AMR in Orthopedics – Benefits of topical treatment and latest advances
Michael Harris, chief executive officer of Biocomposites explores the threat of antibiotic resistance and how antibiotics are being used within the orthopaedics industry.
Antimicrobial resistance (AMR) threatens the effective prevention and treatment of a range of infections caused by bacteria, fungi and other microorganisms and is considered one of the most serious global public health threats of this century. The World Health Organisation (WHO) has declared AMR one of the top 10 global public health threats facing humanity and states that AMR is responsible for 700,000 deaths annually, with the numbers increasing year on year by 4%. By 2050, it is believed that AMR could cause more than 10 million deaths a year (World Health Organisation, 2020). AMR is of particular importance especially in healthcare settings such as hospitals, where antibiotics are used routinely, and resistant strains can arise and spread easily (Prestinaci et al., 2015).
AMR management strategies are particularly urgent given the increase in antibiotic resistance. In recent times, bacteria associated with common or serious infection have developed resistance to newly approved antibiotics. This problem is exacerbated by a worldwide shortage of innovative antibiotics to deal with this challenge. The WHO 2021 antibiotic pipeline report indicates that eleven new antibiotics have been approved since 2017. Of these eleven antibiotics, only two represent a new class of antibiotic with a novel antimicrobial action (Shrestha et al., 2021). This slow development of antimicrobial agents has resulted in an acceleration of the emergence and spread of resistant organisms.
Antibiotic resistance in orthopaedic surgery
Antibiotic resistance is a term used to describe the tolerance of a microorganism to an antibiotic drug. Overuse and inappropriate use of antibiotics (through inappropriate antibiotic selection, improper dosing, or poor adherence to treatment guidelines) are considered factors which encourage antibiotic resistance.
In recent years, there has been a dramatic increase in the emergence of antibiotic-resistant bacterial strains making infection control increasingly challenging and limiting the choice of antibiotics available for treatment. A study from 2019 estimated that more than 2.8 million patients in the United States developed an antibiotic-resistant infection, leading to more than 35,000 deaths, with an associated economic burden of $55-70 billion dollars (Dadgostar 2019; Bhandari & Silburt 2021). It is believed that the frequent prescription of antibiotics across medical specialties with a known high risk of infection such as orthopaedics may be a contributing factor to the global increase of antibiotic resistance.
Periprosthetic joint infection (PJI) is a devastating complication of joint replacement surgery, associated with increased patient morbidity and a requirement for complex interdisciplinary management strategies (Aggarwal et al., 2013; Tande et al., 2014). Part of the difficulty in the management of this disease is that the bacteria associated with PJI can form bacterial biofilms. These biofilms are described as communities of microorganisms encased in a polysaccharide matrix. Upon attachment to a surface, biofilms display a high tolerance to antibiotics, compared to their planktonic counterparts which is believed to be one key means of antibiotic resistance in orthopaedic implant-associated infections (Stoodley et al., 2020). More recently, antibiotic resistant bacteria such as vancomycin-resistant enterococci (VRE) and carbapenem-resistant enterococci (CRE) have been reported in PJI infection and are linked to poorer outcomes (Kheir et al., 2017; De Sanctis et al., 2014).
The management of orthopaedic implant-associated infection often involves multiple surgical procedures as well as a combination of systemic and/or local treatment. Combining these treatment modalities is an approach used by surgeons to broaden the spectrum of antimicrobial activity as well as prevent resistance mechanisms from evolving. The prophylactic administration of antibiotics locally is an additional strategy used by surgeons to reduce the risk of infection following total joint arthroplasty or open fracture surgery. Typically, these antibiotics are embedded within polymethyl methacrylate (PMMA) bone cement or added as a coating on an implantable device to achieve high antibiotic concentrations locally within the surgical site (Bhandari & Silburt 2021).
Local antibiotic treatment in orthopedic surgery for prevention of antimicrobial resistance
Coating implant materials with antibiotics is a common practice and has proven to be an effective strategy in reducing orthopaedic implant-associated infection (van Vugt et al., 2019), along with the use of antibiotic loaded PMMA bone cement. An alternative bioabsorbable local antibiotic administration method is the use of calcium sulfate. Bioabsorbable mineral-based calcium sulfate is primarily used as a bone void filler to manage dead space. Antibiotics can be added to calcium sulfate to add antimicrobial functionality to the material, in the same manner that surgeons have mixed antibiotics into bone cement. Unlike PMMA, calcium sulfate is able to release 100% of its antibiotic load as it resorbs, resulting in a more efficient and superior delivery of sustained high antibiotic concentrations (often several times higher than the minimum inhibitory concentration for the relevant pathogen) over a number of weeks compared with PMMA (Cooper et al., 2015; Abosala 2020). Moreover, recent in-vitro research demonstrated that the local release of antibiotics from calcium sulfate may be a useful strategy in the management of biofilms of multidrug-resistant strains of bacteria including CRE and VRE (Stoodley et al., 2020).