No bullet silver

31 October 2017

Nanosilver is gaining a reputation as a fix to the problem of easily contaminated fixtures in hospitals that harbour germs. But not everyone agrees. We speak to nanobiologist Dr Cindy Gunawan from the University of Technology Sydney, whose research that shows nanosilver could lead to mass resistance in patients.

Doctors are at loggerheads over the use of nanosilver and its commercialisation, arguing about whether it is a positive or negative for the medical devices industry. Some have raised questions about the ability of specialised nanosilver fabrics to mitigate the environmentally harmful release of silver ions, and how the slow release of silver would also reduce the bacteria’s ability to form a resistance to silver.

Dr Cindy Gunawan is a nanobiologist working in the interface of nanomaterials engineering and microbiology, specialising in nanoparticle-cell interactions. She is currently a Chancellor’s Research Fellow in the ithree institute (infection, immunity and innovation) at the University of Technology Sydney in Australia, where she leads a nano-bio research programme. Gunawan’s research seeks to unravel the mode of actions of antimicrobial nanoparticles on bacteria, the emergence and genetic basis of bacterial resistance, and the ecotoxicological impacts of these nanoparticles. Gunawan is critical of nanosilver, arguing that the use of these materials will give rise to resistance that would spread to microorganisms in the human body as well as the environment.

Medical Device Developments: Can you explain your research, how it came about, its intentions and what it means?

Dr Cindy Gunawan: Like the extensive use of any antimicrobial, there are escalating concerns that the widespread and indiscriminate use of nanosilver (NAg) may lead to a health crisis of antimicrobial resistance.

In 2013, our research discovered the natural ability of bacteria to develop adaptation to NAg toxicity. The initially susceptible bacteria became resistant following prolonged exposure to NAg. The bacteria were capable of proliferating under an otherwise toxic NAg dosage, ultimately dominating the microbial communities. Further studies by other scientists reported resistance development in gut bacteria – again, manifesting following prolonged exposure to NAg.

In our recent investigation, we found that the use of NAg in commercially available products could facilitate prolonged exposure of microbes to ‘bioavailable silver’ and therefore the threat of resistance. ‘Bioavailable silver’ here refers to silver species deriving from NAg that can exert toxicity on microbes. The emphasis is not on whether the products contain NAg but rather on the generation of bioavailable silver from the products. This is because not all forms of silver exert toxicity on microorganisms.

We studied more than 140 commercially available medical care and dietary supplement products, looking at the potential release of bioavailable silver from the products and, subsequently, their absorption and build-up in organs and tissues that are populated by microbes in the human body. The sites for exposure that we identified included wound beds, the oral cavity, and the gastrointestinal and urinary tracts, all of which are densely populated microbial habitats. This could establish the potential for resistance development.

Research inquiries have also reported the presence of NAg in the environment, released either via direct discharge of effluents from wastewater treatment plants (WWTPs) into oceans, rivers and estuaries, or through the use of biosolids from WWTPs in agriculture. Indeed, studies have observed the occurrence of NAgresistant bacteria in microbial communities sampled from natural waters and even in those originating from sewage.

Our work seeks to raise awareness of the real potential of the current commercialisation of NAg to lead to development of microbial resistance, and we advocate for a more judicious and effectively regulated use of NAg. We argue for the need to implement a targeted surveillance strategy for the occurrence and spread of NAg microbial resistance. Where NAg applications are considered effective, such as in wound dressings and catheters, regular monitoring for resistance development is microbial communities is recommended on contact sites, as well as in other human body microbial habitats with a persistent presence of systemically absorbed bioavailable silver. Beyond a weakened antimicrobial arsenal, the unnecessary application of NAg will change the balance and dynamics of native microbial communities – not only those that dwell in the human body but also in the environment. The effect of such disruptions has a multitude of impacts on human and environmental health, and should not be ignored.

We also hope that our work can trigger more research into the phenomena of microbial resistance to NAg and other antimicrobial nanoparticles, to understand the mechanisms of toxicity and resistance. With no new antibiotic discoveries in the past 30 years, the work’s ultimate purpose is to save NAg for successful long-term use, to preserve its efficacy to fight untreatable infections from multidrug-resistant bacteria, saving lives and billions in healthcare costs.

Nanosilver is being increasingly used in the world of medical devices. Can you explain why this is and what your thoughts are on the matter?

The increasing prevalence and spread of multidrug-resistant bacteria has obliged us to seek and increasingly rely on less conventional antimicrobial treatments. NAg is an ultra-tiny silver particle with up to 100nm size or 10,000th of a millimetre. It exhibits potent and broad spectrum antimicrobial activity, including on the ‘priority pathogens’ on which antibiotics are no longer effective. Over the years, NAg has been incorporated as core and co-antimicrobial ingredients in medical devices, most prominently in wound dressings and internal catheters, to prevent or fight established infections. Studies have reported antimicrobial efficacies of NAg used for the treatments of burn wounds and chronic wounds, such as diabetic and pressure ulcers, as well as to inhibit infections with the use of urinary, central venous and tracheal catheters.

You’re quoted as saying that “nanosilver is a proven antimicrobial agent, the reliability of which is being jeopardised by the commercialisation of people’s fear of bacteria”. Can you explain what you mean by this? Would you like to see nanosilver used in a different way?

Apart from its use in medical devices, companies have also been incorporating NAg in vast arrays of ‘everyday’ products, ranging from clothing and personal care products – such as toothbrushes, soaps and hairdryers – to household appliances such as washing machines and air conditioners, and even as coatings in food containers and baby bottles. This widespread and indiscriminate use of NAg has led to the release and build-up of toxic silver species into microbial habitats in the human body and the environment, which underpins the emergence of bacterial resistance and its spread.

Bacteria have the natural ability to develop resistance to NAg. Researchers first discovered the resistance phenomena in the environmental bacteria Bacillus sp. and recently, in the gut bacteria E. coli. Studies have also observed occurrence of NAgresistant bacteria in microbial communities, such as in natural aquatic water and in sewage. If left unaddressed, NAg will lose its efficacy and we will lose NAg as an alternative antimicrobial weapon in this era of increasing antibiotic resistance.

I would like to see, again, a more judicious and effectively regulated use of NAg. Only use NAg where it is needed and refrain from incorporating nanoparticles into everything. The use of NAg in consumer products requires a validated risk and benefits assessment, which is currently lacking.

Hospital-acquired infections are an increasingly important topic in healthcare, with many sectors of the population now at risk of developing antimicrobial resistance. What would you say are the steps that should be taken to achieve better safety in this field, and to reduce the rate of those exposed developing resistance?

We need to practice high standards of hygiene to prevent or minimise the occurrence of healthcare-associated infections in the first place. These are precautionary actions, from simple things like thorough hand cleaning for everyone in the hospital, and executing standardised sterile techniques for the insertion and care of catheters and other medical devices, to identifying and isolating patients who are infected by multidrug-resistant bacteria. Equally important is the practice of antimicrobial stewardship: a careful and evidence-based prescription of antimicrobials by medical practitioners. This is to stop the overuse of not just antibiotics but also relevant alternative antimicrobials, like NAg, and to ultimately reduce the rate of resistance development.

What products, such as polymers and plastics or metals, would you say are better than nanosilver or a good alternative to use in medtech and hospital designs?

NAg is a broad spectrum antimicrobial with research data showing potent activities on bacteria, yeast, fungi and even viruses. Other inorganic particles, such as zinc oxide and copper oxide, have also been increasingly incorporated in products as antimicrobials; for example in topical creams and antifouling paints. Emerging research has also explored the potential use of zinc oxide nanoparticles in wound care.

At this stage, we cannot really pinpoint which alternative antimicrobials are better than NAg. More research is required for optimum potency and, equally importantly, to identify their potential impacts on the human and environmental health, including the emergence of microbial resistance.

Where do you see this research heading in the future?

Since the initial discovery in 2013, research efforts have been dedicated to the investigations of the span of the resistance phenomena. A number of bacteria, including those that inhabit the wounds, have been found to resist the NAg toxicity. Scientists are also trying to unravel the genetic mechanisms of the resistance phenomena, in the hope of using the identified genes to track the spread of NAg resistance in other bacteria.

Research trends are also moving towards the clarification of the environmental and health impacts of NAg use. New evidence has emerged on the ability of NAg to select and enrich specific antibiotic resistance genes in microbial communities. NAg has also been shown to affect the nitrification potential of microbial communities, an important step in the nitrogen cycle.

Nanosilver explained

Nanosilver (NAg) is different from soluble silver ions such as AgNO3 or silver sulphadiazine. NAg exerts its antimicrobial activity through the actions of the solid silver particulates and the released soluble silver from the particulates. When they come in contact with aqueous systems such as water, wound fluids or the bloodstream, NAg particulates and the released Ag+ ions will interact with the presence of silver-precipitating and silver-complexing agents. These include halides – such as chloride, bromide and iodide – phosphates and sulphides, as well as biomolecules and proteins. These interactions will form a variety of silver species with different toxicity effects on bacteria or in other words, different bioavailability.

Dr Cindy Gunawan Dr Cindy Gunawan is a nanobiologist and Chancellor’s Research Fellow at the ithree institute at University of Technology Sydney. She was a University Medallist during her bachelor’s degree in bioprocess engineering at the University of New South Wales (UNSW) and has a PhD in biotechnology from UNSW.

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