Using calcium sulphate in the fight against antimicrobial resistance


AMR is becoming a bigger and bigger problem every year and is having to be dealt with on many different fronts. One way is incorporating antimicrobial agents into products due to be placed into a human body during their sterile production. Written by Michael Harris

Antimicrobial resistance (AMR) arises when a range of infections caused by bacteria, fungi and other microorganisms become resistant to available treatments (such as antibiotics, antifungals etc.). AMR is a global epidemic responsible for 700,000 deaths annually, with the numbers increasing by 4% year on year. The World Health Organisation (WHO) has declared AMR as one of the top 10 global public health threats facing humanity. It is believed that by 2050 AMR could cause more than 10 million deaths a year. AMR is particularly prevalent in healthcare settings such as hospitals, where antibiotics are used routinely, and resistant strains can arise and spread easily.

Overuse and inappropriate use of antibiotics (through inappropriate antibiotic selection, improper dosing, or poor adherence to treatment guidelines) are considered factors which encourage the tolerance of a microorganism to an antibiotic drug or antibiotic resistance. A worldwide shortage of innovative antibiotics to fight these infections has exacerbated the crisis with only 11 new antibiotics approved since 2011.

Microorganisms tend to form biofilms

Worryingly, microorganisms have been found to develop resistance to newly approved antibiotics. The slow development of antimicrobial agents has resulted in resistant strains emerging faster. Given the global increase in antibiotic resistance, strategies to mitigate AMR are desperately needed.

A dramatic increase in the emergence of antibiotic-resistant bacterial strains in recent year has made infection control an increasing challenge with a limited choice of antibiotics available for treatment. A 2019 study 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.

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.

In orthopaedics, surgical wounds and bone void resulting from procedures and/or fractures require careful management to avoid infection. Prophylaxis involving irrigation with antibiotic solution or direct application of powdered antibiotics on a wound (topical application) have proven effective in preventing infection, in combination with intravenous (systemic administration) antibiotic treatment. When infections do occur, these can be difficult to manage as microorganisms tend to form biofilms, communities encased in a polysaccharide matrix, colonising the wound and any other adjacent space available for growth. Upon attachment to a surface, biofilms display a high tolerance to antibiotics, compared to their planktonic counterparts. This is believed to be a key mechanism of antibiotic resistance in orthopaedic implant-associated infections.

Calcium sulphate can release 100% of its antibiotic load as it resorbs

One example of such infection is Periprosthetic joint infection (PJI), a devastating complication of joint replacement surgery, associated with increased patient morbidity and a requirement for complex interdisciplinary management strategies. 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.

Managing outcomes

To manage orthopaedic implant-associated infection multiple surgical procedures as well as a combination of systemic and/or local antibiotic treatment are required. This strategy allows surgeons to broaden the spectrum of antimicrobial activity and prevent resistance mechanisms from evolving. 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.

An alternative bioabsorbable local antibiotic administration method is the use of calcium sulphate. Bioabsorbable mineral-based calcium sulphate is primarily used as a bone void filler to manage dead space. Antibiotics can be added to calcium sulphate to add antimicrobial functionality to the material, in the same manner that surgeons have mixed antibiotics into bone cement. Unlike PMMA, calcium sulphate can 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. Moreover, recent in vitro research demonstrated that the local release of antibiotics from calcium sulphate may be a useful strategy in the management of biofilms of multidrug-resistant strains of bacteria including CRE and VRE.

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When it comes to calcium sulphate, they are not all the same. Manufacturing processes can deliver quite distinct performance characteristics that make some more suitable than others to carry antibiotics to target local points of infection. Stimulan for example is made possible through a proprietary DRy26 recrystallisation methodology. Each and every synthesis of Stimulan undergoes a 26-step process that starts with pharmaceutical grade precursors and takes over 6 weeks to reach maturity. This recrystallisation method dehydrates and then rehydrates to precisely restructure the calcium sulphate. Ensuring a uniform starting point from which the material is rebuilt under strictly controlled clean room conditions for the highest level of consistency. This is one of the reasons why Stimulan is the only calcium matrix to receive European approval for mixing with antibiotics for use in bone and soft tissue.

Antibiotic resistance is one of the biggest threats facing healthcare today caused by excessive and inappropriate use of antibiotics. The reduced availability of new antibiotics leads to many routine surgical procedures such as hip and knee replacements becoming increasingly challenging and potentially life threatening.

Absorbable mineral-based bone void fillers, such as calcium sulphate, offer surgeons a solution for the management of infected wounds and may provide a solution to tackle antimicrobial resistance. Collaborating with innovative companies that produce these mineral based bone void fillers to improve the outcome of orthopaedic procedures will be key to developing the solutions of the future.