Topical pravibismane as adjunctive therapy for moderate or severe diabetic foot infections: A phase 1b randomized, multicenter, double-blind, placebo-controlled trial.

This Phase 1b study was designed to evaluate the safety and efficacy of pravibismane, a novel broad-spectrum topical anti-infective, in managing moderate or severe chronic diabetic foot ulcer (DFU) infections. This randomized, double-blind, placebo-controlled, multicenter study consisted of 39 individuals undergoing pravibismane treatment and 13 individuals in the placebo group. Assessment of safety parameters included clinical observations of tolerability and pharmacokinetics from whole blood samples. Pravibismane was well-tolerated and exhibited minimal systemic absorption, as confirmed by blood concentrations that were below the lower limit of quantitation (0.5 ng/mL) or in the low nanomolar range, which is orders of magnitude below the threshold of pharmacological relevance for pravibismane. Pravibismane treated subjects showed approximately 3-fold decrease in ulcer size compared to the placebo group (85% vs. 30%, p = 0.27). Furthermore, the incidence of ulcer-related lower limb amputations was approximately 6-fold lower (2.6%) in the pooled pravibismane group versus 15.4% in the placebo group (p = 0.15). There were no treatment emergent or serious adverse events related to study drug. The initial findings indicate that topical pravibismane was safe and potentially effective treatment for improving recovery from infected chronic ulcers by reducing ulcer size and facilitating wound healing in infected DFUs (ClinicalTrials.gov Identifier NCT02723539).

Diagnostic imaging of the diabetic foot: an EANM evidence-based guidance.

PURPOSE: Consensus on the choice of the most accurate imaging strategy in diabetic foot infective and non-infective complications is still lacking. This document provides evidence-based recommendations, aiming at defining which imaging modality should be preferred in different clinical settings. METHODS: This working group includes 8 nuclear medicine physicians appointed by the European Association of Nuclear Medicine (EANM), 3 radiologists and 3 clinicians (one diabetologist, one podiatrist and one infectious diseases specialist) selected for their expertise in diabetic foot. The latter members formulated some clinical questions that are not completely covered by current guidelines. These questions were converted into statements and addressed through a systematic analysis of available literature by using the PICO (Population/Problem-Intervention/Indicator-Comparator-Outcome) strategy. Each consensus statement was scored for level of evidence and for recommendation grade, according to the Oxford Centre for Evidence-Based Medicine (OCEBM) criteria. RESULTS: Nine clinical questions were formulated by clinicians and used to provide 7 evidence-based recommendations: (1) A patient with a positive probe-to-bone test, positive plain X-rays and elevated ESR should be treated for presumptive osteomyelitis (OM). (2) Advanced imaging with MRI and WBC scintigraphy, or [18F]FDG PET/CT, should be considered when it is needed to better evaluate the location, extent or severity of the infection, in order to plan more tailored treatment. (3) In a patient with suspected OM, positive PTB test but negative plain X-rays, advanced imaging with MRI or WBC scintigraphy + SPECT/CT, or with [18F]FDG PET/CT, is needed to accurately assess the extent of the infection. (4) There are no evidence-based data to definitively prefer one imaging modality over the others for detecting OM or STI in fore- mid- and hind-foot. MRI is generally the first advanced imaging modality to be performed. In case of equivocal results, radiolabelled WBC imaging or [18F]FDG PET/CT should be used to detect OM or STI. (5) MRI is the method of choice for diagnosing or excluding Charcot neuro-osteoarthropathy; [18F]FDG PET/CT can be used as an alternative. (6) If assessing whether a patient with a Charcot foot has a superimposed infection, however, WBC scintigraphy may be more accurate than [18F]FDG PET/CT in differentiating OM from Charcot arthropathy. (7) Whenever possible, microbiological or histological assessment should be performed to confirm the diagnosis. (8) Consider appealing to an additional imaging modality in a patient with persisting clinical suspicion of infection, but negative imaging. CONCLUSION: These practical recommendations highlight, and should assist clinicians in understanding, the role of imaging in the diagnostic workup of diabetic foot complications.

Initial antibiotic therapy for postoperative moderate or severe diabetic foot infections: Broad versus narrow spectrum, empirical versus targeted.

AIM: To retrospectively evaluate clinical and microbiological outcomes after combined surgical and medical therapy for diabetic foot infections (DFIs), stratifying between the empirical versus the targeted nature, and between an empirical broad versus a narrow-spectrum, antibiotic therapy. METHODS: We retrospectively assessed the rate of ultimate therapeutic failures for each of three types of initial postoperative antibiotic therapy: adequate empirical therapy; culture-guided therapy; and empirical inadequate therapy with a switch to targeted treatment based on available microbiological results. RESULTS: We included data from 332 patients who underwent 716 DFI episodes of surgical debridement, including partial amputations. Clinical failure occurred in 40 of 194 (20.6%) episodes where adequate empirical therapy was given, in 77 of 291 (26.5%) episodes using culture-guided (and correct) therapy from the start, and in 73 of 231 (31.6%) episodes with switching from empirical inadequate therapy to culture-targeted therapy. Equally, a broad-spectrum antibiotic choice could not alter this failure risk. Group comparisons, Kaplan-Meier curves and Cox regression analyses failed to show either statistical superiority or inferiority of any of the initial antibiotic strategies. CONCLUSIONS: In this study, the microbiological adequacy of the initial antibiotic regimen after (surgical) debridement for DFI did not alter therapeutic outcomes. We recommend that clinicians follow the stewardship approach of avoiding antibiotic de-escalation and start with a narrow-spectrum regimen based on the local epidemiology.

Timing of Revascularization and Parenteral Antibiotic Treatment Associated with Therapeutic Failures in Ischemic Diabetic Foot Infections.

For ischemic diabetic foot infections (DFIs), revascularization ideally occurs before surgery, while a parenteral antibiotic treatment could be more efficacious than oral agents. In our tertiary center, we investigated the effects of the sequence between revascularization and surgery (emphasizing the perioperative period of 2 weeks before and after surgery), and the influence of administering parenteral antibiotic therapy on the outcomes of DFIs. Among 838 ischemic DFIs with moderate-to-severe symptomatic peripheral arterial disease, we revascularized 608 (72%; 562 angioplasties, 62 vascular surgeries) and surgically debrided all. The median length of postsurgical antibiotic therapy was 21 days (given parenterally for the initial 7 days). The median time delay between revascularization and debridement surgery was 7 days. During the long-term follow-up, treatment failed and required reoperation in 182 DFI episodes (30%). By multivariate Cox regression analyses, neither a delay between surgery and angioplasty (hazard ratio 1.0, 95% confidence interval 1.0-1.0), nor the postsurgical sequence of angioplasty (HR 0.9, 95% CI 0.5-1.8), nor long-duration parenteral antibiotic therapy (HR 1.0, 95% CI 0.9-1.1) prevented failures. Our results might indicate the feasibility of a more practical approach to ischemic DFIs in terms of timing of vascularization and more oral antibiotic use.

Influence of Skin Commensals on Therapeutic Outcomes of Surgically Debrided Diabetic Foot Infections-A Large Retrospective Comparative Study.

In diabetic foot infections (DFI), the clinical virulence of skin commensals are generally presumed to be low. In this single-center study, we divided the wound isolates into two groups: skin commensals (coagulase-negative staphylococci, micrococci, corynebacteria, cutibacteria) and pathogenic pathogens, and followed the patients for ≥ 6 months. In this retrospective study among 1018 DFI episodes (392 [39%] with osteomyelitis), we identified skin commensals as the sole culture isolates (without accompanying pathogenic pathogens) in 54 cases (5%). After treatment (antibiotic therapy [median of 20 days], hyperbaric oxygen in 98 cases [10%]), 251 episodes (25%) were clinical failures. Group comparisons between those growing only skin commensals and controls found no difference in clinical failure (17% vs. 24 %, p = 0.23) or microbiological recurrence (11% vs. 17 %, p = 0.23). The skin commensals were mostly treated with non-beta-lactam oral antibiotics. In multivariate logistic regression analysis, the isolation of only skin commensals was not associated with failure (odds ratio 0.4, 95% confidence interval 0.1-3.8). Clinicians might wish to consider these isolates as potential pathogens when selecting a targeted antibiotic regimen, which may also be based on oral non-beta-lactam antibiotic agents effective against the corresponding skin pathogens.

Nutritional Interventions May Improve Outcomes of Patients Operated on for Diabetic Foot Infections: A Single-Center Case-Control Study.

Aim: While a patient's nutritional status is known to generally have a role in postoperative wound healing, there is little information on its role as therapy in the multifaceted problem of diabetic foot infections (DFIs). Methods: We assessed this issue by conducting a retrospective case-control cohort study using a multivariate Cox regression model. The nutrition status of the DFI patients was assessed by professional nutritionists, who also orchestrated the nutritional intervention (counselling, composition of the intrahospital food) during hospitalization. Results: Among 1,013 DFI episodes in 586 patients (median age 67 years; 882 with osteomyelitis), 191 (19%) received a professional assessment of their nutrition accompanied by between 1 and 6 nutritional interventions. DFI cases who had professional nutritionists' interventions had a significantly shorter hospital stay, had shorter antibiotic therapies, and tended to fewer surgical debridements. By multivariate analysis, episodes with low Nutritional Risk Status- (NRS-) Scores 1-3 were associated with significantly lower failure rates after therapy for DFI (Cox regression analysis; hazard ratio 0.2, 95% confidence interval 0.1-0.7). Conclusions: In this retrospective cohort study, DFI episodes with low NRS-Score were associated with lower rates of clinical failure after DFI treatment, while nutritional interventions improved the outcome of DFI. We need prospective interventional trials for this treatment, and these are underway.

Correction of hyperglycemia after surgery for diabetic foot infection and its association with clinical outcomes.

OBJECTIVE: Constantly high glycemia levels might influence outcomes in the management of patients undergoing surgery for diabetic foot infections (DFI). In our center for DFI, we performed a case-control study using a multivariate Cox regression model. Patients developing a new DFI could participate in the study several times. RESULTS: Among 1013 different DFI episodes in 586 individual adult patients (type I diabetes 148 episodes [15%], 882 [87%] with osteomyelitis; median antibiotic therapy of 21 days), professional diabetes counselling was provided by a specialized diabetes nurse in 195 episodes (19%). At admission, blood glucose levels were elevated in 110 episodes (11%). Treatments normalized glycemia on postoperative day 3 in 353 episodes (35%) and on day 7 for 321 (32%) episodes. Glycemia levels entirely normalized for 367 episodes (36%) until the end of hospitalization. Overall, treatment of DFI episodes failed in 255 of 1013 cases (25%), requiring surgical revision. By multivariate analysis, neither the provision of diabetes counseling, nor attaining normalizations of daily glycemic levels at day 3, day 7, or overall, influenced the ultimate incidence of clinical failures. Thus, the rapidity or success of achieving normoglycemia do not appear to influence the risk of treatment failure for operated DFI episodes.

Pseudomonal Diabetic Foot Infections: Vive la Différence?

Objective: To assess the outcomes of diabetic foot infections (DFIs) due to Pseudomonas aeruginosa. Patients and Methods: From April 24, 2013 to July 31, 2016, we analyzed data from patients prospectively enrolled in our clinical pathway of DFIs, comparing those with infection due to Pseudomonas with those without infection due to Pseudomonas. Results: Overall, we assessed 1018 cases of DFIs: 392 with osteomyelitis and 626 with only soft tissue infections. The prevalence of P aeruginosa in deep wound cultures was 10% (104/1018); of the 1018 cultures, 22 were monomicrobial, 82 were polymicrobial, and 46 were with osteomyelitis. Overall, the patients were treated with a median of 1 surgical debridement and a total of 20 days of antibiotic therapy. In a comparison of crude groups, the proportion of clinical failures was significantly higher with Pseudomonas than with other pathogens (36/104 [35%] vs 218/914 [24%], respectively; P=.02). A multivariate analysis showed that pseudomonal DFIs did not recur more often than nonpseudomonal DFIs (hazard ratio, 1.0; 95% confidence interval, 0.6-1.7). Among the 104 cases of pseudomonal DFIs, there was no association between failure of treatment and the total duration of antibiotic therapy, duration of intravenous therapy, duration of combined antibiotic therapy with more than 1 agent, or duration of oral (fluoroquinolone) therapy. Among 15 cases of pseudomonal recurrence, 2 (13%) developed resistance to the antibiotic agent used for the index episode. Conclusion: For DFIs caused by P aeruginosa, other than choosing an antibiotic agent that is active against the organism, it does not appear necessary to treat with a different therapeutic regimen compared with the treatment of nonpseudomonal DFIs. There is no difference!

Moderate to Severe Soft Tissue Diabetic Foot Infections: A Randomized, Controlled, Pilot Trial of Post-debridement Antibiotic Treatment for 10 versus 20 days.

BACKGROUND: The optimal duration of antibiotic therapy for soft-tissue infections of the diabetic foot remains unknown. OBJECTIVE: We determine if antibiotic therapy after debridement for a short (10 days), compared with a long (20 days), duration for soft-tissue infections of the diabetic foot results in similar rates of clinical remission and adverse events (AE). SUMMARY OF BACKGROUND DATA: The optimal duration of systemic antibiotic therapy, after successful debridement, for soft tissue infections of diabetic patients is unknown. Because of the high recurrence risk, overuse is commonplace. METHODS: This was a randomized, controlled, non-inferiority pilot trial of cases of diabetic foot infection (excluding osteomyelitis) with the primary outcome of "clinical remission at 2-months follow-up". RESULTS: Among 66 enrolled episodes (17% females; median age 71 years), we randomized 35 to the 10-day arm and 31 to the 20-day arm. The median duration of the parenteral antibiotic therapy was 1 day, with the remainder given orally. In the intention-to-treat population, we achieved clinical remission in 27 (77%) patients in the 10-day arm compared to 22 (71%) in the 20-days arm ( P = 0.57). There were a similar proportion in each arm of AE (14/35 versus 11/31; P = 0.71), and remission in the per-protocol population (25/32 vs 18/27; P = 0.32). Overall, 8 soft tissue DFIs in the 10-day arm and 5 cases in the 20-day arm recurred as a new osteomyelitis [8/35 (23%) versus 5/31 (16%); P = 0.53]. Overall, the number of recurrences limited to the soft tissues was 4 (6%). By multivariate analysis, rates of remission (intention-to-treat population, hazard ratio 0.6, 95%CI 0.3-1.1; per-protocol population 0.8, 95%CI 0.4-1.5) and AE were not significantly different with a 10-day compared to 20-day course. CONCLUSIONS: In this randomized, controlled pilot trial, post-debridement antibiotic therapy for soft tissue DFI for 10 days gave similar (and non-inferior) rates of remission and AEs to 20 days. A larger confirmatory trial is under way. TRIAL REGISTRATION: ClinicalTrials NCT03615807.

Short and oral antimicrobial therapy for diabetic foot infection: a narrative review of current knowledge.

Diabetic foot infection is a frequent complication in long-standing diabetes mellitus. For antimicrobial therapy of this infection, both the optimal duration and the route of administration are often based more on expert opinion than on published evidence. We reviewed the scientific literature, specifically seeking prospective trials, and aimed at addressing two clinical issues: (1) shortening the currently recommended antibiotic duration and (2) using oral (rather than parenteral) therapy, especially after the patient has undergone debridement and revascularization. We also reviewed some older key articles that are critical to our understanding of the treatment of these infections, particularly with respect to diabetic foot osteomyelitis. Our conclusion is that the maximum duration of antibiotic therapy for osteomyelitis should be no more than to 4-6 weeks and might even be shorter in selected cases. In the future, in addition to conducting randomized trials and propagating national and international guidance, we should also explore innovative strategies, such as intraosseous antibiotic agents and bacteriophages.

Treatment Failures in Diabetic Foot Osteomyelitis Associated with Concomitant Charcot Arthropathy: The Role of Underlying Arteriopathy.

OBJECTIVE: Therapy for diabetic foot osteomyelitis (DFO) with Charcot neuroosteoarthropathy is challenging. In patients with diabetic Charcot osteomyelitis (DCO), both the anatomic deformity and infection must be addressed. This study assessed the outcomes of DCO therapy and variables associated with treatment failure and compared them with outcomes of DFO cases. METHODS: A single-center, retrospective, case-control study was performed to compare 93 DCO episodes with 530 DFO episodes, using Kaplan-Meier survival curves and multivariate Cox regression analyses. RESULTS: Clinical failure occurred in 21.5% of DCO compared with 22.3% in DFO episodes (p=0.89) and was associated with peripheral arterial disease (PAD) stages 3 or 4 (HR 6.1; CI 2.0-18.1) and chronic treatment with immunosuppressives (HR 7.4; CI 2.0-27.1). Major amputations were significantly more frequent in DCO (28% versus 13.6%; p<0.01) and associated with PAD stages 3 and 4 (HR 8.0; CI 2.2-29.4), smoking (HR 5.4; CI 1.2-24.6), alcohol abuse (HR 3.5; CI 1.1-10.6), and renal dialysis (HR 4.9; CI 1.3-18.9). CONCLUSIONS: Clinical treatment failures did not differ between DCO and DFO. However, patients with DCO underwent major amputation twice as often as those with DFO. Unlike widespread belief, treatment failure in DCO patients may, similar to DFO, be associated with a striking epidemiological link to severe PAD.

The association of chronic, enhanced immunosuppression with outcomes of diabetic foot infections.

We investigated if a chronic, enhanced immunosuppressed condition, beyond the immunodeficiency related to diabetes, is associated with clinical failures after combined surgical and medical treatment for diabetic foot infection (DFI). This is a case-control cohort study in a tertiary centre for diabetic foot problems, using case-mix adjustments with multivariate Cox regression models. Among 1013 DFI episodes in 586 patients (median age 67 years; 882 with osteomyelitis), we identified a chronic, enhanced immune-suppression condition in 388 (38%) cases: dialysis (85), solid organ transplantation (25), immune-suppressive medication (70), cirrhosis (9), cancer chemotherapy (15) and alcohol abuse (243). Overall, 255 treatment episodes failed (25%). By multivariate analysis, the presence (as compared with absence) of chronic, enhanced immune-suppression was associated with a higher rate of clinical failures in DFI cases (hazard ratio 1.5, 95% confidence interval 1.1-2.0). We conclude that a chronic, enhanced immune-suppressed state might be an independent risk factor for treatment failure in DFI. Validation of this hypothesis could be useful information for both affected patients and their treating clinicians.

How good are clinicians in predicting the presence of Pseudomonas spp. in diabetic foot infections? A prospective clinical evaluation.

Introduction: The most frequently prescribed empirical antibiotic agents for mild and moderate diabetic foot infections (DFIs) are amino-penicillins and second-generation cephalosporins that do not cover Pseudomonas spp. Many clinicians believe they can predict the involvement of Pseudomonas in a DFI by visual and/or olfactory clues, but no data support this assertion. Methods: In this prospective observational study, we separately asked 13 experienced (median 11 years) healthcare workers whether they thought the Pseudomonas spp. would be implicated in the DFI. Their predictions were compared with the results of cultures of deep/intraoperative specimens and/or the clinical remission of DFI achieved with antibiotic agents that did not cover Pseudomonas. Results: Among 221 DFI episodes in 88 individual patients, intraoperative tissue cultures grew Pseudomonas in 22 cases (10%, including six bone samples). The presence of Pseudomonas was correctly predicted with a sensitivity of 0.32, specificity of 0.84, positive predictive value of 0.18 and negative predictive value 0.92. Despite two feedbacks of the interim results and a 2-year period, the clinicians' predictive performance did not improve. Conclusion: The combined visual and olfactory performance of experienced clinicians in predicting the presence of Pseudomonas in a DFI was moderate, with better specificity than sensitivity, and did not improve over time. Further investigations are needed to determine whether clinicians should use a negative prediction of the presence of Pseudomonas in a DFI, especially in settings with a high prevalence of pseudomonal DFIs.

Treating Diabetic Foot Osteomyelitis: A Practical State-of-the-Art Update.

Background and Objectives: Diabetic foot osteomyelitis (DFO) can be difficult to treat and securing optimal clinical outcomes requires a multidisciplinary approach involving a wide variety of medical, surgical and other health care professionals, as well as the patient. Results of studies conducted in the past few years have allowed experts to formulate guidelines that can improve clinical outcomes. Material and Methods: We conducted a narrative review of the literature on treat- ment of DFO, with an emphasis on studies published in the last two years, especially regarding antimicrobial therapies and surgical approached to treatment of DFO, supplemented by our own extensive clinical and research experience in this field. Results: Major amputations were once com- mon for DFO but, with improved diagnostic and surgical techniques, "conservative" surgery (foot- sparing, resecting only the infected and necrotic bone) is becoming commonplace, especially for forefoot infections. Traditional antibiotic therapy, which has been administered predominantly in- travenously and frequently for several months, can often be replaced by appropriately selected oral antibiotic regimens following only a brief (or even no) parenteral therapy, and given for no more than 6 weeks. Based on ongoing studies, the recommended duration of treatment may soon be even shorter, especially for cases in which a substantial portion of the infected bone has been resected. Using the results of cultures (preferably of bone specimens) and antimicrobial stewardship princi- ples allows clinicians to select evidence-based antibiotic regimens, often of a limited pathogen spec- trum. Intra-osseous antimicrobial and surgical approaches to treatment are also evolving in light of ongoing research. Conclusions: In this narrative, evidenced-based review, taking consideration of principles of antimicrobial stewardship and good surgical practice, we have highlighted the recent literature and offered practical, state-of-the-art advice on the antibiotic and surgical management of DFO.

Is routine measurement of the serum C-reactive protein level helpful during antibiotic therapy for diabetic foot infection?

Clinicians frequently monitor serum C-reactive protein (CRP) levels during therapy for diabetic foot infections (DFIs), but evidence supporting this is unclear. Using a database from prospective controlled DFI trials, with fixed duration of antibiotic therapy, we correlated the CRP levels at study enrolment and at end of therapy (EOT). Among 159 DFI episodes, 93 involved the bone and 66 the soft tissues. Overall, treatment cured 122 infections (77%), while 37 episodes (23%) recurred after a median of 53 days. The median CRP in the groups with cure versus failure differed minimally at enrolment (median 67 vs. 81 mg/L) or EOT (7 vs. 10 mg/L). Similarly, there was negligible difference in the percentage of CRP levels that normalized at EOT (39% vs. 35%). In our prospective cohorts, a blunt iterative monitoring of CRP during DFI treatment, without correlation with clinical findings, failed to predict treatment failures.

Three Weeks Versus Six Weeks of Antibiotic Therapy for Diabetic Foot Osteomyelitis: A Prospective, Randomized, Noninferiority Pilot Trial.

BACKGROUND: In patients with diabetic foot osteomyelitis (DFO) who underwent surgical debridement, we investigated whether a short (3 weeks) duration compared with a long (6 weeks) duration of systemic antibiotic treatment is associated with noninferior results for clinical remission and adverse events (AEs). METHODS: In this prospective, randomized, noninferiority pilot trial, we randomized (allocation 1:1) patients with DFO after surgical debridement to either a 3-week or a 6-week course of antibiotic therapy. The minimal duration of follow-up after the end of therapy was 2 months. We compared outcomes using Cox regression and noninferiority analyses (25% margin, power 80%). RESULTS: Among 93 enrolled patients (18% females; median age 65 years), 44 were randomized to the 3-week arm and 49 to the 6-week arm. The median number of surgical debridements was 1 (range, 0-2 interventions). In the intention-to-treat (ITT) population, remission occurred in 37 (84%) of the patients in the 3-week arm compared with 36 (73%) in the 6-week arm (P = .21). The number of AEs was similar in the 2 study arms (17/44 vs 16/49; P = .51), as were the remission incidences in the per-protocol (PP) population (33/39 vs 32/43; P = .26). In multivariate analysis, treatment with the shorter antibiotic course was not significantly associated with remission (ITT population: hazard ratio [HR], 1.1 [95% confidence interval {CI}, .6-1.7]; PP population: HR, 0.8 [95% CI: .5-1.4]). CONCLUSIONS: In this randomized controlled pilot trial, a postdebridement systemic antibiotic therapy course for DFO of 3 weeks gave similar (and statistically noninferior) incidences of remission and AE to a course of 6 weeks. CLINICAL TRIALS REGISTRATION: NCT03615807; BASEC 2016-01008 (Switzerland).

The dynamic wound microbiome.

BACKGROUND: Diabetic foot ulcers (DFUs) account for the majority of all limb amputations and hospitalizations due to diabetes complications. With 30 million cases of diabetes in the USA and 500,000 new diagnoses each year, DFUs are a growing health problem. Diabetes patients with limb amputations have high postoperative mortality, a high rate of secondary amputation, prolonged inpatient hospital stays, and a high incidence of re-hospitalization. DFU-associated amputations constitute a significant burden on healthcare resources that cost more than 10 billion dollars per year. Currently, there is no way to identify wounds that will heal versus those that will become severely infected and require amputation. MAIN BODY: Accurate identification of causative pathogens in diabetic foot ulcers is a critical component of effective treatment. Compared to traditional culture-based methods, advanced sequencing technologies provide more comprehensive and unbiased profiling on wound microbiome with a higher taxonomic resolution, as well as functional annotation such as virulence and antibiotic resistance. In this review, we summarize the latest developments in defining the microbiology of diabetic foot ulcers that have been unveiled by sequencing technologies and discuss both the future promises and current limitations of these approaches. In particular, we highlight the temporal patterns and system dynamics in the diabetic foot microbiome monitored and measured during wound progression and medical intervention, and explore the feasibility of molecular diagnostics in clinics. CONCLUSION: Molecular tests conducted during weekly office visits to clean and examine DFUs would allow clinicians to offer personalized treatment and antibiotic therapy. Personalized wound management could reduce healthcare costs, improve quality of life for patients, and recoup lost productivity that is important not only to the patient, but also to healthcare payers and providers. These efforts could also improve antibiotic stewardship and control the rise of "superbugs" vital to global health.

Characterization of Proangiogenic Monocytes from Blood in Patients with Chronic Ischemic Diabetic Foot Ulcers and Controls.

Many persons with diabetes mellitus have limb ischemia, which is a major clinical problem. A subset of human monocytes that expresses TIE-2 may enhance neovascularization. We performed 179 phlebotomies on 142 patients (or donors), including 61 patients/donors without diabetes or ischemia (controls), 39 diabetic nonischemic patients (controls), and 42 diabetic patients with severe limb ischemia requiring amputation. We compared these groups for the presence of TIE-2-positive proangiogenic monocytes. The proportion of proangiogenic monocytes in the venous blood (on hospital admission) was significantly increased in diabetic patients without ischemia (9.22% ± 1.19%), compared to controls (6.53% ± 0.58%) or ischemic diabetic patients (5.44% ± 0.56%) (P < 0.05). In this pilot evaluation, we succeeded in extracting potential proangiogenic TIE-2 monocytes from the blood of diabetic patients without ischemia, but less in patients with ischemia. The implications for therapeutic neoangiogenesis require further studies.