Antimicrobials Are Not Created Equal
The most effective antimicrobial for the management of both chronic & acute wounds has long been debated. In order to really determine which is the most effective and in which scenario it is at maximum efficacy, it is important to understand the mechanism of action. In this article we will take a detailed look at the mechanism of action and antimicrobial properties of 4 of the most commonly used antimicrobial agents: ionic silver (Ag+), iodine, medical grade honey, and polyhexamethylenebiguanide (PHMB).
Silver:
The usefulness of silver for wound treatment has been known for thousands of years. While silver metal (Ag) has no medicinal activity, Ag+ has a broad antimicrobial spectrum, and is cytotoxic to bacteria, viruses, yeast, and fungi. Ag+ binds to DNA, RNA, and various proteins, leading to cell death via multiple mechanisms, such as protein and nucleic acid denaturation, increased membrane permeability, and poisoning of the respiratory chain. For this reason, resistance against the silver ion has only rarely been reported. While the silver ion has great antimicrobial and bactericidal properties, it is also toxic to fibroblasts when present in high concentration. Careless use of silver-containing dressings can lead to impaired wound healing (Khansa et al., 2019).
It was noticed that silver acts as an antiseptic with a wide biocidal effect against various microbial species via disruption of enzyme activity and membrane function (Kailasa et al., 2019). Because silver ions might be destabilized and increase permeability of bacterial membranes, this results in the inhibition of functions of essential proteins and respiratory enzymes, which results in breaking up the replication of nucleic acids of bacteria and inhibiting the ion transport process (Kailasa et al., 2019).
“For better understanding of the antimicrobial property of Ag [nano particles] (NPs), it is essential to describe the mode of action and role of Ag NPs and Ag ion in inhibiting the growth of microbial species. In antimicrobial action, two distinctive steps are involved in controlling the growth of microbial species. The first step involves modification stabilization of Ag NPs surfaces according to the microbial environment. The second step is the interaction of Ag ion — Ag NPs with the cell walls of bacteria, resulting in inhibition of the functions of bacterial proteins, which stops bacteria growth and leads to bacterial cell death. However, the degree of antimicrobial activity of Ag NPs also depends on various factors including physicochemical properties, size, morphology, and ligand chemistry of Ag NPs, medium and microbial environment and concentration of Ag NPs, respectively” (Kailasa et al., 2019).
Iodine:
Iodine is a highly effective topical antimicrobial that has been used clinically in the treatment of wounds for more than 170 years. It has a broad spectrum of antimicrobial activity with efficacy against bacteria, mycobacteria, fungi, protozoa and viruses and can be used to treat both acute and chronic wounds. It is also relatively inexpensive and easy to use but is often underused as a topical antiseptic due to its perceived toxicity. “The microbicidal activity of iodine appears to involve the inhibition of vital bacterial cellular mechanisms and structures, and oxidizes nucleotides fatty/amino acids in bacterial cell membranes, in addition to cytosolic enzymes involved in the respiratory chain, causing them to become denatured and deactivated” (Bigliardi, Paul Lorenz, et al, 2017).
“Iodine’s exact antimicrobial mode of action is not fully understood, but it is believed to be associated with its ability to rapidly penetrate the cell wall of micro-organisms. Schreier also investigated the effects of PVP-1 on microbial cells and found that it affects the structure and functions of enzymes and cell proteins and damages bacterial cell function by blocking hydrogen bonding and altering the membrane structure. These multiple modes of action ensure the rapid death of microbes and help to prevent the development of bacterial resistance. Because the microbicidal action of iodine is related to several directly toxic effects on the cell wall, rather than through specific molecular pathways (as used by antibiotics), resistance is highly unlikely and reports of iodine resistant strains are exceptionally rare” (Sibbald RG, et al, 2011).
Honey:
“Honey is a complex sweet food stuff with well-established antimicrobial and antioxidant properties. It has been used for millennia in a variety of applications, but the most noteworthy include the treatment of surface wounds, burns and inflammation. A variety of substances in honey have been suggested as the key component to its antimicrobial potential; polyphenolic compounds, hydrogen peroxide, methylglyoxal and bee-defensin” (Nolan et al., 2019). The first observations of the antimicrobial activity of honey were made in 1892, and since then honey has been observed to have a broad spectrum of activity, inhibiting both Gram positive and Gram negative organisms (Nolan et al., 2019). Interestingly, it has been observed that no organism has gained resistance to honey.
Initial studies into honey have outlined some key factors contributing to its antimicrobial effects, these were high sugar content, low pH, hydrogen peroxide, polyphenolic compounds and the identification of an inhibine. More recent studies have also identified a bee-derived protein, bee defensin-1, as a potential antimicrobial component within honey. This furthers the argument that honey samples contain various antimicrobial compounds and their activity cannot be attributed to a single antimicrobial agent (Nolan et al., 2019). Moreover, honey contains multiple components that act synergistically, enhancing its potency as an antimicrobial.
“[T]his alternative antimicrobial agent represents a promising therapeutic avenue to help curb the increasing incidence of antibiotic-resistant bacterial infections. Furthermore, the complete elucidation of the mechanisms of activity and synthesis of all components of honey could lead to the generation of an optimally antimicrobial synthetic or semisynthetic honey. Discovery of the precise concentrations of these synergistic components would enable us to develop the most effective, broad-spectrum honey with activity against a wide range of antibiotic-resistant bacterial species” (Nolan et al., 2019).
PHMB:
The commonly accepted mechanism of action for PHMB involves the disruption of cellular membranes. This theory suggests that the positively-charged PHMB polymer binds to the negatively-charged cellular membranes of microbes leading to disruption and eventual cell lysis. It is through this type of physical interaction that PHMB’s broad-spectrum coverage and high tissue-compatibility was assumed. However, newer studies on the mechanism of action for PHMB suggest that the polymer enters the cells where it is able condense chromosomes leading to eventual cell death. When considering the membrane disruption model and possible alternatives, it may be important to recognize that PHMB has a capacity for both electrostatic and H-bonding interactions, which could occur at many possible targets in cells. (Chindera, Kantaraja, et al., 2016).
The results of a 2016 study demonstrate that PHMB can enter bacterial cells, arrest cell division and condense chromosomes, resulting in intracellular foci of DNA. PHMB is revealed as the first example of a drug that binds and condenses bacterial chromosomes (Chindera, Kantaraja, et al., 2016).
“A chromosome condensation model for the antibacterial action of PHMB can explain how PHMB kills bacteria, but also raises a new and difficult question. How can chromosome condensation provide a selective antibacterial mechanism, given that all organisms have chromosomes? In other words, if PHMB enters cells and condenses bacterial chromosomes, why doesn’t it also kill mammalian cells and display toxic effects when used in clinical applications? Specifically, it localizes within endosomes and is excluded from nuclei. Therefore, PHMB’s antibacterial selectivity appears to involve differential target access through drug partitioning inside cells, rather than by the well-established principles of target recognition and structure conservation” (Chindera, Kantaraja, et al., 2016).
Mammalian cell uptake and nuclear exclusion of PHMB are unexpected observations; however, they may reflect aspects of how mammalian cells evolved together with microbes (Chindera, Kantaraja, et al., 2016).
Utilization Best Practices:
When it comes to antimicrobials, making the right choice for your patient can be overwhelming. Based on a thorough evaluation of current research, the follow recommendations can be made for individual antimicrobials:
1.) “In infected wounds, silver is beneficial for the first few days/weeks, after which non-silver dressings should be used instead. For clean wounds and closed surgical incisions, silver confers no benefit. The ideal silver formulations are nanocrystalline silver and silver-coated polyurethane sponge for negative pressure wound therapy. Silver sulfadiazine impairs wound healing” (Khansa et al., 2019).
2.) “Studies have confirmed the in vitro efficacy of povidone iodine against S. epidermidis and S. aureus growth, as well as the inhibition of staphylococcal biofilm formation at sub-inhibitory concentrations. Furthermore, in a CDC-reactor model, povidone iodine was efficacious in the presence of biofilms grown in a mixed culture comprising MRSA and C. albicans, even at highly diluted concentrations” (Bigliardi, Paul Lorenz, et al., 2017). When aggressive debridement cannot be tolerated, iodine’s unique ability to penetrate biofilm makes it incredibly useful for the management of bioburden.
3.) “There may still be a role for honey in specialized patients where autolytic debridement is required for hard, fibrous surfaces or in wounds that need an increased moisture content” (Sibbald , et al., 2017) “Honey has the potential to vastly reduce the requirement of drugs of last resort for highly drug-resistant bacterial infections, since current resistance to antimicrobial mechanisms of honey is largely unseen” (Nolan et al., 2019).
4.) Current evidence shows that topical PHMB has the ability promote healing of chronic stalled wounds, reduce bacterial burden, and alleviate wound-related pain. PHMB is the ideal antimicrobial for wounds stalled in the inflammatory phase. Its high tissue compatibility and broad spectrum coverage makes it especially effective in preventing the reformation of biofilm following sharp debridement.
A concrete understating of the mechanism of action for each of these antimicrobials is still premature according to recent studies, with commonly accepted mechanisms being debunked as a result of new evidence. Evaluating wounds based on type, size, and duration, can allow you to make the best choice for your patients. If you trust the data, and trust your gut, I have no doubt that whichever antimicrobial you choose, you’ll be able to get wounds moving in the right direction.
If you enjoyed this article or have further insight to offer on your regular antimicrobial use, please feel free to share in the comment section.
References:
Chindera, Kantaraja, et al. “The Antimicrobial Polymer PHMB Enters Cells and Selectively Condenses Bacterial Chromosomes.” Scientific Reports, vol. 6, no. 1, 2016, doi:10.1038/srep23121.
Bigliardi, Paul Lorenz, et al. “Povidone Iodine in Wound Healing: A Review of Current Concepts and Practices.” International Journal of Surgery, vol. 44, 2017, pp. 260–268., doi:10.1016/j.ijsu.2017.06.073.
Sibbald RG, Leaoer DJ, Queen D. Iodine Made Easy. Wounds International 2011; 2(2): Available from http://www.woundsinternational.com
Nolan, Victoria C., et al. “Dissecting the Antimicrobial Composition of Honey.” Antibiotics, vol. 8, no. 4, 2019, p. 251., doi:10.3390/antibiotics8040251.
Khansa, Ibrahim, et al. “Silver in Wound Care — Friend or Foe?” Plastic and Reconstructive Surgery — Global Open, vol. 7, no. 8, 2019, doi:10.1097/gox.0000000000002390.
Kailasa, Suresh Kumar, et al. “Antimicrobial Activity of Silver Nanoparticles.” Nanoparticles in Pharmacotherapy, 2019, pp. 461–484., doi:10.1016/b978–0–12–816504–1.00009–0.
“Update.” Advances in Skin & Wound Care, vol. 30, no. 10, 2017, doi:10.1097/01.asw.0000525581.73952.b2.
