Received: 28 August 2023 Revised: 8 January 2024 Accepted: 10 February 2024 DOI: 10.1111/wrr.13162 ORIGINAL ARTICLE-CLINICAL SCIENCE The infected diabetic foot: Analysis of diabetic and non-diabetic foot infections Lawrence A. Lavery DPM, MPH 1 | Mehmet A. Suludere MD 1 | Easton Ryan MD 2 | Peter A. Crisologo DPM 1 | Arthur Tarricone DPM, MPH 1 | Matthew Malone DPM, PhD 3 | Orhan K. Oz MD, PhD 4 1 Department of Plastic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA Abstract The aim of this study was to compare outcomes of moderate and severe foot infec- 2 Resident Department of Orthopedics, Harvard University Medical School, Boston, Massachusetts, USA 3 tions in people with and without diabetes mellitus (DM). We retrospectively evaluated 382 patients (77% with DM and 23% non-DM). We collected demographic data, School of Medicine, Infectious Diseases and Microbiology, Western Sydney University, Sydney, New South Wales, Australia co-morbidities and one-year outcomes including healing, surgical interventions, num- 4 required more surgeries (2.3 ± 2.2 vs. 1.7 ± 1.3, p = 0.01), but did not have a longer Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA ber of surgeries, length of stay, re-infection and re-hospitalisation. DM patients hospital length of stay during the index hospitalisation (DM 10.9 days ±9.2 vs. nonDM = 8.8 days ±5.8, p = 0.43). After the index hospitalisation, DM patients had Correspondence Lawrence A. Lavery, Department of Plastic Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, USA. Email: larry.lavery@utsouthwestern.edu increased rates of re-hospitalisation for any reason (63.3% vs. 35.2%, CI 1.9–5.2, OR 3.2, p < 0.01), re-infection at the index wound infection site (48% vs. 30.7%, CI 1.3– 3.5, OR 2.1, p < 0.01), re-hospitalisation for a foot pathology (47.3% vs. 29.5%, CI 1.3–3.6, OR 2.1, p < 0.01), and longer times to ulcer healing (151.8 days ±108.8 vs. 108.8 ± 90.6 days, p = 0.04). Patients with DM admitted to hospital with foot infections have worse clinical outcomes during the index hospitalisation and are more likely to have re-infection and re-admission to hospital in the next year. KEYWORDS amputation, diabetic foot, infection, osteomyelitis, outcomes 1 | I N T RO DU CT I O N all of which may increase the risk of lower extremity amputation.1 The risk of ulcers, infections and amputation is much less common in Persons with diabetes mellitus (DM) have high rates of foot complica- adults without diabetes, although there are only a few studies that tions such as ulcerations, infections of the skin, soft tissue and bone, evaluate non-diabetic foot infections.2 Persons with DM requiring hospitalisation for a foot infection, are associated with poor healing, increased risks of re-infections, and repeated hospitalizations. There is Abbreviations: AKA, above knee amputation; BKA, below knee amputation; CI, confidence interval; CKD, chronic kidney disease; CRP, C-reactive protein; DM, diabetes mellitus; ESRD, end-stage renal disease; HbA1c, glycosylated haemoglobin; IWGDF, International Working Group on The Diabetic Foot; MRI, magnetic resonance imaging; OM, osteomyelitis; OR, odds ratio; SIRS, systemic inflammatory response syndrome; SPEC-CT, single-positron emission computed tomography; STI, soft tissue infection; WBC, white blood cell count. scant evidence comparing clinical outcomes and resource utilisation in patients with foot infections in people with and without DM. Suaya et al.3 analysed 2,227,401 patients from insurance claims data and reported that persons with DM were five times more likely to have a This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2024 The Authors. Wound Repair and Regeneration published by Wiley Periodicals LLC on behalf of The Wound Healing Society. 360 wileyonlinelibrary.com/journal/wrr Wound Rep Reg. 2024;32:360–365. skin or soft tissue infection (STI). Similarly, Wukich et al.4 retrospec- rates and mortality. Foot amputations include toe amputations up to tively analysed post-operative foot infections to compare outcomes in Chopart's amputations. Below the knee amputations involved ampu- patients with and without DM and identified that persons with DM tation through the tibia and fibula below the knee joint. Above the were five times more likely to have a postoperative infection after knee amputations involved amputation through the femur above elective surgery than patients without DM. the knee joint. Lavery and colleagues reported that persons with ankle fractures with DM were 2.8 times more likely to develop infection and 6.6 times more likely to require amputation than persons without DM.5 2.1 | Statistical analysis We identified two studies that compared diabetic and non-diabetic patients with foot infections as a result of penetrating injuries.2,6 The Clinical data were summarised using descriptive statistics. Median, primary objective of this study was to compare risk factors and clinical mean and standard deviation for continuous variables and frequency outcomes in persons with and without DM admitted to hospital with and percentages for categorical variables are presented. Clinical and infected foot ulcers. surgical outcomes between persons with and without DM were compared using parametric (Student t-test, χ2 test) and non-parametric tests (Mann–Whitney U test, Fisher exact test) as appropriate. Odds 2 | M E TH O DO LO GY ratios (OR) and confidence intervals (CI) were calculated for dichotomous risk factor and outcome variables. In this article, we compare This was a retrospective cohort study, approval was obtained from risk factors and outcomes for patients with and without diabetes. the IRB at the Parkland Hospital and University of Texas Southwest- SPSS version 25, (IBM, Chicago, IL) was used in the analysis of ern Medical Center. We evaluated the medical records of 382 patients the data. (294 with DM [77%] and 88 without DM [23%]) admitted to hospital with moderate and severe foot infections over a period of 8 years. All the patients were 18–90 years of age with at least 12 months follow- 3 | RE SU LT S up or until they were deceased. Infection was stratified based on; the presence of osteomyelitis (OM) and/or soft tissue infection (STI), and The medical records of 294 patients with DM and 88 patients without on the severity of infection. STIs were defined by clinical signs DM were evaluated. In the patient demographics, there were no dif- and symptoms of infection in addition to ruling out OM through MRI, ferences in age or gender between individuals with diabetes and those single-positron emission computed tomography (SPECT CT), or a neg- without diabetes (Table 1). (75.2% DM and 73.9% non-DM, CI 0.6 to ative bone biopsy. The criteria for osteomyelitis were based on a posi- 1.8, p = 0.80). Persons with DM had more co-morbidities than people tive bone culture or bone histopathology. The International Working without DM such as ESRD (eGFR <15 mL/min) (DM 9.5% vs. non-DM Group on the Diabetic Foot (IWGDF) foot infection classification was 0.0%, 1.1 to 313.3, OR 18.9, p = 0.04), retinopathy (DM 30.6% used to define moderate and severe foot infection.7 Severe infection vs. non-DM 0.0%, 4.8 to 1276.1, OR 78.3, p < 0.01), peripheral neu- was identified by clinical recognition of two or more of the following ropathy (DM 90.8% vs. non-DM 53.4%, CI 4.8–15.4, OR 8.6, systemic inflammatory response syndrome (SIRS) criteria8: heart rate p < 0.01), peripheral arterial disease (DM 70.1% vs. non-DM 37.5%, >90 beats per minute, temperature >38 C or <36 C, respiratory rate CI 2.4–6.4, OR 3.9, p < 0.01), previous foot ulcer (DM 63.9% vs. non- >20 breaths per minute or white blood cell count (WBC) DM 36.4%, CI 1.9–5.1, OR 3.1, p < 0.01), and previous amputation >12,000 cells/mm3 or <4000 cells/mm3. (DM 35.4% vs. non-DM 10.2%, CI 2.3–710.0, OR 4.8, p < 0.01). In In our facility, emergency physicians routinely order standard lab- addition, at the time of admission persons with DM had higher white oratory tests including WBC's, erythrocyte sedimentation rate (ESR) blood cell counts (DM 10.9 109/L ± 4.3 vs. non-DM 10.4 109/L and C-reactive protein (CRP), and albumin at the time of admission. ± 4.01, p = 0.04), more severe infection based on SIRS criteria Broad demographic and clinical data were collected including medical (DM 37.4% vs. no DM 25.0%, CI 1.0–3.0, OR 1.8, p = 0.03), erythro- history, wound characteristics, laboratory tests and clinical and surgi- cyte sedimentation rates (ESR) (DM 72.5 mm/h ± 36.3 vs. non-DM cal outcomes. Data on sensory neuropathy, peripheral arterial disease, 38.2 mm/h ± 24.9, previous foot ulcerations and lower extremity amputations, and cur- (DM 7.34 mg/L ± 8.5 vs. non-DM 4.74 mg/L ± 7.0, p < 0.01). How- rent dialysis status were collected. The diagnosis of diabetes was ever, there was no difference in the proportion of people with a white based on the American Diabetes Association criteria.7 Peripheral arte- blood cell count higher than 12.0 109/L in both groups (DM 47.3 rial disease was defined as non-compressible vessels at the ankle, an vs. non-DM 39.8, CI 0.8 to 2.2, OR 1.4, p = 0.22). p < 0.01), and C-reactive protein (CRP) ankle-brachial index <0.9, claudication symptoms, or history of vascu- Many adverse clinical outcomes were more common in persons lar surgery in the extremity. Sensory neuropathy was defined as with DM compared to those without DM (Table 2). Persons with DM abnormal vibration sensation or abnormal sensation with 10 g required more surgical procedures during the index admission Semmes-Weinstein monofilament. We evaluated the need for sur- (DM 2.3 ± 2.4 vs. non-DM 1.7 ± 1.3, CI 2.0–2.4, p = 0.01), and had gery, the number of procedures, the need for lower extremity amputa- more lower limb amputations (DM 56.8% vs. non-DM 44.3, CI 1.0– tions, amputation level, duration of anti-microbials, hospital length of 2.7, OR 1.7, p = 0.04). There was no difference in the hospital length stay, wound healing, time to healing, re-infection rates, re-admission of stay during the index hospitalisation (DM 10.9 days ±9.2 vs. 1524475x, 2024, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/wrr.13162 by Cochrane Mexico, Wiley Online Library on [26/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 361 LAVERY ET AL. LAVERY ET AL. TABLE 1 Demographics and co-morbidities. Diabetes (N = 294) No diabetes (N = 88) Odds ratio 1.1 Male 221 (75.2) 65 (73.9) Age (years) 53.0, 52.73 (10.85) 52.0, 50.22 (15.13) 95% CI p-value 0.6–1.8 0.80 51.0–53.4 0.61 Retinopathy 90 (30.6) 0 (0.0) 78.3 4.8–1276.1 <0.01 Peripheral neuropathy 267 (90.8) 47 (53.4) 8.6 4.8–15.4 <0.01 Peripheral arterial disease 206 (70.1) 33 (37.5) 3.9 2.4–6.4 <0.01 Nephropathy 129 (43.5) 17 (19.3) 3.3 1.8–5.8 <0.01 CKD I–IV 101 (34.4) 17 (19.3) 2.2 1.2–3.9 0.01 ESRD/dialysis 28 (9.5) 0 (0.0) 18.9 1.1–313.3 0.04 Previous foot ulcer 188 (63.9) 32 (36.4) 3.1 1.9–5.1 <0.01 Previous amputation 104 (35.4) 9 (10.2) 4.8 2.3–10.0 <0.01 IWGDF – Severe 110 (37.4) 22 (25.0) 1.8 1.0–3.0 0.03 Osteomyelitis 157 (53.4) 45 (51.1) 1.1 0.7–1.8 0.71 8.9, 9.2 (2.5) 5.5, 5.4 (0.47) 8.1–8.7 <0.01 10.0–10.8 0.04 0.8–2.2 0.22 Infection severity Laboratory values Glycated haemoglobin WBC 9.6, 10.9 (4.3) 8.8, 10.4 (4.0) WBC > 12,000 139 (47.3) 35 (39.8) 1.4 Note: Dichotomous variables presented as N (%). Continuous variables presented as median, mean (SD). Abbreviations: A1c, glycosylated haemoglobin; CKD, chronic kidney disease; CRP, C-reactive protein; ESRD, end-stage renal disease; WBC, white blood cell count. TABLE 2 1-year outcomes. Foot amputations included toe amputations up to Chopart's amputation. Diabetes (N = 294) No diabetes (N = 88) Odds ratio 95% CI p-value Index outcomes Index length of stay (days) 8.0, 10.9 (9.2) 8.0, 8.8 (5.8) 9.6–11.3 0.43 Antibiotic duration (days) 22.0, 39.0 (43.0) 23.0, 34.1 (30.4) 33.7–10.8 0.32 Surgical intervention 232 (78.9) 72 (83.0) 0.5–1.5 0.55 Number of surgeries 2.0, 2.3 (2.4) 2.0, 1.7 (1.3) 2.0–2.4 0.01 0.83 Lower limb amputation 167 (56.8) 39 (44.3) 1.7 1.0–2.7 0.04 Foot amputation 139 (47.3) 38 (43.2) 1.2 0.7–1.9 0.50 BKA & AKA 28 (9.5) 1 (1.1) 9.2 1.2–68.3 0.03 0.9 1-year outcomes Healed 205 (69.7) 64 (72.7) Time to heal (days) 115.0, 151.8 (108.8) 73.0, 108.8 (90.6) Re-infection 141 (48.0) 27 (30.7) Re-admission for foot 139 (47.3) 26 (29.5) Re-admission, all cause 186 (63.3) 31 (35.2) Length of stay for foot (days) 13.0, 18.8 (13.7) 10.0, 13.7 (11.5) Mortality 9 (3.1) 0 (0.0) 0.5–1.5 0.59 129.0–154.4 0.04 2.1 1.6–3.5 <0.01 2.1 1.3–3.6 <0.01 3.2 1.9–5.2 <0.01 16.0–19.3 0.01 0.3–102.2 0.22 5.9 Note: Dichotomous variables presented as N (%). Continuous variables presented as median, mean (SD), the p-value was calculated by comparison of the means. The length of stay during the 1-year study period, represents the days hospitalised for study foot related complications, including the index procedure. Abbreviations: AKA, above knee amputation; BKA, below knee amputation. non-DM 8.8 days ±5.8, CI 9.6 to 11.3, p = 0.43). After the index hospitalisation, DM patients had worse outcomes and 3.2, p < 0.01), re-infection at the index wound site (48.0% vs. 30.7%, more CI 1.3–3.6, OR 2.1, p < 0.01), re-hospitalisation for a foot pathology complications over a 12-month period (Figure 1); increased rates of (either new problem or at index wound site) (47.3% vs. 29.5%, CI 1.9– re-hospitalisation for any reason (63.3% vs. 35.2%, CI 1.9–5.2, OR 5.2, OR 3.2, p = 0.01), and longer times to ulcer healing (151.8 days 1524475x, 2024, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/wrr.13162 by Cochrane Mexico, Wiley Online Library on [26/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 362 F I G U R E 1 Outcomes during the year following the index hospitalisation in people with and without diabetes. This bar chart compares the outcomes of foot infections in people with and without diabetes. The outcomes are from the study period of 1-year after the initial hospitalisation. There was a significant difference between the two groups. AKA, above knee amputation; BKA, below knee amputation. F I G U R E 2 Kaplan–Meier function for time to heal comparing people with and without diabetes. Kaplan–Meier survival curve showing the days to heal trajectories in people with and without diabetes. People with diabetes had a significantly longer mean number of days to wound healing compared to people without diabetes. ±108.8 vs. 108.8 days ±90.6, CI 129.0–154.0, p = 0.04) (Figure 2). with DM admitted to hospital for a foot infection in comparison to There were no significant differences in the proportion of wounds those without DM. The population with DM had more co-morbidities, that healed, foot amputations, surgical interventions, length of the risk factors for foot complications, and poor outcomes during the index hospitalisation and 1 year mortality (Table 2). index hospitalisation including re-infection and re-hospitalisation within 12 months post-discharge. There are few studies that have compared the type of infection, 4 | DISCUSSION the severity of infection, and clinical outcomes among people with and without diabetes. One of the limitations to the work by Suaya To the best of our knowledge, this is the first study to compare out- and colleagues is that it is from a large administrative database and comes in persons with and without DM with infected foot ulcers. The does not report consistent operational definitions for risk factors or results illustrate the poor outcomes and recurrent infections in people procedures. They provide a very broad look at foot infections by 1524475x, 2024, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/wrr.13162 by Cochrane Mexico, Wiley Online Library on [26/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 363 LAVERY ET AL. LAVERY ET AL. evaluating claims data for skin and soft tissue infections. In contrast was evaluated. Our group has used the same structured examination, to our single centre, retrospective study during the one-year evalua- imaging and surgical approach for the duration of this study, so opera- tion period, they used a large repository database that included tional definitions are likely to have better consistency than if many, 2,227,401 episodes of skin and soft tissue infections, with 10% of independent physicians provided assessments and treatments. The the population with a diagnosis of DM. In the ambulatory setting, patients included in this study were seen at a safety net hospital that the incidence of infection in people with diabetes was five times disproportionately treats people of lower social economic status higher than people without DM (4.9% vs. 0.8%). In the hospital, set- that are under- and uninsured. The study population may not reflect ting the same trend was observed. The incidence of infection was patients' characteristics in different clinical settings. This patient pop- 4.9% in people with diabetes and 1.1% in persons without DM.3 In ulation probably suffers health care disparities and less access to contrast, we used patient level data based on standardised assess- health care than other populations. The uneven group sizes could ment and treatment protocols. pose a limitation. Specifically, the diabetes (DM) group had signifi- We have previously compared the incidence of osteomyelitis, sur- cantly more patients, which could impact the statistical robustness of gery and amputations in persons with and without DM with foot the study's findings. However, traditional statistical approach rou- infections as a result of a puncture wound injury.2,6 The mechanism of tinely addresses this issue, and it should not have impacted our results injury in this population may predispose these patients to worse clini- and conclusions. cal outcomes. Puncture wounds often initiate a deeper infection than To conclude, we found that patients with moderate to severe those that result from foot ulcers, because the puncturing object foot infections with DM had significantly worse outcomes than pushes foreign materials such as pieces of shoes, stockings, and dirt patients without diabetes, with higher risk for re-infection, re- into deeper anatomic structures that are closed off within d these admission, more surgery and longer healing times. compartments. In a study of 77 persons with DM and 69 people without DM, DM subjects were 3.6 times more likely to develop OM, five CONFLIC T OF INTER E ST STATEMENT times more likely to require multiple operations, and 46 times more The authors declare no conflicts of interest. likely to require amputation than non-DM patients. Truong evaluated 114 people with infected puncture wounds (83 DM and 31 no DM). DATA AVAILABILITY STAT EMEN T Like our study, DM patients had a higher prevalence of co-morbidities The data that support the findings of this study are available from the such as PAD, neuropathy and CKD, and they were 9 times more likely corresponding author, upon reasonable request. to have OM, 2.7 times more likely to require surgery, and 14 times more likely to require amputation than people without DM.2 The comparison of patients with infected punctures wounds have larger odds ratios for clinical outcomes than our evaluation of infected foot ulcers. This study has several advantages and limitations that warrant discussion. First, it is one of the largest studies that compares foot infections in people with and without diabetes. In addition, this study used strong operational definitions for osteomyelitis and soft tissue infections. We used bone culture or histopathology to confirm the diagnosis of OM. When radiographs or clinical examination was suggestive of osteomyelitis, we obtained bone for culture and histology for two reasons. First, bone biopsy is the gold standard to confirm that there is in fact a bone infection. Second, if the culture is positive, we have antibiotic sensitivity results to help direct antibiotic therapy. Other studies usually use a mix of clinical criteria such as “probe to bone” or imaging with radiographs or clinical signs, and do not confirm the diagnosis with bone culture/histology. In addition, a negative OM diagnosis was confirmed based on a negative MRI, SPECT/CT, or bone biopsy result. When we did not suspect osteomyelitis, we did not routinely obtain bone to prove a negative MRI or SPECT CT. It is uncommon to have a false negative using these studies,9 and we did not want to disrupt the integrity of the joint capsule, periosteum or cortex if it was not necessary. The retrospective design of the study may have suffered from selection bias, and the operational definitions may have varied among providers. However, we have had a dedicated limb salvage service for several years before this retrospective cohort OR CID Mehmet A. Suludere Matthew Malone https://orcid.org/0000-0002-2285-0909 https://orcid.org/0000-0002-2946-8841 RE FE RE NCE S 1. Raspovic KM, Wukich DK. Self-reported quality of life and diabetic foot infections. J Foot Ankle Surg. 2014;53(6):716-719. doi:10.1053/j. jfas.2014.06.011 2. Truong DH, Johnson MJ, Crisologo PA, et al. Outcomes of foot infections secondary to puncture injuries in patients with and without diabetes. J Foot Ankle Surg. 2019;58(6):1064-1066. doi:10.1053/j.jfas. 2019.08.013 3. Suaya JA, Eisenberg DF, Fang C, Miller LG. Skin and soft tissue infections and associated complications among commercially insured patients aged 0–64 years with and without diabetes in the U.S. PLoS One. 2013;8(4):e60057. doi:10.1371/journal.pone.0060057 4. Wukich DK, Lowery NJ, McMillen RL, Frykberg RG. Postoperative infection rates in foot and ankle surgery: a comparison of patients with and without diabetes mellitus. J Bone Joint Surg Am. 2010;92(2):287295. doi:10.2106/JBJS.I.00080 5. Lavery LA, Lavery DC, Green T, et al. Increased risk of nonunion and Charcot arthropathy after ankle fracture in people with diabetes. J Foot Ankle Surg. 2020;59(4):653-656. doi:10.1053/j.jfas.2019.05.006 6. Armstrong DG, Lavery LA, Quebedeaux TL, Walker SC. Surgical morbidity and the risk of amputation due to infected puncture wounds in diabetic versus nondiabetic adults. J Am Podiatr Med Assoc. 1997;87(7): 321-326. doi:10.7547/87507315-87-7-321 7. American Diabetes A2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2019. Diabetes Care. 2019;42(1):S13S28. doi:10.2337/dc19-S002 1524475x, 2024, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/wrr.13162 by Cochrane Mexico, Wiley Online Library on [26/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 364 8. Lavery LA, Walker SC, Harkless LB, Felder-Johnson K. Infected puncture wounds in diabetic and nondiabetic adults. Diabetes Care. 1995; 18(12):1588-1591. doi:10.2337/diacare.18.12.1588 9. La Fontaine J, Bhavan K, Jupiter D, Lavery LA, Chhabra A. Magnetic resonance imaging of diabetic foot osteomyelitis: imaging accuracy in biopsy-proven disease. J Foot Ankle Surg. 2021;60(1):17-20. doi:10. 1053/j.jfas.2020.02.012 How to cite this article: Lavery LA, Suludere MA, Ryan E, et al. The infected diabetic foot: Analysis of diabetic and nondiabetic foot infections. Wound Rep Reg. 2024;32(4):360‐365. doi:10.1111/wrr.13162 1524475x, 2024, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/wrr.13162 by Cochrane Mexico, Wiley Online Library on [26/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 365 LAVERY ET AL.
