Diabetic Foot Ulcers and Osteomyelitis: Use of Biodegradable Calcium Sulfate Beads Impregnated With Antibiotics for Treatment of Multidrug-Resistant Organisms

Diabetes is a life-impacting condition that can be characterized by the presence of persistent hyperglycemia. Additional microvascular and macrovascular complications, such as cardiovascular disease, retinopathy, nephropathy, neuropathy, and impaired wound healing, have also been associated with the disease. The macrovascular complications (eg, stroke, heart disease) are not specific to diabetes; however, the risk of cardiovascular disease increases up to 8-fold in people with diabetes or impaired glucose tolerance.¹ 

Prolonged exposure to hyperglycemia plays an important role in the development of type 2 diabetes. Over time, glucose reacts with several different macromolecules, including proteins, lipoproteins, and nucleic acids to form irreversible advanced glycation end products that can modify both extracellular matrix and plasma proteins. This can lead to a number of complications, including foot ulceration, peripheral arterial disease, and peripheral neuropathy. Foot ulcers are common in patients with diabetes, with a reported prevalence as high as 25%.^2,3 The ulcers are frequently complicated by infection, which regularly results in increased patient morbidity and mortality as well as treatment costs. As a result of infection, these patients are often readmitted to hospital owing to several complications, which can ultimately lead to higher level amputation.⁴ Up to 25% of all hospital admission days for patients with diabetes mellitus in the United States are related to foot complications as a result of infection.⁵

Treatment of diabetic foot infection (DFI) generally involves prolonged antibiotics, surgical debridement, or amputation as well as management of the patient’s comorbidities. Given that infection is frequently the reason for lower limb amputation, infection control is important in preventing amputation and promoting healing.⁶ Systemic antibiotics are often prescribed when an ulcer is showing clinical signs of infection^6,7; however, resolution of infection after treatment of DFI with systemic antibiotics varies widely, with reported rates of clearance of infection between 5.6% and 77.8%.⁸ 

Typically, systemic antibiotics are considered to have achieved sufficient concentrations if they reach the minimum inhibitory concentration (MIC) for the target bacteria.⁹ However, it is widely acknowledged that bacteria form biofilms in most or all cases of soft tissue infection.¹⁰ This is significant because biofilms have substantially increased tolerance to antibiotics, sometimes by a factor of 1000,¹¹ and therefore, the MIC is not a useful predictor of successful treatment.¹² In addition, antibiotic penetration to the distal areas of the foot can be difficult.¹³

Local delivery systems have been studied to minimize systemic toxicity and eliminate concerns about antibiotic penetration, while also achieving high local doses of antibiotics in the management of the diabetic foot.¹⁴ For many years, antibiotic-loaded polymethyl methacrylate (PMMA) cement in the form of beads or spacers has been used in the treatment of foot and ankle infection.^15-18 A promising alternative to PMMA is calcium sulfate. Absorbable mineral-based bone cements such as calcium sulfate are not as mechanically strong as PMMA cements, but they provide some advantages for antibiotic delivery and infection control. Unlike PMMA, mineral-based cements do not require removal (because they are naturally absorbed) and, because there is little temperature increase during setting, they have the capacity to accommodate a wider range of heat-sensitive antibiotics. Evidence in the literature has shown improved antibiotic release from calcium sulfate relative to that of PMMA beads and, importantly, complete biodegradation of the calcium sulfate.^19-21 

Stimulan Rapid Cure (Biocomposites Ltd) is a pharmaceutical-grade calcium sulfate hemihydrate. It is manufactured using a synthetic process, which results in a material with 100% purity.^22,23 The material has a low set temperature, which aids in the mixing of heat-sensitive antibiotics. The biodegradable nature of the product eliminates the need for subsequent surgical removal, and previous work has indicated that it may be an effective tool in preventing the formation of biofilms.^11,24 The clinical use of antibiotic-loaded calcium sulfate has been shown to be safe and effective as a treatment for radiologically confirmed osteomyelitis, particularly in the management of diabetic foot ulcers (DFUs).^25,26 

The purpose of this study was to examine the use of commercially pure, synthetic, antibiotic-loaded, dissolvable  calcium sulfate beads in treating 106 patients with DFI. 

A combined prospective-retrospective review of 106 patients treated at a single tertiary referral center from January 2015 to July 2018 was performed. The average time to follow-up was 92 days (range, 48–158 days). Preoperatively, all patients underwent clinical and radiological evaluation for the presence of infection. Inflammatory markers, including complete blood counts and C-reactive protein levels, were used to provide indirect evidence for the presence of infection. Final confirmation was provided by a tissue biopsy taken during the surgical procedure. 

Inclusion criteria

All patients presenting with type 1 or  type 2 diabetes (according to World Health Organization criteria) with DFUs of Wagner grades 2 to 5 were recruited into this study. Also recruited into this study were patients presenting with associated neuropathy or poor peripheral circulation as well as persistent high bacterial counts after debridement requiring prolonged antibiotic therapy. The patients were assessed by a multidisciplinary team, including a podiatrist and an orthopedic surgeon, as well as a vascular surgeon, microbiologist/infectious disease physician, and nephrologist if necessary. Vascular interventionalists and plastic surgeons were also part of the team. Exclusion criteria included patients with either a negative culture or positive cultures for a single bacterial species that was sensitive to oral antibiotics. 

Surgical management 

Patients in this study underwent radical debridement. Thorough debridement of any devitalized or infected bone was performed until healthy cancellous and cortical bone was reached. Any infected soft tissue was removed as well, and the infection site irrigated with saline. Deep extracted tissue was sent for culture. Calcium sulfate beads were combined with appropriate antibiotics based on antibiotic susceptibility from microbiological cultures (Table 1). The calcium sulfate paste was prepared according to the instructions for use. The result was antibiotic-impregnated pellets measuring 6 mm in diameter. A total of 28 patients received supplementary oral antibiotics for a period of 2 weeks, as advised by the infectious disease specialist. Empiric, broad-spectrum antibiotics (cefoperazone and sulbactam) were administered until culture reports were obtained. Patients who presented with sepsis or septic shock were given meropenem and tigecycline, with the doses adjusted to the serum creatinine value. After obtaining culture reports, a combination of calcium sulfate beads mixed with the appropriate antibiotic was used. Patients were not given systemic antibiotics along with antibiotic beads after the 2-week postoperative window. Only regular dressing changes were done on follow-up visits. No patient in this study received intravenous (IV) antibiotics.

Data collection

Patient demographics, comorbidities, etiology of infection, clinical features, diagnostic tests, and antibiotic treatment choice and duration were collected. White blood cell count as well as serum C-reactive protein levels were measured. Ulcer healing was defined as complete skin closure with a normal appearance of the skin without callus. The date at which this stage was reached was used as an end point. Healing time was expressed in days. 

Clearance of infection was conducted by clinical assessment of the wound for classic signs and symptoms of infection (redness, heat, swelling). Clearance of infection was also confirmed by serially monitoring wound size, serum creatinine level, and clinical improvement in patient symptoms such as increased appetite or improvements in patients’ blood sugar levels.

Of the 106 patients included in this study, 42 presented within 3 days of wound development, 20 patients presented within 3 to 7 days after wound development, and 44 patients presented 7 days after wound development. All patients were reviewed at 2 weeks, 4 weeks, 6 weeks, and 8 weeks, and thereafter as necessary. 

The average patient age was 62 years (range, 49–77 years), with 78 males and 28 females. A total of 21 patients required minor debridement, and 18 required major debridement. Of those who required toe amputation, 35 patients required single toe amputation and 19 patients required multiple toe amputations. Forefoot amputation was required in 7 patients, and 2 patients underwent below-knee amputation. Of note, 4 patients were treated for necrotizing fasciitis (Table 2). Patients were managed postoperatively by means of skin grafting, regular dressing changes, delayed wound closure, or negative pressure wound therapy followed by skin grafting (Table 3). All patients were given calcium sulfate beads mixed with antibiotics as part of the treatment pathway. The beads were mixed with meropenem in 64 cases, colistin in 35 cases, and vancomycin in 7 cases. The volume of implanted beads ranged from 5 cc to 20 cc depending on the size of the wound cavity. The beads were packed into the wound and around any remaining bone to ensure thorough coverage and mitigate any dead space. No systemic adverse reactions to the local delivery of antibiotics were observed in this study.

In patients with positive culture, a total of 7 major organisms were isolated (Table 4). The most common of these organisms were Pseudomonas aeruginosa (n = 72) and Klebsiella pneumoniae (n = 70). Cultures from 78 patients indicated the presence of multiple organisms.  At final follow-up, 92% of the patients (98/106) had no recurrence of infection (mean follow-up, 10 weeks [range, 6–16 weeks]). A total of 8 patients required repeat outpatient minor debridement of the same wound for clearance of slough. Of the 18 patients who required skin grafting for wound closure, small ulcers developed at the junction of normal skin and graft in 5 patients. However, these were “clean” ulcers that were managed with regular dressing changes.

A summary of average healing times by procedure is noted in Table 5. Patients who underwent minor or major debridement followed by the application of calcium sulfate beads mixed with antibiotics healed on average in 47 days and 64 days, respectively.  The average duration of wound healing following a single toe amputation or multiple toe amputations was 50 days and 65 days, respectively. Patients who were treated for wounds associated with necrotizing fasciitis had the longest time to wound healing, with an average of 90 days (Table 5). This investigation demonstrates that a wide range of antibiotics can be incorporated into calcium sulfate beads and retain their potency against many  common pathogens, including Pseudomonas and Staphylococcus (Figure 1, Figure 2, Figure 3, Figure 4).  

Despite preventive measures, many patients with diabetes will experience a foot infection ranging in severity from cellulitis around the ulcer to deep infection and osteomyelitis. In this series, the authors used antibiotic-impregnated calcium sulfate beads as a vehicle for the local delivery of antibiotics to infected DFUs and recorded the healing outcomes and costs associated with treating this patient cohort.  

Management of patients with DFI pose several critical clinical challenges. Such patients often present with peripheral arterial disease, which may reduce the effectiveness of any systemic therapy due to poor local tissue perfusion. Additionally, to be effective, antibiotic levels must reach the MIC of the pathogens at the site of infection. In these patients, infections are often complicated by bacterial biofilms, which may reduce the efficacy of a standard oral or IV antibiotic regimen. This may explain the high rate of nonhealing ulcers in this typical patient group.²⁷ Local delivery of antibiotics via calcium sulfate has been shown to release antibiotics at an MIC of more than 50 times that for many bacteria found in periprosthetic joint infection.^28-31 

Calcium sulfate is increasingly being used as a local antibiotic delivery system in the management of musculoskeletal infections.^32-35 Medical-grade calcium sulfate is widely used as a bone graft substitute as a means of reducing dead space because of its biocompatible and osteoconductive properties; more recently, however, it has been used in an off-label fashion as an antibiotic drug delivery system in the setting of arthroplasty, chronic osteomyelitis, open fracture, and DFI.^26,36-38 At final follow-up in this study, 98 of 106 patients (92%) had no recurrence of infection (mean follow-up, 10 weeks [range, 6–16 weeks]). Using high-purity calcium sulfate, successful clinical outcomes have been reported in a range of indications, including DFIs of both bone and soft tissue.^25,26,39,40 In a study published in 2011, Gauland³⁹ reported the use of locally implanted antibiotic-impregnated calcium sulfate tablets for the treatment of lower extremity osteomyelitis, without the use of oral and/or IV antibiotics, in 354 patients over a 5-year period. More than 86% of the patients (279 of 323) showed resolution of infection and resurfacing of the wound without the use of IV or oral antibiotics following treatment with a combination of surgical debridement and the antibiotic-impregnated tablets. In a study by Jogia et al²⁵ published in 2015, no recurrence of infection or amputation was observed at 12-month follow-up in 20 patients treated with debridement of forefoot ulcers along with routine use of calcium sulfate. 

This investigation demonstrates that a wide range of antibiotics can be incorporated into calcium sulfate beads and retain their potency against many common pathogens, including Pseudomonas and Staphylococcus. The material cures at a low temperature, thus allowing mixing of heat-sensitive antibiotics. Previous studies have demonstrated that the material can be mixed with a range of antibiotic and antifungal agents including, but not limited to, vancomycin,^26,37,39,41 gentamicin,^39,42 tobramycin,^35,37 amphotericin B,⁴³ and daptomycin.⁴⁴ Consideration should be given to the selection of antibiotics used to incorporate into a local dead space management strategy to protect the site from bacterial colonization. Moreover, concentrations of the released antibiotic are influenced by the content as well as by the size, surface, and composition of the carrier.  

As the use of calcium sulfate has increased, so has the understanding of the benefits and complications associated with its use. One concern about the use of calcium sulfate–based materials, particularly in the soft tissues, is the potential for drainage, which may lead to maceration of the surrounding tissues. McPherson et al³⁷ analyzed wound drainage rates following the use of antibiotic-impregnated calcium sulfate in a series of 250 revision hip and knee arthroplasties. In that study, drainage was observed in patients in whom a higher volume of bead had been used, with more subcutaneous placement. Based on the authors’ experience, excessive discharge with antibiotic beads can be minimized by reducing the amount of antibiotic beads used (ie, using just enough to fill the wound cavity) in addition to the combined use of negative pressure wound therapy over beads (for larger wounds). The goal of a local antibiotic delivery system is to avoid the potential systemic toxicity of IV antibiotics. No systemic adverse reactions to the local delivery of antibiotics were observed in this study. Maale et al⁴⁵ assessed the local elution of antibiotics from calcium sulfate beads loaded with vancomycin and tobramycin in 50 patients undergoing revision arthroplasty. No adverse reactions were observed in 11 patients in whom the transient presence of elevated serum concentrations of antibiotics was observed.

Of the 62 million persons in India with diabetes, 25% develop DFUs; of that 25%, 50% become infected, requiring hospitalization, and 20% require amputation.⁴⁶  Similar analyses performed in European countries estimated the direct and indirect cost of treating patients with DFUs to be $13 561 (US) per patient per year.⁴⁷ In 2017, the economic burden of each DFU treated in India was $1960 (US).⁴⁸ Local antibiotic treatment is less expensive than systemic therapy, which can cost hundreds of dollars per day in an outpatient setting and much more in the hospital setting. The cost of 1 vial of meropenem or colistin in this study was either 3000 or 2500 rupees, respectively ($40 or $33 US, respectively). For a 15-day treatment course, costs were as much as 1 lakh (100 000 rupees [$1340 US]). This price excludes the cost of hospital stay and associated nursing charges. One unit of calcium sulfate (5 cc) costs approximately 17,000 rupees ($227 US). Combining it with 1 vial of meropenem, colistin, or vancomycin costs approximately 20 000 rupees ($268 US). This calculates almost an 80% saving compared with a complete course of IV antibiotics and hospital admission. Additionally, there is no requirement for hospital stays or nursing care as the patients can be discharged, highlighting the potential cost-effectiveness of this treatment. The average duration of wound healing for patients in this study ranged from 47 days to 90 days. This is in line with other reports of healing rates using calcium sulfate as part of a treatment protocol for DFI. Jogia et al²⁵ reported that all infected ulcers of the forefoot healed using calcium sulfate when combined with gentamicin and tobramycin, with a median time to wound healing of 5 weeks. 

This study has several limitations, including its retrospective nature and lack of a control group. The main limitation of this case series is the lack of randomization of the study design. Future prospective, randomized clinical trials with a more standardized protocol are necessary to further evaluate the clinical effectiveness of the treatment reported here. Additionally, the potential for cost-benefit analysis in terms of reduced rate of admission to the hospital, reduced need for surgery, and reduced need for systemic antibiotics warrants further investigation. The duration of follow-up in this study may be insufficient to show the outcomes in all patients, which may influence recurrence or amputation rates. 

The use of locally released antibiotics from synthetic recrystallized calcium sulfate may offer substantial benefits in the management of infected DFU that is compromised by poor circulation, polymicrobial growth, and associated renal and cardiac comorbidities. The flexibility of combining different antibiotics enables a strategy that is specifically tailored to pathogens. Additionally, this treatment is less expensive and requires fewer resources (eg, no hospital admission required, nursing care not required for 24 hours) than conventional IV antibiotic therapy. The present authors conclude that there is a need for well-designed and adequately powered trials with suitable blinding to investigate whether the use of local antibiotics improves wound healing and reduces the reoperation rate in the management of DFI.

Authors: Prashant Patil, MCh, FDFS; Rajeev Singh, MS; Apurva Agarwal, MS; Rajiv Wadhwa, MS; Aran Bal, MS, PhD; and Sanjay Vaidya, MS, MCh

Affiliation: Department of Diabetic Foot Surgery, S.L. Raheja Hospital, Mumbai, India

Correspondence: Prashant S. Patil, MCh, FDFS, Assistant Professor, SMBT Institute of Medical Sciences and Research Centre, General Surgery, c/o S.T.Bhadane; SAPTASHRUNGI Niwas, behind Pramila lawns, Ravishankar Colony, Pimpalgaon, Maharashtra 422209 India; docprashant2010@gmail.com 

Disclosure: The authors disclose no financial or other conflicts of interest.