Friday, December 29, 2017

Third Wave Prevention of Infectious Disease

Michael Norden MD
Paul Herscu ND, MPH
Herscu Laboratory

The rapid emergence of superbugs, resistant to essentially all drugs, threatens to return us to the horrors of the pre-antibiotic era, where countless people died from common infections. The answer to this crisis may eventually come from advances in biotechnology, which ironically helped create the problem to begin with, but until that day, we would like to propose an ancient approach as a potential answer. Here, I condense a 4-year conversation I have had with my friend Michael Norden MD, involving copper, which reflects part of my 40-year interest in this element. What follows are our thoughts on using copper as a passive yet potent antibacterial.

Some of the most exciting aspects of living in these times are the rapid discoveries occurring in science, related to our habitat in the natural world and especially on the cellular and subcellular level. As we are discovering more and more types of germs, we are having to come to terms with the implications of our discoveries. There are more types of germs than we ever imagined; the germs that surround us and are in us determine to a significant extent, our health. Regarding prevention, the concept of developing an individual vaccine for a specific germ soon becomes unwieldy, as it seems impractical to vaccinate ourselves against hundreds or thousands of potentially pathogenic bugs. Even the common influenza vaccine sometimes fails us. For example, this year, vaccine manufacturers predicted incorrectly and the vaccine developed appears to be only 10 to 20% effective. Regarding treatment, we have learned that we can not simply kill infectious agents, because germs adapt to become more virulent. The rapid and ubiquitous use of antimicrobials has led to superbugs threatening our therapeutic efficacy and creating dire challenges to our species. We often lose the battle with germs that perhaps we should not be fighting in the current manner in first place. Instead of active antimicrobial use, and instead of prevention solely by developing a specific vaccine for each germ, we may need to develop a third wave of thought, one focusing on passive antimicrobial coatings that do not create superbugs, which is where copper stands as one possibility. 

The EPA has now certified over 400 alloys as “antimicrobial copper.” Certification allows the claim of 99.9% of bacteria will be killed within 2 hours. Published studies show this efficacy against all types of pathologic microbes including resistant bacteria such as MRSA as well as many viruses and fungi. Microorganisms tested succumb to the copper effect.

What are the Potential Advantages of Antimicrobial Copper?

Safety: With a 5,000-year history of use, copper should offer few surprises. As a primary constituent of coins and water pipes for millennia, lack of human toxicity is well established. Moreover, with hundreds of millions of years of shared history with copper, microbes have not readily developed resistance to copper’s killing impact. It seems unlikely that a strategic intentional use of copper will change that.

Cost: The economic case for copper looks strong. Any reductions in acquired infections will translate into substantial savings. Moreover, there is the potential of slashing costs more than an order of magnitude by using copper foil adhesives or a small amount of copper added to paints applied especially in medical settings for equipment and touch surfaces. Importantly, there is a net environmental benefit, as using this tiny amount of copper offsets a great amount of medical waste.

Speed of Implementation: A number of companies now offer various medical products utilizing EPA-certified antimicrobial copper. In the case of copper foil adhesives, these are apparently ready to ship in whatever size and quantity required, and this compact and relatively light cargo is appropriate for air shipment. Installation takes less than a day and requires minimal labor.

Visual Reinforcement of Hygiene: While antimicrobial copper alloys come in a range of colors including the same silver color as the American quarter, it may be helpful to use copper colored surfaces as both visual reassurance that the facility is providing relatively safe touch surfaces, and a reminder to be careful and wash hands especially if touching non-copper surfaces.

Cheap and practical water purification: Clean water is of vital importance everywhere and often a challenge in developing countries. A simple copper coil in a vessel of water for 12 hours renders it safe to consume and does not introduce significant levels of copper into the water.

Third Wave Concepts

For me, the most important advantages, what I term a Third Wave rationale, gives us three invaluable attributes: Broad Range Application, Passive Practicality, and Continuous Action.

Broad Range Efficacy: Unlike many other antimicrobial approaches, it is well established that copper has the ability to quickly kill a wide range of viruses, bacteria, and fungi. Evidence also confirms drastic reduction of bioburden. Recent studies have now begun to show that this translates into substantial reductions in acquired infection.

Taking Ebola virus as an example, is copper effective against Ebola virus? Although no disinfectant is specifically established to kill Ebola virus, the CDC guidelines suggest using ones that kill similar viruses, and copper meets their guideline. Antimicrobial copper has been shown to inactivate the two major types of viruses: those with and without a viral envelope. Ebola virus and Influenza A are negative sense single-stranded RNA viruses, both with an envelope protecting the viral genome. Thus, since copper inactivates Influenza A, because of their similar characteristics there is good basis to assume, and to test, whether copper may also inactivate Ebola virus.

Passive Practicality: A key consideration is that this is a passive technology. This approach has distinct advantages not just in the USA, but in the developing world. There is no training required for staff and no maintenance needed other than routine cleaning. This passive approach is not dependent on electricity, adherence to protocol, or any other human behavior or error. The remarkable challenge of simply getting staff to wash their hands illustrates the importance of this aspect even in top Western facilities.

Continuous Action: Most other approaches are only active when applied and leave surfaces unprotected in the intervals between applications, subject to recontamination. In the case of something like Ebola virus, where as little as one virion may cause infection, this continuous action critically allows copper to more readily eliminate all microbes.


What are the implications concerning Superbugs? There is increasing concern about infectious germs developing resistance to common disinfectants. Moreover, there is startling evidence that disinfectants may simultaneously promote the development of antibiotic resistance. One study showed that a commonly used disinfectant made Pseudomonas aeruginosa 256 times more resistant to the widely prescribed antibiotic Ciprofloxacin – even though the bacteria had never been exposed to it. The European Commission concurs that, “the use or misuse of certain active substances in biocidal products in various settings, may contribute to the increased occurrence of antibiotic resistant bacteria, both in humans and animals.

In stark contrast, antimicrobial copper alloys are unlikely to promote resistance. There are a few organisms that show higher tolerance to copper, but despite human use of copper and copper alloys for thousands of years, “no bacteria fully resistant to contact killing has been discovered.” The reasons for this include that: “transfer of genetic determinants from antibiotic-resistant microbes is dramatically reduced on copper alloyed surfaces through the destruction of the nucleic acid within the microbes in contact with the copper surfaces, and also “contact killing is very rapid, and cells are not dividing on copper surfaces.”

Mechanism of Action

It is not completely clear why copper is so effective in this role. The prevailing thought is that there are numerous pathways that copper uses to kill germs, all working together to achieve this impact. For example, I believe there is a biphasic nature to copper. At low doses copper helps bugs grow, and at higher doses, it disturbs many cell structures, forming free radicals, oxygen species, oxidative stress, which kills germs. In addition, copper damages cell walls, allowing internal contents to leak out of the cell, thereby drying out the germ.

Clinical Outcomes

Are there clinically important outcomes? A recent publication reported the results of a 7.7 million dollar trial, under contract with the Department of Defense, conducted at 3 medical centers, including Memorial Sloan-Kettering in New York City. It found a greater than 80% reduction of microbes present on surfaces in ICU rooms outfitted with copper on six frequently touched surfaces. Over the 2-year period of the trial, antimicrobial efficacy was maintained with no interventions other than routine cleaning. The microbial burden on critical surfaces was kept at levels typically achieved after terminal cleaning. The trial further established this reduction in bioburden, was associated with a 58% reduction in acquired infections.

Furthermore, an Israeli study in a long-term head injury unit using only copper infused linens and clothing, similarly showed a 24% reduction in Hospital Acquired Infections (HAI) and a 46% decrease in fever days. There is potential for even greater effect if antimicrobial copper surfaces and copper infused linens and clothing are used simultaneously.

Need for more data:

1) More data is needed to test if antimicrobial copper consistently reduces bioburden and if that reduction will translate into reduced HAI.

2) Evidence of specific effectiveness against Ebola virus would be extremely helpful. This should be fast and inexpensive if a sanctioned laboratory agrees to conduct a trial. Publicity generated around findings would raise awareness of the potential of Third Wave concepts of passive antimicrobial touch surface technology, such as copper, as suggested here.

What can Research do to Help?
1) Continue to study effects of antimicrobial copper in terms of mortality, morbidity, and economic impact.
2) Test copper specifically against particular contact germs, such as Ebola virus.
3) Provide copper equipment copper foil adherents or copper infused paints to treatment centers, if not in the USA, then in developing countries. Study impact of centers thus equipped in contrast to similar centers to test in-field proof of concept.

As I sit and write this, I am cognizant of a few populations particularly vulnerable. Hospital acquired infections remain a major concern. Having at least some touch surfaces become passively germ-free may offer some protection. For example, can anyone actually justify why is it that door handles are made of metals that let germs survive, passing from person to person as we touch that surface, instead of having that surface passively clean itself? Stainless steel does not kill germs. You have to constantly and actively clean that surface, a virtual impossibility. This rationale is also true in rehabilitation facilities and geriatric care homes. There are a half dozen surfaces that if changed to copper would lower bioburden dramatically. Lastly, developing countries may not be able to afford expensive equipment or expensive training of skilled personnel to use that equipment. It may be difficult to keep appropriate disinfecting supplies in stock. Generating data here would demonstrate low cost, high yield technology suitable in developing countries. This remains true for the nationals that live and work in that country or to the medical missionaries that travel to assist in health care delivery.

As we come to terms with the reality of germs outside of and within us, it is time to consider, not just killing germs in an active manner, which unfortunately leads to resistance and superbugs. It is time to think about not just preventing illness one germ at a time as with vaccinations, but rather, learning to limit the bioburden without accelerating evolutionary resistant strains, using a more passive method. Copper may just be one winning candidate, where the technology is affordable, understood and easy to implement. This approach potentially can save countless lives without any other innovation needed.