Abandon or Administer? Moving Beyond Oversimplified Approaches and Developing Strategies That Target the Composite-infected Wound Microecosystem

The article “Time to Abandon Antimicrobial Approaches in Wound Healing: A Paradigm Shift” published in the November 2018 issue¹ presents an account on the use of micropore particle technology (MPPT) for wound infections. Based on the results, it appears MPPT could be explored as an adjunct or alternative therapeutic strategy for certain types of infected wounds. However, the authors go further to propose a radical approach, which is to abandon the usage of conventional antibiotics and antimicrobials, in favor of strategies that support the immune system and native skin microbiome.¹ This rather extreme approach fails to take several factors into consideration.

The chronic wound infection microenvironment consists of a dynamic wound bed capillary interface with several key players, including host and immune cells, matrix elements, and microbial components, which communicate via an intricate network of inflammatory mediators, growth factors, and enzymes. For example, certain wound bacteria produce short-chain fatty acids that enhance the migration and activation of neutrophils as well as the production and release of chemokines.² Therapeutic agents also contribute to this complex interplay; doxycycline (in addition to its antimicrobial effect) decreases the expression of the matrix-degrading enzyme, matrix metallopeptidase 9 (MMP-9), thereby promoting the resolution of wound infections.³ This underscores the complexity of the infected wound microecosystem, eg, maintaining a high microbial burden may be beneficial at an early stage, whereas later in the healing process the composite effects of antibiotics could be leveraged. Hence, oversimplified approaches such as abandoning antibiotics or consistently supporting a high microbial burden are both suboptimal and perilous.

Perhaps, a more comprehensive approach could be to better understand the effects of newer approaches (such as MPPT), with and without current antibiotics, on key factors (ie, host elements, immune signaling, and microbial products). This would provide insights into specific conditions (types of wounds, types of microbes, immune status of patient, and stage of healing) in which these newer approaches can be adopted in favor of or in conjunction with antibiotics. In the process, this could reveal precision-based therapeutic strategies that harness the complexity of the infected wound microecosystem rather than one size fits all approaches, such as administering or abandoning antibiotics.

Sincerely,

Karishma Kaushik, MD, PhD; and Snehal Kadam, BS-MS

Ramalingaswami Re-entry Fellowship, Department of Biotechnology, Government of India

Dear Authors:

We appreciate your interest in our paper¹ and the opportunity to clarify some points.

First, the statement that antibiotics and antiseptics are ineffective against wound infections and in supporting wound healing is based on a number of published meta-analyses (cited in the paper¹) and the conclusions reached by the US Food and Drug Administration and the National Institute for Health and Care Excellence. Therefore, this was not a conclusion drawn by us. The reason for referring to these studies was that, in theory, it could have been possible that antibiotics and antiseptics were the best treatments possible and, due to the complexity of the wound healing process, it was simply not possible to achieve a better therapeutic effect. However, the data with MPPT clearly show that it is possible to develop more effective treatments than those currently used.

This conclusion is important for at least 2 reasons:

A.
It is known that the skin and the wound have a microbiome. Antimicrobials act by indiscriminate killing, and from a theoretical viewpoint, it therefore would be logical that antimicrobials would disrupt this system that the body clearly goes to great lengths to establish and protect. In contrast, an approach that would protect this system and return the control of it to the immune system in the event of infection, would work in concert with the body and, as clinical findings cited in the paper¹ demonstrate, such an approach is considerably more successful. Sir Alexander Fleming was of the opinion that treatments would only be of benefit if they stimulated or conserved natural defence [sic] mechanisms,⁴ and the findings with MPPT¹ seem to be in line with this position.

Antibiotics, if effective, will result in a clear treatment effect within 3 days, as normally seen in internal infections. However, in wound care and in some dermatological conditions, antibiotic and antiseptic use is continued for weeks and with variable outcomes, and, although their use may be warranted due to lack of alternatives, the effect is considerably inferior to that seen for internal infections. In relation to wounds, MPPT was on average able to remove an infection within 3 days (ie, the same timeframe as seen for antibiotics for internal infections).

It is based on these biological and physiological fundamental differences as well as observed treatment effects that we conclude that infections on internal versus external regions should be treated differently.

B.
Both antibiotics and antiseptics give rise to antimicrobial resistance (clinical tolerance may be a more appropriate term), and their use under conditions that do not result in a successful outcome will contribute strongly to the creation of antimicrobial resistance. Antiseptics have usually not been associated with resistance, but Wand et al⁵ and Shephard et al⁶ have reported that antiseptics also give rise to increased tolerance (ie, clinical resistance). This resistance or tolerance is particularly worrying, because it results in cross-tolerance to other antiseptics as well as to antibiotics. The continued use of antimicrobials without clear medical benefit consequently introduces an unnecessary risk to society. In contrast, MPPT is not antimicrobial and will not contribute to the creation of antimicrobial resistance.

Second, the authors mention the article¹ fails to consider the complexity of the wound environment. We cannot agree that an approach based on supporting the immune system and the highly complex microbiome, which is known to be essential for skin health, would be simplistic. Instead, this represents the recognition that the wound environment is so complex and constantly shifting that only the immune system possesses the required and, at any point in time, updated knowledge to be able to control the wound healing process.

Third, the authors refer to the chronic wound (ie, a nonhealing wound) as a dynamic system with components that communicate with each other and mention short-chain fatty acids secreted by bacteria and changes in MMP-9 levels caused by the antibiotic doxycycline as examples of findings that will allow the identification of precision-based therapeutic strategies that harness the complexity of the infected wound microecosystem. Studies of the wound necessarily will identify factors that rise and fall, but this does not mean they are causal or the interference with these factors will advance healing. For many years, the pharmaceutical industry has followed this target-based approach in which certain physiological observations were used to identify possible drug targets, such as those mentioned in the authors’ letter. The approach sounds appealing, logical, effective, and scientific, but it almost brought all the big companies to their knees because it was unsuccessful.^7,8 For already validated targets in which clinical efficacy studies in patients clearly demonstrate their value, the target-based approach is preferable because it offers access to highly efficient drug discovery technologies, but for new unvalidated targets, the success rate is extremely low. The consulting company Accenture and CMR International⁹ found that for novel targets only 3% ever made it to preclinical development, and if they made it to a clinical trial, they mostly failed due to lack of efficacy. Even though something changes in a disease state, it does not mean increasing or decreasing this factor will have an effect on the disease state itself. If it were that simple, the pharma-companies would have full late-stage pipelines, but that is not the case.

In relation to wound healing, we do not understand the healing process, and when data are published on the microbiome and how it changes, we may find it interesting, but we do not know how to interpret the findings. Consequently, until clinicians and researchers gain sufficient knowledge to be able to identify the causal factors in the process and understand their role, we will not be able to identify targets for drug discovery that have a reasonable probability of being effective. In turn, this means the concept of precision-based therapeutic strategies, as proposed in your letter, is unrealistic for many years to come.

A field relevant to this discussion is cancer research. Here, the simplistic approach has for many years been to administer compounds that kill cells indiscriminately (ie, similar to antimicrobials). However, it was only possible to reach a certain (suboptimal) therapeutic effect by using this approach, and the field has now moved into immunotherapy with a focus on the disruption of the mechanisms used by cancer cells to hide from the immune system. When their invisibility cloak is removed, the immune cells can suddenly see the aberrant cells and effectively remove them. Micropore particle technology is a passive approach not associated with side-effects, but it builds on the same principle to remove the blocking of the immune cells such that these with a high degree of precision can remove obstacles to healing, and this can take place without us understanding the process.

In wound healing, it is known that antibiotics have limited effects, and it also is well known that bacteria will develop strategies to circumvent any approach we come up with that targets them directly. In addition, the composition of the microbiome is unique to the individual and depends upon the anatomical location, diet, hormonal status, and geographical location.¹⁰ The only system that continuously adapts to changing conditions in the local environment, develops and improves in response to the threats, and targets specific cells with precision is the immune system.¹¹

Thus, it would seem more forward thinking to pursue strategies that rely on the immune system, which must be the epitome of personalized medicine for nongenetic disorders. In this context, MPPT can be used as a tool, as well as a treatment, to achieve an even better understanding of wound physiology and how we can help the immune system do its job — to support the natural defenses as Sir Alexander Fleming suggested, which is an approach data clearly show is feasible.

Regards,

Jeanette Sams-Dodd, BSc, BScVet; and Frank Sams-Dodd, PhD, Dr.med.

Willingsford Ltd, Southampton, Hampshire, United Kingdom