Different drugs, different sides: injection use of opioids alone, and not stimulants alone, predisposes to right-sided endocarditis.

OBJECTIVES: Many studies suggest that infective endocarditis (IE) in people who inject drugs is predominantly right sided, while other studies suggest left sided disease; few have differentiated by class of drug used. We hypothesised that based on differing physiological mechanisms, opioids but not stimulants would be associated with right sided IE. METHODS: A retrospective case series of 290 adult (age ≥18) patients with self-reported recent injection drug use, admitted for a first episode of IE to one of three hospitals in London Ontario between April 2007 and March 2018, stratified patients by drug class used (opioid, stimulant or both), and by site of endocarditis. Other outcomes captured included demographics, causative organisms, cardiac and non-cardiac complications, referral to addiction services, medical versus surgical management, and survival. RESULTS: Of those who injected only opioids, 47/71 (69%) developed right-sided IE, 17/71 (25%) developed left-sided IE and 4/71 (6%) had bilateral IE. Of those who injected only stimulants, 11/24 (46%) developed right-sided IE, 11/24 (46%) developed left-sided IE and 2/24 (8%) had bilateral IE. Relative to opioid-only users, stimulant-only users were 1.75 (95% CI 1.05 to 2.93; p=0.031) times more likely to have a left or bilateral IE versus right IE. CONCLUSIONS: While injection use of opioids is associated with a strong predisposition to right-sided IE, stimulants differ in producing a balanced ratio of right and left-sided disease. As the epidemic of crystal methamphetamine injection continues unabated, the rate of left-sided disease, with its attendant higher morbidity and mortality, may also grow.

Risk of New Bloodstream Infections and Mortality Among People Who Inject Drugs With Infective Endocarditis.

Importance: People who inject drugs (PWID) who are being treated for infective endocarditis remain at risk of new bloodstream infections (BSIs) due to ongoing intravenous drug use (IVDU). Objectives: To characterize new BSIs in PWID receiving treatment for infective endocarditis, to determine the clinical factors associated with their development, and to determine whether new BSIs and treatment setting are associated with mortality. Design, Setting, and Participants: This retrospective cohort study was performed at 3 tertiary care hospitals in London, Ontario, Canada, from April 1, 2007, to March 31, 2018. Participants included a consecutive sample of all PWID 18 years or older admitted with infective endocarditis. Data were analyzed from April 1, 2007, to June 29, 2018. Main Outcomes and Measures: New BSIs and factors associated with their development, treatment setting of infective endocarditis episodes (ie, inpatient vs outpatient), and 90-day mortality. Results: The analysis identified 420 unique episodes of infective endocarditis in 309 PWID (mean [SD] patient age, 35.7 [9.7] years; 213 episodes [50.7%] involving male patients), with 82 (19.5%) complicated by new BSIs. There were 138 independent new BSIs, of which 68 (49.3%) were polymicrobial and 266 were unique isolates. Aerobic gram-negative bacilli (143 of 266 [53.8%]) and Candida species (75 of 266 [28.2%]) were the most common microorganisms. Ongoing inpatient IVDU was documented by a physician in 194 infective endocarditis episodes (46.2%), and 127 of these (65.5%) were confirmed by urine toxicology results. Multivariable time-dependent Cox regression demonstrated that previous infective endocarditis (hazard ratio [HR], 1.89; 95% CI, 1.20-2.98), inpatient treatment (HR, 4.49; 95% CI, 2.30-8.76), and physician-documented inpatient IVDU (HR, 5.07; 95% CI, 2.68-9.60) were associated with a significantly higher rate of new BSIs, whereas inpatient addiction treatment was associated with a significantly lower rate (HR, 0.53; 95% CI, 0.32-0.88). New BSIs were not significantly associated with 90-day mortality (HR, 1.76; 95% CI, 0.78-4.02); significant factors associated with mortality included inpatient infective endocarditis treatment (HR, 3.39; 95% CI, 1.53-7.53), intensive care unit admission (HR, 9.51; 95% CI, 4.91-18.42), and methicillin-resistant Staphylococcus aureus infective endocarditis (HR, 1.77; 95% CI, 1.03-3.03), whereas right-sided infective endocarditis was associated with a significantly lower mortality rate (HR, 0.41; 95% CI, 0.25-0.67). Conclusions and Relevance: In this study, new BSIs were common in PWID receiving parenteral treatment for infective endocarditis. Discharging patients to outpatient treatment was not associated with an increase in new BSI incidence or mortality; carefully selected PWID may therefore be considered for such treatment.

Risk factors of infective endocarditis in persons who inject drugs.

BACKGROUND: The rising incidence of infective endocarditis (IE) among people who inject drugs (PWID) has been a major concern across North America. The coincident rise in IE and change of drug preference to hydromorphone controlled-release (CR) among our PWID population in London, Ontario intrigued us to study the details of injection practices leading to IE, which have not been well characterized in literature. METHODS: A case-control study, using one-on-one interviews to understand risk factors and injection practices associated with IE among PWID was conducted. Eligible participants included those who had injected drugs within the last 3 months, were > 18 years old and either never had or were currently admitted for an IE episode. Cases were recruited from the tertiary care centers and controls without IE were recruited from outpatient clinics and addiction clinics in London, Ontario. RESULTS: Thirty three cases (PWID IE+) and 102 controls (PWID but IE-) were interviewed. Multivariable logistic regressions showed that the odds of having IE were 4.65 times higher among females (95% CI 1.85, 12.28; p = 0.001) and 5.76 times higher among PWID who did not use clean injection equipment from the provincial distribution networks (95% CI 2.37, 14.91; p < 0.001). Injecting into multiple sites and heating hydromorphone-CR prior to injection were not found to be significantly associated with IE. Hydromorphone-CR was the most commonly injected drug in both groups (90.9% cases; 81.4% controls; p = 0.197). DISCUSSION: Our study highlights the importance of distributing clean injection materials for IE prevention. Furthermore, our study showcases that females are at higher risk of IE, which is contrary to the reported literature. Gender differences in injection techniques, which may place women at higher risk of IE, require further study. We suspect that the very high prevalence of hydromorphone-CR use made our sample size too small to identify a significant association between its use and IE, which has been established in the literature.

New hepatitis C diagnoses in Ontario, Canada are associated with the local prescription patterns of a controlled-release opioid.

Increases in acute hepatitis C virus (HCV) incidence may be a result of the rising prevalence of injection drug use and the opioid epidemic. Among persons who inject drugs, sharing of needles/syringes is less common and leads to a smaller proportion of incident cases than does sharing of injection drug preparation equipment. In Canada and Europe, hydromorphone controlled release has been associated with frequent reuse and sharing of IDPE. Drug excipients within HCR have been shown to preserve virus survival within IDPE. We hypothesized that regional differences in HCV incidence would mirror regional differences in HCR prescribing. We reviewed HCV incidence data across Ontario, Canada for 2016. Opioid prescribing patterns in each Health Unit were reviewed. Multivariable Poisson regression analyses were performed to test the strength of hydromorphone controlled release dispensing patterns in explaining HCV incidence compared to all opioids. Less vehicle access, lack of education, lower income, less population density, higher white race/ethnicity and more opioid substitution therapy recipients remained significant positive predictors of hepatitis C incidence in the Ontario model. Higher hydromorphone controlled release dispensing rate was a stronger predictor of HCV incidence than all opioid prescriptions (standardized risk ratio = 1.17, P < .0001 vs sRR = 1.11, P = .02). When hydromorphone controlled release was excluded from the opioid prescription variable, dispensing patterns of all other opioids no longer remained a significant predictor (sRR = 1.042, P = .34). The observed relationship between HCV incidence and hydromorphone controlled release dispensing suggests that the type of opioid prescribed locally may contribute to variations in HCV incidence. These data add support to evidence that hydromorphone controlled release use is contributing to HCV spread in Ontario.

Hydromorphone and the risk of infective endocarditis among people who inject drugs: a population-based, retrospective cohort study.

BACKGROUND: The incidence of infective endocarditis related to injection drug use is increasing. On the basis of clinical practice and epidemiological and in-vitro data, we postulated that exposure to controlled-release hydromorphone is associated with an increased risk of infective endocarditis among people who inject drugs. METHODS: We used linked health administrative databases in Ontario, Canada, to assemble a retrospective cohort of adults (aged 18-55 years) who inject drugs for the period of April 1, 2006, to Sept 30, 2015. Cases of infective endocarditis among this cohort were identified using International Classification of Diseases 10 codes. We estimated exposure to hydromorphone and risk of infective endocarditis among this cohort in two ways. First, in a population-level analysis, we identified patients living in regions with high (≥25%) and low (≤15%) hydromorphone prescription rates and, after matching 1:1 on various baseline characteristics, compared their frequency of infective endocarditis. Second, in a patient-level analysis including only those with prescription drug data, we identified those who had filled prescriptions (ie, received the drug from the pharmacy) for controlled-release or immediate-release hydromorphone and, after matching 1:1 on various baseline characteristics, compared their frequency of infective endocarditis with that of patients who had filled prescriptions for other opioids. RESULTS: Between April 1, 2006, and Sept 30, 2015, 60 529 patients had evidence of injection drug use, 733 (1·2%, 95% CI 1·1-1·3) of whom had infective endocarditis. In the population-level analysis of 32 576 matched patients, we identified 254 (1·6%) admissions with infective endocarditis in regions with high hydromorphone use and 113 (0·7%) admissions in regions with low use (adjusted odds ratio [OR] 2·2, 95% CI 1·8-2·8, p<0·0001). In the patient-level analysis of 3884 matched patients, the frequency of infective endocarditis was higher among patients who filled prescriptions for hydromorphone than among those who filled prescriptions for non-hydromorphone opioids (2·8% [109 patients] vs 1·1% [41 patients]; adjusted OR 2·5, 95% CI 1·8-3·7, p<0·0001). This significant association was seen for controlled-release hydromorphone (3·9% [73 of 1895 patients] vs 1·1% [20 of 1895]; adjusted OR 3·3, 95% CI 2·1-5·6, p<0·0001), but not for immediate-release hydromorphone (1·8% [36 of 1989] vs 1·1% [21 of 1989]; 1·7, 0·9-3·6, p=0·072. INTERPRETATION: Among people who inject drugs, the risk of infective endocarditis is significantly higher for those exposed to controlled-release hydromorphone than to other opioids. This association might be mediated by the controlled-release mechanism and should be the subject of further investigation. FUNDING: Ontario Ministry of Health and Long-Term Care, Academic Medical Organization of Southwestern Ontario, Schulich School of Medicine and Dentistry (Western University), and Lawson Health Research Institute.

Recurrent Endocarditis in Persons Who Inject Drugs.

BACKGROUND: Infective endocarditis (IE) is increasing among persons who inject drugs (PWID) and has high morbidity and mortality. Recurrent IE in PWID is not well described. METHODS: This was a retrospective cohort study conducted between February 2007 and March 2016. It included adult inpatients (≥18) at any of 3 tertiary care centers in London, Ontario, with definite IE based on the Modified Duke's Criteria. The objectives were to characterize recurrent IE in PWID, identify risk factors for recurrent IE, identify the frequency of fungal endocarditis, and establish whether fungal infection was associated with higher mortality. RESULTS: Three hundred ninety patients had endocarditis, with 212/390 in PWID. Sixty-eight of 212 (32%) PWID had a second episode, with 28/212 (12%) having additional recurrences. Second-episode IE was more common in PWID (11/178 [6.2%] vs 68/212 [32.1%]; P < .001). Peripherally inserted central catheter (PICC) line abuse was associated with increased risk of recurrent endocarditis (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.01-3.87; P = .04). In PWID, fungal IE was more common in second episodes than first episodes (1/212 [0.5%] vs 5/68 [7.4%]; P = .004). Additionally, fungal infections were associated with mortality in second-episode IE in PWID with an adjusted OR of 16.49 (95% CI, 1.12-243.17; P = .041). Despite recurrent infection, likely due to continued drug use, there was a low rate of referral to addiction treatment (14/68 [20.6%]). CONCLUSIONS: PWID have a high risk of recurrent endocarditis, particularly in patients who abuse PICC lines. Fungal endocarditis is more common in second-episode endocarditis and is associated with increased mortality. Consideration of empiric antifungal therapy in PWID with IE history and suspected IE should be considered.

Correction: A controlled-release oral opioid supports S. aureus survival in injection drug preparation equipment and may increase bacteremia and endocarditis risk.

[This corrects the article DOI: 10.1371/journal.pone.0219777.].

A controlled-release oral opioid supports S. aureus survival in injection drug preparation equipment and may increase bacteremia and endocarditis risk.

BACKGROUND: Injection drug use-associated endocarditis (IDUaIE) incidence in Ontario has recently been associated with hydromorphone prescribing rates. Staphylococcus aureus causes the majority of cases of IDUaIE in Ontario and across North America. Hydromorphone controlled-release (Hydromorphone-CR) requires a complex technique for injection and therefore provides multiple opportunities for contamination. Hydromorphone-CR contains several excipients, which could enhance staphylococcal survival and increase risk of contaminating the injectate. METHODS: Used injection drug preparation equipment (cookers/filters) was collected from persons who inject drugs (PWID), rinsed with water, and plated on Mannitol salt agar. Bacterial isolates from bacteremic PWID were used to assess the survival of S. aureus and Streptococcus pyogenes on cookers/filters with Hydromorphone-CR, hydromorphone immediate-release (Hydromorphone-IR) or oxycodone controlled-release (Oxycodone-CR). The solutions spiked with S. aureus were heated and the remaining viable bacteria enumerated. RESULTS: S. aureus was detected in 12/87 (14%, 95%CI 8-23%) cookers/filters samples used for injection of Hydromorphone-CR. Hydromorphone-CR was the only opioid associated with greater survival of methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) on cookers/filters when compared to sterile water vehicle control. There was a ~2 log reduction in the number of S. aureus that survived when cookers/filters were heated. CONCLUSION: 14% of all cookers/filters used in the preparation of Hydromorphone-CR were contaminated with S. aureus. Hydromorphone-CR prolongs the survival of MRSA and MSSA in cookers/filters. Heating cookers/filters may be a harm-reduction strategy.

Sharing of Injection Drug Preparation Equipment Is Associated With HIV Infection: A Cross-sectional Study.

BACKGROUND: Sharing needles/syringes and sexual transmission are widely appreciated as means of HIV transmission among persons who inject drugs (PWIDs). London, Canada, is experiencing an outbreak of HIV among PWIDs, despite a large needle/syringe distribution program and low rates of needle/syringe sharing. OBJECTIVE: To determine whether sharing of injection drug preparation equipment (IDPE) is associated with HIV infection. METHODS: Between August 2016 and June 2017, individuals with a history of injection drug use and residence in London were recruited to complete a comprehensive questionnaire and HIV testing. RESULTS: A total of 127 participants were recruited; 8 were excluded because of failure to complete HIV testing. The remaining 35 HIV-infected (cases) and 84 HIV-uninfected (controls) participants were assessed. Regression analysis found that sharing IDPE, without sharing needles/syringes, was strongly associated with HIV infection (adjusted odds ratio: 22.1, 95% confidence interval: 4.51 to 108.6, P < 0.001). CONCLUSIONS: Sharing of IDPE is a risk factor for HIV infection among PWIDs, even in the absence of needle/syringe sharing. Harm reduction interventions to reduce HIV transmission associated with this practice are urgently needed.

Heating Injection Drug Preparation Equipment Used for Opioid Injection May Reduce HIV Transmission Associated With Sharing Equipment.

BACKGROUND: London, Canada, experienced an HIV outbreak among persons who inject drugs despite widespread distribution of harm reduction equipment. Hydromorphone controlled-release (HMC) is the local opioid of choice. Injection drug preparation equipment (IDPE; ie, cookers and filters) is often shared and reused because of the perception that there is residual HMC in the IDPE after use. The purpose of this study was to investigate the mechanisms of HIV transmission in this context. METHODS: Residual hydromorphone, (controlled-release or immediate-release), remaining in the IDPE, was measured with liquid chromatography-tandem mass spectrometry, in conditions replicating persons who inject drug use. HIV was added to IDPE in the presence HMC, hydromorphone immediate-release, or microcrystalline cellulose (an HMC drug excipient). HIV viral persistence was measured by reverse transcriptase activity and infectivity of indicator Tzm-bl cells. RESULTS: Forty-five percent of HMC remained in the IDPE after the first aspiration of solution, with no change after heating. HIV persistence and infectivity were preserved in the presence of HMC, and less so with microcrystalline cellulose. Heating the IDPE rapidly inactivated HIV. CONCLUSIONS: Sharing of IDPE is a potential means of HIV transmission. HMC encourages IDPE sharing because of the residual drug in the IDPE, and the HMC excipients preserve HIV viability. Heating IDPE before aspiration of the opioid may be a harm reduction strategy.

The risk of infective endocarditis among people who inject drugs: a retrospective, population-based time series analysis.

BACKGROUND: Infective endocarditis is an increasingly common complication among people who inject drugs. We conducted this study to determine whether the removal of traditional controlled-release oxycodone from the Canadian market would be associated with an increase in the use of hydromorphone and an increased risk of infective endocarditis. METHODS: We conducted a retrospective, population-based time series analysis using the linked health administrative databases of Ontario, Canada. We measured the quarterly risk of admissions for infective endocarditis related to injection drug use and changes in opioid prescription rates from 2006 to 2015. We set the intervention point at the fourth quarter of 2011, when traditional controlled-release oxycodone was removed from the Canadian market. RESULTS: We observed an increase in the risk of admissions for infective endocarditis related to injection drug use during the study period. Before the intervention point, we observed a mean of 13.4 admissions per quarter, and after the intervention, we observed a mean of 35.1 admissions per quarter. However, no significant change in this risk occurred at the intervention point. Rather, the risk of infectious endocarditis appeared to have increased earlier and in parallel with the rise in hydromorphone prescriptions. Hydromorphone represented 16% of all opioid prescriptions at the start of the observation period and 53% by the end. INTERPRETATION: The risk of infective endocarditis related to injection drug use is increasing and is temporally associated with increasing prescriptions for hydromorphone. This relation warrants further exploration.

Validation of an Algorithm to Identify Infective Endocarditis in People Who Inject Drugs.

INTRODUCTION: Infective endocarditis is associated with high morbidity and mortality. Currently, there is concern that the incidence of infective endocarditis associated with people who inject drugs (PWID) is increasing. However, it is difficult to monitor population-wide trends in PWID-associated infective endocarditis, as there is no International Statistical Classification of Diseases, 10th Revision (ICD-10) code for injection drug use. To address this barrier, we sought to develop a validated algorithm using ICD-10 discharge diagnosis codes. MATERIALS AND METHODS: We constructed a cohort of patients whose hospital discharge diagnosis included infective endocarditis. We reviewed 100 patients with incident infective endocarditis from 2014 to 2016 for their infective endocarditis and injection drug use status. We calculated the operating characteristics for algorithms constructed using permutations of ICD-10 codes associated with injection drug use. We repeated this analysis in a cohort of 100 patients with incident infective endocarditis from 2009 to 2011 to examine the temporal stability of the operating characteristics of each algorithm. RESULTS: We found that a combination of hepatitis C virus, drug use, and mental/behavioral disorder codes yielded the highest sensitivity (93%) and positive predictive value (83%) of the algorithms analyzed. DISCUSSION: We have described the first algorithm, validated against chart review data, for identifying PWID-associated infective endocarditis cases using ICD-10 codes. The high sensitivity and positive predictive value indicate that this algorithm can be used for surveillance and research with confidence. CONCLUSIONS: This algorithm will enable researchers to examine epidemiological trends in PWID-associated infective endocarditis.

Clinical Characteristics and Factors Associated With Mortality in First-Episode Infective Endocarditis Among Persons Who Inject Drugs.

Importance: Persons who inject drugs (PWID) represent a distinct demographic of patients with infective endocarditis. Many centers do not perform valvular surgery on these patients owing to concerns about poor outcomes. Addiction services are underused in hospitals. Objectives: To compare clinical characteristics in first-episode infective endocarditis in PWID who are surgically vs medically managed and to identify variables associated with mortality. Design, Setting, and Participants: This case series studied PWID treated for a first episode of infective endocarditis between April 1, 2007, and March 30, 2016. Participants were adult patients (aged ≥18 years) admitted to any of 3 hospitals in London, Ontario, Canada. Analysis occurred between July 2016 and November 2017. Main Outcomes and Measures: Survival among PWID; the causative organisms, site of infection, and cardiac as well as noncardiac complications; referral to addiction services; and surgical vs medical management. Results: Of 370 total first-episode cases of infective endocarditis, 202 (54.6%) were in PWID. Among PWID, 105 (52%) were male, the median (interquartile range) age was 34 (28-42) years, and patients were predominantly positive for the hepatitis C virus (69.8% [141 of 202]). Right-sided infection was more common (61.4% [124 of 202]), and most infections were caused by Staphylococcus aureus (77.2% [156 of 202]). Surgery occurred in 19.3% of patients (39 of 202). The all-cause mortality rate was 33.7% (68 of 202). Adjusting for age and sex, survival analysis demonstrated that surgery was associated with lower mortality (hazard ratio [HR], 0.44; 95% CI, 0.23-0.84; P = .01), as was referral to addiction treatment (HR, 0.29; 95% CI, 0.12-0.73; P = .008). Higher mortality was associated with left-sided infection (HR, 3.26; 95% CI, 1.82-5.84; P < .001) and bilateral involvement (HR, 4.51; 95% CI, 2.01-10.1; P < .001). Conclusions and Relevance: This study presents the demographic characteristics of first-episode infective endocarditis in PWID. Results highlight the potentially important role of addictions treatment in this population. Further study to optimize selection criteria for surgery in PWID is warranted.

Surgical and Medical Management of Isolated Tricuspid Valve Infective Endocarditis in Intravenous Drug Users.

BACKGROUND: Tricuspid valve (TV) infective endocarditis (IE) is a known complication of intravenous drug use (IVDU). This study assessed long-term outcomes of surgically and medically treated cases of TV IE. METHODS: This was a retrospective cohort study of all cases of native TV IE treated in London, Ontario between 2008 and 2011. Outcomes for medically and surgically managed cases were assessed at two years. Outcomes related to the timing of surgery were also assessed. RESULTS: Thirty-eight patients were included; seven received valve surgery: five repairs, two replacements. All patients had a history of IVDU. Baseline characteristics were equal in both groups. Death at two years was 43% in the surgical group and 26% in the nonsurgical group (p = 0.522). In those who received surgery within 30 days versus after 30 days from admission, death was 33% and 50%, respectively (p = 1.00). No patients received emergent surgery (within seven days of admission). Twenty-nine percent of the surgical group survived disease free versus 52% of the nonsurgical group. Survival with morbidity was mainly related to ongoing IVDU. The highest risk for mortality in both groups was ongoing IVDU. CONCLUSIONS: In IVDU-related TV IE the highest risk for mortality appears to be ongoing IVDU and persistent or recurrent endocarditis.