaire was 66 administered and a swab of any open wound was collected by a physician or a study nurse. If more than one open wound was present, then only one wound swab was collected per participant. If wounds were infected and required additional medical treatment, participants were referred to the Emergency Department (ED) or his or her general practitioner. Informed consent was obtained for all participants. The University of British Columbia‐Providence Health Care Research Ethics Board approved the study. Wounds were swabbed for aerobic organisms using Venturi trans system culture swabs (COPAN, Brescia, Italy). To identify all aerobic organisms, swabs at the microbiology lab were streaked onto 5% sheep’s blood agar plates (Columbia Agar PML, Microbiologicals, Wilsonville, Oregon). MRSA was identified using selective, chromogenic media (MRSASelect, Bio‐Rad, Marnes‐la‐ Coquette, France) and confirmed by a combination of cefoxitin disk testing and/or penicillin‐binding protein 2a detection. Presence of CA‐MRSA was determined by PVL testing based on previous studies showing >95% correlation between PVL positivity and USA 300 PFGE pattern (personal communication M Romney). The presence of the LukS‐PV and LukF‐PV genes encoding the PVL toxin was tested using polymerase chain reaction techniques. Wound cultures with a MRSA positive PVL result were considered to be CA‐MRSA positive. 67 In vitro antimicrobial susceptibility was determined by automated micro‐ broth susceptibility testing according to current Clinical and Laboratory Standards Institute (CLSI) guidelines [14]. Confirmatory disk‐diffusion testing for clindamycin resistance by D‐test was also performed. A wound was considered culture negative if it grew no species or normal skin flora ‐ diphtheroids, bacillus or coagulase‐negative staphylococci. Comparisons of the overall SEOSI cohort to this subsample were explored. Differences in age (per year older), sex (female vs. male), aboriginal ethnicity (yes vs. no), and years injecting (per year) were considered between participants who had an open wound compared to those who did not. Pearsons chi‐square test was used for categorical variables and the Wilcoxon rank sum test was used for continuous variables. Antibiotic use in the last six months among those with a positive CA‐MRSA and MSSA culture were examined. The statistical software used for these analyses was SAS (9.1, Cary, North Carolina). A p‐value of < 0.05 was considered significant and all p‐values were two sided. 3.3 RESULTS There were 218 participants overall, of whom 59 (27%) were found to have a wound. Compared to the overall SEOSI cohort, participants of this sub‐sample were more likely to live in unstable housing (Odds Ratio (OR) = 1.64 [95% 68 Confidence Interval {CI}: 1.19 – 2.27]) and reside in the Downtown Eastside (DTES) of Vancouver (OR = 2.62 [95% CI: 1.80 – 3.81]). This sub‐sample was not different in terms of age, sex, requiring help injecting, borrowing a syringe or frequent cocaine or heroin injection. The median age among individuals who presented with a wound was 38 years (Interquartile range: 31‐44). Twenty‐four (41%) participants with a wound were female and 9 (15%) were Aboriginal. No significant differences in age, sex, ethnicity, or number of years injecting were seen between individuals who presented with a wound compared to those who did not present with a wound (Appendix 2: Table 3.2). Further, there were no significant differences in those with or without a wound positive for CA‐MRSA, except those with a positive wound for CA‐MRSA were more likely to have had an abscess in the last six months (OR = 2.16 [95% CI: 1.31 – 3.54]; Appendix 2: Table 3.3). A majority of wounds were located on the extremities: upper extremity (n=26; 44%) or lower extremity (n=19; 32%). Wounds were also located on the head (n=12; 20%) and trunk (n=2; 3%) (Appendix 2: Table 3.4). Amongst the 59 participants who had a wound present, 37 (63%) had a positive wound culture (Figure 3.1). In total, 16 (27%) of participants with a wound had wounds positive for CA‐MRSA; of those, 4 had wounds positive for CA‐MRSA and one other species (1 with Group A Streptococcus, 1 with Group B Streptococcus, 1 with coliforms and 1 with MSSA). In total, 20% (n = 12) wounds 69 were polymicrobial. Of those with a positive CA‐MRSA culture, 11 (69%) reported antibiotic use for a skin infection in the last six months, whereas 8 (40%) participants with MSSA reported recent antibiotic use. The antimicrobial susceptibility patterns of CA‐MRSA, MRSA, MSSA isolates from wound cultures are displayed in Table 1. 100% of the CA‐MRSA cultures were susceptible to tetracycline, rifampin, vancomycin and linezolid. Trimethoprim‐sulfamethoxazole (TMP‐SMX) was 94% susceptible, while only 13% of the CA‐MRSA isolates were susceptible to clindamycin compared to 60% of MSSA isolates. 3.4 DISCUSSION More than 25% of IDU surveyed in our study had at least one wound, a majority of which were culture positive for S. aureus. Among those with wounds, 27% of participants have a wound positive for CA‐MRSA and among MRSA, 16/18 (89%) had positive CA‐MRSA cultures. Our results indicate that CA‐MRSA is widespread among IDU in our setting. Injection drug use has been associated as a broad risk factor for CA‐MRSA infection [6]. Skin and soft tissue infections may be caused by the elucidation of PVL toxin of CA‐MRSA strains that are capable of destroying leukocytes and leading to severe tissue damage [15]. There may be an additional risk of CA‐ 70 MRSA transmission during the injection process, such as the preparation of drugs prior to injection, injection paraphernalia or the injecting environment. Microbiologic assessments from a hospital in Los Angeles have shown a explosive increase in MRSA prevalence in arm abscesses (5% MRSA of S. aureus cultures in 1999 and 82% in 2005) [16]. Consistent with the literature, S. aureus was the most prevalent microbiology found in wounds [2, 6, 17]. However, the proportion of CA‐MRSA among total S. aureus found in our study (43%) is lower than a hospital‐based study in Atlanta, where 63% of S. aureus skin and soft tissue infections were due to CA‐MRSA [11]. Similarly, a study that examined acute purulent skin and soft tissue infections in the ED of 11 cities across the United States in 2004 found that S. aureus was present in 76% of all wounds. Of S. aureus isolates, 78% were MRSA (59% prevalence overall) and the USA300 strain accounted for 97% of MRSA isolates [18]. The disparities in proportion may be related to recruitment methods. Hospital‐based studies capture more serious wounds that require medical attention compared to the wounds collected in our community‐based sample that did not necessarily require medical treatment. Although susceptibility to antibiotics varies in different settings and longitudinally, it is clinically relevant that only 13% of CA‐MRSA was susceptible to clindamycin in our study. CA‐MRSA strains have been reported 71 to be 95% susceptible to clindamycin [18]. However, this study did report a shift in antimicrobial susceptibility in different settings [18], which may reflect particular bias in antibiotic use. Further, 14 (24%) wounds contained a Streptococcus species and 11 were polymicrobial wounds with either MRSA or MSSA, which supports antibiotic prescription that includes coverage for Streptococcal species [19]. However, a recent randomized control trial on the treatment of uncomplicated abscesses in a population at risk of CA‐MRSA suggested antibiotic prescription after incision and drainage was unnecessary [20]. Our results should be confirmed by a larger sample of CA‐MRSA culture positive wounds. There are limitations to this research. This study was based on a convenience sample of SEOSI participants who visited the research study office during periods of recruitment. It is possible that participants in periods of intense drug use or who had a serious medical condition may have been less likely to attend the research site during office hours. Since individual characteristics related with intense drug use are known to be associated with cutaneous injection‐related infection (CIRI) development [21‐24], if this selection bias was present, then our results may have underestimated the proportion of individuals with wounds and CA‐MRSA. Information on antibiotic use in the last six months was collected in the present study, but not specifically on current 72 use. However, it is possible that individuals with wounds who were currently on antibiotics had culture negative wounds. This limitation would have led to an underreporting of the estimate of positive wound cultures. In addition, information on size of wounds was not included in this study. Finally, our results are based on a sub‐sample of SEOSI participants and may not be representative of the injection drug using community in this setting or others. In summary, we observed a high prevalence of CA‐MRSA infection among active IDU. Since the prevalence of CA‐MRSA in wounds was found to be high in our setting, it is recommended that antibiotic therapy include coverage for CA‐MRSA that reflects the antimicrobial susceptibility of the local strains. 73 Total population screened n = 218; 100% Total number wounds n = 59; 27% Culture negative wounds n = 17; 29% Culture positive wounds n = 42; 63% MRSA only n = 14; 24% (*CA‐MRSA = 12) MRSA plus Group A Strep* n = 1 Group B Strep* n = 1 Coliform* n = 1 MRSAMSSA* n = 1 Group A Strep n = 1 Group G Strep n = 1 Viridans Strep and Group G Strep n = 1 Enterococcus n = 1 Pseudomonas n = 1 MSSA only n = 11; 19% MSSA plus Group A Streptococcus n = 3 Group A Strep and Enterococcus n = 1 Group A Strep and Pseudomonas n = 1 Group C Strep n = 1 Group G Strep n = 1 Viridans Strep n = 1 Note: *denotes CA‐MRSA, among all wound n=16, 16/59 = 27% culture positive wounds 16/37 = 43% Figure 3.1: Microbiology distribution of wounds among a sub‐sample of the Scientific Evaluation of Supervised Injection cohort 74 Table 3.1: Antimicrobial susceptibility patterns of Staphylococcus aureus isolates from wound cultures according to pulsed‐field type Antibiotic Erythromycin Clindamycin Tetracycline Fusidic acid Rifampin TMP‐SMX Vancomycin Linezolid CA‐MRSA n = 16 (%) MRSA n = 2 (%) MSSA n = 20 (%) 0 0 60 13 0 60 100 0 90 81 100 70 100 100 100 94 0 95 100 100 100 100 100 100 Note: CA‐MRSA = community‐associated methicillin‐resistant Staphylococcus aureus; MSSA = methicillin‐sensitive S. aureus, TMP‐SMX = trimethoprim‐ sulfamethoxazole 75 3.5 REFERENCES 1. 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Epidemiology, Treatment, and prevention of community‐acquired methicillin‐resistant Staphylococcus aureus infections. Mayo Clinic Proceedings 2005; 80: 1201‐1208. 76 6. Huang H, Cohen SH, King JH, Monchaud C, Nguyen H, Flynn NM. Injecting drug use and community‐associated methicillin‐resistant Staphylococcus aureus infection. Diagn Microbiol Infect Dis 2008; 60: 347‐ 350. 7. Saravolatz LD, Markowitz N, Arking L, Pohlod D, Fisher E. Methicillin‐ resistant Staphylococcus aureus. Epidemiologic obervations during a community‐acquired outbreak. Ann Intern Med 1982; 1: 11‐16. 8. King MD, Humphrey BJ, Wang YF, Kourbatova EV, Ray SM, Blumberg HM. Emergence of community‐acquired methicillin‐resistant Staphylococcus aureus USA 300 clone as the predominant cause of skin and soft‐tissue infections. Ann Intern Med 2006; 144: 309‐317. 9. Shannon K, Ishida T, Lai C, Tyndall MW. The impact of unregulated single room occupancy hotels on the health status of illicit drug users in Vancouver. Int J Drug Policy 2006; 17: 107‐114. 10. Nelson KE, Masters Williams CF. Infectious Disease Epidemiology: Theory and Practice. 2nd ed. Sudbury, MA: Jones & Bartlett Publishers; 2007. 11. Huang H, Flynn NM, King JH, Monchaud C, Morita M, Cohen SH. Comparisons of community‐associated methicillin‐resistant Staphylococcus 77 aureus (MRSA) and hospital‐associated MSRA infections in Sacramento, California. J Clin Microbiol 2006; 44: 2423‐2427. 12. Rockwell F, Goh SH, Al‐Rawahi G, Hoang L, Isaac‐Renton J, Gilbert M, et al. A report on the emergence of community‐acquired methicillin‐resistant Staphylococcus aureus (CA‐MRSA) in British Columbia. Vancouver: BCCDC; 2005. 13. Wood E, Kerr T, Lloyd‐Smith E, Buchner C, Marsh D, Montaner J, et al. Methodology for evaluating Insite: Canadaʹs first medically supervised safer injection facility for injection drug users. Harm Reduct J 2004; 1. 14. Clinical and Laboratory Standards Institute. 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Hope V, Kimber J, Vickerman P, Hickman M, Ncube F. Frequency, factors and costs associated with injection site infections: findings from a national multi‐site survey of injecting drug users in England. BMC Infect Dis 2008; 8. 80 CHAPTER 43: RISK FACTORS FOR DEVELOPING A CUTANEOUS INJECTION‐RELATED INFECTION AMONG INJECTION DRUG USERS: A COHORT STUDY 4.1 BACKGROUND Injection drug use remains a major public health concern worldwide. While researchers and policy makers have focused much attention on the transmission of blood‐borne viruses (e.g., human immunodeficiency virus [HIV], hepatitis C virus [HCV]) among injection drug users (IDU) [1‐3], considerably less attention has been devoted to the problem of bacterial infections of the skin [4]. A recent report by the United States Centres for Disease Control and Prevention highlighted the dearth of research on cutaneous injection‐related infections (CIRI) among IDU and cited reports of recent and dramatic increases in CIRI, including abscesses and cellulitis, among IDU in England [5]. In addition, CIRI are the primary reason that IDU seek treatment at an Emergency Department in some settings [6]. 3 A version of this chapter has been published in BMC Public Health. Lloyd‐Smith E, Wood E, Zhang R, Tyndall MW, Montaner JS, Kerr T. Risk factors for developing a cutaneous injection‐ related infection among injection drug users: a cohort study 2008. BMC Public Health; 8; 405 81 The prevalence of CIRI among IDU typically ranges from 10% to 30% [7, 8]. The variability in prevalence estimates may be due to differences in measurement of the occurrence of CIRI (e.g., reporting current vs. ever having a CIRI), the definition of CIRI (e.g., injection‐related vs. any drug‐related) and the fact that there are currently no standard guidelines with regard to reporting of CIRI based on severity [4]. Other factors may be the exploration of different risk factors for developing CIRI across settings, for example differences in types of drugs used (e.g., black tar heroin in California, United States vs. white heroin in British Columbia, Canada), intensity of drug use and availability and access to clean injection paraphernalia [9]. However, certain factors have been shown to be consistently associated with developing a CIRI in particular cities. For example: injecting under the skin (also known as ʺskin poppingʺ) in San Francisco and Glasgow [8, 10, 11]; frequent injection in Amsterdam and Vancouver [12, 13]; and injection of heroin plus cocaine (i.e., ʺspeedballsʺ) in San Francisco and Amsterdam [8, 13] have been associated with CIRI. However, most of these analyses were based on cross‐sectional investigations and few prospective studies exist. We conducted the present longitudinal study to characterize risk factors of developing a CIRI among IDU. 82 4.2 METHODS 4.2.1 Data source: Scientific Evaluation of Supervised Injection In September 2003, a comprehensive evaluation of Insite, North America’s first supervised injection facility (SIF), was initiated. Users of the SIF, located in Vancouverʹs Downtown Eastside (DTES) neighbourhood, were randomly invited to enroll in a prospective cohort study known as the Scientific Evaluation of Supervised Injection (SEOSI) and have since been interviewed semi‐annually [14]. The methodological details have been described elsewhere [15]. Briefly, to be recruited into the SEOSI cohort, individuals had to have performed at least two injections at the SIF, been at least 19 years old and provided informed consent. Furthermore, the questionnaire is interviewer‐administered and elicits a range of information, including information specific to socio‐demographic characteristics, risk behaviours and involvement in addiction treatment. This is followed by blood testing for HIV and HCV for those who previously tested negative and a nurse‐administered questionnaire on health status. A database in the SIF tracks key events, including utilization and the types of drug being injected. The SEOSI cohort has received approval from the Providence Health Care/University of British Columbia Ethics Board. 83 To be eligible for this study, participants must have completed both the interviewer‐administered and nurse‐administered baseline questionnaires during the study period (January 1, 2004 to December 31, 2005.) 4.2.2 Outcome measure and explanatory variables The primary outcome for this analysis (dependent variable) was a current CIRI reported to and visually confirmed (e.g., pain, redness, induration and fluctuation) by the study nurse in response to the question “Do you presently have any sores or abscesses from where you have been injecting?”. Explanatory variables examined in this analysis included: age (per year older); sex (female vs. male); unstable housing, defined as living in a single room occupancy hotel, shelter, recovery or transition house, jail, on the street, or having no fixed address as opposed to living in an apartment or house (yes vs. no); residence in the DTES (yes vs. no); sex trade involvement (yes vs. no); borrowing used syringes (yes vs. no); requiring help injecting (yes vs. no); using puddle water for injecting (yes vs. no); injecting cocaine daily (yes vs. no); injecting heroin daily (yes vs. no), injecting crack cocaine daily (yes vs. no); injecting crystal methamphetamine daily (yes vs. no); injecting ʺspeedballsʺ daily (yes vs. no); the proportion of all injections at SIF (always vs. < always); HIV serostatus (positive vs. negative); and HCV serostatus (positive vs. negative). Variable definitions were consistent with previous work [16‐19]. All variables referred to the six 84 months prior to the interview, except for unstable housing and residence in the DTES, which referred to resident status at the more recent interview. 4.2.3 Statistical analysis The proportion of SEOSI participants who reported having a CIRI was inspected graphically over time. Univariate and multivariate statistics, including generalized linear mixed‐effects modeling, were used to examine factors associated with having a CIRI over time. Generalized linear mixed‐effects modeling is a longitudinal technique that analyzes individual trajectories and produces correlates. This analytic technique was chosen because of its flexibility in variable parameters (e.g., fixed, time‐updated, random), its ability to capture heterogeneity of subjects and within‐subject correlation and its attempt to identify individual‐level factors [20]. Independent variables were either fixed (e.g., sex) or time‐updated (e.g., age, all behavioural variables considered, HIV and HCV serostatus) in this model. Random variation between individuals was accounted for by using random intercepts. Variables significant at the univariate level (p < 0.05) were included in the multivariate model. The data were analyzed using SAS version 9.1 (SAS Institute, Cary, NC, USA.) All reported p‐values were two‐tailed. 85 4.3 RESULTS Of the 1090 participants recruited into the SEOSI cohort since November 2003, 1065 (97%) completed both a baseline interviewer‐administered questionnaire and a nurse‐administered questionnaire after recruitment into SEOSI cohort. Among these participants, 877 (82%) returned for at least one follow‐up visit and 312 (29%) were female. The median age was marginally younger for those who reported a CIRI at baseline when compared with those who did not at baseline (36 [IQR: 31‐43] vs. 39 [IQR: 33‐45], p = 0.095). As shown in Figure 1, the proportion of participants reporting a current CIRI in this study was fairly consistent over the two year study period, ranging from 6% to 10%, although the proportion declined slightly between the baseline and first follow‐ up visit. At baseline, 106 (10%) of participants reported a CIRI. There were 14 (1%) individuals with missing data on HIV serostatus and 33 (3%) individuals with missing data on HCV serostatus at baseline; due to these small counts, these individuals were excluded from further analyses. Using longitudinal methods, factors associated with reporting a current CIRI at the univariate and multivariate level are presented in Table 4.1. In univariate analyses, being older and reporting use of the SIF for all injections was associated with a decreased likelihood of developing a current CIRI. Female sex, living in unstable housing, involvement in the sex trade, borrowing a used 86 syringe, requiring help injecting, injecting cocaine daily, injecting heroin daily and injecting ʺspeedballsʺ daily were positively associated with reporting a current CIRI. As displayed in the multivariate model in Table 1, participants who reported a current CIRI were more likely to be female (Adjusted OR (AOR) = 1.68 [95% Confidence Intervals {CI}: 1.16‐2.43]); live in unstable housing (AOR = 1.49 [95% CI: 1.10‐2.03]); borrow used syringes (AOR = 1.60 [95% CI: 1.03‐2.48]); require help injecting (AOR = 1.42 [95% CI: 1.03‐1.94]); and inject cocaine daily (AOR = 1.41 [95% CI: 1.02‐1.95]). 4.4 DISCUSSION In this study we found that the proportion of IDU reporting a CIRI remained within the range of six to 10 per cent over a median follow‐up of 12.6 months (IQR: 6.2‐17.7) months after SIF recruitment. The level of CIRI is relatively low in the context of previously reported prevalence (10‐30% [7‐8]). However, considering that it is based on reporting a current infection, the level in this study is concerning. Furthermore, our results indicate that being female, living in unstable housing, borrowing syringes, requiring help injecting and injecting cocaine daily were independently associated with developing a CIRI. 87 The observed associations between female sex, daily cocaine injection, living in unstable housing and an elevated risk of having a CIRI are congruent with previous analyses. The link between being female and having a CIRI echoes the findings of previous studies [10, 12, 13] and may reflect, in part, the complex gender dynamics that exist within injection drug using populations where women are often dependent on men for the attainment and administration of drugs [21]. With regard to the association between cocaine injection and development of CIRI [12, 13], cocaine’s anaesthetic properties may make it more difficult for individuals to know whether or not they are hitting a vein (as opposed to injecting in the surrounding tissue or skin), resulting in trauma through repetitive attempts to access the vein [22, 23]. Missing a vein increases vulnerability for CIRI since injecting into the surrounding tissue creates a niche environment in which bacteria can thrive [9]. Further, due to cocaine’s short half‐ life in comparison to heroin, it is often injected many more times than heroin, which also increases the likelihood of CIRI and transmission of blood‐borne viruses such as HIV [16]. Indeed, as indicated by our findings and others, intensity of drug use appears to play a role in CIRI development, as individuals who inject at least daily have been repeatedly identified to be at elevated risk for developing a CIRI [12, 13]. 88 The association between homelessness and an injection site infection has been reported [24]. According to the risk environment framework, as proposed by Rhodes et al., structural and environmental factors are important to consider when assessing risks for drug‐related harms as they shape the context in which individual behaviour occurs [24]. It may be that those in our study who reported living in unstable housing may also frequent risky injecting environments, which in turn lead to rushed injections (i.e., not taking time to go through every step of the injection process to ensure a safer injection) or injecting in a high‐risk location like the groin for a ‘quick fix’ [25]. A recent review of homelessness found that between 15‐50% of homeless individuals inject drugs and it was further reported that breaks of the skin were common among such individuals, often leading to bacterial infections due to a lack of hygiene [26]. In addition, the small size, shared facilities and often unhygienic environment of single room occupancy hotels that are common in the DTES promote disease transmission [27]. Among the novel findings in the present study are the associations between CIRI development and borrowing syringes and requiring help injecting. Borrowing used syringes is known to be a strong risk factor for blood‐borne viral transmission [28, 29]. Our study shows that the transmission of CIRI‐related bacteria via sharing of syringes should also be considered by IDU, health professionals and public health practitioners. However, it is also possible that 89 sharing syringes is not the active vector in this transmission and that this transmission is by other injection drug paraphernalia. Requiring help injecting, a risk factor for CIRI in this study, may increase risk of exposure to bacteria when the individual who is administering the injection injects themselves before injecting the person who requires assistance (i.e., “second on the needle”). This study has several limitations. Firstly, we were unable to examine ʺskin poppingʺ as an independent variable in this study due to a low number of participants reporting this behaviour. This may be due to the fact that the practice is more commonly associated with injection of “black tar” heroin, a type rarely used in Vancouver. Given that our “skin popping” question in the study questionnaire pertained to intentional ʺskin poppingʺ it is also possible that participants who injected subcutaneously or intramuscularly by mistake were not captured. Secondly, our study relies on self‐report and therefore is potentially vulnerable to social desirability bias. However, we know of no reason to suspect differential reporting between participants with or without CIRI. Thirdly, it is possible that individuals who inject at the SIF are different from those who do not. A study by Wood et al. found that IDU that used the SIF were more likely to be at a higher risk of blood‐borne disease infection and overdose compared with IDU who did not use the SIF [30]. Therefore, our results may not be generalizable to the broader local IDU population. However, 90 the SEOSI cohort was randomly recruited from within the SIF [15]. Therefore, we believe that our sample is representative of SIF users. Fourthly, the external validity of this study should be interpreted with caution, as Vancouver’s DTES neighbourhood is unique due to its large open drug scene and the high prevalence of cocaine injection. Finally, this study investigates only CIRI related to injection drug use and not uncommon behaviours for example. However, we feel this is an important distinction as it serves to reduce misclassification bias based on reporting CIRI that may be related to other factors such as picking the skin induced by cocaine psychosis [16]. The prevalence of CIRI among IDU in this study suggests that a higher priority should be placed on reducing the incidence of these preventable infections. Since a positive impact of the SIF on access to assessment, care and treatment of CIRI has been noted [31], it is likely that the rate of CIRI observed here may be lower than the rate observed in the broader community. Combining harm reduction (e.g., needle distribution programs and supervised injection facilities) and treatment services may be of value to prevent and/or reduce the risk for CIRI development. Specifically, integrating wound management care into existing harm reduction services, such as needle exchange programs and SIF, in community settings has been found to be feasible, cost‐effective and beneficial for preventing and treating CIRI and other related skin infections such 91 as necrotizing fasciitis [32]. Expansion of such programs among harm reduction services may be reasonable, especially as many IDU remain medically underserved [33]. 4.5 CONLCUSION In summary, we found that over a two‐year period that between six and 10 percent of IDU attending the SIF and enrolled in the SEOSI cohort presented with a CIRI. Risk factors for CIRI development included being female, living in unstable housing, borrowing used syringes, requiring help injecting and injecting cocaine daily. These findings collectively point to the need to develop a range of interventions that target the various individual, social and environmental risks for CIRI development. 92 20% 18% 16% 14% 12% 10% 8% 6% 4% 2% J u n -0 5 J a n -0 5 J u n -0 4 J a n -0 4 0% Follow-up Figure 4.1: Proportion of Scientific Evaluation of Supervised Injection participants reporting a cutaneous injection‐related infection (January 1, 2004 ‐ December 31, 2005, n = 1065) 93 Table 4.1: Univariate and multivariate analysis of developing a cutaneous injection‐related infection among Scientific Evaluation of Supervised Injection participants (n = 1065) Variable Odds Ratio Adjusted OR OR (95% CI) AOR (95% CI) 0.98 (0.96 ‐ 1.00) 1.00 (0.98 ‐ 1.02) (Female vs. Male) 1.90 (1.39 ‐ 2.58) 1.68 (1.16 ‐ 2.43) Unstable housing 1.56 (1.15 ‐ 2.12) 1.49 (1.10 ‐ 2.03) 1.33 (0.96 ‐ 1.85) 1.74 (1.24 ‐ 2.45) 1.02 (0.67 ‐ 1.56) 1.88 (1.22 ‐ 2.88) 1.60 (1.03 ‐ 2.48) 1.85 (1.37 ‐ 2.50) 1.42 (1.03 ‐ 1.94) 1.32 (0.83 ‐ 2.11) (Daily vs. Not) 1.66 (1.23 ‐ 2.25) 1.41 (1.02 ‐ 1.95) Heroin injection* (Daily vs. Not) 1.53 (1.14 ‐ 2.04) 1.26 (0.93 ‐ 1.72) Crack injection* (Daily vs. Not) 1.54 (0.96 ‐ 2.46) 1.48 (0.73 ‐ 3.02) 2.00 (1.35 ‐ 2.96) 1.37 Age (per year older) Sex (Yes vs. No) DTES residence (Yes vs. No) Sex trade* (Yes vs. No) Borrowing syringes* (Yes vs. No) Requiring help inject* (Yes vs. No) Use puddle to inject* (Yes vs. No) Cocaine injection* Crystal meth. injection* (Daily vs. Not) Speedball injection* (Daily vs. Not) (0.89 ‐ 2.11) 94 Variable Odds Ratio (95% CI) OR Adjusted OR (95% CI) AOR 0.47 (0.23 ‐ 0.94) 0.58 (0.29 ‐ 1.19) HIV serostatus (Yes vs. No) 1.23 (0.85 ‐ 1.77) 1.35 (0.81 ‐ 2.25) SIF use* (Always vs. Not) HCV serostatus (Yes vs. No) Note: *Behaviours refers to activities in the past 6 months, CI = confidence interval, DTES = Downtown Eastside, meth. = methamphetamine, SIF = supervised injection facility 95 4.6 REFERENCES 1. 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Murphy EL, DeVita D, Liu H, Vittinghoff E, Leung P, Ciccarone DH, et al. Risk factors for skin and soft‐tissue abscesses among injection drug users: a case‐control study. Clin Infect Dis 2001, 33: 35‐40. 96 9. Ciccarone D, Bourgois P. Explaining the geographical variation of HIV among injection drug users in the United States. Subst Use Misuse 2003, 38: 2049‐2063. 10. Taylor A, Hutchinson S, Lingappa J, Wadd S, Ahmed S, Gruer L, et al. Severe illness and death among injecting drug users in Scotland: a case‐ control study. Epidemiol Infect 2005, 13: 193‐204. 11. CDC. Soft tissue infections among injection drug users‐San Francisco, California, 1996‐2000. MMWR Morb Mortal Wkly Rep 2001, 50: 381‐384. 12. Lloyd‐Smith E, Kerr T, Hogg RS, Li K, Montaner JSG, Wood E: Prevalence and correlates of abscesses among a cohort of injection drug users. Harm Reduct J 2005, 2. 13. Spijkerman IJ, van Ameijden EJ, Mientjes GH, Coutinho RA, van den Hoek A. 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Arch Surg 2004, 139: 947‐953. 100 CHAPTER 54: DETERMINANTS OF CUTANEOUS INJECTION‐RELATED INFECTION CARE AT A SUPERVISED INJECTION FACILITY 5.1 INTRODUCTION Cutaneous injection‐related infections (CIRI), which includes abscesses and cellulitis, are prevalent among persons who inject drugs (IDU) [1, 2]. Although these infections are known to constitute a primary cause of morbidity among IDU [2, 3], there is a paucity of research in this area [4]. Most of the literature on the treatment of CIRI has been derived from hospital and Emergency Department (ED) based chart reviews and most has been carried out in the United States [5‐9]. Financially the burden of CIRI in the medical system is substantial. A general hospital in San Francisco reported a conservative estimate of ED costs in excess of $20 million per year [10]. Several models of care have been shown to effectively incorporate both CIRI treatment and wound care and result in cost savings [8, 11, 12]. In San Francisco, the Integrated Soft Tissue Infection Services (ISIS) clinic has been found to be a valuable and cost saving program [8]. The program has changed a predominately inpatient model to that of an outpatient model of care that offers 4 A version of this chapter has been published in Annals of Epidemiology. Lloyd‐Smith E, Wood E, Zhang R, Tyndall MW, Montaner JS, Kerr T, Determinants of cutaneous injection‐related infection care at a supervised injection facility. Ann Epidemiol. 101 surgical interventions, counseling and social services for individuals with soft tissue infections [8]. In the first year of operation, results from the clinic reported a 47% decrease in surgical service hospital admissions, a 34% reduction in ED visits and an estimated savings of over $8 million [8]. Another example of effective treatment for CIRI outside the hospital setting is a wound management clinic that operates in conjunction with a syringe exchange program in New Haven [12]. Notably, individuals who access syringe exchange programs that provide primary care services have reported reduced ED utilization [13]. Medically supervised safer injection facilities (SIF), where IDU can inject pre‐obtained illicit drugs under the supervision of medical staff, operate in several cities in Europe and in Sydney, Australia [14‐16]. Within SIF, individuals are typically provided with sterile injecting equipment and emergency intervention in the event of an accidental overdose, as well as medical care and addiction treatment, either on site or through referral [17, 18]. On September 22, 2003, Vancouver, Canada opened North America’s first government sanctioned SIF [14]. The objectives of this study were to examine receiving CIRI care as well as factors associated with receiving CIRI care among users of Vancouver’s SIF. 102 5.2 METHODS 5.2.1 Study sample The Vancouver SIF is being evaluated through the Scientific Evaluation of Supervised Injection study, a prospective cohort that has been described in detail previously [19]. The SIF is located in Vancouver’s Downtown Eastside (DTES), which is the epicenter of Vancouver’s IDU population, known as one of the poorest urban postal codes in Canada. The neighbourhood is also home to a large open drug and sex work scene and the site of an explosive epidemic of HIV infection. Briefly, since December 2003 participants were recruited during random times from within the SIF. SIF users were eligible to be randomized for selection by the SIF intake computer after their second visit. Among individuals who were recruited, an interviewer‐administered questionnaire elicited socio‐ demographic and behavioural information. In addition, participants completed a nurse‐administered questionnaire regarding health status and provided venous blood samples for hepatitis C virus (HCV) and HIV at baseline and at semi‐ annual follow‐up visits. Interviewees received $20 for their participation. The SIF intake computer is equipped with a database that tracks utilization of services within the facility (e.g., care by nurse, sessions with addictions counselor, etc.) as well as referrals to other services (e.g., hospital or 103 detoxification services) [19]. Informed consent was obtained from all participants. The Research Ethics Board at the University of British Columbia approved the present study. 5.2.2 Study outcome The endpoint in this study was the provision of care at the SIF. Both abscesses and cellulitis were considered to be CIRI. The occurrence of CIRI care events was determined by examining relevant entries by the nurse in the SIF database. Specifically, instances of CIRI care were identified by searching the SIF database for: (1) entries describing the provision of care by a nurse for an abscess, a wound, or a skin infection; (2) notes containing ‘abscess’, ‘cellulitis’; or (3) entries describing the provision of nursing care supplies for CIRI, including ‘alleyn’, ‘combiderm’, ‘mesalt’ and ‘iodasorb’. Multiple visits per participant were counted unless a participant had more than one CIRI care episode in one day. In this case, only the first CIRI care event was counted (i.e., one CIRI care episode considered per day). Multiple visits for each participant reflect that CIRI care by nurses often involves numerous visits per infection plus more than one infection per participant during the study period. 104 5.2.3 Statistical analysis As an initial step, we examined the total number of CIRI care events at the SIF reported by each participant. We also examined the socio‐demographic and behavioural variables, collected as part of the baseline Scientific Evaluation of Supervised Injection questionnaire, stratified by whether receiving CIRI care was or was not obtained at the SIF. Potential explanatory factors considered in subsequent analyses included: age, sex (female vs. male), living in unstable housing (yes vs. no), DTES residence (yes vs. no), requiring help injecting (yes vs. no), daily cocaine injection (yes vs. no), daily heroin injection (yes vs. no) and daily speedball injection (yes vs. no), and HIV serostatus (yes vs. no). Unstable housing was defined as living in a single room occupancy (SRO) hotel, shelter, recovery or transition house, jail, on the street, or having no fixed address. Requiring help injecting was based on the question “Have you needed some one to help you inject?” Daily injection of cocaine, heroin and speedball referred to at least once daily injection. Behavioural variables referred to self reported activity in the last six months. Variable definitions have been used in previous studies [20, 21]. Categorical variables were analyzed using chi‐squared tests and continuous variables were analyzed by the Wilcoxon rank sum test. 105 The incidence of CIRI care, stratified by sex, was estimated using Kaplan‐ Meier methods. Kaplan‐Meier curves were compared by the log‐rank test. Significant differences (p‐value < 0.05) between participants who did and did not receive CIRI care determined variable selection for the unadjusted and adjusted Cox proportional hazard regression with recurrent events analyses. Robust variance estimates were applied to calculate confidence intervals. Cox proportional hazard regression with recurrent events (provision of CIRI care) allowed for consideration of more than one event per participant. This recurrent event analyses permitted the modeling of the length of time and allowed for an assessment of associations between recurrent events. This was appropriate as CIRI are typically acute, not chronic infections. In addition, nursing care for CIRI often included debridement and dressing changes, which often needed to be repeated; this type of analysis was well suited to this type of care regime. Cox proportional hazard regression with recurrent events can also estimated valid standard errors in the presence of correlated data over time [22, 23]. A counting process framework was used whereby individuals were considered to be at risk from time zero to first event, from first event to second event and so forth. For all participants, time zero was defined as the date of recruitment into the Scientific Evaluation of Supervised Injection study. Participants who did not seek CIRI care were right censored at the end of January 31st, 2008 or if one of the 106 following occurred: the participant was lost to follow‐up or moved out of province. The multivariate model was fit using a fixed model with a defined model‐building approach in which we adjusted for all variables that were statistically significant at p < 0.05 in the bivariate analyses. All p‐values are two‐ sided. 5.3 RESULTS By the end of January 2008, 1083 individuals were enrolled in Scientific Evaluation of Supervised Injection and 901 (83%) had at least one follow‐up visit. After examining care patterns for all participants, three individuals were seen to have had markedly different patterns reporting receiving CIRI care for 73, 74 and 85 times respectively. The next most frequent number of times that CIRI care was received was 37 times; therefore, those three individuals were determined to be outliers and excluded from all subsequent analyses. Among the remaining 1080 study participants, the median age was 38.4 (interquartile range (IQR): 32.7‐ 44.3) and 314 (29%) were female. The median follow‐up duration after recruitment into the cohort was 21.4 months (IQR: 13.1‐24.6). 296 (27%) Scientific Evaluation of Supervised Injection participants received nursing care for CIRI at the SIF. Importantly, the majority of care provided by nurses within the SIF was related to CIRI care (65%) (Appendix 3: Table 5.3). Other reasons for nurse care included foot care (6%), respiratory care 107 (3%), pregnancy test (2%), psychosocial support (7%) or other (17%) (Appendix 3: Table 5.3). Reasons for nurse visits, as opposed to reason for nurse treatment in Table 5.3, were also predominantly related to CIRI (72%) (Appendix 3: Table 5.4) As shown in Table 5.1, Scientific Evaluation of Supervised Injection participants receiving CIRI care were more likely at baseline to be female (Odds Ratio [OR] = 1.89 [95% Confidence Interval {CI}: 1.35 – 2.63]), DTES residents (OR = 1.75 [95% CI: 1.20 – 2.54]), daily cocaine injectors (OR = 1.57 [95% CI: 1.13 – 2.19]), daily heroin injectors (OR = 1.41 [95% CI: 1.02 – 1.95]) and daily speedball injectors (OR = 1.96 [95% CI: 1.30 – 2.95]). During the study period (December 1, 2003 to January 31, 2008), the incidence density of Scientific Evaluation of Supervised Injection participants receiving CIRI care was 22.0 per 100 person‐years (95% CI: 19.6 – 24.6). As displayed in Figure 5.1, females were more likely to receive CIRI care (incidence density 34.7 per 100 person‐years [95% CI: 29.0 – 41.3]) as opposed to males (incidence density 17.5 per 100 person‐years [95% CI: 15.1 – 20.3]). Factors that were associated with receiving CIRI care in univariate analyses are shown in Table 5.2 in the Cox proportional hazard model. As displayed, being female (Hazard Ratio [HR] = 2.08 [95% CI: 1.49 – 2.92]), living in unstable housing (HR = 1.61 [95% CI: 1.17 – 2.22]), having a DTES residence (HR = 1.68 [95% CI: 1.13 – 2.49]) and daily heroin injection (HR = 1.82 [95% CI: 1.37 – 108 2.42]) were associated with receiving CIRI care in univariate analyses. When the coefficients were tested for time dependence, we found that the assumptions of the Cox analysis were met, except for the variable requiring help injecting. Therefore, in the multivariate analysis, an interaction term between requiring help injecting and logarithm of time was included. As displayed in Table 5.2, in the multivariate model, being female (AHR = 1.87 [95% CI: 1.32 – 2.64]), living in unstable housing (AHR = 1.39 [95% CI: 1.02 – 1.88]) and daily heroin injection (AHR = 1.52 [95% CI: 1.13 – 2.04]) were independently associated with receiving CIRI care. We also considered an interaction term involving requiring help injecting and time; this interaction was found to be significant (AHR = 1.25 [95% CI: 1.02 – 1.55]). Since homelessness may also be associated with our outcome, but is likely collinear with the variable unstable housing, a sub‐analysis was conducted to examine the impact of homelessness on our outcome of interest. The multivariate results remained virtually unchanged (Appendix 3: Table 5.6). In addition, given that HIV positive IDU are known to have heightened susceptibility to CIRI, we conducted a sub‐analysis that considered the effect of HIV status. At baseline, HIV status was not associated with receiving care for CIRI (OR = 1.18 [95%CI: 0.78 – 1.79]) (Appendix 3: Table 5.5). 109 5.4 DISCUSSION In the present study, 27% of Scientific Evaluation of Supervised Injection participants received CIRI care within the SIF. We found that being female, living in unstable housing and daily heroin injection were independent predictors of receiving CIRI care among a cohort of IDU recruited from within Vancouver’s SIF. This paper is the first we are aware of to describe the epidemiology of CIRI care receipt within an SIF. Our finding that female sex was associated with receiving CIRI care at the SIF is consistent with previous work that has identified females as being more likely to seek medical treatment [24]. In addition, females are at a heightened risk of CIRI development [25‐29] and this may be due to smaller, less easily accessible veins [2]. Furthermore, females are known to be particularly marginalized in drug using relationships, such as being more likely to require assistance with injection (which is a known marker of high risk injection and associated with an increased risk of HIV and HCV transmission and CIRI [25, 26]). Nevertheless, this finding demonstrates that female SIF users are accessing CIRI care at the SIF. This situation represents a unique opportunity for nurses to offer additional targeted care to this subpopulation. Acknowledging that gender dynamics are a challenge for nurses at the SIF to confront, nurses promote self‐ injection and could ensure females are provided with injection education in an 110 attempt to reduce the proportion of females that rely on males for their injections. In addition, if needed nurses could provide referrals to other health or relationship counseling services. Individuals who live in unstable housing as well as daily heroin injectors were more likely to receive CIRI care at the SIF. Differences between the baseline and Cox proportional hazard regression results may be due to differences in the cross‐sectional versus time‐updated nature of the techniques. Research has demonstrated that among a DTES community recruited cohort, participants who reported living in unstable housing and daily heroin injection were significantly more likely to use the SIF [21]. Therefore, this result may simply reflect the fact that individuals who live in unstable housing and are daily heroin injectors are over represented in this sample. Alternatively, this finding may indicate that these particular individuals are more likely to receive CIRI care in this setting. Given that IDU remain a population medically underserved [29], this finding may be related to a proposed benefit of the SIF, whereby hard to reach IDU populations can be drawn into a healthcare setting so that service delivery to this population can be improved [17]. Furthermore, it may be that individuals living in unstable housing may be unwilling to carry materials that can prevent CIRI, such as alcohol swabs, out of fear of confrontations with the police [30]. While cocaine use has been associated with having CIRI [26, 27], cocaine injection was 111 not associated with receiving care for CIRI. This may be due to unique barriers to care that cocaine injectors face that could be, in part, related to greater intensity of injecting among cocaine injectors. Our study found that over time individuals who reported requiring help injecting were more likely to receive CIRI care. In general, this finding is consistent with previous research indicating that individuals who require help injecting are more likely to be inexperienced and inadequately educated on how to inject safely [31]. However, IDU with vascular problems, for example IDU who have been injecting over many years, may also require help injecting. Further, a recent study on safer injecting education administered by nurses at the SIF reported that Scientific Evaluation of Supervised Injection participants who require help injecting are more likely to engage with nurses on education around injecting [32]. Collectively, what these studies and our findings may suggest is that individuals who require help injecting, despite being at heightened risk of blood‐borne disease transmission including HIV [33, 34], are engaging in nurse‐ administered care at the SIF. There are limitations of this research. First, these results are derived from an observational cohort and it is possible that unmeasured factors may explain our findings. For example, Scientific Evaluation of Supervised Injection participants who were more concerned for their health may have used the SIF 112 more. However, previous research has suggested that greater use of the SIF is associated with markers of reduced access to care, including high intensity drug injection and living in unstable housing [21]. In addition, this study examined nursing care for CIRI at the SIF and we did not have existing information on other health service utilization in Vancouver’s DTES. Second, although our key endpoints were based on database linkages rather than self‐report, our explanatory variables were based on self‐report and therefore the possibility of social desirability bias cannot be eliminated. Nevertheless, studies have suggested self‐report among IDU to be valid [35]. Third, although results from this study may be generalizable to SIF users in this and other settings, it is not appropriate to extend these findings to all IDU, either in the DTES or elsewhere. In conclusion, 27% Scientific Evaluation of Supervised Injection participants received nursing care for CIRI and we observed that the majority of care provided by the nursing staff at a local SIF was related to CIRI. Receiving CIRI care at the SIF was independently associated with being female, living in unstable housing and daily heroin injection. These results describe who is more likely to receive CIRI care, which is of use to those engaged with developing and improving policy and programs of comprehensive treatment regimens involving this population. 113 50 Incidence of CIRI care (%) 45 40 35 30 25 20 15 females 10 males 5 0 0 6 12 18 24 Tim e (m onths) Figure 5.1: Incidence of cutaneous injection‐related infection (CIRI) care among Scientific Evaluation of Supervised Injection participants, stratified by sex (n = 1080); log rank p‐value < 0.001 114 Table 5.1: Baseline profile of Scientific Evaluation of Supervised Injection participants receiving cutaneous injection‐related infection care at a supervised injection facility (n = 1080) No CIRI care CIRI care n = 901 n = 179 n (%) n (%) 38.5 [32.9‐44.3] 37.8 [29.5‐44.4] 0.99 (0.97 ‐ 1.01) Female 241 (27%) 73 (41%) 1.89 (1.35 ‐ 2.63) Male 660 (73%) 106 (59%) Yes 484 (54%) 104 (58%) 1.19 (0.86 ‐ 1.65) No 417 (46%) 75 (42%) Yes 593 (66%) 138 (77%) 1.75 (1.20 ‐ 2.54) No 308 (34%) 41 (23%) Yes 289 (32%) 67 (37%) 1.27 (0.91 ‐ 1.77) No 612 (68%) 112 (63%) Daily 270 (30%) 72 (40%) 1.57 (1.13 ‐ 2.19) Not daily 631 (70%) 107 (60%) Daily 442 (49%) 103 (58%) 1.41 (1.02 ‐ 1.95) Not daily 459 (51%) 76 (42%) Daily 109 (12%) 38 (21%) 1.96 (1.30 ‐ 2.95) Not daily 792 (88%) 141 (79%) 145 (16%) 33 (19%) 1.18 (0.78 – 1.79) 744 (84%) 144 (81%) Variable Age Median [IQR] Sex Unstable housing* DTES residence* Require help inject* Cocaine injection* Heroin injection* Speedball injection* HIV serostatus Odds Ratio (95% CI) Note: *Behaviours refer to activities in the last 6 months. Note: CIRI = cutaneous injection‐related infection, CI = confidence interval, IQR = interquartile range, DTES = Downtown Eastside. 115 Table 5.2: Univariate and multivariate Cox proportional hazard analyses of receiving cutaneous injection‐related infection care among Scientific Evaluation of Supervised Injection participants (n = 1065) Unadjusted Hazard Ratio (HR) Variable Age (per year) Sex (Female vs male) Unstable housing* (Yes vs no) DTES residence* (Yes vs no) Cocaine injection* (Daily vs not daily) Heroin injection* (Daily vs not daily) Speedball injection* (Daily vs not daily) HR Adjusted Hazard Ratio (AHR) (95% CI) AHR (95% CI) 0.99 (0.97 – 1.00) 2.08 (1.49 ‐ 2.92) 1.87 (1.32 – 2.64) 1.61 (1.17 – 2.22) 1.39 (1.02 – 1.88) 1.68 (1.13 – 2.49) 1.33 (0.90 – 1.96) 1.14 (0.82 – 1.58) 1.82 (1.37 – 2.42) 1.52 (1.13 – 2.04) 1.92 (1.21 – 3.05) 1.47 (0.95 – 2.26) Note: *Behaviours refer to activities in the last 6 months. Model was fit adjusted for all variables p < 0.05 in unadjusted analyses. CI = confidence interval, DTES = Downtown Eastside. 116 5.5 REFERENCES 1. White AG. Medical disorders in 200 consecutive admissions. JAMA 1973; 223: 1469‐1471. 2. Murphy EL, DeVita D, Liu H, Vittinghoff E, Leung P, Ciccarone DH, et al. Risk factors for skin and soft‐tissue abscesses among injection drug users: a case‐control study. Clin Infect Dis 2001; 33: 35‐40. 3. Palepu A, Tyndall MW, Leon H, Muller J, OʹShaughnessy MV, Schechter MT, et al. Hospital utilization and costs in a cohort of injection drug users. CMAJ 2001; 165: 415‐420. 4. del Giudice P. Cutaneous complications of intravenous drug abuse. Br J Dermatol 2004; 150: 1‐10. 5. Bergstein JM, Baker EJ, Aprahamian C, Schein M, Wittmann DH. Soft tissue abscesses associated with parenteral drug abuse: presentation, microbiology, and treatment. Am Surg 1995; 61: 1105‐1108. 6. Biller JA, Murr AH. 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Int J Drug Policy 2005; 16: 137‐138. 12. Grau LE, Arevalo S, Catchpool C, Heimer R. Expanding harm reduction services through a wound and abscess clinic. Am J Public Health 2002; 92: 1915‐1917. 13. Pollack HA, Khoshnood K, Blankenship KM, Altice FL. The impact of needle exchange‐based health services on emergency department use. J Gen Intern Med 2002; 17: 341‐348. 14. Wood E, Kerr T, Montaner JS, Strathdee SA, Wodak A, Hankins CA, et al. Rationale for evaluating North Americaʹs first medically supervised safer injecting facility. Lancet Infect Dis 2004; 4: 301‐306. 118 15. Kimber J, Dolan K, van Beek I, Hedrich D, Zurhold H. Drug consumption facilities: an update since 2000. Drug Alcohol Rev 2003; 22: 227‐233. 16. Lorvick J, Kral AH, Seal K, Gee L, Edlin BR. Prevalence and duration of hepatitis C among injection drug users in San Francisco, Calif. Am J Public Health 2001; 91: 46‐47. 17. Dolan K, Kimber J, Fry C, Fitzgerald J, McDonald D, Frautmann F. Drug consumption facilities in Europe and the establishment of supervised injecting centres in Australia. Drug Alcohol Review 2000; 19: 337‐346. 18. Wright NM, Tompkins CN. Supervised injecting centres. BMJ 2004; 328: 100‐102. 19. Wood E, Kerr T, Lloyd‐Smith E, Buchner C, Marsh DC, Montaner JSG, et al. Methodology for evaluating Insite: Canadaʹs first medically supervised safer injection facility for injection drug users. Harm Reduct J 2004; 1. 20. Kerr T, Tyndall M, Li K, Montaner JS, Wood E. Safer injection facility use and syringe sharing in injection drug users. Lancet 2005; 366: 316‐318. 21. Wood E, Tyndall M, Li K, Lloyd‐Smith E, Small W, Montaner J, et al. Do supervised injecting facilities attract higher‐risk injection drug users? Am J Prev Med 2005; 29: 126‐130. 119 22. Wei L, Lin DY, Weissfeld L. Regression analysis of multivariate incomplete failure time data by modeling marginal distributions. J Am Stat Assoc 1989; 84: 1065‐1073. 23. Reid N, Crepeau H. Influence fuctions for proportional hazard regression. Biometrika 1985; 72: 1‐9. 24. Palepu A, Strathdee SA, Hogg RS, Anis AH, Rae S, Cornelisse PG, et al. The social determinants of emergency department and hospital use by injection drug users in Canada. J Urban Health 1999; 76: 409‐418. 25. Spijkerman IJ, van Ameijden EJ, Mientjes GH, Coutinho RA, van den Hoek A. Human immunodeficiency virus infection and other risk factors for skin abscesses and endocarditis among injection drug users. J Clin Epidemiol 1996; 49: 1149‐1154. 26. Topp L, Iversen J, Conroy A, Salmon AM, Maher L. Prevalence and predictors of injecting‐related injury and disease among clients of Australiaʹs needle and syringe programs. Aust N Z J Public Health 2008; 32: 34‐37. 27. Lloyd‐Smith E, Kerr T, Hogg RS, Li K, Montaner JSG, Wood E. Prevalence and correlates of abscesses among a cohort of injection drug users. Harm Reduct J 2005; 2. 120 28. Shannon K, Kerr T, Bright V, Gibson K, Tyndall M. Drug sharing with clients as a risk marker for increased violence and sexual and drug‐related harms among survival sex workers. AIDS Care 2008; 20: 235‐241. 29. French MT, McGeary KA, Chitwood DD, McCoy CB. Chronic illicit drug use, health services utilization and the cost of medical care. Soc Sci Med 2000; 50: 1703‐1713. 30. Small W, Rhodes T, Wood E, Kerr T. Public injection settings in Vancouver: physical environment, social context and risk. Int J Drug Policy 2007; 18: 27‐36. 31. Wood E, Tyndall MW, Zhang R, Stoltz J.A., Montaner JSG, Kerr T. Attendance at supervised injection facilities and use of detoxification services. N Engl J Med 2006; 354: 2512‐2514. 32. Wood RA, Wood E, Lai C, Tyndall MT, Montaner JSG, Kerr T. Nurse‐ delivered safer injection education among a cohort of injection drug users: Evidence from the evaluation of Vancouverʹs supervised injection facility. Int J Drug Policy 2008; 19: 183‐188. 33. Wood E, Spittal PM, Kerr T, Small W, Tyndall MW, OʹShaughnessy MV, et al. Requiring help injecting as a risk factor for HIV infection in the Vancouver epidemic: Implications for HIV prevention. Can J Public Health 2003; 94: 355‐359. 121 34. OʹConnell JM, Kerr T, Li K, Tyndall MW, Hogg RS, Montaner JS, et al. Requiring help injecting independently predicts incident HIV infection among injection drug users. J Acquir Immune Defic Syndr 2005; 40: 83‐88. 35. Darke S. Self‐report among injecting drug users: a review. Drug Alcohol Depend 1998; 51: 253‐263. 122 CHAPTER 65: DETERMINANTS OF CUTANEOUS INJECTION‐RELATED INFECTIONS AMONG INJECTION DRUG USERS AT AN EMERGENCY DEPARTMENT 6.1 INTRODUCTION Cutaneous injection‐related infections (CIRI), abscesses and cellulitis, are a primary reason why people who inject drugs (IDU) access the Emergency Department (ED) [1‐4]. Dramatic increases of hospital admissions for CIRI have been reported in several settings [5, 6]. For example, in the United Kingdom, from 1997‐1998 to 2003‐2004, the number of abscess cases increased 566%, while the number of cellutitis cases increased 469% [5]. A recent study by Hope et al. highlighted that health care costs associated with these infections is high, conservatively ranging from £15.5 to £30.0 million annually [7] . Collectively, there is increasing awareness that improvement in treatment paradigms for CIRI is warranted [7]. In order for relevant and appropriate improvements in treatment of CIRI at the ED to occur, an understanding of the population using the ED for CIRI care is required. The present study was conducted to examine predictors of ED 5 A version of this chapter has been submitted for publication. Lloyd‐Smith E, Tyndall M, Zhang R, Grafstein E, Sheps S, Wood E, Montaner JS, Kerr T. Determinants of cutaneous injection‐ related infections among injection drug users at an Emergency Department. 123 use for CIRI among IDU using a supervised injection facility (SIF) in Vancouver, Canada. Since one of the objectives of the evaluation of the SIF was to assess the impact of the SIF on uptake of various treatment services [8‐11], we also sought to assess whether the SIF is facilitating treatment for CIRI. Further, it has been previously shown that female IDU are more likely to develop CIRI [2, 12] and to be hospitalized [13, 14] and so we also sought to compare the incidence and risk factors for ED use for CIRI between female and male IDU. 6.2 METHODS 6.2.1 Study setting SIF provide a service whereby IDU can inject pre‐obtained illicit drugs under the supervision of medical staff [15, 16]. Within SIF, individuals are provided with sterile injecting equipment, emergency intervention in the event of an overdose, plus routine primary medical care as well as addiction treatment, either on site or through referral [17]. North America’s first government sanctioned SIF opened in Vancouver, Canada, in September, 2003. The SIF is located in the Downtown Eastside (DTES), which is home to many of Vancouver’s IDU and is one of the poorest urban postal codes in Canada. The SIF has been designed to minimize barriers to medical care utilization among 124 attendees, including onsite nursing care and referrals to other health and detoxification services [17]. 6.2.2 Study sample The SIF in Vancouver is being evaluated through the Scientific Evaluation of Supervised Injection (SEOSI) cohort, which has been described previously in detail [17]. Briefly, the cohort was assembled through random recruitment of IDU from within the SIF. Since January 1 2004, 1083 participants had been recruited to the SEOSI cohort. 6.2.3 Data collection and measures SEOSI participants are asked to provide a venous blood sample for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) and to complete an interviewer‐administered questionnaire at baseline and at semi‐annual follow‐up visits. The questionnaire takes approximately 45 minutes to complete and collects information on a range of topics including socio‐demographic, drug use patterns, personal history and the uptake of social services. Since health service use may be over‐reported by IDU [2, 12], informed consent that was obtained from all participants included a request to perform linkages with administrative health databases. In this study, a linkage to St. Paul’s Hospital ED database was performed to track patient use. St. Paul’s 125 Hospital is considered to serve the majority of IDU residing in Vancouver’s DTES. To be considered an ED visit for a CIRI, the following International Classification of Disease (ICD) 9 codes (Abscess and/or Cellulitis: 682.9) and the ICD 10 codes (Abscess: G061, G062, L020, L021, L022, L024, J851 and Cellulitis: L0300, L0310, L0311, L032, L0335, L038) from a patient’s hospital records were used. ICD is a World Health Organization endorsed international standard for classification of diagnoses of disease that is of use for epidemiological and clinical research and healthcare management [18, 19]. In addition, a linkage to the SIF database was performed to examine nurse contact and referrals issued. For this task, we conducted a record linkage to each participant’s record in the SIF database to examine whether the nurse placed an entry in the SIF database indicating that they referred the participant to hospital prior to the censor or event date. We also examined whether individuals who were referred by nurses were more likely to be subsequently hospitalized using in‐patient hospital record linkage. The Research Ethics Board at the University of British Columbia approved the present study. 6.2.4 Statistical analysis The endpoint for these analyses was an ED visit for a CIRI. Since females are known to display different patterns of health care utilization [10, 11], as well as CIRI development [20], we examined baseline characteristics stratified by sex 126 and factors associated with an ED visit for a CIRI in two separate models, stratified by sex. Variables considered included: age, sex (female vs. male), currently residing in the DTES (yes vs. no), living in unstable housing (yes vs. no), daily cocaine injection (yes vs. no), daily heroin injection (yes vs. no), daily crack injection (yes vs. no), daily speedball injection (yes vs. no) and being HIV positive (yes vs. no). Variables refer to behaviour during the last six months unless otherwise specified. Living in unstable housing refers to living in a single room occupancy (SRO) hotel, shelter, recovery or transition house or having no fixed address. We also examined whether, at the SIF, a nurse referral to hospital was associated with an increased likelihood of ED use for a CIRI. Variable selection was based on previously published literature on CIRI or hospitalization among IDU in our setting [1, 2, 10]. Variables associated with an increased risk of ED visit for a CIRI were examined using unadjusted and adjusted Cox proportional hazard regression analyses. All behavioural variables were time‐updated based on semi‐annual follow‐up. Time zero was defined as the date of recruitment into the SEOSI study for all participants and participants who had not attended the ED at St. Paul’s Hospital were censored as of 31 January 2008. The multivariate model was fit using a fixed model that we adjusted for all variables that were statistically significant at the p < 0.05 level in the univariate analyses. Separate Cox proportional hazard models were run for 127 males and females. A model was also run with males and females combined (Appendix 4). All statistical analyses were performed using SAS 9.1 and all p‐ values were two‐sided. 6.3 RESULTS During our study period, from 1 January 2004 to 31 January 2008, 1083 individuals were recruited into the SEOSI cohort. Fifteen persons had missing data on HIV serostatus and were excluded from all analyses. Female participants comprised 315 (29%) of the sample. The median age among SEOSI participants was statistically different (p <0.001) between females and males, 35.1 (interquartile range (IQR): 28.7‐41.5) and 39.7 (IQR: 33.7‐45.3) respectively. Median duration of follow‐up after recruitment into the cohort was not statistically different between the males and females (p = 0.200). During the study period, 289 (27%) participants used the ED for a CIRI. Of those with at least one visit, 81 (28%) visited the ED for a CIRI once only during the study period, 54 (19%) twice, 39 (13%) three times, 32 (11%) four times, 83 (29%) five or more times for a total of 1213 identified visits (Appendix 4: Table 6.5). Individuals with an ED visit who were referred by a nurse were more likely to be hospitalized within three days (p = 0.011). 128 The incidence density of first ED visit for CIRI among females was 23.8 per 100 person‐years (95% Confidence Interval [CI]: 19.3 – 29.0) and among males 19.2 per 100 person‐years (95% CI: 16.7 ‐ 22.1). The difference between these densities did not reach statistical significance (p = 0.090). Baseline characteristics, stratified by sex, among IDU at a SIF are provided in Table 6.1. Unadjusted odds ratio indicate that females are more likely to be younger (0.94 [95% CI: 0.93 – 0.96]), require assistance with injection (2.27 [95% CI: 1.73 – 2.97]), be daily heroin injectors (1.46 [95% CI: 1.12 – 1.90]), be daily crack users (2.29 [95% CI: 1.74 – 3.00]), speedball injectors (1.76 [95% CI: 1.23 – 2.52]), be HIV positive (1.42 [1.01 – 1.99]) and be referred to hospital by a nurse at the SIF (2.16 [95% CI: 1.31 – 3.54]). The univariate and multivariate Cox proportional hazard analyses of ED use for a CIRI among females is displayed in Table 6.2. In the multivariate model for females, residing in the DTES (adjusted hazard ratio [AHR] = 2.06 [95% CI: 1.13 – 3.78]) and being referred by a study nurse to hospital (AHR = 4.48 [95% CI: 2.76 – 7.30]) were risk factors independently and positively associated with ED use for a CIRI. For males, the univariate and multivariate Cox proportional hazard analyses of ED use for a CIRI is shown in Table 6.3. The factors associated with an increased risk of ED use for a CIRI among males were requiring help injecting 129 (AHR = 1.38 [95% CI: 1.01 ‐ 1.90]), being HIV positive (AHR = 1.85 [95% CI: 1.34 – 2.55]) and being referred by a nurse at the SIF to hospital (AHR = 2.97 [95% CI: 1.93 – 4.57]). An unadjusted and adjusted Cox proportional hazard regression that has not been stratified by sex may be found in Appendix 4 (Table 6.4). 6.4 DISCUSSION Over a three year period, close to one third of SEOSI participants visited the ED for a CIRI, yielding incidence densities of ED use for CIRI of 23.8 visits per 100 person‐years and 19.2 visits per 100 person‐years for females and males, respectively. The most significant predictor of ED use for a CIRI for both females and males respectively, and in the combined Cox proportional hazard model, was being referred to hospital by a nurse from the SIF. Other determinants of ED use for a CIRI differed between female and male IDU. For females, ED use for a CIRI was also associated with residing in the DTES. For males, requiring help injecting and being HIV positive were also associated with an increased risk of an ED visit for a CIRI. Importantly, the strongest predictor of ED use for a CIRI, which was also the only significant predictor for both females and males, was being referred to hospital by a nurse working at the SIF. This finding is of significance given that a goal of the SIF is to provide assessment and referral of CIRI onsite and given that 130 the ED provides unique CIRI treatment that is not available at the SIF (e.g., incision and drainage or intravenous antibiotic therapy). Findings from this study demonstrate that nurses at the SIF play a critical role in referring individuals who use the SIF to the ED. Further, results indicated that individuals referred to the ED were more likely to be hospitalized within three days. This suggests that nurses are referring individuals to the hospital who have severe infections requiring hospitalization. Infectious complications among IDU that may require hospitalization include osteomyelitis and endocarditis [2]. However, if timely referrals are made before an infection has escalated to a point of requiring a lengthy and expensive hospitalization and if individuals can avoid hospitalization or are hospitalized for a shorter period of time, then these referrals may ultimately result in saving healthcare dollars. However, future analyses are needed to confirm the effect of SIF nurse referral on hospital costs. Among females, residing in the DTES was a determinant of ED use for a CIRI. Females residing in the DTES often lead chaotic and unstable lifestyles that place them at an elevated risk of developing both acute and chronic health conditions [20]. A recent study by Shannon et al, found that females in the DTES frequently require emergency care, with 39% of female participants reporting an ED visit in the last six months [20]. These dynamics are complicated by the fact that outpatient or neighborhood health clinic hours are limited and often 131 coincide with work hours among females in this setting [1], which may result in a heavy use of the ED for health concerns. Further, this finding may reflect the close proximity of the DTES to St. Paul’s Hospital [1, 2], but otherwise it is unclear why neighborhood status would be associated with females and not males. Male participants who were HIV positive visited the ED for a CIRI significantly more often than HIV negative participants. This is not surprising given previous reports of increased hospital use among HIV positive IDU in this setting [21, 22]. An increased susceptibility to bacterial infections [1] and other opportunistic infections among HIV positive individuals may contribute to the greater risk of ED use for a CIRI observed among HIV positive males during the study period [23]. However, since a similar trend was seen among females, it is likely that this study was under powered to detect this association among females. In addition, these males may have continued high risk injection practices [24, 25], as indicated by our finding that requiring assistance with injecting was also a predictor of ED use for a CIRI among males. Requiring assistance with injecting has been reported to be related to an elevated risk of HIV [26] as well as the development of CIRI . There were limitations to this analysis that need to be considered when interpreting this data. Firstly, we were only able to include one hospital in this 132 study, which would have resulted in an underestimation of ED use as some participants would have accessed the ED in other hospitals. However, St. Paul’s Hospital serves the majority of the IDU in this setting [2]. Although there were differences between males and females in our study, some trends were similar and there may have been inadequate numbers of females to produce statistically significant differences. Secondly, our study relies on self report to obtain drug use and other behavioural variables. However, self report among IDU related to drug use and behavioural factors is considered to be generally valid [17] and ED use and nurse referrals were accessed directly from databases within the ED and the SIF respectively. Further, inconsistencies in ICD reporting may have impacted our results, however, ICD reporting is considered to be a valid method of disease classification [18] and there is no reason to suggest that this reporting bias would be different between groups in this study. Thirdly, while the SEOSI cohort was randomly recruited from within the SIF and therefore is representative of IDU using Vancouver’s SIF, results from this study may not be appropriate to generalize to IDU in other settings. To reduce requiring ED treatment of CIRI, there needs to be expanded capacity to treat and manage CIRI in a community setting. Several examples of efficient and cost effective community‐based treatment have been developed in California. The operation of the Integrated Soft Tissue Infection Services (ISIS) 133 clinic in San Francisco resulted in a 47% decrease in surgical service admissions, a 34% reduction in ED visits and an estimated savings of over $8 million for costs related to CIRI in its first year [27]. It effectively changed a predominately inpatient model of care to an outpatient model that offered quality surgical interventions integrated with counseling and social services for individuals with CIRI [27]. In addition, a wound management clinic operated in collaboration and conjunction with a syringe exchange program in Oakland, California and provided efficient and cost effective care [28]. The average cost per individual treated was $5, substantially lower than equivalent hospital costs, which are averaged to be between $185 and $360, not including medication and physician fees [28]. Increased resources to improve capacity (e.g., scope of practice) for nurses to care for CIRI and to expand primary care (e.g., incision and drainage or provision of antibiotic therapy) of CIRI in an integrated manner are recommended in this setting. In summary, we found high levels of ED use for CIRI among both female and male IDU who use the SIF. Residing in the DTES and being referred to hospital by a nurse at the SIF was associated with an increased risk of an ED visit for a CIRI among females. For males, requiring help injecting, being HIV positive and being referred to hospital by a nurse at the SIF was associated with an increased risk of an ED visit for a CIRI. Results from this study support the 134 need for a better understanding of how health care workers in different settings may work together to provide more efficient, streamlined and cost‐effective treatment for CIRI. Moreover, our findings suggest that the SIF could play a more intensive role in providing primary and secondary level services that could reduce both ED and in hospital utilization for CIRI treatment. 135 Table 6.1: Baseline characteristics, stratified by sex, among injection drug users at a supervised injection facility (n = 1083) Variable Odds Ratio (OR) Females Males N (%) n (%) 35.1 (28.7–41.5) 39.7 (33.7 – 45.3) 166 (53) 149 (47) 425 (55) 343 (45) 216 (69) 99 (31) 518 (67) 250 (33) 146 (46) 169 (54) 212 (27) 556 (72) 102 (32) 213 (68) 241 (31) 527 (69) Daily Not daily Crack use * Daily Not daily Speedball injection* 180 (57) 135 (43) Daily Not daily HIV serostatus* Positive Negative Hospital referral† Yes No Age Median Interquartile range Unstable housing* Yes No DTES residence Yes No Requiring help inject* Yes No Cocaine injection* Daily Not daily Heroin injection OR (95% CI) p‐value (0.93 – 0.96) <0.001 0.460 0.94 0.90 (0.69 – 1.17) 1.05 (0.79 – 1.40) 2.27 (1.73 ‐ 2.97) 0.775 < 0.001 0.749 1.05 (0.79 – 1.39) 367 (48) 401 (52) 1.46 (1.12 – 1.90) 208 (66) 107 (34) 353 (46) 415 (54) 59 (19) 256 (81) 89 (12) 679 (88) 62 (20) 244 (80) 116 (15) 646 (85) 1.42 (1.01 – 1.99) 0.046 31 (10) 284 (90) 37 (5) 731 (95) 2.16 (1.31 – 3.54) 0.002 2.29 (1.74 – 3.00) 1.76 (1.23 – 2.52) 0.005 <0.001 0.002 Note: *Behaviours refer to activities in the last six months. †Indicates data derived from SIF database and by a study nurse. Note: CI = confidence interval, DTES = Downtown Eastside 136 Table 6.2: Univariate and multivariate Cox proportional hazard analyses of time to Emergency Department use for a cutaneous injection‐related infection among 306 female injection drug users Unadjusted Hazard Ratio (HR) Adjusted Hazard Ratio (AHR) Variable HR Age (per year older) 1.00 Unstable housing* (Yes vs No) 1.68 DTES residence (Yes vs No) Requiring help inject* (Yes vs No) Cocaine injection* (Daily vs Not daily) p‐value AHR (95% CI) 0.738 (1.09 – 2.61) 0.020 2.46 (1.41 – 4.28) 0.001 1.56 1.37 (1.03 – 2.37) (0.88 – 2.11) 0.038 0.163 (0.97 ‐1.02) Heroin injection* (Daily vs Not daily) (95% CI) 1.55 Crack use* 1.12 (0.69 – 1.82) 0.647 2.06 (1.13 – 3.78) 0.019 1.40 (0.79 ‐ 1.90) 0.121 0.044 (1.01 – 2.37) p‐value 1.22 (0.79 ‐ 1.90) 0.361 (Daily vs Not daily) 1.42 (0.90 – 2.24) 0.131 Speedball injection* (Daily vs Not daily) 1.61 (0.97 – 2.65) 0.064 HIV serostatus* (Positive vs Negative) Hospital referral† (Yes vs No) 1.57 (0.62 – 1.66) 0.958 5.06 (3.14 – 8.17) <0.001 4.48 (2.76 – 7.30) <0.001 Note: *Behaviours refer to activities in the last six months. †Indicates data derived from SIF database and by a study nurse. Model was fit adjusted for all variables p < 0.05 in unadjusted analyses. CI = confidence interval, DTES = Downtown Eastside 137 Table 6.3: Univariate and multivariate Cox proportional hazard analyses of time to Emergency Department use for a cutaneous injection‐related infection among 762 male injection drug users Unadjusted Hazard Ratio (HR) Adjusted Hazard Ratio (AHR) Variable HR (95% CI) p‐value AHR (95% CI) p‐value Age (per year older) 0.99 (0.97 – 1.01) 0.287 Unstable housing* (Yes vs No) 1.60 (1.18 – 2.17) 0.002 DTES residence (Yes vs No) 1.52 (1.10 – 2.11) 0.012 1.19 (0.83 – 1.72) 1.59 (1.16 – 2.17) 0.004 1.38 (1.01 – 1.90) 1.18 (0.87 – 1.60) 0.296 Requiring help inject* (Yes vs No) Cocaine injection* (Daily vs Not daily) Heroin injection* (Daily vs Not daily) Crack use* 1.13 (0.85 – 1.51) 0.385 1.37 0.063 (0.98 – 1.92) 1.30 (0.97 – 1.74) 1.46 (1.10 – 1.94) 0.008 Speedball injection* (Daily vs Not daily) 1.28 (0.82 – 2.02) 0.281 0.043 (Daily vs Not daily) 0.342 0.079 HIV serostatus* (Positive vs Negative) Hospital referral† (Yes vs No) 1.90 (1.38 – 2.61) <0.001 1.85 (1.34 – 2.55) <0.001 3.28 (2.14 – 5.04) <0.001 2.97 (1.93 – 4.57) <0.001 Note: *Behaviours refer to activities in the last six months. †Indicates data derived from SIF database and by a study nurse. 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Spijkerman IJ, van Ameijden EJ, Mientjes GH, Coutinho RA, van den Hoek A. Human immunodeficiency virus infection and other risk factors for skin abscesses and endocarditis among injection drug users. J Clin Epidemiol 1996; 49: 1149‐1154. 12. Floris‐Moore M, Lo Y, Klein RS, Budner N, Gourevitch MN, Moskaleva G, et al. Gender and hospitalization patterns among HIV‐infected drug users before and after the availability of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2003; 34: 331‐337. 140 13. Kimber J, Dolan K, van Beek I, Hedrich D, Zurhold H. Drug consumption facilities: an update since 2000. Drug Alcohol Rev 2003; 22: 227‐233. 14. Lorvick J, Kral AH, Seal K, Gee L, Edlin BR. Prevalence and duration of hepatitis C among injection drug users in San Francisco, Calif. Am J Public Health 2001; 91: 46‐47. 15. Dolan K, Kimber J, Fry C, Fitzgerald J, McDonald D, Frautmann F. Drug consumption facilities in Europe and the establishment of supervised injecting centres in Australia. Drug Alcohol Rev 2000; 19: 337‐346. 16. Wright NM, Tompkins CN. Supervised injecting centres. BMJ 2004; 328: 100‐102. 17. Wood E, Kerr T, Lloyd‐Smith E, Buchner C, Marsh D, Montaner J, et al. Methodology for evaluating Insite: Canadaʹs first medically supervised safer injection facility for injection drug users. Harm Reduct J 2004; 1. 18. Quan H, Parsons G, Ghali WA. Validity of procedure codes in International Classification of Diseases, 9th revision, clinical modification administrative data. Medical Care 2004; 42: 801‐809. 19. International Statistical Classification of Diseases and Related Health Problems. Tenth Revision ed. Geneva, Switzerland: WHO; 1992. 141 20. Shannon K, Bright V, Duddy J, Tyndall MW. Access and utilization of HIV treatment and services among women sex workers in Vancouverʹs downtown eastside. J Urban Health 2005; 82: 488‐497. 21. Flanigan TP, Hogan JW, Smith D, Schoenbaum E, Vlahov D, Schuman P, et al. Self‐reported bacterial infections among women with or at risk for human immunodeficiency virus infection. Clin Infect Dis 1999; 29: 608‐612. 22. Selwyn PA, Alcabes P, Hartel D, Buono D, Schoenbaum EE, Klein RS, et al. Clinical manifestations and predictors of disease progression in drug users with human immunodeficiency virus infection. N Engl J Med 1992; 327: 1697‐1703. 23. Archibald CP, Ofner M, Strathdee SA, Patrick DM, Sutherland D, Rekart ML, et al. Factors associated with frequent needle exchange program attendance in injection drug users in Vancouver, Canada. J Acquir Immune Defic Syndr 1998; 17: 160‐166. 24. OʹConnell JM, Kerr T, Li K, Tyndall MW, Hogg RS, Montaner JS, et al. Requiring help injecting independently predicts incident HIV infection among injection drug users. J Acquir Immune Defic Syndr 2005; 40: 83‐88. 25. Wood E, Spittal PM, Kerr T, Small W, Tyndall MW, OʹShaughnessy MV, et al. Requiring help injecting as a risk factor for HIV infection in the 142 Vancouver epidemic: Implications for HIV prevention. Can J Public Health 2003; 94: 355‐359. 26. Lloyd‐Smith E, Wood E, Zhang R, Tyndall MW, Montaner JS, Kerr T. Risk factors for developing a cutaneous injection‐related infection among injection drug users: a cohort study. BMC Public Health 2008; 8: 405. 27. Harris HW, Young D.M. Care of injection drug users with soft tissue infections in San Francisco, California. Arch Surg 2002; 137: 1217‐1222. 28. Grau LE, Arevalo S, Catchpool C, Heimer R. Expanding harm reduction services through a wound and abscess clinic. Am J Public Health 2002; 92: 1915‐1917. 143 CHAPTER 76: DETERMINANTS OF HOSPITALIZATION FOR CUTANEOUS INJECTION‐ RELATED INFECTIONS AMONG INJECTION DRUG USERS 7.1 BACKGROUND Cutaneous injection‐related infections (CIRI), which include cellulitis and abscesses, are among the primary causes of hospitalization among people who inject drugs (IDU) [1]. Hospitalizations due to CIRI carry considerable economic burden [2, 3]. Complications of CIRI that are more likely to require hospitalization include, but are not limited to: osteomyelitis [4], bacteremia and sepsis [5, 6], endocarditis [7, 8], septic arthritis [4, 9], ulcer [6], thrombophlebitis [10, 11] and myositis [6]. A recent report by Hope et al. from 2008 suggested that healthcare associated costs for CIRI among IDU in England were substantial, ranging from £15.5 million to £30 million per annum [2]. In 2001, Palepu et al. reported that of the IDU seen at an urban hospital in Vancouver, Canada, 35% had been hospitalized and a third of these hospitalizations were due to CIRI or related infectious complication [1]. Hospitalization was expensive, with hospital utilization cost per day reported to be $610.33 (95% CI: $575.50‐$644.96) [1]. 6 A version of this chapter has been submitted for publication. Lloyd‐Smith E, Wood E, Zhang R, Tyndall MW, Sheps S, Montaner JS, Kerr T. Determinants of hospitalization for cutaneous injection‐related infections among injection drug users. 144 North America’s first supervised injection facility (SIF) opened in Vancouver’s Downtown Eastside (DTES) in 2003. Within the SIF, IDU can inject pre‐obtained drugs under the supervision of nurses. Individuals visiting the SIF are provided with sterile injecting equipment and emergency intervention in the event of an overdose, as well as primary medical care and addiction treatment, either on site or through referral. While several studies have pointed to the positive impact of the SIF on public disorder [12], HIV risk behaviour [13], management of overdose [14, 15] and use of addiction treatment [16], its role with regard to hospitalizations for CIRI remains unknown. Using longitudinal data, we examined hospitalization for CIRI or related infectious complications among IDU using the SIF. 7.2 METHODS 7.2.1 Design and participants The SIF in Vancouver is being evaluated through the Scientific Evaluation of Supervised Injection (SEOSI) cohort, which has been described in detail [17]. Briefly, the cohort was assembled through random recruitment of IDU from within the SIF. Random recruitment is based on inviting users of the SIF to be referred to the research study during random blocks of time. Among individuals 145 who were recruited, a venous blood sample was drawn and an interviewer‐ administered questionnaire was conducted at baseline and at semi‐annual follow‐up visits. The informed consent agreement, obtained for all participants, included a request to link the SIF evaluation with administrative health databases. In Vancouver, hospitals are equipped with a database that tracks patient admission. The SIF is also equipped with a similar database. In this study, a linkage of SEOSI participant data, SIF data and St. Paul’s Hospital in‐ patient data was performed. St. Paul’s Hospital is the major urban hospital serving the DTES community, one of Canada’s poorest postal codes. The University of British Columbia‐Providence Health Care Research Ethics Board approved the present study. 7.2.2 Measurements The start point for these analyses was enrollment into the SEOSI cohort and the endpoint was hospitalization for a CIRI or related infectious complication. The infectious complications included were based on previous literature [5, 6]. The definition of a hospitalization was based on International Classification of Diseases (ICD) 10 codes on patients’ hospital records and included: abscess (G061, G062, L020, L021, L022, L024, J851), cellulitis (L0300, L0310, L0311, L032, L0335, L038), osteomyelitis (M4620, M4625, M4629, M8617, M8618, M8661, M8663, M8666, M8681, M8691, M8695), staphylococcal infection 146 {(A490, A499, B956) including, septicaemia (A410, A412, A419) and methicillin‐ resistant Staphylococcus aureus (MRSA), (U000)}, endocarditis (I330), septic arthritis (M0000, M0002, M0004, M0005, M0006, M0008, M0009), ulcer (L089, L979), thrombophlebitis (I802, I808) and myositis (M6005, M6008). We first examined the frequency of CIRI or related infectious complications. Then, we evaluated length of stay in hospital among study participants and examined this outcome as a continuous variable in a linear model that adjusted for the following confounding variables age, sex, SIF nurse referral and HIV serostatus. We then considered the cost of hospitalization, associated with CIRI, which was estimated at $712 per hospital day, based on a fully‐allocated costing model for the province of British Columbia from 2001 [1]. This estimate was updated to Canadian dollars in 2005 [18]. Fully‐allocated costing includes costs associated with nursing care, medications, investigations, physician visits and length of stay as well as overhead, opportunity cost of hospital resources and a 5% depreciation of capital equipment [1]. Potential healthcare savings were estimated by multiplying the cost per day value ($712) by the difference in number of days hospitalized among individuals who were referred by a nurse within the SIF and those who were self referred to hospital. 147 We investigated baseline characteristics stratified by hospitalization or not bivariately. Using Cox proportional hazard regression, we examined factors potentially associated with hospitalization. Variables considered for our analyses included: age; sex at birth (female vs. male); current residence in DTES (yes vs. no); living in unstable housing (yes vs. no); daily cocaine injection (yes vs. no); daily heroin injection (yes vs. no); daily speedball injection (yes vs. no); and HIV serostatus (positive vs. negative). As used previously, unstable housing was defined as living in a single room occupancy (SRO) hotel, shelter, recovery or transition house, jail, on the street, or having no fixed address [19]. Variables from the semi‐annual questionnaire referred to behaviour that occurred in the last six months unless otherwise specified. We also examined, whether a SIF nurse referral to hospital was associated with hospitalization and, if so, whether length of stay was different given referral versus self nurse referral. For this task, we conducted a record linkage matching their SEOSI identifying code to each participant’s record in the SIF database to examine if the nurse had referred the participant to hospital. Then, we linked his or her SEOSI identifying code with his or her unique personal health number to examine hospital records prior to the censor or event date. Variable selection was based on previously published literature on CIRI and related infectious complications and hospitalization among IDU [1, 2, 5, 6]. 148 Variables considered associated with hospitalization were analyzed in unadjusted analyses and an adjusted Cox proportional hazard regression model. Time zero was defined as the date of recruitment into the SEOSI study for all participants and participants not hospitalized at St. Paul’s Hospital were censored as of 31 January 2008. All behavioral variables were treated as time‐ updated covariates based on semi‐annual follow‐up data. The multivariate model was fit using a fixed model whereby we included all variables that were statistically significant at the p < 0.05 level in univariate analyses. All statistical analyses were performed using SAS 8.0 (Cary, NC) and all p‐values were two‐ sided. 7.3 RESULTS During the study period (1 January 2004 to 31 January 2008), 1083 individuals were recruited into the SEOSI cohort and 901 (83%) reported at least one follow‐up visit. The median age among SEOSI participants was 38.4 years (IQR: 32.7‐44.3) and 314 (29%) were female. The median follow‐up duration after recruitment into the cohort was 21.4 months (IQR: 13.1‐24.6). During the study period, 99 (9%) participants were admitted to St. Paul’s Hospital, yielding an incidence density of hospitalization for CIRI of 6.07 per 100 person‐years (95% 149 CI: 4.96 – 7.36). A total of 217 hospitalization events occurred. Among the 99 hospitalized SEOSI participants, 47 received CIRI care at the SIF during the study period. Importantly, 60% (28/47) of those who received CIRI care at the SIF were referred to hospital by a nurse at the SIF and subsequently sought treatment at the hospital. Virtually all patients are admitted to hospital from the Emergency Department. Table 7.1 displays the frequency of CIRI or related infectious complications (refer to Appendix 5: Table 7.3 and 7.4). Cellulitis was the most common reason for hospitalization. Fifteen persons had missing data on HIV serostatus and were excluded from all analyses. Therefore, all results on HIV were based on a sample size of 1068. Participants who had been referred to hospital by an SIF nurse had a significantly shorter length of stay in hospital as compared to those who were not referred (4 days [interquartile range {IQR}: 2‐ 7days], 12 days [IQR: 5‐33]). The eight day reduction in the length of hospital stay remained significant (p = 0.001) after adjustment for confounding variables. Considering the total potential healthcare saving based on a fully allocated hospital cost per day calculation, each referral from the SIF would have resulted in a saving of $5,696 (IQR: $2,136 – $18,512). Baseline characteristics may be found in Appendix 5: Table 7.5. The factors associated with an increased risk of hospitalization after recruitment into 150 the SEOSI cohort are shown in Table 7.2. In the multivariate model being HIV positive (adjusted hazard ratio [AHR] = 1.79 [95% CI: 1.16 – 2.75]) and being referred to hospital by a nurse at the SIF (AHR = 5.38 [95% CI: 3.39 – 8.55]) were positively and independently associated with an increased likelihood of hospitalization. 7.4 DISCUSSION In the present study, being referred by a nurse at a supervised injection facility was independently associated with an elevated rate of hospitalization. Importantly, participants who had been referred to hospital by a nurse at the SIF had a significantly shorter length of stay in hospital despite adjustment for HIV infection and other potential confounders. This finding indicates that nurses facilitate hospital utilization as well as providing early intervention that prevents lengthy and expensive hospital visits for CIRI or related infectious complications. According to the cost savings calculation based on the length of stay reduction, SIF nurse referral resulted in a minimum of $2,136 per admission. An increased risk of hospitalization for a CIRI or related infectious complication was observed among HIV positive participants. This finding is consistent with previous research on hospitalization among IDU in this setting [1]. A potentially elevated susceptibility to bacterial infections [5, 20] as well as 151 known high‐risk drug injection practices in this subpopulation [21] are possible explanations for why HIV positive participants in this study had elevated rates of hospitalization. Further elucidation of this finding with a larger sample of HIV positive IDU is necessary to examine this important research question. After controlling for factors that are known to be associated with hospitalization [1, 22], referral from an SIF nurse remained a strong predictor of hospitalization. Findings from this study confirm existing qualitative research indicating that nurses at the SIF provide CIRI‐related care and play a key role in enhancing access to medical care among participants who have infections or injuries of greater severity [23]. Hospital care for more severe forms of CIRI is essential since local hospitals provide treatment of CIRI not available at the SIF (e.g., incision and drainage of an abscess, intravenous antibiotic therapy as well as diagnostic tools and therapy appropriate for complications). Further, given that the average length of stay in hospital for those referred to hospital by a nurse at the SIF was significantly shorter, it may be that nurses at the SIF may be helping reduce the incidence of late presentation of complications, such as osteomyelitis, that are often lengthy and are particularly costly to the healthcare system [4]. Although our study design does not allow us to infer causation, it is noteworthy that this association persisted in multivariate analyses. This may 152 reflect prompt referral as well as the preventative effect of the SIF on serious infections [13]. There are several examples of efficient and cost effective community‐ based treatment services that may inform changes in the provision of care that is required in order to reduce the incidence of hospitalization of CIRI and related infectious complications in our setting. In its first year of operation, the Integrated Soft Tissue Infection Services (ISIS) Clinic in San Francisco, California, resulted in a 47% decrease in surgical service admissions and an estimated savings of over $8 million for costs related to CIRI [26]. In addition, a wound management clinic operated in conjunction with a syringe exchange program in Oakland, California [25]. It was found that the average cost per individual treated at this wound management clinic was $5, substantially lower than equivalent hospital costs of $185 and $360 [25]. In our setting, expanding the capacity to provide primary care in an integrated manner is warranted. There are limitations of the present study. Firstly, St. Paul’s Hospital was the only facility linkage that was conducted. However, this is the primary hospital serving the SIF catchment area and is accessed extensively by the IDU population in the DTES [1, 22, 26]. Secondly, our study relies on self report to obtain drug use and other behavioural variables. However, self report among IDU is considered valid [27] and hospital utilization and nurse referral were 153 accessed directly from databases within the hospital and at the SIF, respectively. Further, a limitation of this analysis is that a low sample size of HIV positive participants precluded our ability to conduct further analyses on this association. Additional research is required with a larger sample of HIV positive individuals to better elucidate this finding. 7.5 CONCLUSION In summary, we found high levels of hospitalization for CIRI or related infectious complications among local IDU. Being HIV positive and being referred to hospital by a nurse at the SIF, as opposed to self referral to hospital, were both independently and positively associated with an increased likelihood of hospitalization. Participants who had been referred to hospital by a nurse at the SIF had a much shorter length of stay in hospital as compared to those who were not. These findings indicate that nurses at the SIF play a critical role in terms of referring individuals who require hospitalization for a CIRI or related infectious complication to hospital, which results in shorter and less expensive hospital stays. 154 Table 7.1: Description of primary diagnosis for hospitalization events among Scientific Evaluation of Supervised Injection participants Classification First event n = 99 (%) Total events n = 217 (%) Cellulitis 33 (33) 59 (27) Abscess 14 (14) 26 (12) Osteomyelitis 10 (10) 39 (18) Staphylococcal infection 22 (22) 42 (17) Endocarditis 9 (9) 24 (12) Septic arthritis 7 (7) 12 (6) Ulcer 1 (1) 6 (3) Thrombophlebitis 1 (1) 4 (2) Myositis 2 (2) 4 (2) † Note: † Classification is based on ICD 10 codes; 155 Table 7.2: Univariate and multivariate Cox proportional hazard analyses of hospitalization for a cutaneous injection‐related infection or related infectious complication among injection drug users Unadjusted Hazard Ratio (HR) Variable HR (95% CI) p‐value AHR (95% CI) Age (per year older) Sex* (Female vs Male) Unstable housing* (Yes vs No) Cocaine injection* (Daily vs Not daily) Speedball injection* (Daily vs Not daily) HIV serostatus* (Positive vs Negative) Hospital referral† (Yes vs No) 0.98 (0.96 – 1.01) 1.59 (1.07 – 2.39) 1.36 (0.90 – 2.05) 1.65 (1.08 – 2.53) 1.26 (0.79 – 2.02) 1.46 (0.94 – 2.25) 1.19 (0.69 – 2.07) 1.79 (1.16 – 2.75) 5.38 (3.39 – 8.55) 1.75 (1.17 – 2.62) 1.90 (1.15 – 3.14) 2.12 (1.39 – 3.24) 2.41 (1.55 – 3.77) Adjusted Hazard Ratio (AHR) 0.146 0.024 0.021 0.006 0.012 <0.001 <0.001 p‐value 0.139 0.328 0.090 0.528 0.008 <0.001 Note: *Behaviour refers to activities in the last 6 months. †Indicates data derived from SIF database and by a study nurse. CI = confidence interval. 156 7.6 REFERENCES 1. Palepu A, Tyndall MW, Leon H, Muller J, OʹShaughnessy MV, Schechter MT, et al. Hospital utilization and costs in a cohort of injection drug users. CMAJ 2001; 165: 415‐420. 2. Hope V, Kimber J, Vickerman P, Hickman M, Ncube F. Frequency, factors and costs associated with injection site infections: findings from a national multi‐site survey of injecting drug users in England. BMC Infect Dis 2008; 8. 3. DiNubile MJ, Lipsky BA. Complicated infections of the skin and skin structures: when the infection is more than skin deep. J Antimicrob Chemother 2004; 53: ii37‐ii50. 4. Kak V, Chandrasekar PH. Bone and joint infections in injection drug users. Infect Dis Clin North Am 2002; 16: 681‐695. 5. Gordon RJ, Lowy FD. Bacterial infections in drug users. N Engl J Med 2005; 353: 1945‐1954. 6. del Giudice P. Cutaneous complications of intravenous drug abuse. Br J Dermatol 2004; 150: 1‐10. 157 7. DiNubile MJ. Short‐course antibiotic therapy for right‐sided endocarditis caused by Staphylococcus aureus in injection drug users. Ann Intern Med 1994; 121: 873‐876. 8. Moss R, Munt B Injection drug use and right sided endocarditis. Heart 2003; 89: 577‐581 9. 10. Ebright JR, Pieper B. Skin and soft tissue infections in injection drug users. Infect Dis Clin North Am 2002; 16: 697‐712. Schulz S, Beckenbach C, Philipp M, Hengstmann J. Color coded duplex sonography of inguinal vessels in i.v. drug addicts. Vasa 2002; 31: 7‐13. 11. Roszler MH, McCarroll KA, Donovan KR, Rashid T, Kling GA. The groin hit: complications of intravenous drug abuse. Radiographics 1989; 9: 487‐ 508. 12. Wood E, Kerr T, Small W, Palepu A, Tyndall MW. Changes in public order after the opening of a medically supervised safer injecting facility for illicit injection drug users. CMAJ 2004; 169: 759‐763. 13. Kerr T, Tyndall M, Li K, Montaner J, Wood E. Safer injection facility use and syringe sharing in injection drug users. 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Corneil TA, Kuyper LM, Shoveller J, Hogg RS, Li K, Spittal P, et al. Unstable housing, associated risk behaviour, and increased risk for HIV infection among injection drug users. Health Place 2006; 12: 79‐85. 20. Brettle RP. Bacterial infections in HIV: the extent and nature of the problem. Int J STD AIDS 1997; 5: 5‐15. 21. Spijkerman IJ, van Ameijden EJ, Mientjes GH, Coutinho RA, van den Hoek A. Human immunodeficiency virus infection and other risk factors 159 for skin abscesses and endocarditis among injection drug users. J Clin Epidemiol 1996; 49: 1149‐1154. 22. Palepu A, Strathdee SA, Hogg RS, Anis AH, Rae S, Cornelisse PG, et al. The social determinants of emergency department and hospital use by injection drug users in Canada. J Urban Health 1999; 76: 409‐418. 23. Small W, Wood E, Lloyd‐Smith E, Tyndall M, Kerr T. Accessing care for injection‐related infections through a medically supervised injecting facility: a qualitative study. Drug Alcohol Depend 2008; 98: 159‐162. 24. 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Drug Alcohol Depend 1998; 51: 253‐263. 160 CHAPTER 8: SUMMARY, CONTRIBUTIONS, RECOMMENDATIONS, FUTURE RESEARCH AND CONCLUSIONS 8.1 SUMMARY OF OBJECTIVES The objectives of this research project were: to review the biomedical literature on cutaneous injection‐related infections (CIRI); to assess the prevalence of community‐associated methicillin‐resistant Staphylococcus aureus (CA‐MRSA) in wounds among a cohort of injection drug users (IDU); to evaluate risk factors for developing a CIRI; and to investigate the socio‐demographic and behavioural predictors of 1) receiving CIRI care by a nurse at the supervised injection facility (SIF), 2) Emergency Department (ED) use for a CIRI and 3) hospitalization for a CIRI or related infectious complication at St. Paul’s Hospital. 8.2 SUMMARY OF FINDINGS This research project adds to the growing body of literature indicating that CIRI among injection drug users (IDU) are prevalent and lead to serious morbidity. The project began with a review of the available literature describing the epidemiology, microbiology, risk factors, complications and treatment of CIRI. In general, little research has been conducted on these topics. This 161 research project then addressed several research gaps through analyses involving a consistent community‐based sample of IDU (i.e., Scientific Evaluation of Supervised Injection cohort [SEOSI]) and it considered the agent, host and environment triad of infectious disease epidemiology as well as the risk environment framework introduced in Chapter 1. Chapter 3 provided a description of microbiology found in wounds among participants in the SEOSI cohort. Chapter 4 included a study to investigate longitudinally the individual and environmental correlates of CIRI development. The next three chapters investigated determinants of CIRI treatment. Chapter 5 was a study that identified the individual and environmental level characteristics associated with the provision of nursing care for CIRI at the SIF. The study that comprised Chapter 6 examined the individual and environmental level factors associated with ED use for CIRI. Chapter 7 was an investigation of the individual and environmental determinants of hospitalization for a CIRI or related infectious complication at St. Paul’s Hospital in Vancouver. 8.2.1 Microbiology Convenience sampling of SEOSI participants revealed that a large proportion of participants had wounds (27%), a high prevalence of wounds was infected with CA‐MRSA (27%) and many were polymicrobial (20%). Since CA‐ 162 MRSA has been associated with increased morbidity [1, 2], this finding indicated that many SEOSI participants are at an elevated risk of developing difficult to treat bacterial infections, such as abscesses [3‐5]. These findings also highlighted that participants are at risk of transmitting CA‐MRSA, both within the drug‐ using community and to the general public [1, 2]. For example, transmission of MRSA has been well documented in health care settings [1]. This reinforces the importance of vigilant infection prevention and control practices among IDU as well as staff at the SIF and at treatment settings in the community. Furthermore, this study presented the antibiotic susceptibility to wound cultures. Of clinical relevance in the local setting was the finding of high resistance to clindamycin for CA‐MRSA strains (87%). Clindamycin has previously been reported to be appropriate antibiotic therapy for CA‐MRSA [1]. This represents the rapid shift in the acquisition of resistance to this antibiotic. In the clinical setting, if a physician suspects CA‐MRSA, then clindamycin should not be the antibiotic of choice. Based on in vitro antibiotic sensitivity assessment, rifampin, tetracycline, Trimethoprim‐sulfamethoxazole (TMP‐SMX), vancomycin and linezolid should be considered. 163 8.2.2 Risk factors The research on the individual and environmental risk factors represented a fundamental step towards understanding the increased likelihood of developing CIRI among some SEOSI participants. Over a two year period, between 6% and 10% of participants had a CIRI at the time of their interview. The longitudinal statistical methodology chosen – generalized linear mixed‐effect modeling – indicated that being female, living in unstable housing, borrowing syringes, requiring help injecting and injecting cocaine at least daily were independently and positively associated with developing CIRI. Discussed in this study was that, in accordance with the risk environment framework [6], environmental level factors such as living in unstable housing were important to consider. As proposed by Rhodes and colleagues, such environmental factors are important to consider when assessing risks for drug‐related harms as they shape the contexts in which individual behaviour occurs [6]; this in turn impacts the potential development of CIRI. Particularly relevant to the discussion of CIRI is consideration of the risk environment framework in terms of how it relates to bacterial infectious disease transmission. For example, the small, shared and often unhygienic environments of single room occupancy hotels that are common in Vancouver’s Downtown Eastside (DTES) promote disease 164 transmission [7]. In addition, requiring assistance with injection may increase risk of exposure not only to blood‐borne viruses (e.g., HIV, HCV) but also to bacteria since the assistant may self inject prior to injecting the person who requires assistance (i.e., the phenomenon of “second on the needle”) [8]. Importantly, the factors associated with developing CIRI in this study were used to guide subsequent variable selection for analyses in Chapters 5, 6 and 7. For instance, given that females were found to be more likely to develop CIRI, gender was considered in statistical analyses in Chapter 5 and 7 and stratified in analyses of Chapter 6. 8.2.3 Nurse care at supervised injection facility The analyses in Chapter 5 demonstrated that the majority (65%) of visits to the nurse within the SIF were related to CIRI care. Twenty‐seven percent of SEOSI participants received nursing care for CIRI at the SIF. The incidence density of participants receiving CIRI care was 22.0 per 100 person‐years (95% Confidence Interval [CI]: 19.6 – 24.6). Interestingly and importantly, requiring assistance with injecting over time was independently associated with receiving CIRI care at the SIF. It has been well documented that these individuals are more likely to have borrowed syringes [8], which places them at high risk of infectious disease transmission of HIV [8, 9] and CIRI [10]. This subpopulation (37% at 165 baseline) is prohibited from seeking assistance for injection within the SIF and therefore more likely to have drugs injected in a less hygienic and more uncontrolled public space [11]. However, in time, engagement with nursing staff at the point of CIRI care enables a unique opportunity to provide individually catered injection education and to refer to other services including further CIRI treatment and drug detoxification programs [12, 13]. Chapter 5 provided insights into the critical contributions of nurses with regard to care of CIRI and these findings led to the inclusion of an SIF nurse referral variable in analyses in Chapters 6 and 7 that examined determinants of hospital utilization and related cost estimates. 8.2.4 Emergency Department treatment The analyses in Chapter 6 showed that 29% of participants visited the ED at St. Paul’s Hospital for CIRI. The incidence density for females was 23.8 per 100 person‐years (95% CI: 19.3 – 29.0) and for males was 19.2 per 100 person‐ years (95% CI: 16.7 ‐ 22.1). This chapter revealed that the most significant determinant for males and females visiting the ED for CIRI was referral by a nurse at the SIF. Females were over four times more likely to visit the ED for CIRI if referred to hospital by a nurse at the SIF and males were three times more likely. Importantly, nurses at the SIF have the important role of facilitating 166 referral to the ED for definitive treatment of CIRI [12], including incision and drainage of an abscess or the administration of intravenous antibiotic therapy. In addition, males and females also had different determinants of ED use for CIRI. Males visiting the ED for a CIRI were more likely to require assistance with injecting, a practice generally more common among females [8]. Consequently, interventions that aim to reduce the burden of CIRI should target individuals who require assistance with injection irrespective of sex. These findings also highlight the need for continued development of efficient and streamlined interventions to reduce the incidence of CIRI, such as expanding primary care in the DTES community. 8.2.5 Hospitalization The analyses in Chapter 7 revealed that SEOSI participants have a large burden of severe infections that require hospitalization. Almost one in ten participants (9%) were hospitalized for CIRI or related infectious complications at St. Paul’s Hospital over the study period. The incidence density for hospitalization for CIRI or related infectious complications was 6.07 per 100 person‐years (95% CI: 4.96 – 7.36). Further, SEOSI participants referred by nurses at the SIF had shorter stays in hospital compared to individuals who were not referred by a SIF nurse. This is a particularly critical finding since IDU are 167 known to resist protracted in‐hospital care, including care required to optimally treat infections or related complications. This can result in IDU prematurely leaving against medical advice [14]. In support of this finding, a cost estimate that considered the total potential healthcare saving in a cost per day calculation suggested that each referral from the SIF would have resulted in a saving of $5,696 (95% CI: $2,136 – $18,512). There are important implications in terms of the benefit of SIF use since these results suggest that nurses at the SIF referred individuals in advance of the development of severe infections (such as osteomyelitis) that may have required weeks of intravenous antibiotics and in‐ patient hospital treatment. 8.3 SUMMARY OF RISK ENVIRONMENT FRAMEWORK Rhodes’ risk environment framework was incorporated in this research project to counter individualistic understandings of drug‐related risk that are prevalent within the public health literature [15]. Further, the inclusion of the risk environment framework is important as it extends the physical definition of environment to include social, economic and policy aspects of environment that shape the production of risk among IDU. These four environmental domains may occur at the micro‐level and macro‐level [15]. However, this research project does not extend to the macro‐level. According to Rhodes, at the micro‐ 168 level, an example of a physical risk would be the injection of drugs in public, a social risk would be injection peer norms, an economic risk would be the cost of living, and a policy risk would be the availability and access of injecting paraphernalia [15]. Rhodes also discusses interventions at the micro‐level that can be categorized into these four domains. An example of a physical micro‐ environment intervention would be an SIF, a social intervention would be a low threshold service for drug users, an economic intervention would be free treatment, and a policy intervention would be a housing development. However, it is evident that there may be overlap in categorization and, as expected a risk or intervention may not fit neatly into a single environmental domain. The production or reduction of an individual’s experience of risk is shaped by the interplay of the physical, social, economic and policy environment. In other words, risk arises from and is dependent on this broad and complex definition of environment. At the micro‐level, in this thesis, environmental variables were examined, such as DTES residence and unstable housing, which conferred elevated risk for CIRI development or treatment for CIRI. Among individuals living in unstable housing, there may be a social context or peer norms that hinder individual efforts to safely inject, while physical environmental factors such as shared washroom facilities may be conducive to bacterial transmission. Therefore, variation in risk among IDU may 169 be due not only to individual differences, but also to the broader physical, social, economic and policy environmental domains. This has implications in terms of interpreting significant associations of individual and environmental factors in relation to drug related harm. 8.3.1 Host, agent, environment interaction The interaction of the host, agent and environment has been included to acknowledge that it is critical to examine all three of these elements when investigating infectious disease, such as CIRI. Returning to Figure 1.1 from Chapter 1, this thesis has proposed the incorporation of the risk environment framework to the interaction of the host, agent and environment in order to expand the understanding of environment beyond the physical environment to also consider social, economic and policy domains. This research provides information on individual characteristics that should be interpreted in the context that Rhodes’ risk environment framework provides. Variables, such as sex, age, drug use behaviours are considered to be related to characteristics of the host, while variables such as unstable housing and DTES residence are considered related to environment in the infectious disease triad. The interaction of the host, agent and environment provides an overall structure to the different chapters. In this dissertation, Chapter 3 explored the aspect of agent by examining the prevalence of CA‐MRSA, which plays a role in 170 the development of CIRI. Chapter 4 examined features of the host and environment that contribute to the development of CIRI. Chapter 5‐7 investigated factors associated with the host and environment that predict the receipt of treatment for CIRI in three different settings (nurse care at the SIF, utilization at the ED, and hospitalization). 8.3.2 Summary of “illness path” In addition, this thesis incorporated the risk environment framework to inform our understanding of an “illness path” as introduced in Chapter 1, Figure 1.2. The risk environment, when incorporated into the “illness path”, provides a structure for understanding complex contextual factors that affect progression to infection and treatment. The progression through the “illness path” is impacted by different or combined environmental factors, physical, social, economic, policy. These factors can either enhance or diminish the risk and severity of disease and consequently speed or slow movement through the pathway. For example, SEOSI participants are known to be more likely than other IDU to live in unstable housing, which puts them at elevated risk of exposure to bacteria responsible for developing a CIRI. Therefore, unstable housing, including single room occupancy hotels, can be categorized according to Rhodes economic risk environment, which may speed the progression of the early half of the “illness 171 path” from exposure to development of CIRI. However, the SIF with its sterile injecting paraphernalia and equipment is a physical intervention that provides an environment that can mitigate the development of CIRI. If an IDU already has developed a CIRI, then nurse contact at the SIF results in referral to hospital where definitive CIRI treatment, such as incision and drainage and intravenous antibiotics, is provided. Therefore, this would speed the progression from the development of CIRI to treatment and towards cure. Qualitative research from the SIF supports the notion that nursing care has facilitated connecting to other medical care facilities for treatment of CIRI [12]. Further, Small et al. found that nurses at the SIF have not only increased access to care, assessment and information in relation to CIRI but also addressed barriers to care since the nursing staff was perceived as non‐judgmental and experienced in working with IDU [12]. 8.4 CONTRIBUTIONS TO RESEARCH These analyses make several major contributions to research worth highlighting. First, the finding that unstable housing was related to CIRI development (Chapter 4) and CIRI treatment (Chapter 5) was a novel environmental‐level variable in the literature and reflects how an individual’s environment shapes or impacts his or her susceptibility to bacterial infection. 172 Individuals have an elevated likelihood of CIRI development if their living or injecting environment is unhygienic or in a public space that requires rushed injection [7, 10, 15], relating to the risk environment framework [6]. Second, the finding that requiring assistance with injection was associated with CIRI development (Chapter 4) and CIRI treatment (Chapter 5, 6) was a new individual‐level variable in the literature. Requiring assistance with injecting may elevate an individual’s likelihood of exposure to bacteria when the individual administering the injection injects themselves first before injecting the person who requires assistance [10]. Also, IDU may require assistance with injecting because of venous access difficulties. These two groups of IDU require assistance with injecting for different reasons and this has implications in terms of developing and delivering interventions. Third, the role of nurses in CIRI care (Chapter 5) and the finding that nurse referral at the SIF was a strong predictor of hospital treatment (Chapter 6, 7) is an original and important addition to the literature as it acknowledges and emphasizes the diverse contribution of front‐ line nurses of CIRI care and facilitation of additional CIRI treatment. 8.5 UNIQUE CONTRIBUTIONS Strengths and limitations of this research have been presented in detail in each of the study chapters (3‐7). The methodology and findings of these analyses 173 make important contributions to the epidemiological literature on CIRI. Collectively, the research papers highlight the value in conducting longitudinal analyses with prospective cohort data and the benefits of linking these data with health service databases. The examination of the microbiology of wounds and the proportion of participants with wounds positive for CA‐MRSA (Chapter 3) was the first study to collect in‐depth microbiology and related antibiotic susceptibility of wounds from a community‐recruited cohort of active IDU. In addition, the study was unique due to its collaboration between front‐line staff at the SEOSI site, researchers and doctors from the British Columbia Centre for Excellence in HIV/AIDS, laboratory technicians and doctors at the microbiology laboratory at St. Paul’s Hospital and a pharmaceutical company. In addition, this is the first longitudinal analysis of risk factors of CIRI development from a community‐recruited cohort of IDU. To investigate correlates of developing CIRI (Chapter 4), generalized linear mixed‐effects modeling was used. This methodology analyzes trajectories of CIRI as an individually experienced outcome. This analytic technique was chosen because of its flexibility in variable parameters including fixed, time‐updated and random variable definition (e.g., random variation between individuals was accounted for by using random intercepts) and because of its ability to capture 174 heterogeneity of subjects, within‐subject correlation and individual‐level factors [16]. Cox proportional hazard regression models with recurrent events analyses were used to examine CIRI care by nurses at the SIF (Chapter 5). This novel methodology allowed for the consideration of more than one event per individual and allowed for an assessment of associations between recurrent events. This consideration was important as nursing care for CIRI often includes debridement and repeated dressing changes. The methodology was well suited to incorporate this type of care regime since the number of CIRI care visits to nurses at the SIF ranged from 1 to 38. This research project also included extensive linkages between data sources that permitted the investigation of determinants of multiple locations of CIRI care and treatment. Specifically, information from the SEOSI cohort questionnaire was linked to the database at the SIF and to both the ED and in‐ patient databases at St. Paul’s Hospital. The extensive linkage to St. Paul’s Hospital for ED and in‐patient hospitalization (Chapter 6 and 7 respectively) was critical for the comparison of service utilization among SEOSI participants. Further, the linkage to in‐patient hospitalization was crucial to characterize the more severe morbidity of CIRI or related infectious complications. 175 8.6 LIMITATIONS There are limitations of this research project that warrant consideration for interpretation. First, socio‐demographic, drug use and behavioural variables were based on self‐report. We reduced the level of self‐reporting in our studies by examining outcomes that required the presence of CIRI (Chapter 4‐7) or data linkages of treatment (Chapter 5, 6, 7) as opposed to self‐reported treatment. Also, although self report of drug use and behavioural data by IDU are generally considered valid [17], several studies have recorded over‐reporting of health service utilization by this population. Hospital use and nurse referrals were accessed directly from databases within the hospital and the SIF respectively. However, our findings may be vulnerable to social desirability bias as well as recall bias. Second, this research project only included one hospital. This limitation would have resulted in an underestimation of hospital use as some participants would have accessed other hospitals during our study period. However, it is known that St. Paul’s Hospital serves the majority of the IDU in this setting [18]. Third, it is not possible to generalize results from this study to IDU in other settings. Although the SEOSI cohort was randomly recruited from within the SIF and is therefore considered representative of IDU using Vancouver’s SIF [19], the SEOSI cohort is comprised of IDU who are more likely 176 to be frequent and public injectors who reside in unstable housing [20]. Therefore, results of the SEOSI cohort are based on a particularly marginalized IDU population in Vancouver. Consequently, this may result in overestimating the extent of injecting and health‐related harms among the IDU population in Vancouver. Fourth, individual and environmental hygiene plays a critical role in the transmission of bacterial infection. Therefore, the investigation of CIRI development would have been strengthened if variables related to hygiene (e.g., hand washing) had been apart of the study questionnaire. However, the variable of unstable housing, which includes living in single room occupancy hotels that are known to be conducive of bacterial transmission [7], has been considered a proxy for inconsistent hygiene in these analyses. Fifth, there were many linkages to CIRI treatment included in the analyses contained herein. Although ICD codes have been standardized in medical practice, the various codes in the database at the SIF have not. Given that the database at the SIF is used primarily for documentation and not diagnostic purposes, it may be expected that nurses underutilize the database. If this were the case, then the level of CIRI treatment at the SIF would be underestimated. Further, it may be that staff who work at the SIF do not capture interventions in the same fashion and the extent to which information is accurately recorded in the database may have changed over time. 177 8.7 RECOMMENDATIONS While each of the study chapters (3‐7) provides recommendations for policy and prevention that are specific to each of the research findings, there are several recommendations that are worth highlighting due to their importance or recurrence across studies. These recommendations have implications for aspects of prevention, treatment and harm reduction, which are three of the four pillars in the “Framework for Action: A Four Pillars Approach to Drug Problems in Vancouver” policy [21]. Notably, recommendations on prevention may also be referred to as harm reduction [21]. While there has been some recognition of the problem of CIRI among IDU, there is still a predominant focus on viral infections. This research project has clearly demonstrated that CIRI are common and result in extensive health care utilization in a variety of settings. The heavy burden of CIRI, both at an individual level and on the health care system, supports the need for additional funding for research, prevention, treatment and harm reduction efforts in order to reduce CIRI and related infectious complications. With regard to prevention of CIRI, bacterial infections among IDU are inextricably linked to hygiene during the injection process. Individuals who report requiring assistance with injection and borrowing syringes have an increased likelihood of CIRI development and should be targeted for 178 intervention, including individually‐catered education on safer injection practices and additional access to injection paraphernalia. Qualitatively, this type of injection education has been reported to be of benefit to individuals that require assistance with injection [13]. Also, since individuals who require assistance with injection are accessing nursing care at the SIF for CIRI, this presents an opportunity for targeted prevention and harm reduction strategies. A second broad recommendation regarding prevention stems from the increased likelihood of developing CIRI if an individual has unstable housing or resides in the DTES. Single room occupancy (SRO) hotels are common in the DTES and are widely thought to facilitate the spread of infectious disease [7]. Policy reform involving changes in the living conditions of IDU in the DTES would assist in reducing the burden of CIRI. In terms of treatment, this research provides empirical evidence of the importance of nursing‐led CIRI care at the SIF and referral to hospital when necessary. This service should continue. In addition, at the SIF, consideration should be given to developing increased capacity for primary care for more vigorous management of SIF users, including more definitive CIRI treatment, to further reduce the need for ED visits and hospitalization. Specifically, incision and drainage or provision of antibiotics of CIRI should be considered at the SIF. 179 Services that combine treatment with harm reduction have been set up and found to be successful in treating CIRI and in reducing health care costs [22, 23]. A second recommendation that may inform treatment is the establishment of a longitudinal surveillance system into the antibiotic susceptibility of CA‐ MRSA among IDU. This recommendation based on findings from Chapter 3 indicating that CA‐MRSA is mostly resistant to clindamycin and is due to the rapid and significant change in antibiotic susceptibility of CA‐MRSA among IDU in this setting from 2006 to 2008 (personal communication, Dr. Hull). This surveillance of SEOSI participants could take place at the research office in the community or at St. Paul’s Hospital. This type of surveillance system could be undertaken in collaboration with the Infection Prevention and Control Team of St. Paul’s Hospital. 8.8 FUTURE RESEARCH There are several key areas for future research. Reflecting on infectious disease transmission, there are individual and environmental factors that relate to prevention, treatment and harm reduction that require additional research. First, based on the microbiology study and given the role played by unstable housing and DTES residency in CIRI development, hygiene is clearly an important component of prevention. The role of personal hygiene (including 180 hand washing, regular showering, clothes and bedding washing) in CIRI development is clearly of importance. Among IDU, most infectious disease literature is focused on reducing transmission of blood‐borne viruses (e.g., HIV and HCV). Personal hygiene has not been emphasized but should be a focus in future research in this population. Second, CA‐MRSA is a relatively new bacterial strain causing infection that has not been extensively researched among IDU. Much has yet to be determined, including what proportion of CIRI is due to CA‐MRSA, the interrelationship between CIRI and CA‐MRSA, plus the individual and environmental risk factors for CA‐MRSA transmission among IDU. Third, a consistent risk factor associated with CIRI development and determinant of CIRI treatment was female sex. Future investigation of risk factors stratified by sex may clarify why women are more likely to develop CIRI. In addition, based on recent qualitative research that highlighted the importance of nursing care for CIRI treatment at the SIF [12], qualitative methods are an alternative research method that should be employed in investigations of CIRI. Fourth, there is uncertainty whether the treatment of abscesses by incision and drainage alone is adequate or whether the treatment is optimized by the addition of antibiotics [24]. This question merits further research to guide clinical practice and to improve efficiency of CIRI treatment. 181 Fifth, the impacts of nursing care at the SIF for CIRI identification and treatment and nurse referral versus self‐referral to hospital for CIRI warrant additional attention. It would be beneficial to investigate the criteria and factors associated with being referred to hospital for CIRI among nurses at the SIF. Finally, a more comprehensive cost analysis of CIRI should be initiated. This could start with an estimate of the total costs of CIRI treatment, which have been reported to be high in other settings [25]. 8.9 CONCLUSION This thesis makes important contributions to the existing CIRI literature. The microbiological distribution of wounds among IDU was explored. In addition, individual and environmental variables associated with developing CIRI were established. Determinants of care for CIRI at different locations were also investigated. Extensive efforts have been instituted to curtail the viral infectious epidemics of HIV and HCV among IDU. Despite these efforts, this study demonstrated that major steps are required to prevent and reduce the heavy burden of CIRI in this setting. This research project identified opportunities for improvement in prevention and treatment and supports the need for future studies in the area of CIRI. 182 8.10 REFERENCES 1. Huang H, Flynn NM, King JH, Monchaud C, Morita M, Cohen SH. Comparisons of community‐associated methicillin‐resistant Staphylococcus aureus (MRSA) and hospital‐associated MSRA infections in Sacramento, California. J Clin Microbiol 2006; 44: 2423‐2427. 2. Huang H, Cohen SH, King JH, Monchaud C, Nguyen H, Flynn NM. Injecting drug use and community‐associated methicillin‐resistant Staphylococcus aureus infection. Diagn Microbiol Infect Dis 2008; 60: 347‐ 350. 3. Ma XX, Ito T, Tiensasitorn C, Jamklang M, Chongtrakool P, Boyle‐Vavra S, et al. Novel type of staphylococcal cassette chromosome mec identified in community‐acquired methicillin‐resistant Staphylococcus aureus strains. Antimicrob Agents Chemother 2002; 46: 1147‐1152. 4. Saravolatz LD, Pohlod DJ, Arking LM. Community‐acquired methicillin‐ resistant Staphylococcus aureus infections: a new source for nosocomial outbreaks. Ann Intern Med 1982; 97: 325‐329. 5. Young DM, Harris HW, Charlebois ED, Chambers H, Campbell A, Perdreau‐Remington F, et al. An epidemic of methicillin‐resistant 183 Staphylococcus aureus soft tissue infections among medically underserved patients. Arch Surg 2004; 139: 947‐953. 6. Rhodes T. The ʹrisk environmentʹ: a framework for understanding and reducing drug‐related harm. Int J Drug Policy 2002; 13: 85‐94. 7. Shannon K, Ishida T, Lai C, Tyndall MW. The impact of unregulated single room occupancy hotels on the health status of illicit drug users in Vancouver. Int J Drug Policy 2006; 17: 107‐114. 8. Wood E, Spittal PM, Kerr T, Small W, Tyndall MW, OʹShaughnessy MV, et al. Requiring help injecting as a risk factor for HIV infection in the Vancouver epidemic: Implications for HIV prevention. Can J Public Health 2003; 94: 355‐359. 9. OʹConnell JM, Kerr T, Li K, Tyndall MW, Hogg RS, Montaner JS, et al. Requiring help injecting independently predicts incident HIV infection among injection drug users. J Acquir Immune Defic Syndr 2005; 40: 83‐88. 10. Lloyd‐Smith E, Wood E, Zhang R, Tyndall MW, Montaner JS, Kerr T. Risk factors for developing a cutaneous injection‐related infection among injection drug users: a cohort study. BMC Public Health 2008; 8: 405. 11. Wood E, Kerr T, Montaner JS, Strathdee SA, Wodak A, Hankins CA, et al. Rationale for evaluating North Americaʹs first medically supervised safer‐ injecting facility. Lancet Infect Dis 2004; 4: 301‐306. 184 12. Small W, Wood E, Lloyd‐Smith E, Tyndall M, Kerr T. Accessing care for injection‐related infections through a medically supervised injecting facility: a qualitative study. Drug Alcohol Depend 2008; 98: 159‐162. 13. Fast D, Wood E, Small W, Kerr T. The perspectives of injection drug users regarding safer injecting education delivered through a supervised injecting facility. Harm Reduct J 2008; 5. 14. Anis AH, Sun H, Guh DP, Palepu A, Schechter MT, OʹShaughnessy MV. Leaving hospital against medical advice among HIV‐positive patients. CMAJ 2002; 167: 633‐637. 15. Rhodes T, Stoneman A, Hope V, Hunt N, Martin A, Judd A. Groin injection in the context of crack cocaine and homelessness: from ʹrisk boundaryʹ to ʹacceptable riskʹ? Int J Drug Policy 2006; 17: 164‐170. 16. Fitzmaurcie GM, Laird NM, Ware JH. Applied Longitudinal Analysis. John Wiley & Sons, Inc. New Jersey, United States of America; 2004. 17. Darke S. Self‐report among injecting drug users: a review. Drug Alcohol Depend 1998; 51: 253‐263. 18. Palepu A, Tyndall MW, Leon H, Muller J, OʹShaughnessy MV, Schechter MT, et al. Hospital utilization and costs in a cohort of injection drug users. CMAJ 2001; 165: 415‐420. 185 19. Wood E, Kerr T, Lloyd‐Smith E, Buchner C, Marsh D, Montaner J, et al. Methodology for evaluating Insite: Canadaʹs first medically supervised safer injection facility for injection drug users. Harm Reduct J 2004; 1. 20. Wood E, Tyndall M, Li K, Lloyd‐Smith E, Small W, Montaner J, et al. Do supervised injecting facilities attract higher‐risk injection drug users? Am J Prev Med 2005; 29: 126‐130. 21. MacPherson D. A framework for action: A four pillar approach to drug problems in Vancouver. Vancouver, Canada; 2001. 22. Grau LE, Arevalo S, Catchpool C, Heimer R. Expanding harm reduction services through a wound and abscess clinic. Am J Public Health 2002; 92: 1915‐1917. 23. Harris HW, Young D.M. Care of injection drug users with soft tissue infections in San Francisco, California. Arch Surg 2002; 137: 1217‐1222. 24. Hankin A, Everett WW. Are antibiotics necessary after incision and drainage of a cutaneous abscess. Ann Emerg Med 2007; 50: 49‐51. 25. Hope V, Kimber J, Vickerman P, Hickman M, Ncube F. Frequency, factors and costs associated with injection site infections: findings from a national multi‐site survey of injecting drug users in England. BMC Infect Dis 2008; 8. 186 APPENDIX 1: HUMAN ETHICS APPROVAL CERTIFICATE UBC-Providence Health Care Research Institute Office of Research Services 11th Floor Hornby Site - SPH c/o 1081 Burrard St. Vancouver, BC V6Z 1Y6 Tel: (604) 806-8567 Fax: (604) 806-8568 ETHICS CERTIFICATE OF EXPEDITED APPROVAL PRINCIPAL INVESTIGATOR: DEPARTMENT: UBC-PHC REB NUMBER: UBC/Medicine, Faculty of Samuel B. Sheps School of Population and Public H08-01430 Health INSTITUTION(S) WHERE RESEARCH WILL BE CARRIED OUT: Institution Providence Health Care Site St. Paul's Hospital Other locations where the research will be conducted: N/A COINVESTIGATOR(S): Robert S. Hogg Thomas Kerr Mark W. Tyndall SPONSORING AGENCIES: Canadian Institutes of Health Research (CIHR) Michael Smith Foundation for Health Research Pfizer Canada Inc. - "Methicillin-Resistant Staphylococcus aureus (MRSA) in the Downtown Eastside of Vancouver: A surveillance and susceptibility study among injection drug users of the supervised injection facility (a sub-study of H03-50057: Supervised Injection Site Evaluation)" PROJECT TITLE: Sub Study: The epidemiology of cutaneous injection-related infections among injection drug users Sub Study of the following main studies: (H07-03019) - Methicillin-Resistant Staphylococcus aureus (MRSA) in the Downtown Eastside of Vancouver: A surveillance and susceptibility study among injection drug users of the supervised injection facility (a sub-study of H03-50057: Supervised Injection Site Evaluation) (H03-50057) - The Scientific Evaluation of Supervised Injecting (SEOSI) Cohort THE CURRENT UBC-PHC REB APPROVAL FOR THIS STUDY EXPIRES: July 4, 2009 The UBC-PHC Research Ethics Board Chair or Associate Chair, has reviewed the above described research project, including associated documentation noted below, and finds the research project aceeptable on ethical grounds for research involving human subjects and hereby grants approval. 187 DOCUMENTS INCLUDED IN THIS APPROVAL: APPROVAL DATE: July 4, 2008 Document Name Protocol: Thesis proposal (Lloyd-Smith) Version Date N/A June 18, 2008 CERTIFICATION: 1. The membership of the UBC-PHC REB complies with the membership requirements for research ethics boards defined in Part C Division 5 of the Food and Drug Regulations of Canada. 2. The UBC-PHC REB carries out its functions in a manner fully consistent with Good Clinical Practices. 3. The UBC-PHC REB has reviewed and approved the research project named on this Certificate of Approval including any associated consent form and taken the action noted above. This research project is to be conducted by the principal investigator named above at the specified research site(s). This review of the UBC-PHC REB have been documented in writing. Approval of the UBC-PHC Research Ethics Board or Associate Chair, verified by the signature of one of the following: 188 189 APPENDIX 2: Chapter 3 Table 3.2 Baseline characteristics of a sub‐sample of Scientific Evaluation of Supervised Injecting cohort, stratified by presence or not of a wound Variable Sex Odds Ratio (OR) No Wound Wound n (%) n (%) OR (95% CI) p‐value female 41 (37) 22 (50) 0.119 1.83 (0.95–3.50) male 109 (63) 32 (50) Aboriginal ethnicity* yes 36 (83) 8 (64) 0.55 (0.24 – 1.27) 0.181 no 114 (17) 46 (36) Age total sub‐sample Median; Interquartile Range (IQR) = 40.2 (33.9 – 45.0) with wounds Median; IQR = 38.0 (30.6 – 44.1) Years injecting total sub‐sample Median; IQR = 18.7 (11.4 – 28.9) with wounds Median; IQR = 17.7 (11.8 – 25.7) 190 Table 3.3 Baseline characteristics among sub‐sample of Scientific Evaluation of Supervised Injecting cohort, stratified by the presence or not of a wound community‐associated methicillin resistant Staphylococcus aureus (CA‐MRSA) culture positive Variable Odds Ratio (OR) No CA‐ MRSA CA‐MRSA OR Sex Female Male Unstable housing* Yes No Single room hotel* 15 (37) 25 (63) 33 (83) 7 (17) 7 (50) 7 (50) 9 (64) 5 (36) Yes No DTES residence* Yes No Cocaine injection* Daily Not daily Heroin injection* 23 (58) 17 (42) 36 (90) 4 (10) 12 (30) 28 (70) 5 (36) 9 (64) 11 (79) 3 (21) 6 (43) 8 (57) 0.41 15 (37) 25 (63) 15 (37) 25 (63) 8 (57) 6 (43) 3 (21) 11 (79) 2.22 3 (7) 37 (93) 0 (0) 14 (100) Daily Not daily p‐value (0.91–12.64) 0.119 0.075 n (%) n (%) Daily Not daily Crack use * Daily Not daily Speedball injection* (95% CI) 3.38 0.28 (0.07 – 1.08) 1.05 1.75 (0.12 – 1.45) 0.218 0.775 (0.79 – 1.40) (0.50 – 6.15) 0.45 0.512 (0.64 – 7.66) 0.201 0.339 (0.11 – 1.90) Note: *Behaviours refer to activities in the last six months. CI = confidence interval, DTES = Downtown Eastside; information not available for 2 CA‐MRSA and 3 non‐CA‐MRSA participants 191 Variable No CA‐ MRSA HIV serostatus* Positive Negative Abscess† Yes No n (%) 14 (35) 26 (65) 14 (36) 25 (64) CA‐MRSA n (%) 3 (21) 11 (79) 5 (38) 8 (62) Odds Ratio (OR) (95% CI) p‐value 0.51 (0.12 – 2.12) 0.507 2.16 (1.31 – 3.54) 0.002 Note: *Behaviours refer to activities in the last six months. †Reported abscess in last six months. CI = confidence interval, DTES = Downtown Eastside; information not available for 2 CA‐MRSA and 3 non‐ CA‐MRSA participants 192 Table 3.4 Frequency of wound locations among a sub‐sample of Scientific Evaluation of Supervised Injection cohort Location Frequency Head scalp 1 forehead 2 cheek 3 nose 2 chin 2 neck 2 Trunk chest 2 Upper extremities elbow 3 arm 3 forearm 11 hand 4 wrist 5 Lower extremities lower leg 7 leg 2 thigh 1 knee 1 calf 3 foot 4 toe 1 Total 59 193 APPENDIX 3: Chapter 5 Table 5.3 Frequency of reason for nurse treatment among Scientific Evaluation for Supervised Injection participants at the supervised injection facility Frequency Percent Abscess/vein care 1443 23 Wound care 2467 38 Skin care 267 4 Foot care 366 6 Respiratory care 191 3 Pregnancy test 155 2 Psychosocial support 506 7 Other 1099 17 Total 6494 100 Reason for nurse visit 194 Table 5.4 Frequency of reason for visit to nurses among Scientific Evaluation for Supervised Injection participants at the supervised injection facility Reason Frequency Percent Abscess 2159 35 Ulcer 203 3 Wound 1854 29 Skin infection 341 5 Foot 390 6 Respiratory 150 2 Pregnancy 52 1 Psychosocial 293 5 Other 896 14 Total 6337 100 195 Comment on the decision to examine drug use by frequent use specific to different drugs and why frequent use was not examined in a separate variable. Drug‐specific injecting frequency was considered so that the consequences of specific drugs could be determined. This approach to analysis is also consistent with a large of number of studies from Vancouver that have revealed that the frequent injection of heroin impacts health outcomes differently than the frequent injection of cocaine. For example, IDU often inject cocaine many more times a day than heroin due to the short half‐life of cocaine (i.e., higher potential exposure). Therefore, individuals who inject cocaine frequently may be at an increased risk of infectious disease because of having to inject many more times per day. Indeed, previous studies have shown frequent cocaine injection to be associated with HIV infection in a dose‐dependent fashion [1]. As well, there may be different environmental risks particular to users of different drugs, for example, frequent cocaine injectors are more likely to reside in unstable housing [2], including single room occupancy hotels that are known to be conducive to bacterial transmission [3]. These drug specific analyses of frequent injection have implications for the understanding of these infections among IDU. Further, it is important to appreciate the baseline levels of frequent injection in this community, especially considering that SEOSI participants are among the more frequent injectors in this community. A separate measure of injecting frequency was not included due to potential problems related to co‐ linearity with other drug frequency variables. However, the drug use variables considered allow for consideration of both injecting frequency and drug type. 1. Tyndall M, Spittal P, Li K, Wood E, O’Shaughnessy MV, Schechter MT. Intensive injection cocaine use as the primary risk factor in the Vancouver HIV‐1 epidemic. AIDS 2003; 17: 887‐893. 2. Lloyd‐Smith E, Wood E, Li K, Montaner JSG, Kerr T. Incidence and determinants of initiation into cocaine injection and correlates of frequent cocaine injectors. Drug Alcohol Depend 2008; 1‐3: 176‐182. 3. Shannon K, Ishida T, Lai C, Tyndall MW. The impact of unregulated single room occupancy hotels on the health status of illicit drug users in Vancouver. Int J Drug Policy 2006; 17: 107‐114. 196 Table 5.5 Baseline profile of Scientific Evaluation of Supervised Injection participants receiving cutaneous injection‐related infection care at a supervised injection facility (n = 1080) No CIRI care CIRI care n = 901 n = 179 n (%) n (%) 38.5 [32.9‐44.3] 37.8 [29.5‐44.4] 0.99 (0.97 ‐ 1.01) Female 241 (27%) 73 (41%) 1.89 (1.35 ‐ 2.63) Male 660 (73%) 106 (59%) Yes 484 (54%) 104 (58%) 1.19 (0.86 ‐ 1.65) No 417 (46%) 75 (42%) Yes 167 (19%) 45 (25%) 1.48 (1.01 – 2.15) No 734 (81%) 134 (75%) Yes 593 (66%) 138 (77%) 1.75 (1.20 ‐ 2.54) No 308 (34%) 41 (23%) Yes 289 (32%) 67 (37%) 1.27 (0.91 ‐ 1.77) No 612 (68%) 112 (63%) Daily 270 (30%) 72 (40%) 1.57 (1.13 ‐ 2.19) Not daily 631 (70%) 107 (60%) Daily 442 (49%) 103 (58%) 1.41 (1.02 ‐ 1.95) Not daily 459 (51%) 76 (42%) Variable Age Median [IQR] Sex Unstable housing* Homelessness* DTES residence* Require help inject* Cocaine injection* Heroin injection* Odds Ratio (95% CI) Note: *Behaviours refer to activities in the last 6 months. Note: CIRI = cutaneous injection‐related infection, CI = confidence interval, IQR = interquartile range, DTES = Downtown Eastside. 197 Variable No CIRI care CIRI care n = 901 n = 179 n (%) n (%) Positive 145 (16%) 33 (19%) 1.18 (0.78 – 1.79) Negative 744 (84%) 144 (81%) HIV serostatus Odds Ratio (95% CI) Note: *Behaviours refer to activities in the last 6 months. Note: CIRI = cutaneous injection‐related infection, CI = confidence interval, IQR = interquartile range, DTES = Downtown Eastside. 198 Table 5.6 Univariate and multivariate Cox proportional hazard analyses of receiving cutaneous injection‐related infection care among Scientific Evaluation of Supervised Injection participants: a model on with the variable homelessness in place of unstable housing Unadjusted Adjusted Hazard Ratio (HR) Hazard Ratio (AHR) Variable HR (95% CI) Age (per year) Sex (Female vs male) Homelessness* (Yes vs no) DTES residence* (Yes vs no) Cocaine injection* (Daily vs not daily) Heroin injection* (Daily vs not daily) Speedball injection* (Daily vs not daily) (0.97 – 1.00) (1.49 ‐ 2.92) (1.01 – 2.15) (1.13 – 2.49) (0.82 – 1.58) (1.37 – 2.42) (1.21 – 3.05) 0.99 2.08 1.48 1.68 1.14 1.82 1.92 AHR 1.89 1.38 1.54 1.55 1.50 (95% CI) (1.35 – 2.64) (1.04 – 1.82) (1.05 –2.29) (1.16 – 2.06) (0.95 – 2.29) Note: *Behaviours refer to activities in the last 6 months. Model was fit adjusted for all variables p < 0.05 in unadjusted analyses. CI = confidence interval, DTES = Downtown Eastside. 199 APPENDIX 4: Chapter 6 Comment on decision to stratify analyses in Chapter 6 by sex. The decision to stratify this analysis was based on a desire to control for sex. Indeed, previous literature on CIRI development and CIRI treatment has shown that females are more likely to both develop and seek treatment for CIRI. Further, stratification was useful for interpretation of study findings. A case in point is the variable requiring help injecting. When the analysis was not stratified (as displayed in the appendix), this variable was significant. Based on previous literature on requiring assistance with injecting, it would have been possible to attribute this finding to being female since this is a practice that is known to be more common among women. However, in the stratified analysis, among males, individuals that required assistance with injecting were more likely to receive treatment at the Emergency Department for a CIRI. This result indicates that requiring help injecting, when practiced among male participants, is of concern. Further, although the concern regarding a potential problem related to insufficient statistical power is appreciated, a review of individual cells and the number of statistically significant associations identified suggests that statistical power was not a problem in the stratified analysis. Finally, the Canadian Institutes for Health Research has issued statements calling for the application of gender‐based analyses of health issues in instances where gender differences have been observed previously. 200 Table 6.4: Univariate and multivariate Cox proportional hazard analyses of time to Emergency Department use for a cutaneous injection‐related infection among injection drug users Unadjusted Hazard Ratio (HR) Variable HR Age (per year older) 0.99 (0.97 ‐1.00) Sex (Female vs. Male) (95% CI) p‐ value Adjusted Hazard Ratio (AHR) AHR (95% CI) 0.185 p‐value 1.23 (0.96 – 1.58) 0.095 1.06 (0.82 – 1.37) 0.653 Unstable housing* (Yes vs No) 1.62 (1.27 – 2.08) <0.001 1.31 (0.99 – 1.72) 0.647 DTES residence (Yes vs No) 1.73 (1.31 – 2.29) <0.001 1.44 (1.06 – 1.96) Requiring help inject* (Yes vs No) Cocaine injection* (Daily vs Not daily) 1.64 (1.29 – 2.10) 1.26 (0.98 – 1.61) <0.001 0.071 1.43 (1.11 ‐ 1.84) 0.005 Heroin injection* 0.021 (Daily vs Not daily) 1.25 (0.99 – 1.58) 0.060 Speedball injection* (Daily vs Not daily) 1.43 (1.03 – 2.00) 0.034 1.18 (0.84 – 1.66) 0.339 HIV serostatus* (Positive vs Negative) Hospital referral† (Yes vs No) 1.57 4.12 0.001 <0.001 1.43 3.55 (1.09 – 1.87) (2.58 – 4.88) 0.010 <0.001 (1.20 – 2.05) (3.02 – 5.62) Note: *Behaviours refer to activities in the last six months. †Indicates data derived from SIF database and by a study nurse. Model was fit adjusted for all variables p < 0.05 in unadjusted analyses. CI = confidence interval, DTES = Downtown Eastside 201 Table 6.5 Number of Emergency Department (ED) visits among Scientific Evaluation of Supervised Injection cohort Number ED visits Frequency Percent 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 19 20 23 24 28 57 794 81 54 39 32 11 24 10 8 7 3 6 3 1 1 2 1 1 2 1 1 1 73.31 7.48 4.99 3.60 2.95 1.02 2.22 0.92 0.74 0.65 0.28 0.55 0.28 0.09 0.09 0.18 0.09 0.09 0.18 0.09 0.09 0.09 Cumulative Frequency 794 875 929 968 1000 1011 1035 1045 1053 1060 1063 1069 1072 1073 1074 1076 1077 1078 1080 1081 1082 1083 202 APPENDIX 5: CHAPTER 7 Table 7.3 Overlap in diagnoses of cutaneous injection‐related infections or related infectious complications among Scientific Evaluation of Supervised Injection participants Illness Primary + + + + + + + + +9 +1 +1 +1 +2 +3 +3 +4 +5 +9 >2 diagnosis 1 2 3 4 5 6 7 8 &2 &4 &7 &4 &4 &7 &7 &4 &4 only 1cellulitis 45 ‐ 4 0 9 0 0 2 1 0 ‐ ‐ ‐ 0 0 2 3 0 0 0 2abscess 9 1 ‐ 0 5 0 0 0 0 0 ‐ 3 0 ‐ 2 0 0 1 1 0 3osteomyelitis 14 0 5 ‐ 5 0 0 0 1 2 0 1 1 3 ‐ ‐ 2 0 0 1 4staph.infection ‐ ‐ ‐ 0 18 3 0 1 ‐ 4 0 0 0 0 1 ‐ 0 ‐ ‐ 0 5endocarditis 12 0 1 0 5 ‐ 0 0 0 0 0 1 0 0 0 0 0 ‐ 0 0 6septic arthritis 8 0 3 0 2 0 ‐ 0 0 0 0 1 0 0 0 0 0 0 0 0 7ulcer 3 0 0 0 1 0 0 ‐ 0 0 0 0 ‐ 0 0 ‐ ‐ 0 0 0 8thrombophlebitis 3 1 0 0 0 0 0 0 ‐ 0 0 0 0 0 0 0 0 0 0 0 9myositis 1 0 0 0 3 0 0 0 0 ‐ 0 0 0 0 0 0 0 0 ‐ 0 Note: Total number of events refers to cutaneous injection‐related infection or related infectious complication as a primary, secondary, tertiary, quaternary, or quinary diagnoses according to relevant ICD 10 codes Total number events* 76 41 37 135 29 12 13 7 7 203 Table 7.4 Frequency of diagnoses of cutaneous injection‐related infections or related infectious complications among Scientific Evaluation of Supervised Injection participants Illness Illness only once Illness twice Illness 3x 1cellulitis 2abscess 3osteomyelitis 4staph.infection 5endocarditis 6septic arthritis 7ulcer 8thrombophlebitis 9myositis 19 11 5 10 11 6 1 1 3 7 5 2 2 0 3 0 0 0 3 2 2 0 1 0 1 1 1 Illness Illness Total 4x. 5 or more number times primary diagnosis 0 2 57 0 0 26 0 3 39 3 2 42 0 1 24 0 1 12 0 0 6 0 0 4 0 0 4 Note: The definition of a cutaneous injection‐related infection or related infectious complication was based on International Classification of Diseases (ICD) 10 codes on patients’ hospital records and included: abscess (G061, G062, L020, L021, L022, L024, J851), cellulitis (L0300, L0310, L0311, L032, L0335, L038), osteomyelitis (M4620, M4625, M4629, M8617, M8618, M8661, M8663, M8666, M8681, M8691, M8695), staphylococcal infection {(A490, A499, B956) including, septicaemia (A410, A412, A419) and methicillin‐resistant Staphylococcus aureus (MRSA), (U000)}, endocarditis (I330), septic arthritis (M0000, M0002, M0004, M0005, M0006, M0008, M0009), ulcer (L089, L979), thrombophlebitis (I802, I808) and myositis (M6005, M6008). 204 Expanded information on cost estimate: Cost estimate was based on hospital admission information retrieved from medical records. This estimate was based on the nursing ward, medication, investigative procedures, physician contact and length of stay. Further, inpatient costs included expenditures such as overhead, opportunity cost of hospital resources as well as a 5% global depreciation of capital equipment. Costs were based on the first 105 IDU hospital visits from the Vancouver injection drug users study (VIDUS) cohort and calculation procedures were clarified by personal communication with the first author of the following paper: 1. Anita Palepu, Mark W. Tyndall, Hector Leon, Jennifer Muller, Michael V. OʹShaughnessy, Martin T. Schechter, and Aslam H. Anis Hospital utilization and costs in a cohort of injection drug users CMAJ 2001; 165: 415 – 420. We then updated the cost in Canadian dollars from 2005 based on the following reference: 2. Organisation for Economic Co‐operation and Development (OECD) Health data 2007; 2007. 205 Table 7.5: Baseline characteristics among injection drug users at a supervised injection facility who were hospitalized for a cutaneous injection‐related infection or related infectious complication Variable Sex Male Female Unstable housing* Yes No DTES residence Yes No Requiring help inject* Yes No Cocaine injection* Daily Not daily Heroin injection Not Hospitalized Odds Ratio (OR) hospitalized n (%) OR (95% CI) p‐value n (%) 708 (72) 60 (61) 1.67 (1.09 – 2.55) 0.020 276 (28) 39 (39) 528 (54) 63 (64) 1.51 (0.98 – 2.32) 0.071 456 (46) 36 (36) 661 (67) 73(74) 1.37 (0.86 – 2.19) 0.215 323 (33) 26 (26) 320 (33) 664 (67) 300 (30) 684 (70) 38 (38) 61 (62) 43 (43) 56 (57) Daily Not daily Crack use * Daily Not daily Speedball injection* 495 (50) 489 (50) 86 (9) 898 (91) 52 (53) 47 (47) 14 (14) 85 (86) Daily Not daily HIV serostatus* Positive Negative 124 (13) 860 (87) 149 (15) 820 (85) 24 (24) 75 (76) 29 (29) 70 (71) 1.29 (0.84 ‐ 1.98) 0.262 1.75 (1.15 – 2.66) 0.012 1.09 (0.72 – 1.65) 0.752 1.72 (0.94 – 3.16) 0.098 2.22 (1.35 – 3.65) 0.003 2.28 (1.43 – 3.63) <0.001 Note: *Behaviours refer to activities in last six months. †Data derived from SIF database by a study nurse. Note: CI = confidence interval, DTES = Downtown Eastside, HIV information missing on 15 206 Variable Sex Male Female Not Hospitalized Odds Ratio (OR) hospitalized n (%) OR (95% CI) p‐value n (%) 708 (72) 60 (61) 1.67 (1.09 – 2.55) 0.020 276 (28) 39 (39) Note: *Behaviours refer to activities in last six months. †Data derived from SIF database by a study nurse. Note: CI = confidence interval, DTES = Downtown Eastside, HIV information missing on 15 207
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The epidemiology of cutaneous injection-related infection among injection drug users at a supervised… Lloyd-Smith, Elisa 2009
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