Outpatient Parenteral Antibiotic Therapy for Diabetic Foot Osteomyelitis in an Uninsured and Underinsured Cohort

Abstract

Background 

Diabetic foot osteomyelitis (DFO) is usually treated with prolonged outpatient parenteral antibiotic therapy (OPAT). Evaluation and treatment of nonantibiotic aspects of DFO (eg, peripheral artery disease) are also recommended. There are limited data regarding OPAT practice patterns and outcomes for DFO.

Methods 

Single-center observational study of patients receiving OPAT for DFO in a large United States public hospital between January 2017 and July 2019. We abstracted data regarding microbiology test, antibiotics, clinical outcomes, and nonantibiotic DFO management.

Results 

Ninety-six patients were included and some had >1 DFO-OPAT course during the study period (106 DFO-OPAT courses included). No culture was obtained in 40 (38%) of courses. Methicillin-resistant Staphylococcus aureus was cultured in 15 (14%) and Pseudomonas aeruginosa in 1 (1%) of DFO-OPAT courses. An antibiotic with methicillin-resistant S. aureus activity (vancomycin or daptomycin) was used in 79 (75%) of courses, and a parenteral antibiotic with antipseudomonal activity was used in 7 (6%) of courses. Acute kidney injury occurred in 19 (18%) DFO-OPAT courses. An ankle-brachial index measurement was obtained during or 6 months before the first DFO-OPAT course for 44 (49%) of patients. Forty-two patients (44%) died or had an amputation within 12 months of their initial hospital discharge.

Conclusions 

We found high rates of empiric antibiotic therapy for DFO and low uptake of the nonantibiotic aspects of DFO care. Better implementation of microbiological tests for DFO in addition to stronger integration of infectious disease and noninfectious diseases care could improve DFO outcomes.

Diabetes is the leading cause of lower-extremity amputations globally with most diabetes-related amputations being preceded by osteomyelitis (diabetic foot osteomyelitis [DFO]).^1,2 Diabetic foot osteomyelitis is a multifactorial disease and usually occurs by contiguous spread from an infected foot ulcer in the setting of foot deformities, peripheral neuropathy, and/or peripheral artery disease (PAD).¹ Parenteral antibiotics are commonly used for DFO despite emerging evidence of the efficaciousness of oral antibiotics for osteomyelitis.^3,4 Diabetic foot osteomyelitis is generally treated with a 4- to 6-week course of antibiotics,^5,6 which is commonly given through outpatient parenteral therapy (OPAT) programs to decrease hospital length of stay.⁷ Although osteomyelitis is one of the most common indications for OPAT in the United States,⁸ scarce data exist reporting outcomes among DFO patients receiving OPAT.^9–12 It is important to measure DFO OPAT outcomes given the resurgence of diabetes-related amputations in the United States.¹³ It is also necessary to understand the integration of OPAT with nonantibiotics aspects DFO care given the increasing appreciation of the importance of multidisciplinary limb salvage care.

Our primary aims were to report on OPAT treatment characteristics, adverse events, and outcomes among patients with DFO. We hypothesized that patients receiving OPAT for DFO would receive broad-spectrum antibiotics despite lack of supporting microbiological data. In addition to antibiotics, optimal DFO treatment requires addressing the noninfectious factors contributing to the disease process. This includes wound care, offloading, reconstructive foot surgery, and PAD management.^14–17 To evaluate adherence to these interventions, our secondary aim was to measure the receipt of nonantibiotic DFO therapies among patients on OPAT. We hypothesized that patients receiving OPAT for DFO would seldom receive these therapies. The overall goal of our work is to provide data that will help in developing programs to optimize the care of DFO.

METHODS

Study Design and Inclusion Criteria

We conducted retrospective cohort study in large public hospital in Atlanta, GA, that cares for a high-volume of patients with diabetic foot disease¹⁸ between January 2017 and July 2019. We included all patients receiving OPAT for DFO in an infectious diseases pharmacist-led program that cares for underinsured and uninsured patients receiving home-based or facility-based (eg, nursing facility) OPAT. In this program, patients have at least 1 weekly encounter with a designated pharmacist where they are assessed for adverse effects and medication adherence and undergo laboratorial monitoring. Intravenous antibiotics are dispensed on a weekly basis contingent on an encounter with the pharmacist. Outpatient parenteral antibiotic therapy is always initiated in the inpatient setting in this program, and therefore all included patients were hospitalized before OPAT was initiated. Included patients could have >1 DFO-OPAT course.

Intravenous antibiotics are dispensed on a weekly basis contingent on an encounter with the pharmacist. OPAT is always initiated in the inpatient setting in this program, and therefore all included patients were hospitalized before OPAT was initiated. Included patients could have >1 DFO-OPAT course.

Diabetes was defined by documentation of the diagnosis, and/or receipt of antihyperglycemic agents, and/or HbA1c ≥6.5%. In this program, the indication for OPAT is documented in a treatment plan. We included all patients where the treating clinician determined OPAT was used to treat DFO, and diabetes was confirmed by the aforementioned criteria. We reviewed the records for clinical evidence supporting the DFO diagnosis including radiologist report of x-rays and/or magnetic resonance (MR), presence of exposed bone, positive probe to bone, and/or erythrocyte sedimentation rate ≥70 mm/h. Data were abstracted using a standardized case report form (Supplemental File, https://links.lww.com/IDCP/xxx) and entered into a REDCap database.¹⁹ Analyses were conducted in R version 4.0.2.

Study Definitions and Data Analyses

Baseline demographic and comorbidity characteristics and final outcomes were determined for each unique patient based on characteristics present at their first DFO-OPAT course. Baseline amputations refer to amputations present before the DFO episode where OPAT was started. DFO-OPAT treatment characteristics and adverse events were calculated including all DFO-OPAT courses. A DFO-OPAT course was considered “finished” based on completing the planned treatment course, stopping antibiotics due to vascular access issues or antibiotic adverse events as determined by the treating clinician, or medication nonadherence. A repeat DFO-OPAT course was based on a hospital readmission to initiate a new OPAT course. To initiate a repeat OPAT course, the prior OPAT course had to be classified as finished.

Bacterial cultures were classified as surgical if obtained in an operating room and nonsurgical if obtained at bedside. Surgical cultures consisted of bone and/or deep soft tissue samples. Nonsurgical cultures generally consisted of superficial ulcer swabs. No percutaneous bone biopsies were performed. Cultures obtained during or 2 weeks before the hospital admission OPAT was initiated were included. We used χ² tests to compare antibiotic regimens between patients that did and did not have surgical cultures. Comorbidities including hypertension and heart failure were based on clinical documentation. Peripheral artery disease was defined based on clinical documentation and/or an ankle-brachial index (ABI) ≤0.9.¹⁶ Baseline renal function was calculated using the creatinine measurement on the day of initial hospital admission using the Modification of Diet in Renal Disease study equation.²⁰

We measured acute kidney injury (AKI) rates and severity based on serum creatinine trends according to the RIFLE criteria.²¹ RIFLE AKI stages are defined as risk, injury, and failure based on a serum creatinine elevation of 50%, 100%, and 200% above baseline, respectively. An absolute serum creatinine elevation of ≥4.0 mg/dL is also a criterion for failure. Urine output and glomerular filtration rate trends were not used as AKI criteria. We used 2 AKI definitions. The first definition (“overall AKI rate”) aimed at ascertaining AKI rates after inpatient initiation of antibiotics used for OPAT through OPAT completion. The baseline creatinine for the overall AKI rate was defined as the creatinine measurement the first day of hospital admission. The rationale for this definition is that OPAT antibiotics are always started in the inpatient setting at our institution, and thus patients are at risk for antibiotic-related adverse events before hospital discharge and until OPAT completion. The second definition (“OPAT AKI rate”) aimed at ascertaining AKI rates after hospital discharge during the OPAT course. The baseline creatinine for the OPAT AKI rate was defined as using the creatinine measurement the day of hospital discharge. We also recorded adverse effects other than AKI that led to stopping OPAT as determined by the treating clinician. To characterize uptake of nonantibiotic DFO therapies, we measured the proportion of patients receiving an offloading device, the proportion of patients receiving reconstructive foot surgery (eg, Achilles tendon lengthening), and the proportion of patients who had an ABI test ≤6 months before hospital discharge in line with the Society for Vascular Surgery guidelines.¹⁶ We also measured the proportion of patients with a postdischarge outpatient visit with providers that wound care in this institution (wound care nurse and surgeons, including podiatrist).

Outcomes

All records were reviewed ≥12 months after OPAT initiation for amputations, emergency department (ED) visits, and readmissions. We report separately amputations during and 12 months after the hospitalization where OPAT was started, in addition to all-cause mortality. Posthospital discharge amputations are defined as ipsilateral to the DFO. We classified amputation as minor (below ankle) and major (above ankle). We recorded all ED visits and readmissions during the OPAT course and 30 days after discharge.

RESULTS

Baseline Cohort Characteristics

Ninety-six patients contributing a total of 106 DFO-OPAT courses were included. Six patients had 2 DFO-OPAT courses and 2 patients had 3 DFO-OPAT courses. The following data are regarding unique patients (n = 96) at the time of the first DFO-OPAT course (Table 1). The median age was 51 years (interquartile range [IQR], 42–56). Most patients were male 73 (76%), and most patients were African American 72 (75%). Eleven (12%) patients had a history of homelessness. Regarding comorbidities, 82 (85%) had hypertension, 61 (64%) had chronic kidney disease, 45 (47%) were obese (body mass index ≥30 kg/m²), and 12 (13%) had heart failure. Regarding PAD, an ABI measurement was obtained within 6 months of starting OPAT for 44 (49%) patients and 5 had an ABI ≤0.9. Ten (10%) patients had PAD by clinical documentation and/or ABI criteria. The median baseline hemoglobin A1c was 9.3% (IQR, 7.8%–11.5%).

TABLE 1 - Baseline Cohort Characteristics

Characteristics	n = 96
Demographics and comorbidities
Age, median (IQR), y	51 (42–56)
Male	73 (76.0)
African American	72 (75.0)
History of homelessness	11 (12)
Heart failure	12 (13)
Chronic kidney disease	61 (64)
Stage 2	27 (28)
Stage 3	29 (30)
Stage 4	5 (5)
Hypertension	82 (85)
Peripheral artery disease*	10 (10)
ABI test during or ≤6 months before hospital admission	44 (49)
Obesity (BMI ≥ 30 kg/m2)	45 (47)
Current or before tobacco use	43 (45)
Baseline HbA1c, median (IQR), %	9.3 (7.7–11.5)
Baseline amputation history†,‡
No amputation	62 (65)
Minor amputation	31 (32)
Major amputation	3 (3)
Diagnostic tests	n = 106
Erythrocyte sedimentation rate ≥70	66 (62)
X-ray suggestive of DFO	51 (48)
MRI suggestive of DFO	83 (78)
MRI and/or x-ray suggestive of DFO	95 (90)
Exposed bone	8 (8)

Data presented as n (%) unless stated otherwise.

IQR, interquartile range; ABI, ankle brachial index; BMI, body mass index; HbA1c, hemoglobin A1c.

*Among all outpatient parenteral antibiotic therapy episodes.

^†ABI ≤ 0.9 n = 5 (6%). Inpatient vascular surgery consultation n = 37 (39%).

^‡Amputations before current DFO episode. Minor amputation, below ankle. Major amputation, above ankle.

DFO Diagnosis and Treatment Characteristics

The following data include all DFO-OPAT courses (n = 106). X-ray and/or MR were suggestive of osteomyelitis in 95 (90%) courses. Exposed bone on physical examination was present in 8 of these 95 courses. Among 11 courses without radiological evidence of osteomyelitis and/or exposed bone, intraoperative findings were suggestive of osteomyelitis in 4 courses, and ESR was ≥70 mm/h in 5. DFO diagnosis was not supported by imaging, intraoperative, or laboratory findings in 2 courses. OPAT was used to treat postamputation residual DFO in 31 (29%) courses.

Culture data are presented in Figure 1. Surgical cultures were obtained in 43 (41%), nonsurgical cultures were obtained in 37 (35%), and both types of cultures were obtained in 14 (13%) of DFO courses. Staphylococcus aureus was the most common organism isolated in both types of cultures. Combining surgical and nonsurgical cultures, S. aureus was isolated in 37 (34%) DFO-OPAT courses of which 15 (41%) were methicillin-resistant. Pseudomonas aeruginosa was grown in 1 DFO-OPAT course in both a surgical and nonsurgical sample.

FIGURE 1: Culture results (n = 106).

Home-based OPAT was used in most courses (100 [94%]) (Table 2). Antibiotics used for OPAT are described in Table 3. Vancomycin was used in 41 (39%), and daptomycin was used in 38 (26%) DFO-OPAT courses (Table 3). Overall, a parenteral antibiotic with anti–methicillin-resistant S. aureus (MRSA) activity was used in 79 (75%) DFO-OPAT courses. Parenteral beta-lactams were used in 48 (45%) DFO-OPAT courses. Overall, a parenteral antibiotic with anti–Pseudomonas aeruginosa activity was used in 7 (6%) courses (ie, cefepime or piperacillin-tazobactam). A concomitant oral antibiotic was used in 50 (47%) DFO-OPAT courses, and oral fluoroquinolones were the most common concomitant oral antibiotic (42 [40%] DFO-OPAT courses). Most OPAT-DFO courses included ≥2 antibiotics (n = 80 [76%]). A parenteral antibiotic with anti-MRSA activity was less likely to be used when a surgical culture was obtained (27 [25%]) compared with when a surgical culture was not obtained (52 [49%], P = 0.03). Conversely, a parenteral beta-lactam was more likely to be used when a surgical culture was obtained (26 [25%]) compared with when a surgical culture was not obtained (22 [21%], P = 0.01).

TABLE 2 - Posthospital Discharge Care

Characteristics	n = 106
OPAT care characteristics
Initial hospital admission length of stay, median (IQR), d	10 (8–13)
Home-based OPAT	100 (94)
Facility-based OPAT	6 (6)
Attended ≥1 OPAT visit	101 (95)
Wound care and offloading characteristics
Wound care ≤30 days of discharge*	44 (42)
Podiatry visit scheduled	43 (41)
Podiatry visit ≤30 days of hospital discharge	11 (10)
Offloading offered	52 (49)
Total contact cast (n = 52)	4 (7)

Data presented as n (%) unless stated otherwise.

OPAT, outpatient parenteral antibiotic therapy; DFO, diabetic foot osteomyelitis; ABI, ankle brachial index.

*Defined as attending an outpatient visit with a wound care nurse, orthopedic surgeon, vascular surgeon, or podiatrist within 30 days of hospital discharge.

TABLE 3 - Antibiotic Regimens

	n = 106
Parenteral antibiotics
Vancomycin	41 (39)
Daptomycin	38 (26)
Parenteral beta-lactam, nonpseudomonal*	41 (39)
Parenteral antipseudomonal†	7 (6)
One parenteral antibiotic	85 (80)
Two parenteral antibiotics	21 (20)
Oral antibiotics
Concomitant oral antibiotic	50 (47)
Oral fluoroquinolone‡	42 (40)
Oral metronidazole	29 (3)
Total number of antibiotics
One antibiotic	26 (24)
Two antibiotics§	58 (55)
Three antibiotics∥	22 (21)
Antibiotic treatment duration
Total antibiotic days, median (IQR)	42 (31–43)
Outpatient parenteral antibiotic days, median (IQR)	33 (23–38)
Completed planned OPAT course¶,#	76 (72)

Data presented as n (%) unless stated otherwise.

OPAT, outpatient parenteral therapy; IQR, interquartile range.

*Cefazolin (n = 14), ceftriaxone (n = 13), ertapenem (n = 12), ampicillin-sulbactam (n = 1), ampicillin (n = 1).

^†Cefepime (n = 6), piperacillin-tazobactam (n = 1).

^‡Ciprofloxacin (n = 21), levofloxacin (n = 16), moxifloxacin (n = 5).

^§1 parenteral and 1 oral antibiotic (n = 38), 2 parenteral antibiotics (n = 20).

^∥1 parenteral and 2 oral antibiotics (n = 21), 2 parenteral and one oral antibiotics (n = 1).

^¶Reasons therapy not completed (patients could have >1 reason). Antibiotic-related adverse events (n = 16); medication nonadherence (n = 7); missing (n = 5); catheter complications (n = 4).

^#Total antibiotic days for completed planned OPAT courses (median, 42 days; IQR, 41–45). Total antibiotics days for noncompleted planned OPAT courses (median, 28 days; IQR, 18–31).

The median total duration of antibiotic therapy (from inpatient start date to OPAT end date) was 42 days (IQR, 31–43) with a similar median duration (41 days) in the subset treated for residual osteomyelitis after an amputation. The median total duration of antibiotic therapy was similar when comparing patients that died or had an amputation (42 days) to patients that were alive and did not have an amputation (41.5 days) within the 12 months after hospital discharge.

Posthospital Discharge Care

A posthospital discharge follow-up appointment with any health care provider was scheduled in all courses, but the first appointment was missed in 37 (35%) courses, and no follow-up appointments were attended in 3 (2%) courses. A follow-up appointment with an OPAT provider was scheduled in all courses. No OPAT provider follow-up appointment was attended in 5 (4%) courses. A follow-up appointment with a provider that preforms wound care was scheduled in 89 (84%) courses and 44 (41%) attended ≥1 of these appointments within 30 days of hospital discharge. A follow-up appointment with a podiatrist was scheduled in 43 (41%) of DFO-OPAT courses, and 11 (10%) attended a podiatry appointment within 30 days of hospital discharge. Foot ulcer offloading was provided at hospital discharge for 52 (49%) DFO-OPAT courses. Total contact casting was provided in 4 courses. No patients received foot reconstructive surgery during the DFO-OPAT course.

Outcomes

The overall AKI rate was 33 (31%). Among these 33 AKI events, 17 (51%) occurred in the inpatient setting and 15 (49%) in the outpatient setting. The OPAT AKI rate was 19 (18%). RIFLE classifications of severity for these AKI episodes are listed in Table 4. OPAT AKI rates were 13/41 (37%) among patients receiving OPAT with vancomycin and 3/38 (8%) among patients receiving OPAT with daptomycin. The planned antibiotic course was not completed in 30 (78%) DFO-OPAT courses, and antibiotic-related adverse events were the most common reason for noncompletion (n = 18). OPAT was not completed due to nonadherence in 7 (6%) courses. The median total duration of antibiotic therapy was 42 days for DFO-OPAT courses completed as planned, and 28 days for DFO-OPAT courses not completed as planned. Emergency department visits and hospital readmissions during OPAT-DFO were common, 44 (41%) and 27 (25%), respectively.

TABLE 4 - Outcomes

Characteristics
Acute kidney injury rates	n = 106
Acute kidney injury, overall*,†	33 (31)
Acute kidney injury, during OPAT‡,§	19 (18)
ED visits and hospital readmissions	n = 106
ED visit during OPAT	44 (42)
30-day ED visit	38 (36)
Readmission during OPAT	26 (25)
30-day readmission	21 (20)
12-month outcomes among patients without amputation at initial admission	n = 68
No amputation∥	54 (80)
Minor amputation	10 (15)
Major amputation	3 (4)
Death	1 (1)
12-month outcomes among patients with a minor amputation at initial admission	n = 27
No further amputation¶	16 (60)
Further minor amputation	8 (30)
Major amputation	2 (7)
Death	1 (3)

Data are shown as number (%) unless stated otherwise.

OPAT, outpatient parenteral therapy; ED, emergency department; DFO, diabetic foot osteomyelitis.

*Peak creatinine after inpatient antibiotic start/creatinine day of hospital admission ≥1.5.

^†RIFLE class risk (n = 13), injury (n = 14), and failure (n = 6).

^‡Peak creatinine during OPAT/creatinine day of hospital discharge ≥1.5.

^§RIFLE class risk (n = 13), injury (n = 15), and failure (n = 1).

^∥18 patients had <12 months of follow-up.

^¶Five patients had <12 months of follow-up.

Data regarding amputation-free survival are presented using unique patients as the denominator (n = 96), and discharge date from the first hospitalization DFO for OPAT was initiated as reference. Supplemental Figure 1 (https://links.lww.com/IDCP/A51) is a survival curve of posthospital discharge amputations and deaths. Among the 68 patients that did not undergo an amputation during the initial admission, 1 died, 3 had a major amputation, and 10 had a minor amputation within 12 months of hospital discharge. In this group, the posthospital discharge 12-month amputation-free survival was 80%. Among the 27 patients that had residual DFO after a minor amputation at the initial hospital admission, 1 died, 2 had a major amputation, and 8 had a subsequent minor amputation. In this group, the posthospital discharge 12-month amputation-free survival was 60%. Overall, including initial hospital admission amputations, 42 (44%) patients with DFO had amputation or died within 12 months of hospital discharge. Among the 54 patients that did not die or have an amputation during or 12 months after hospital discharge, 18 (33%) had less than 12 months of follow-up.

DISCUSSION

To our knowledge, this is the largest published cohort reporting on DFO-OPAT practice patterns and outcomes. Our study highlights challenges in the management of this disease. Specifically, broad-spectrum antibiotics are commonly used, and adequate microbiological tests are seldom obtained. This practice could be mitigated by better implementation of diagnostic tests including percutaneous bone biopsies. Moreover, there was poor uptake of nonantibiotic therapies with demonstrated positive impact on diabetic foot disease such as PAD diagnostics, wound care, and wound offloading in this cohort.^14–16 These data highlight the need to better integrate infectious diseases care into a broader multidisciplinary limb salvage teams.²²

Osteomyelitis is a strong predictor of amputation among people with diabetic foot ulcers.²³ To our knowledge, published OPAT studies that included patients with DFO have not reported on amputation outcomes.^10–12 Forty-two (44%) patients in our cohort had at least 1 amputation or died within 12 months of hospital discharge (including 6 patients with a major amputation and 2 deaths). This amputation rate may be an underestimate as 18/54 (33%) of patients that did not undergo an amputation or die within 12 months of hospital discharge in our cohort had less than 12 months of follow-up. By comparison, Lavery et al²⁴ recently reported on the outcomes of patients with DFO with at least 12 months of follow-up in Texas (n = 157) and found a major and/or minor amputation rate of 83%. In a French multicenter observational study (n = 136), the 12-month major and/or minor amputation rate among patients with DFO was 61%.²⁵ Altogether, the evidence suggests that many patients with DFO will require an amputation.

This study highlights the lack of adequate microbiological testing among patients with DFO. No cultures (surgical and/or nonsurgical) were obtained for 40 (38%) of DFO-OPAT courses. Surgical (ie, bone or deep soft tissue) cultures were only collected in 43 (41%) of DFO-OPAT courses. Guidelines discourage the usage of superficial swabs to guide DFO antibiotic therapy given the poor correlation between superficial soft tissue and bone cultures.^5,6,26 As in other cohorts, S. aureus was the most common bacteria cultured (37 [34%] of DFO-OPAT courses).²⁶ Methicillin-resistant S. aureus was cultured in 15 (14%) DPO-OPAT courses, but a parenteral antibiotic with potential MRSA activity (vancomycin or daptomycin) was used in 79 (75%) DFO-OPAT courses. This and other data suggest there is a need to better implement DFO diagnostic tools.²² Jhaveri et al,²² for example, found a significant decrease in the length of antibiotic therapy and parenteral antibiotic use for DFO after they implemented a DFO-related educational intervention for infectious diseases, pathologists, and podiatrists.

Although vancomycin is a commonly used for osteomyelitis, this agent has been associated with increased risk of treatment failure.^4,11,12 It is unclear if this association is due to drug characteristics, patient selection, or inadequate dosing regimens as therapeutic drug monitoring was not used in some studies. Interestingly, oral fluoroquinolones were used concomitantly with parenteral antibiotics in 42 (40%) of DFO-OPAT courses in our cohort. The combination of an oral fluoroquinolone with a rifamycin is commonly used in Europe, particularly for fluoroquinolone-susceptible S. aureus, including in clinical trials of bone and joint infections³ and DFO-specific trials.²⁷ Thus, we believe some patients receiving OPAT in our center could have had a fully oral regimen by substituting a rifamycin for vancomycin or daptomycin. Similarly, in cases of known or suspected fluoroquinolone-resistant S. aureus, there are data to support other oral antibiotics (eg, linezolid and cotrimoxazole) in place of vancomycin.^3,4

Although it is difficult to compare our AKI rates with other studies due to differences in AKI and baseline creatinine definitions, our overall AKI rate of 31% was slightly higher compared with the AKI rate reported in a large cohort the included all-cause hospitalizations in an academic medical (n = 19,249 hospitalizations, AKI incidence = 22.7%).²⁸ Diabetes is an important AKI risk factor as shown in a cohort of patients hospitalized with foot infections.²⁹ In that cohort, the incidence of AKI was 48.5% among patients with diabetes and 23.9% among patients without diabetes. Our OPAT AKI rate was 18%. This is a much higher rate compared with some cohorts reporting on OPAT outcomes for any indication (eg, 4% in Cox et al).³⁰ Keller et al³¹ reported an AKI rate of 18% among those receiving OPAT with vancomycin for various indications, compared with 37% in our cohort. Vancomycin was associated with higher AKI rates compared with daptomycin in a well-designed propensity score-matched study.³² Similarly, OPAT AKI rates were higher among patients receiving vancomycin compared with patients receiving daptomycin in our cohort despite at least weekly laboratory monitoring, including vancomycin levels. Given the poor long-term outcomes of AKI among people living with diabetes, particularly those with foot ulcers,^29,33 AKI rates could be an important outcome metric for future studies evaluating the impact of DFO diagnostics, biomarkers, and antibiotic regimens.

Regarding nonantibiotic care processes, less than half of patients received an ABI test (49%). Although pharmacokinetic data are scarce,⁴ it is generally accepted that antibiotics will not penetrate the site of infection at sufficient concentrations among patients with DFO and poor foot perfusion. Moreover, large cohort studies have found that PAD is an important prognostic factor for limb salvage among patients with diabetic foot infections,³⁴ and pulse palpation alone is not accurate for PAD diagnosis.¹⁴ We also found low rates of wound care (42%) and podiatry (10%) outpatient care within 30 days of hospital discharge, limited use of offloading devices (49%), and no use of surgical offloading procedures (eg, Achilles tendon lengthening). These low rates contrast with the high proportion of patients who had at least 1 OPAT visit (95%). In our center, the infectious diseases pharmacists carefully follow all patients on OPAT with at least weekly visits (in person or phone). In addition, antibiotics are dispensed on a weekly basis contingent on an encounter with the pharmacist. These data suggest that, with sufficient resources (eg, a patient navigator making frequent contact with the patient), linkage to other outpatient clinics for diabetic foot care is possible. After the landmarks trials comparing oral to intravenous antibiotics for bone and joint infections (OVIVA³) and endocarditis (POET³⁵), it is likely that oral antibiotics will be increasingly used in lieu of OPAT in the United States. Although there have been suggestions that this transition will render OPAT programs obsolete, others have suggested a transition to complex outpatient antibiotic programs (“COpAT”) model where patients receive careful monitoring by infectious diseases pharmacists and physicians irrespective of oral or parenteral antibiotic use.³⁶ In our and other centers, these COpAT clinics could also serve as a hub to coordinate care with other specialists, including for patients with diabetic foot infections.

In summary, we present a large cohort of patients receiving OPAT for DFO. We found high rates of broad-spectrum empiric antibiotic use and low uptake of nonantibiotic DFO therapies. Our study has limitations. First, we could have missed episodes of nonantibiotic care outside this institution, and we could have underestimated the number of patients with negative outcomes because a large proportion of patients had ≤12 months of follow-up. Second, we did not perform an analysis of the association between receipt of nonantibiotic therapies and outcomes. However, this is beyond the scope of the study, and there are robust data on the benefit of these nonantibiotic therapies (eg, offloading) for diabetic foot disease.^6,14–16 Third, we report all-cause mortality and did not ascertain if deaths were directly related to DFO and/or OPAT. Fourth, we did not include fully insured patients because records were not available for review, and we did not compare the outcomes between uninsured and underinsured patients. Thus, we did not investigate the impact of insurance on DFO-OPAT outcomes. Lastly, our main limitation is the single-center design limited to uninsured and underinsured design limits generalization This limitation can be mitigated in the future by leveraging existing large multisite OPAT databases to better understand DFO treatment outcomes. Similarly, future studies could leverage existing clinical databases to investigate the DFO outcomes patients receiving parenteral versus oral antibiotics for DFO given the small number of patients with DFO enrolled in OVIVA.³