Introduction

The joint United Nations Office on Drugs and Crime (UNODC)/World Health Organization (WHO)/United Nations Programmes on HIV/AIDS(UNAIDS)/World Bank estimate for the number of people who inject drugs (PWID) in 2013 was 12.19 million worldwide.¹ PWID are especially susceptible to serious infections such as infective endocarditis, abscesses, and osteomyelitis. These require long-term antibiotic therapy ranging from two weeks to 6 weeks or longer with IV antibiotics comprising a significant portion of the treatment regimen.^2–4 Long-term and durable vascular access are typically established with peripherally inserted central catheters (PICC). In the general population diagnosed with these infections, outpatient parenteral antibiotic therapy (OPAT) is typically organized in the community for the majority of treatment and follow-up.⁵ Depending on the programs available, antibiotics can be given at patients’ homes with home care nurses or at infusion centres daily. Cost savings and improved patient satisfaction are among the benefits of OPAT programs, while risks include non--adherence to care and vascular access issues.^6,7

There are limited studies on the role of OPAT programs in people who use drugs (PWUD). Complex social factors such as concerns for misuse of the PICC (defined as non-authorized or prescribed use of the catheter), the perceived high risk for loss to follow-up, and the lack of stable housing, transportation, and support networks are cited as the major limiting factors for the marginal use of OPAT programs among PWUD.⁸ Other factors cited in the literature include provider discomfort in offering OPAT outside of concurrent substance use treatment programs, lack of safeguards against PICC misuse, and legal concerns.⁹ However, amidst the growing opioid crisis in Canada, substance use disorders and associated treatment and harm reduction interventions remain differentially addressed in managing injection-related infections.^10,11 Furthermore, it remains inconclusive whether imposing conditions such as residential treatment for substance use as a condition for OPAT is effective in terms of treatment success and patient satisfaction.¹² There has been documented success in implementing OPAT among PWUD in Asia; however, a common practice pattern in North America for PWUD diagnosed with serious infections is hospital admission for the entire duration of their treatment.¹³ Increased financial costs have been demonstrated in studies conducted in the United States and the primary driver is suggested to be the hospital length-of-stay (LOS).^14,15 Data concerning the demographics and hospital variables of PWUD admitted with serious infections are lacking in Canada. This is a necessary first step to establish a baseline and future direction to improve this population’s healthcare utilization and clinical outcomes.

The OPAT model for PWUD has been piloted in numerous sites worldwide to address increased financial costs in this population. A 2018 literature review identified 10 studies, with 6 based in the United States, 2 in Canada, 1 in Australia, and 1 in Singapore.^7,13,16–21 Eligibility for OPAT relied extensively on discharging patients to medical respite facilities or community treatment housing and selecting patients who were thought to be at low risk of non-adherence to treatment (e.g., having a reliable guardian, establishing behavioral contracts, and having demonstrated compliance with in-hospital care). OPAT completion rates ranged from 72–100%, similar to those among patients without a history of substance use, estimated to be 80–90% worldwide. Cost savings were estimated to be $11,707–$25,000 per episode of OPAT.^18,20 The key pillars of successful OPAT delivery appear to be using post-acute facilities and patient selection using risk assessment tools.²² An integrated model with home OPAT and opioid agonist therapy with comprehensive outpatient follow-up found 100% completion rates in patients randomized to the home OPAT group compared to the inpatient antibiotic therapy.²³ Importantly, the proportion of urine samples negative for non-prescribed opioids in the 12 weeks post-discharge were significantly higher in the intervention group with greater retention in follow-up visits for their substance use. Therefore, a multi-pronged approach to outpatient antibiotic and substance use treatment is crucial for this population.²⁴

In the Canadian context, home-based parenteral programs have been noted in British Columbia, Alberta, Manitoba, Ontario, and Quebec, though limited details are available on the inclusion of the PWUD population.^25,26 The Community Transitional Care Team (CTCT) model in Vancouver, British Columbia is unique in that it is specifically tailored for PWUD, providing shelter and around-the-clock mental health workers, substance use counselling, and case management.¹⁶ Formal OPAT programs are increasingly established across Ontario as a means to reduce the rates of emergency department visits and hospital re--admissions.^27,28 However, there remains a significant care gap for patients with a history of substance use across the country.

The primary objective of this retrospective study is to examine the differences in LOS and hospital costs in patients admitted with serious infections requiring PICC for long-term antibiotics among PWUD compared to those without a documented history of substance use in a tertiary care centre in Ontario, Canada. We also aim to identify significant prognostic and therapeutic parameters in this population, including types of infection, utilization of addictions medicine consultation, opiate-agonist therapy, patient-directed discharge rates, and PICC line complications.

Methods

Setting

Health Sciences North (HSN) is a 454-bed tertiary care hospital in Sudbury, Ontario, Canada. It serves as the regional referral centre for Northeastern Ontario with a catchment population of over 600,000. Patients who require a prolonged course of parenteral antibiotics can be referred for home care services through Ontario’s Community Care Access Centres (CCACs) where community nurses make home visits daily for antibiotic administration. Follow-up visits are completed in the outpatient infectious diseases clinic.

Patients

The study period was December 29, 2018 to January 14, 2021. Inclusion criteria were patients admitted during the study period, received a PICC, and had an infection listed as their most responsible diagnosis on the discharge summary. Exclusion criteria were patients who did not have a serious infection necessitating antibiotic treatment course of longer than 2 weeks, were repatriated to another hospital, had prolonged LOS due to non-infection related causes (e.g., waiting for housing, rehabilitation facility), died, directed their discharges (e.g., leaving against medical advice) before receiving 2 weeks of antibiotic therapy, had no actual infection identified (e.g., inaccurate discharge diagnosis), or had missing data. Substance use was defined as the use of opioids, stimulants, and other non-prescribed drugs at any time point. Re-admission was defined as a hospital stay within 30 days of discharge.

Data Sources

Data were extracted from the hospital electronic medical record system (Meditech). The following data elements were collected: age, sex, LOS, diagnosis (central nervous system infection, infective endocarditis, pulmonary infection, bacteremia, abscess, osteomyelitis/diskitis, septic arthritis, prosthetic joint infection, diabetic foot infection, skin, and soft tissue infection, surgical site infection), mortality, direct costs (calculated using the diagnostics, treatment, and workload allocated using the Ontario Case Costing guide), total costs (including overhead), infectious co-morbidities (hepatitis B and hepatitis C), psychiatric co-morbidities, documented substance use, classes of substance use, involvement of infectious diseases specialists, involvement of addiction medicine specialists, previous opioid agonist therapy (OAT), initiation or change of OAT, initiation of OPAT, duration of OPAT, complications with PICCs (misuse, thrombosis), patient--directed discharges, housing status, and re--admissions.²⁹ If multiple infectious processes were occurring (e.g., bacteremia in the setting of infective endocarditis or septic arthritis), the more severe infection was used as the major diagnosis (e.g., infective endocarditis or septic arthritis).

Study Design

This was a retrospective cohort study comparing the characteristics and outcomes of PWUD and patients without a -documented history of substance use who were admitted with a serious infection requiring a PICC.

Statistical Analysis

Descriptive analyses were used to summarize the demographics of the study population. Continuous data were expressed as medians, and interquartile ranges (IQR) with comparisons performed using Mann-Whitney U ranked sum test. Categorical variables were summarized as proportions and compared using the Chi-squared test. Costs were rounded to the nearest dollar. The primary outcomes were hospital LOS and direct and total hospital costs. Secondary outcomes were the proportions of OPAT initiations, OPAT treatment duration, PICC-related complications, patient-directed discharges, and re-admission rates. The median LOS was also obtained for those in the PWUD group who received OPAT and those who did not. Analysis was conducted using R version 4.1.2 (R Core Team, Vienna, Austria). Statistical significance was considered at a p-value < 0.05.

Ethics Approval

Ethics approval was obtained from the Health Sciences North Research Ethics Board.

Results

During the study period, a total of 445 eligible patients satisfied the inclusion criteria. Among these patients, 234 were excluded: 61 patients did not have a serious infection that would necessitate more than 2 weeks of antibiotics; 54 were repatriated to their home hospital; 49 had a prolonged LOS due to non-infection-related reasons (e.g., waiting for placement at a long-term care home or rehabilitation facility); 39 died; 10 had self-directed discharges before receiving 2 weeks of antibiotics; 8 inaccurately had infection listed as the most responsible diagnosis; 13 had missing data. (Figure 1) The final analysis included the remaining 211 patients, with 55 having a documented history of substance use and 156 did not.

Figure 1. Flowchart for study inclusion.

Baseline characteristics are summarized in Table 1. The PWUD group was significantly younger than the group without substance use with a median age of 43 years to 61 years (IQR 36–49 years compared to IQR 54–73 years; p < 0.001). There were similar proportions of males and females in each group. Fixed housing was documented in 85.5% of PWUD compared to 100% of patients without substance use. Among PWUD, the most common drug of choice was opioids (76.4%), followed by cocaine (56.4%) and methamphetamines (14.5%). The majority of PWUD had a concurrent diagnosis of hepatitis C (74.5%). Infectious diseases specialists were more often consulted in the PWUD group (81.8% vs. 61.5%, p = 0.01). Among the PWUD group, 36.4% were previously on OAT. Addictions medicine specialists were consulted in 50.9% of PWUD cases, and OAT was started in 10 of these patients (35.7%), whereas 12 patients had their OAT continued or switched to a different agent (9 [32.1%] and 3 [10.7%), respectively). Infective endocarditis and osteomyelitis/diskitis occurred more frequently in the PWUD group compared to the group without substance use (18.2% vs. 4.5%; p = 0.003 and 29.1% vs. 10.9%; p = 0.003, respectively). Surgical site infections (18.6%), uncomplicated bacteremias (19.2%), and prosthetic joint infections (14.7%) comprised the majority of the infections in patients without substance use.

Outcomes

Compared to patients without a history of substance use, PWUD had a longer median LOS (30 days, IQR 18–44.5 days vs. 7 days, IQR 5–12 days; p < 0.001), higher median direct costs ($23,036, IQR $13,446–$33,621 vs. $7,478, IQR $5,262–$10,740; p < 0.001), and higher median total costs ($29,790, IQR $16,588–$41,627 vs. $9,391, IQR $6,571–$13,574) (Table 2). The median direct and total costs per day were lower in the PWUD group compared to non-PWUD ($760 vs. $979.4; p < 0.001 and $941.9 vs. $1224; p < 0.001). OPAT was initiated significantly less often in the PWUD group than non-PWUD (95.5% vs. 25.5%; p < 0.001). In the PWUD group, those initiated on OPAT had a shorter LOS than those who remained in hospital for the duration of their treatment (18 days vs. 34 days; p < 0.001). The duration of OPAT did not differ significantly between the PWUD and non-PWUD groups. However, rates of PICC complications in hospital and patient-directed discharges were higher in the PWUD group than non-PWUD (9.1% vs. 0%; p = 0.001 and 6% vs. 0%; p < 0.001). Rates of patient-directed discharges were similar in groups who received Addictions Medicine specialist consultations and those who did not (10.7% and 11%, respectively). Rates of re-admission were similar between PWUD and non-PWUD groups. (Table 2)

Interpretation

In patients hospitalized with a serious infection requiring long-term antibiotics, those with a history of substance use had a longer median LOS and incurred higher hospital costs compared to those who did not have a history of substance use. The higher hospital costs were primarily driven by the longer LOS based on the median costs per day between the groups. OPAT initiation was significantly less frequent in the PWUD group compared to non-PWUD. Among those in the PWUD group who were started on OPAT, their LOS was significantly shorter than those who remained in hospital for the antibiotic therapy. Addictions medicine services were involved in slightly more than half of PWUD hospitalizations, possibly contributing to suboptimal management of their substance use disorders. Additionally, PICC-related complications and patient-directed discharges were higher in PWUD. However, there were no patient--directed discharges among those newly started on OAT during their hospitalization.

Our overall findings are consistent with previously published research. A national study conducted in the United States in 2016 similarly found a longer mean LOS in patients with an opioid use disorder (OUD) admitted with infective endocarditis, epidural abscesses, septic arthritis, or osteomyelitis compared to those without OUD and a lower probability of discharge at any given LOS after adjusting for potential confounders such as age, sex, median household income, and infection type.¹⁴ Patients with OUD were less likely to be discharged to a post-acute facility for the remainder of their treatment, and as a result, the unadjusted average total costs for their hospitalizations were also higher than those without OUD. This is consistent with previous studies demonstrating the barriers to PWUD receiving intravenous antibiotic treatment outside of an acute hospital setting. The main barriers include physician preference for PWUD to remain in hospital and systemic and logistic challenges such as stable housing and transportation to facilitate OPAT delivery.³⁰ The concerns surrounding PWUD and outpatient antibiotic therapy are similarly echoed by infectious diseases physicians in a survey disseminated among members of the Infectious Diseases Society of America (IDSA) in 2017.³¹ The majority of the respondents managed the entire course of parenteral antibiotics on an inpatient unit (41%) or requested a transfer to a supervised facility (35%).

In addition to the need for increased access to OPAT for PWUD, the role of oral antibiotics with good bioavailability should be considered. The dogma of the exclusive use of IV antibiotics for the treatment of deep-seated infections, such as infective endocarditis and osteomyelitis, is being challenged with the emergence of studies demonstrating the safety and efficacy of transitioning to oral antibiotics once clinical stability has been achieved.^32,33 A recently published systematic review of prospective and controlled trials on IV versus oral antibiotic treatment for infective endocarditis, bacteremia, and osteomyelitis found that oral options are as effective and safer as IV-only therapy regimens.³⁴ Duration of parenteral antibiotics varied from 0–14 days before transitioning to an oral antibiotic with excellent oral bioavailability and bone penetration. With increasing research to evaluate the efficacy and non-inferiority of oral versus intravenous antibiotics for these infections, oral regimens may soon become part of the standard treatment options available for both PWUD and non-PWUD with deep-tissue infections. A prospective multicentre quality improvement study in the United States implemented a bundle of interventions including infectious disease and addictions medicine consultations, initiation of OAT, peer recovery specialists counseling, and case managers’ support for patients admitted with an injection-related infection.³⁵ Oral antibiotics contingency plans and methods for contacting the patient in the event of a patient-directed discharge were established by infectious disease consultants and peer recovery specialists during the hospital stay. Compared to the 37% of patients who remained in hospital for the 6 weeks of IV antibiotic therapy, the remaining 63% patients who self-discharged did not have a significant difference in 90-day re-admission rates, with 67% having documented treatment adherence.

Further studies on multi-pronged approaches addressing the underlying substance use disorder with adaptive antibiotic regimens strategies are urgently needed for PWUD hospitalized with serious infections. In addition, community housing requires significant governmental and institutional support, as in the CTCT model. At HSN, a pilot 20-bed inpatient addictions-medicine unit was established in 2021 to address the social and medical needs of patients who use substances. PWUD with serious infections who have achieved clinical stability are offered admission to this unit for the remainder of the treatment course. Future steps will be to evaluate the impact of this unit on hospital costs, patient outcomes, and further involvement of the addiction medicine service in overall hospitalizations and hospital re-admissions.

Limitations

This study is subjected to several limitations. First, this is a single-centre retrospective study; therefore, results may not be extrapolated to other regions with different demographics regarding substance use. For example, in 2020, the public health unit of Sudbury and districts recorded a higher rate of opioid-related morbidity and mortality compared to the province of Ontario.³⁶ Furthermore, this was not a matched cohort; therefore, underlying differences between the two groups could explain the differences seen in the primary and secondary outcomes. The retrospective nature of this data also limits the type of data that were available, such as home environment, degree of support network, previous history of treatment non-adherence, harm-reduction services and interventions offered, and patient satisfaction, as well as the frequency and nature of PICC complications that may not have been captured such as infection, removal of PICCs, and patient-directed discharges with PICC in situ. As a result, the degree of PICC complications in both study groups may be underestimated and partially contribute to the zero complications reported in the non-PWUD group. Lastly, the rate of patient-direct discharge in our study (10.9%) is slightly lower than the range of 12–30% reported in the literature.³⁷ This could be partly due to the timing of certain patient--directed discharges that precluded their inclusion in our study (e.g., left without a PICC inserted) or triggered their exclusion (e.g., did not receive more than 14 days of antibiotic therapy).

Conclusion

In summary, PWUD admitted with a serious infection requiring long-term antibiotics were found to have a longer LOS and to incur higher hospital costs than patients without a documented history of substance use. Rates of PICC-related complications and patient-directed discharges were also higher in this group. While there have been encouraging data on the use of home or community OPAT in PWUD primarily in the United States, there is clearly an urgent need to establish and study multi-pronged approaches to treatment, including substance use disorder treatment, post-acute facilities for patients without stable housing, and adaptive antibiotic treatment regimens for this vulnerable population in Canada.

Contributors Statement

All authors participated in the design of the study. Jollee Fung performed the primary data extraction with the verification of 10 random patient entries from Renée Borkovich. Statistical analyses and drafting of the initial manuscript were performed by Jollee Fung. All authors reviewed the manuscript critically for content, approved the final version to be published, and agreed to be accountable for the work.