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

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

Disclosures

Wounds. 2021;33(3):70-76. 

In This Article

Discussion

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, Gauland[39] 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 al[25] 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 al[37] 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 al[45] 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 al[25] 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.

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