Outcomes of Self-Administered Outpatient Parenteral Antibiotic Therapy in Patients with Osteomyelitis of the Foot

Abstract

The objective of this paper is to compare outcomes for patients treated with healthcare administered Outpatient Parenteral Antimicrobial Therapy (H-OPAT) versus S-OPAT (self-administered antibiotics) for the treatment of foot osteomyelitis. This was a retrospective cohort study of 202 subjects with osteomyelitis that were admitted to the hospital for moderate or severe foot infections and followed for 1 year. There were 134 subjects in the H-OPAT group and 68 in the S-OPAT group. Diabetes was prevalent in 157/202 (77.7%) subjects in the study cohort. The primary outcomes were reinfection, wound healing, time until wounds healed, amputation (minor and major), mortality, rehospitalization of the same foot, and length of stay. Reinfection was defined as infection of the same site from index procedure. S-OPAT patients were more likely to require rehospitalization (O.R = 2.10 [1.11, 3.70]) and less likely to have complete wound healing within 90 days (O.R = 0.49 [0.25, 0.96]). When Kaplan Meier survival analysis was evaluated, S-OPAT patients had longer times to heal (H-OPAT; 136.0 ± 105.2 days vs S-OPAT; 183.7 ± 118.9 days, p = 0.01. There were no differences between S-OPAT and H-OPAT for 1-year wound healing, amputation, rate of reinfection, mortality, or length of stay. Overall, S-OPAT subjects demonstrated an increased association with binary wound healing at 90 days, hospitalization, and require longer antibiotic duration.

Keywords

infection diabetes ulcer osteomyelitis amputation PAD

Viewpoints:

Diabetic foot infections are a costly, high-risk condition leading to amputations and extended hospital stays. This study compares healthcare-administered (H-OPAT) and self-administered (S-OPAT) outpatient antibiotic therapies, focusing on rehospitalization, wound healing, and amputation outcomes.

Foot infections are a common cause for hospitalization among patients with diabetes.¹ Diabetic foot infections are associated with high morbidity and mortality and are the leading cause of non-traumatic lower extremity amputations. It is estimated that the United States alone spends up to $13 billion USD each year for complications arising from diabetic foot infections.^2,3 Much of this expenditure has been attributed to lengthy hospital stays and inpatient care, with the need of prolonged antibiotic therapy.^4–6

Outpatient parenteral antibiotic therapy (OPAT) is a service that provides intravenous antimicrobial medication in the outpatient setting and has been shown to be safe and cost effective.^7–11 Currently in the USA, OPAT can be delivered by health care providers at three locations: infusion centers, nursing homes, or in patients home with skilled nursing services. Each of these options greatly reduces the cost compared to in-hospital administration of antimicrobial therapy. While the cost is greatly reduced in these alternative settings, these options are usually only available for insured patients. Uninsured, low socio-economic patients have been shown to be at higher risk of adverse outcomes¹² and generally will remain hospitalized for the duration of their antibiotic therapy at a cost double the most expensive form of healthcare administered outpatient antibiotic therapy (H-OPAT) at infusion centers. The use of self-administered OPAT (S-OPAT) offers an option for patients to reduce cost and prevent prolonged hospitalization. Previous studies have shown self- administered OPAT to be safe and effective,^13,14 however these studies do not specifically evaluate foot infections. This study aims to compare outcomes for patients treated with healthcare administered OPAT (H-OPAT) versus S-OPAT for the antibiotic treatment of moderate and severe foot infections.

Methods

This study was performed as a retrospective analysis of patients that either received H-OPAT, or S-OPAT. All patients were adults, ≥18 years old, and received either H-OPAT or S-OPAT for antimicrobial management for foot infections. Two-hundred and two patients were included with and without diabetes that were admitted to hospital for a moderate or severe foot infections. The International Working Group on the Diabetic Foot Infection Classification was used to define the presence and severity of infection of all patient regardless of diabetes status.^15,16 All patients were treated with surgical intervention. Once osteomyelitis was confirmed and culture and sensitivity data were available, the infectious disease team determined antibiotic choice and duration.

Peripheral artery disease (PAD) was defined as ABI <0.90 and sensory neuropathy as abnormal 10-gram monofilament exam or abnormal vibration perception with a 128 hertz tuning fork. Osteomyelitis was based on a positive bone culture and/or positive histology. We evaluated clinical outcomes for the index hospitalization and over a 12-month follow-up period. For the index hospitalization, we assessed infection severity, surgeries, amputations, vascular interventions, and length of stay. During the 1-year follow-up, we evaluated wound healing, re-infection, amputation (minor and major), readmissions, length of hospitalizations, and mortality. We assessed co-morbidities, baseline lab data, history of ulceration and amputation. This study was exempted by the Institutional Review Board (IRB) due to its retrospective design, which involved the use of pre-existing, de-identified clinical data, posing minimal risk to subjects.

H-OPAT was classified as the administration of intravenous (IV) antibiotic therapy from a healthcare related entity, including either a skill nursing facility, sub-acute care facility, or visitation by a private nurse to a patient's residence. S-OPAT was self-administered by the patient or members of their household. S-OPAT patients were educated prior to hospital discharge in the self-administration of parenteral antimicrobial therapy through a method of counting droplets of antimicrobial IV fluid delivered by gravity. Education materials were delivered at a fourth grade reading level consisting of pictures of necessary supplies, techniques to maintain a sterile environment when connecting antibiotic solution to the IV catheter, and techniques on proper hand hygiene were provided. Patients were not given infusion pumps. All instructions were explained verbally, followed by the provision of printed handouts in over 12 different languages, including both English and Spanish.

After patient education, S-OPAT subjects were required to demonstrate proficiency in self-administration of antibiotics. This was accomplished by an established protocol created by a multidisciplinary team of physicians, nurses, case managers, and pharmacists. In this protocol, patients were required to repeatedly demonstrate IV self-administration of antibiotics by gravity. After discharge, patients were followed weekly with in-person clinic visits for both laboratory monitoring and maintenance of their peripherally inserted central catheter. Patients were also examined by either an infectious disease physician or nurse practitioner every two weeks. The total number of days a patient was on self-administered antibiotic therapy reflects the total number of days of antibiotic use in S-OPAT subjects.

The primary outcomes of this study were reinfection by one-year, wound healing, wound healing <90 days, time until wounds healed, amputation (minor and major), mortality, rehospitalization for the same foot, and length of stay. Reinfection was defined as infection of the same site from index procedure. Minor amputation was defined as amputations to the digits, or tarso-metatarsal segments and major amputation as defined as any amputation above the ankle. All outcomes were calculated using IBM SPSS (version 30.0 Armonk, NY, USA) and STATA BE17 (College Station, TX, USA). We used chi square and Fisher's Exact test to compare dichotomous variables. Normality of continuous variables was evaluated by the Shapiro-Wilk test. The Mann Whitney U Test (non-parametric data) and student's t-test (parametric data) were used to compare continuous variables. Categorical variables were reported as count (%) and continuous variables were reported as mean ± standard deviation. Logistic regression was used to calculate odds ratios (O.R), and a p value ≤0.05 was considered significant for all relationships. A multivariate model was used to analyze reinfection and was built on univariate significance factors of Table 1.

Table 1.

Patient Demographics.

Variable N (%)	H-OPAT (n = 134)	S-OPAT (n = 68)	p-Value
Age (years), mean ± SD	53.1 ± 12.5	51.1 ± 12.4	0.30
BMI, mean ± SD	31.0 ± 7.8	32.2 ± 11.0	0.36
Male	67 (50.0%)	34 (50.0%)	0.99
Race
White	45 (33.6%)	20 (29.4%)	0.55
African American	37 (27.6%)	14 (20.6%)	0.28
Asian American/Pacific Islander	2 (1.5%)	2 (2.9%)	0.49
Hispanic	49 (36.6%)	32 (47.1%)	0.15
Native American	1 (0.7%)	0 (0.0%)	0.48
Comorbidities
Diabetes	100 (74.6%)	57 (83.8%)	0.14
Peripheral Artery Disease	85 (63.4%)	40 (58.8%)	0.52
Dialysis	7 (5.2%)	6 (8.8%)	0.33
Medications
Statins	58 (43.3%)	32 (47.1%)	0.61
Steroid	4 (3.0%)	0 (0.0%)	0.15
NSAID	90 (67.2%)	50 (73.5%)	0.35
Insulin*	81 (81.0%)	52 (91.2%)	0.03
Chronic Kidney Disease
1–2	93 (69.4%)	49 (72.1%)	0.75
3–4-5	40 (29.9%)	19 (27.9%)	0.31
Index Procedure
Incision & Drainage with bone resection .	15 (11.9%)	22 (32.4%)	0.01
Digit Amputation	81 (60.4%)	23 (33.8%)	0.01
Ray Amputation	28 (19.4%)	17 (25.0%)	0.53
Transmetatarsal Amputation	10 (7.5%)	6 (8.8%)	0.74
IDSA/IWGDF Classifications
Moderate/ Grade 3	88 (65.7%)	38 (55.9%)	0.18
Severe/ Grade 4	46 (34.3%)	30 (44.1%)	0.18
Findings at Index Admission
Sensory Neuropathy	113 (84.3%)	61 (89.7%)	0.30
History of an Ulcer	74 (55.2%)	50 (73.5%)	0.01
Acute Kidney Injury	53 (39.6%)	35 (51.5%)	0.11

*The percent of patients using insulin was calculated using the denominator of diabetic patients as opposed to the total number of subjects within each group.

Results

A total of 202 subjects with osteomyelitis who were hospitalized between 2012 to 2016 were included in this study, with a mean age of 52.0 ± 12.5 years. All subjects were determined to have osteomyelitis confirmed by bone culture or positive histology and were surgically managed. A total of 134 subjects were in the H-OPAT group and 68 were in the S-OPAT group. Among the 202 subjects, 126 subjects had moderate IDSA/IWGDF Grade 3 infections and 76 had severe IDSA/IWGDF Grade 4 infections. Among H-OPAT, 88 had moderate and 46 had severe infections and among S-OPAT, 38 had moderate/Grade 3 and 30 had severe/Grade 4 infections. There was no difference in the rate of moderate and severe infections between either OPAT group (p = 0.175). Overall, baseline demographics, comorbidities and medications were similar between with the exception that S-OPAT subjects were significantly more likely to have their diabetes managed with insulin, (60.5% vs 76.5%, p = 0.02) and have a history of foot ulcers (55.2% vs 73.5%, p = 0.1) (Table 1). All treated subjects had residual osteomyelitis confirmed by bone culture or positive histology. Notable differences were also observed for type of index procedure between H-OPAT and S-OPAT. Significantly more subjects underwent incision and drainage with resection in the S-OPAT group compared to the H-OPAT group and significantly more subjects underwent digit amputation in the H-OPAT group compared to the S-OPAT group (Table 1).

At one year, S-OPAT subjects were more likely to have rehospitalization (O.R = 2.1 [1.1, 3.7]) and less likely to have complete wound healing within 90 days (O.R = 0.49 [0.25, 0.96] Figure 1, Table 2). S-OPAT was observed to require a longer duration of antibiotics compared to H-OPAT, 95.3 ± 61.5 versus 42.6 ± 36.7 (p < 0.01), respectively. There were no differences observed between S-OPAT and H-OPAT for wound healing at 1 year (75.4% vs 72.1%, p = 0.61), mortality (3.0% vs 1.5%, p = 0.52), all amputation (24.6% vs 32.4%, p = 0.26), minor amputation (20.1% vs 25.0%, p = 0.43), major amputation (4.5% vs 7.4%, p = 0.40), or length of stay (11.1 ± 9.5 vs 12.6 ± 7.3 days, p = 0.26, Table 2). When Kaplan Meier survival analysis was evaluated, S-OPAT was associated with a longer time until wounds healed (136.0 ± 105.2 vs 183.7 ± 118.9 days, p = 0.01, Figure 2).

Figure 1.

Odds ratios for clinical outcomes comparing hospital outpatient parenteral antibiotic therapy (H-OPAT) and self-administered outpatient parenteral antibiotic therapy(S-OPAT). Outcomes include rehospitalization, mortality, amputation, wound healing within 90 days, wound healing within 1 year, and reinfection.

Figure 2.

Kaplan Meier Curve showing time to wound healing within 1 year for patients treated with H-OPAT and S-OPAT. The solid line represents H-OPAT and the dashed line represents S-OPAT. H-OPAT demonstrated a significantly shorter time to healing compared with S-OPAT (p = 0.012).

Table 2.

Primary Outcomes of OPAT.

	H-OPAT (n = 134)	S-OPAT (n = 68)	O.R [CI]	p-Value
Reinfection	66 (49.3%)	39 (57.4%)	1.40 [0.77, 2.5]	0.28
Wound Healing	101 (75.4%)	49 (72.1%)	0.80 [0.44, 1.6]	0.61
Wound Healing < 90 days	49 (36.6%)	15 (22.1%)	0.49 [0.25, 1.0]	0.04
Amputation (all)	33 (24.6%)	22 (32.4%)	1.46 [0.77, 2.78]	0.26
Minor Amputation	27 (20.1%)	17 (25.0%)	1.32 [0.66, 2.64]	0.43
Major Amputation	6 (4.5%)	5 (7.4%)	1.69 [0.50, 5.76]	0.40
Time Until Healed (days)	136.0 ± 105.2	183.7 ± 118.9	N/A	0.01
Duration of Antibiotics (days)	42.6 ± 36.7	95.3 ± 61.5	52.71 [39.0, 66.4]	0.01
Mortality	4 (3.0%)	1 (1.5%)	0.49 [0.05, 4.4]	0.52
Rehospitalization	59 (44.0%)	42 (61.8%)	2.10 [1.1, 3.7]	0.02
Length of Stay (days)	11.1 ± 9.5	12.6 ± 7.3	N/A	0.26

Table 3.

Multiple Regression of Reinfection.

	Reinfection		Rehospitalization
Variable	Odds Ratio [C.I]	P value	Odds Ratio [C.I]	P value
History of an Ulcer	1.28 [0.70–2.33]	0.15	2.03 [0.70–5.78]	0.19
Insulin	1.86 [0.99–3.42]	0.05	3.49 [0.97–12.58]	0.06
S-OPAT	1.15 [0.60–2.22]	0.48	0.87 [0.33–2.32]	0.79
Incision & Drainage with bone resection	0.52 [0.22–1.25]	0.14	1.58 [0.47–5.28]	0.46
Digit Amputation	0.44 [0.22, 0.88]	0.02	0.83 [0.29–2.36]	0.73

Multiple Regression comparing major baseline factor and S-OPAT as main contributors to reinfection and rehospitalization.

In multiple regression, digit amputation was found to be protective of reinfection (O.R = 0.44 [0.22,0.88] (Table 3). The remaining factors within the multiple regression analysis did not yield any additional significant associations.

Discussion

This is the first study to evaluate S-OPAT vs H-OPAT in the intermediate term for foot specific osteomyelitis. The results of our study suggest that S-OPAT was associated with a longer duration for wound healing, decreased wound healing within 90 days, increased rehospitalization, and requires longer antibiotic coverage compared to H-OPAT. In addition, digital amputation was protective of reinfection in multiple regression. There were no differences in subsequent amputations (for both minor and major), binary wound healing, or re-infection rates between S-OPAT and H-OPAT.

Previously, the effectiveness of H-OPAT has been studied in lower extremity foot infections. Schecter et al conducted a single center, observational study evaluating H-OPAT outcomes with a 12 month follow up for patients with diabetic foot osteomyelitis (DFO).¹⁷ Schecter et al reported a 44% rate of amputation or death within 12 months of initial hospitalization. This finding contrasts with our study, where we observed amputation rate of 27.2%. A potential explanation to account for this difference could be the large loss of 1-year follow up as reported in the limitation of Schecter et al¹⁷ With fewer subjects and the lack of follow up compliance, this study may overestimate the true number and negative outcomes including amputations. Previous DFO studies report significantly higher amputation results, with rates as high as 90%.¹⁸ Malone et al similarly evaluated a cohort of patients with diabetes who received H-OPAT for diabetic foot infections. This was a retrospective study consisting of 59 subjects with a H-OPAT success rate of 88%. However, the study simultaneously observed a high rate of reinfections among subjects (37%) within the 1-year follow up period. Our cohort's reinfection rates were greater than this study, with rates for H-OPAT patients being 49.25% and S-OPAT patients being 57.35%.

Prior studies have evaluated S-OPAT versus H-OPAT following infections at different anatomic regions as well.^14,19 Brand et al defined treatment failure as readmission for source control or clinical deterioration. They compared treatment failure, cure by 28 days, and complications in 265 patients with various diagnoses including endocarditis, prosthetic joint infections, skin and soft tissue infections, osteomyelitis, and visceral abscesses. Brand and colleagues reported that there were no significant differences in overall treatment failure (p = 0.16) or complication rates (p = 0.63) between S-OPAT and H-OPAT.¹⁹

Bhavan et al conducted a retrospective propensity matched study, examining S-OPAT (n = 994) versus H-OPAT (n = 2240 with the primary outcome of 30 day all cause readmission and a secondary outcome of 1-year all-cause mortality.¹⁴ In this study, the population included patients with bone and joint infections, bacteremia, skin and soft tissue infections, intra-abdominal infections, central nervous system infections, and pulmonary infections. Bhavan reported that readmission rates were significantly less among S-OPAT compared to H-OPAT patients (p = 0.006). There were no differences observed for 1-year all-cause mortality (p = 0.57). While Bhavan and Brand reported no differences in H-OPAT and S-OPAT outcomes, these studies did not specifically analyze foot infections or subjects with diabetes.^14,19

Patients with diabetic foot infections often grapple with a constellation of co-morbidities, including sensory neuropathy, peripheral arterial disease, chronic kidney disease, hypertension, and obesity.¹ These conditions compound the complexity of their care, creating a challenging landscape for treatment. The presence of multiple co-morbidities makes diabetic foot infections more challenging because they contribute to delayed wound healing, increased risk of reinfection, hospitalization and amputation.^20,21 Additionally, the management of co-morbidities often requires a multidisciplinary approach, involving various specialists, medications, and lifestyle modifications, further complicating the overall treatment plan and posing potential challenges for patient adherence.

Our results need to be considered within the context of the study's limitations. Retrospective study designs inherently rely on pre-existing medical records which introduce the possibility of incomplete or inaccurate data, as documentation practices and operational definitions of disease can vary. Selection bias may arise due to the non-random nature of chart selection, potentially skewing the study population. This study did not assess specific antibiotic regiments either as all treatment protocols were determined by the hospital's infectious disease experts. We acknowledge variations in antibiotic choice can impact the clinical outcome of each patient, however antibiotic choice was individualized according to infectious disease clinicians and IDSA guidelines. The study was also unable to determine the type of adverse events subjects experienced or the reason for rehospitalization as this information was not collected during data procurement. Additionally, our study did not control for socioeconomic status, glycemic control, use of advanced wound care therapies, or compliance with offloading procedures. All of these have proven advantageous in the management of diabetic foot complications.

Our results may simply reflect a matter of access. Patients with low socioeconomic status, or patients that are uninsured or underinsured may not have access to parenteral antibiotic therapy at an infusion center or skilled nursing facility. We may have systematically selected for patients with fewer resources for antibiotics, wound care, home health, rehabilitation and transportation. S-OPAT may ameliorate some of these difficulties. This paper however did not assess insurance coverage across individuals and was unable to ascertain a relationship between care coverages and outcomes. Regardless, by itself, S-OPAT may not be enough in people with diabetic foot complications. However, both groups had access to a multidisciplinary teams that included infectious disease, podiatry, vascular surgery, physical therapy and wound nurse specialists.^22,23

Conclusion: S-OPAT patients demonstrated a greater risk of delayed wound healing and rehospitalization. Our study suggests that S-OPAT is associated with higher rehospitalization rates, and slower wound recovery. However, there was no differences in re-infection or amputation between the two groups. Importantly, this is the first study to compare S-OPAT with H-OPAT for foot-specific osteomyelitis over an intermediate-term period.

Footnotes

Acknowledgements

The authors have no acknowledgments to declare.

ORCID iDs

Arthur Tarricone

Nitish Thirugnanasambandam

Ethical Approval

This study was reviewed and determined to be exempt by the Institutional Review Board due to its retrospective design involving previously collected, de-identified clinical data.

Informed Consent

Patient consent was waived due to the retrospective nature of the study and the use of de-identified data.

Consent for Publication

Not applicable.

Author Contributions

Arthur Tarricone: Conceptualization, study design, data analysis and writing of original manuscript.

Allen Gee: Data curation, methodology.

Nitish Thirugnanasambandam: data collection, writing assistance, review.

Dane Wukich: critical review, supervision.

Prakash Krishnan: Supervision, revision of manuscript.

Lawrence A Lavery: Supervision, revision of manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

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