Combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded PMMA in the treatment of chronic osteomyelitis

The significant progress has been made in orthopedic surgery and antibiotic therapy over the past few decades, however, the treatment of chronic post-traumatic and postoperative osteomyelitis is still a difficultly controllable clinical problem. It is considerably difficult to treat because of the factors of patient and pathogen. Besides radical surgical debridement, appropriate treatments consist of long-term systemic antibiotic therapy, local antibiotic therapy by local delivery devices which are composed of biodegradable or non-biodegradable materials, and sometimes removal of internal fixation. In the study, in order to reduce serious side effects and the occurrence of bacterial resistance, intravenous antibiotic therapy was administrated for only 3 to 4 weeks. Preoperatively, it was used for 1 week, while it was used for 2 to 3 weeks postoperatively. Nephrotoxic effects, hepatotoxic effects and other adverse reactions related to intravenous antibiotic therapy did not appear in this study. Generally, systemic antibiotic treatment cannot achieve sufficient release of antibiotic in the area of infected bone due to poor blood supply resulting from soft tissue scarring and bone sclerosis.

Compared with systemic antibiotic treatment, local antibiotic delivery systems implanted with non-biodegradable or biodegradable delivery devices possess several merits, because effective and higher antibiotic concentrations are obtained in the local area of infected bone through the systems for a prolonged period of time. In addition, the period of patient hospitalisation is significantly shortened, the adverse events related to systemic chemotherapy are availably prevented, and the risk of systemic toxicity can be reduced [14]. Local antibiotic therapies play a critical role in the treatment of chronic osteomyelitis. So, local application of bone void filler implanted with antibiotic indicated adequate local concentration of the antibiotic in the area of infected bone, simultaneously, sufficient low systemic exposure in patients suffering from chronic osteomyelitis. It has been revealed, after local application of antibiotic delivery devices, effective antibiotic concentration in the area of infected bone is available for up to 6 weeks in the surrounding tissue.

There are two types of antibiotic delivery devices, non-biodegradable delivery system and biodegradable delivery system. Frequently, the non-degradable antibiotic delivery system is consisted of PMMA carriers. Higher local antibiotic concentrations can obtain by the temporary usage of the antibiotic delivery devices, while lower systemic concentration of antibiotic can achieve, minimizing adverse events. Therefore, PMMA has rapidly turned into a standard protocol for local antibiotic delivery in the treatment of osteomyelitis. PMMA loaded with antibiotic are often used in the form of spacers, which not only increased the local concentration of antibiotics in the infected area, simultaneously minimized the level of systemic antibiotics, but also eliminated the void cavity caused by surgical debridement [14]. Furthermore, it provided immediately structural stabilization [15] that may be advantageous to the treatment of osteomyelitis. PMMA loaded with antibiotic is established as a standard in the treatment of chronic osteomyelitis, which can offer higher local antibiotic concentrations, but it has its own disadvantages, mainly because it shows burst release and consequently sub-therapeutic release kinetics, especially the level of eluted antibiotic declines over time [16]. Therefore, to achieve and maintain the desired level of the antibiotic is very difficult at the expected length of time. When the release levels of antibiotic loaded in PMMA are less than the minimum inhibitory concentration, PMMA carriers themselves can represents a potential nidus for infection and offer a substratum for bacterial colonization and biofilm formation. Bacteria in biofilms are less sensitive to antibiotics, because bacterial biofilms can impede the penetration of antibiotics [17], which may promote progression and recurrence of chronic infection. Comparing with their planktonic counterparts, bacteria in biofilms presented a 1,000-fold tolerance to antibiotics, and significant resistance to host immunity [18]. This may be a part of the reason why a growing number of osteomyelitis relapses occur and antibiotic resistance is becoming increasingly prevalent. Bacterial adhesion and sustained growth of bacteria on the surface of the antibiotic-loaded PMMA have been deeply studied [19–21].

The research for biodegradable alternatives have become highly necessary due to these drawbacks. It is a strongly attractive alternative that the application of biodegradable devices for antibiotic delivery in the treatment of chronic osteomyelitis. Degradable devices produce a zero-order release kinetics, which will not promote the growth of antibiotic-resistant bacterial strains because of lack of long-term and sub-therapeutic concentration tail-release. A reviews including 15 studies showed an outcome range from 80 to 100% eradication in all patients where infection was absent after treatment with the use of antibiotic – impregnated bioabsorbable bone substitutes [22]. Calcium sulfate is one kind of biodegradable delivery devices which can be loaded with antibiotics. The advantages of calcium sulfate is that it can offer the chance to delivery an effective concentration of local antibiotics with the biodegradation after implantation [23–26]. In contrast to PMMA spacers, the porous structure of calcium sulfate can make the antibiotic to sufficiently penetrate, it can be absolutely absorbed in the human tissue and has more adequate elution of antibiotics, moreover, it does not promote inflammation [27–30]. Calcium sulfate can completely release antibiotic load in them after degradation, while absence of substratum for bacterial colonization. Recently, one study revealed that antibiotic-loaded calcium sulfate beads were able to prevent bacterial colonization, and effectively reduce biofilm formation [31]. However, calcium sulfate has its own inherent shortcomings. The absorption of calcium sulfate can occur rapidly in vivo, and the mechanical strength of the material can quickly lose with degradation [32, 33]. So, calcium sulfate are not intended to provide structural support. The degradation products of calcium sulfate carriers generally resulted in persistent drainage from the wound which may aggravate deep infection [34]. Calcium sulfate absorbs plenty of water, subsequently promote seromas formation and increase the risk of secondary infection [35]. Additionally, calcium sulfate pellets cannot be expected to replace PMMA spacers in situations where mechanical support and integrity are important to the procedure (such as spacers in staged revision).

it is envisioned that vancomycin-loaded calcium sulfate pellets can be employed in combination with vancomycin-loaded PMMA spacers in the treatment of osteomyelitis, with calcium sulfate pellets providing the opportunity to deliver higher local antibiotics concentrations with degradation and PMMA spacers providing structural strength and integrity. Radiographic analysis showed that the calcium sulfate pellets were resorbed completely in approximately 30–60 days in this study. In a recent study, local implantation of calcium sulfate beads loaded with antibiotic obtained a good therapeutic effect in the treatment of the lower-extremity osteomyelitis in the absence of systemic antibiotics [35]. In this study, we applied the advantages of PMMA spacers and calcium sulfate pellets respectively to yield synergistic anti-infection effect. The combination therapy with vancomycin-loaded calcium sulfate pellets and vancomycin-loaded PMMA spacers presented a good effect in the treatment of chronic post-traumatic and postoperative osteomyelitis in this study, comparing with PMMA spacers loaded antibiotic. In this study, the group of the combination therapy with calcium sulfate pellets and PMMA spacers showed less rate of persistent or recurrent infection and rate of reoperation because of persistent or recurrent infection than the group of PMMA spacers after the first-stage treatment (P??0.05).

The PMMA spacers loaded with a combination of different antibiotics would potentially increase the antimicrobial spectrum. It has been revealed that PMMA cement loaded with more than one antibiotic could elevate antibiotic elution, compared to only containing one antibiotic [36, 37]. So, in the study vancomycin was loaded in PMMA power with the addition of gentamicin sulphate in order to produce a synergistic effect. In a recent paper, calcium sulfate beads loaded with more than one antibiotic could elevated and prolonged elution of vancomycin, compared with beads only containing vancomycin [38].