Fast-resorbable antibiotic-loaded hydrogel coating to reduce post-surgical infection after internal osteosynthesis: a multicenter randomized controlled trial

The Centers for Disease Control (CDC) healthcare-associated infection (HAI) prevalence survey estimated 157,500 surgical site infections (SSIs) associated with inpatient surgeries in 2011 in the USA [1] (Table 1).

In spite of improved operating room, sterilization methods, barriers, surgical technique and routine systemic antimicrobial prophylaxis [2‐5], SSIs are still considered to be the most common and costly healthcare-associated infection, accounting for 31% of all HAIs among hospitalized patients [6, 7].

After osteosynthesis for closed fractures, early SSI had a reported incidence of 3.9% in a large multicenter trial, with a median time to diagnosis of 30 days [8], while wound healing problems, like those occurring in subcutaneous osteosynthesis [9], and the presence of co-morbidities may increase the risk of septic complications up to 10% [10‐12]. In a more recent retrospective study, the rates of infection within 1 year from internal osteosynthesis after closed and open fractures have been reported to be 4.2 and 14.7%, respectively [13]. Implant-related infections often require implant removal, with high morbidity and possible increased mortality [9] and elevated economic and social costs [14].

In this context, antibacterial coatings of implants may represent an attractive option to reduce post-surgical infections [15]. A strong recommendation was delivered in a recent international Consensus meeting on peri-prosthetic joint infections, concerning the need for developing effective antibacterial surfaces that prevent bacterial adhesion and colonization of implants and proliferation into the surrounding tissues [16]. However, only few anti-bacterial coating technologies are currently available in orthopedics and trauma and, for various reasons, they are still far from large-scale application [17, 18].

Developing a new antibacterial coating appears challenging. Since bacterial colonization, from microbial adhesion to an established mature biofilm layer, only takes a few hours [19], any antibacterial protection should act at the exact time of surgery and possibly only for a few hours or days thereafter, to minimize the risk of long-term bacterial resistance induction. Moreover, any new technology has to demonstrate safety and lack of interference with bone healing and should prove to be effective as well as sufficiently easy to manufacture and implement into the current clinical practice. Finally, it should be available at an affordable price, after having passed the scrutiny of the complex regulatory pathway [20]. Biocompatible hydrogels have been shown to be able to deliver pharmacological agents locally and can be designed to meet the desired elution pattern [21]. Recently, a fast-resorbable hydrogel coating that can be loaded intra-operatively with various antibacterials has been developed [22]. Based on the observation that bacterial colonization occurs within the first hours after implant and that short-term systemic prophylaxis is equally effective as long-term to prevent post-surgical infections [23], this coating technology introduced for the first time the concept of ‘short-term local protection’ of the implant. In fact, a short-term local delivery system may meet the requirements needed to win the ‘run to the surface’, while limiting possible long-term unwanted side-effects [24]. This novel fast-resorbable hydrogel coating (Defensive Antibacterial Coating, DAC^®; Novagenit Srl, Mezzolombardo, Italy) is composed of covalently linked hyaluronan and poly-d,l-lactide and is designed to undergo complete hydrolytic degradation in vivo within 48–72 h as well as being able to completely release a variety of different antibacterials at concentrations ranging from 2−10%. The hydrogel showed synergistic antibacterial and antibiofilm activity with various antibiotics and antibiofilm agents in vitro [25], while in vivo it has been proven effective in a rabbit model of highly contaminated implant both with [26] and without systemic prophylaxis, without interfering with bone growth [27]. Following previous brief reports [28, 29], we present the clinical results of a multicenter European trial comparing the SSI rate between patients treated with DAC hydrogel-coated osteosynthesis implants and patients treated with non-coated implants.

From January 2014 to June 2015, 256 patients (Fig. 1) were included in this prospective multicenter randomized study. The study protocol was approved by the local Ethical Committees of the five participating centers. All patients gave their informed consent to the procedure. The study was performed within the 7th European Framework Programme (project #277988) and funded by the European Commission and the participating partners (clinical institutions and the following private companies: Novagenit SRL, Mezzolombardo, Italy, acting as project leader; AdlerOrtho SRL, Bologna, Italy; Arcos SARL, Brignoles, France; Belgafix SPRL, Drogenbos, Belgium).

The patients, in five European orthopedic centers, were randomly assigned through electronic software to receive antibiotic-loaded DAC or to a control group (without coating).

Inclusion criteria were the presence of a fresh (<7 days) closed fracture requiring surgical reduction and internal fixation with either a metal plate and/or screws or with an intramedullary nail, in patients aged >18 years. Exclusion criteria were pregnancy, breast-feeding or planning to become pregnant during the study, the presence of a previous or active infection at site of fracture, severe malignancies with a life expectancy of <3 months, previous diagnosis of immune depression (including HIV) or immune suppressive treatment for organ transplantation, known allergy to the antibiotics or to DAC hydrogel constituents, patient not willing or not able to present for the follow-up consultations or if the patient did not sign the informed consent documents or was not able to do so.

Overall 253 patients (126 treated and 127 controls) were available with an average follow-up of 18.1 ± 4.5 months (range 12–30) and were considered for further analysis (Fig. 1).

The two groups did not differ significantly regarding age, sex and host type. In particular, approximately half of the patients in both groups presented with one or more relevant co-morbidities known to increase post-surgical infection risk (Table 2).

Perioperative data (Table 3) show that the majority of patients were treated with plate/screws and <10% in both groups underwent nail fixation.

Cefazolin was the most used antibiotic for short-term systemic prophylaxis in both groups, either alone or in association with amikacin or vancomycin.

On average, 5.7 mL (range 1–10 mL) of DAC hydrogel was needed to coat the implant. Gentamicin and vancomycin were the most used antibiotics, at concentrations of 4 or 2%, respectively.

Early wound healing did not show any difference between groups, with an average ASEPSIS score at 7 and 14 days of 1.53 ± 3.94 and 1.93 ± 5.09 in the control group and 1.51 ± 4.14 and 1.33 ± 4.32 in the treated group, respectively. Delayed wound healing occurred in 7 (5.5%) and 5 (3.9%) in the control and treated group, respectively.

At 6 months, average serum laboratory tests (hematological, renal and hepatic function) did not show any significant difference between groups (Table 4).

At an average 12-month follow-up, average SF-12 clinical score did not differ significantly between groups (Table 5).

No adverse events attributable to the DAC hydrogel were reported. No detectable interaction was observed between the hydrogel and bone healing. Six SSIs were reported in the control group (4.7%), compared to none in the treated group (P = 0.03). One patient in the control group underwent early plate removal for plate intolerance, without reported signs of infection. Detailed information regarding septic complications, including treatment and outcomes are provided in Table 6.

This is the first clinical trial reporting on the efficacy and safety of DAC coating for internal osteosynthesis.

Concerning efficacy, this study shows that the studied antibiotic-loaded hydrogel coating is able to significantly reduce early SSIs after osteosynthesis, at an average 18-month follow-up. This finding is in agreement with earlier in vivo studies [26, 27] and with a recently published multicenter clinical trial on the use of DAC coating in total hip and knee cementless or hybrid total joint replacement [34]. It is also the first clinical demonstration that short-term local prophylaxis may significantly reduce post-surgical septic complications in internal osteosynthesis for closed fractures.

Clinical demonstration of safety is a basic requirement of any novel coating technology [18, 35]. The reported combined data from five European centers indicate that the device under study can be considered clinically safe, when used in combination with internal osteosynthesis, without any detectable local side-effects both concerning wound and bone healing, at a medium-term follow-up. Moreover, no changes in organ-specific serum markers or systemic unwanted effects were recorded. This finding is in line with previous data from in vivo and clinical studies [26, 27, 34]. The high biocompatibility of its basic constituents and the short time (<3 days) needed for complete hydrogel resorption [22, 25] make the possible occurrence of longer term side-effects unlikely.

In isolated reports, antibacterial coatings have previously been shown to be clinically effective in reducing septic complications; however their application to osteosynthesis is limited [18, 28].

Silver coating is among the most extensively studied antibacterial agents. Dissolved silver ions are biochemically active agents, able to interfere with bacterial cell membrane permeability and cellular metabolism. Silver also contributes to the formation of reactive oxygen species and to other mechanisms that potentially influence prokaryotic cells [36]. There has been concern, however, about the toxicity of silver ions [37] and to overcome this issue, research efforts have recently focused on new silver-coating technologies, that are reported to reduce or even eliminate toxicity while maintaining antibacterial effects [38, 39]. However, despite a demonstrated clinical efficacy and safety in two comparative studies on a limited series of patients treated with oncological endoprosthesis [40, 41], the routine use of silver-coated implants remains limited while, to the best of our knowledge, its application to fracture fixation devices has never been investigated.

A different approach, consisting of the local administration of antibiotics in order to protect an implant, historically attracted much attention in orthopedics. Buchholz et al. first popularized the incorporation of antibiotics into polymethylmethacrylate (PMMA) bone cement for local antibiotic prophylaxis in cemented total joint arthroplasty [42] and, although the use of antibiotic-loaded PMMA coating of nails is gaining increasing interest to treat osteomyelitis, septic non-unions and contaminated fractures [43], comparative clinical studies are lacking. Moreover, PMMA may not be used as a coating for plate osteosynthesis or screws and antibiotic-loaded PMMA may not overcome biofilm formation and has been found to be associated with the development of antibiotic-resistant ‘small-colony variants’ [44, 45].

Other porous biodegradable materials for local antibiotic delivery, like collagen sponges [46], cancellous bone [47], calcium phosphate [48, 49] and bioceramics [50], were not specifically designed to protect implanted biomaterials and their use for infection prevention in trauma is currently limited.

Biodegradable polymers and sol–gel coatings have also been investigated to provide a controlled antibiotic release on titanium [51, 52] or hydroxyapatite implants [53]. However, the most known clinical applications of this approach are probably antibiotic-loaded d-poly-lactate acid/gentamycin intramedullary coated nails that, until now, only showed some positive results in a limited series of patients [17].

In this setting, an antibiotic-loaded fast-resorbable hydrogel coating may offer ease of use, versatility and large scale applications, opening the way to an affordable wide application of antibacterial implant protection, as recently shown in a multicenter trial focused on infection prevention in total hip and knee replacement [34].

This study has some limitations. First, the follow-up is relatively short. Although the minimum 12-month monitoring appears adequate to detect early post-surgical septic complications, exceeding that defined in the IDSA Guidelines [54], and appears adequate to detect the vast majority of SSIs after osteosynthesis [8, 9], longer follow-up could be useful to further investigate the ability of the tested device to eventually prevent the occurrence of delayed and late infections. Second, the designed study deliberately left the participating centers free to choose the systemic antibiotic used for prophylaxis, as well as the one added to the hydrogel locally. To our knowledge, as there is no clear evidence showing the superiority of one antibiotic prophylaxis over another [55], it was decided to leave each center free to decide the prophylaxis on the basis of their experience and the regional microbiology, instead of imposing a fixed arbitrary regimen. Moreover, the main activity of the DAC hydrogel is thought to be its anti-adhesive effect, as recently reported [56], while the presence of the antibiotic in the hydrogel is intended to eventually kill the remaining planktonic bacteria and is ancillary to the main activity of the device. All things considered, the choice to leave the centers free to choose the type of antibiotic did finally provide homogeneous and comparable data and may actually better simulate the real-life possible clinical scenario once the DAC device will be available to market. Other limitations of the study concern the exclusion of exposed fractures or other potentially challenging clinical situations, in which an antibacterial coating could eventually be useful. This will be the object of further planned studies.