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What Are Superbugs?

Superbugs are microorganisms resistant to one or multiple antimicrobials. As much as 65% of the bacteria that infect wounds are drug-resistant.¹ Major superbugs that impact wound care may include:

• Methicillin-resistant Staphylococcus aureus
• Carbapenem-resistant Enterobacteriaceae
• Vancomycin-resistant Enterococcus
• Multidrug-resistant Pseudomonas aeruginosa
• Multidrug-resistant Escherichia coli

At present, estimates place drug-resistant organisms as causing over 700,000 deaths per year globally. By 2050, predictions say that the number of deaths caused by these organisms could surpass mortalities caused by cancer, nearly 10 million deaths per year.² Thus, it is important to understand how these organisms work and know several strategies for combatting these infections while adhering to antimicrobial stewardship best practices.²

How Do Bacteria Become Resistant to Antibiotics

Antimicrobial agents inhibit bacteria through various mechanisms of action depending on their class. Bacteria can form resistance by developing specific means that counteract these mechanisms of action distinct to each antimicrobial agent. Therefore, antibiotic resistance manifests in 4 primary ways³:

1. An enzyme deactivates the antibiotic (ie, class D carbapenemase)
2. Decreased bacterial cell permeability limits drug uptake
3. Modification/replacement of the antibiotic’s target site
4. Bacterial cells pump out the antibiotic (efflux, seen more in Gram-negative bacteria than in Gram-positive)

Typically, antimicrobial resistance occurs when a microbe’s gene(s) mutate in favor of resistance and then spread that development to other microbes via gene transfer. Recently, experts have reported that misuse of antibiotics has accelerated these processes by "removing drug-sensitive competitors and leaving resistant microbes to reproduce and spread by natural selection.”⁴ In addition to following best practices when preventing infection and prescribing antibiotics, clinicians can take steps to treat antibiotic resistant infections using therapies that account for these mechanisms of resistance.

How to Treat Antibiotic Resistant Infection: Reviewing Available Options

It is important to focus on preventing antibiotic resistant infections, but in the instance where we need to treat them, one can think about the process as addressing both the pathogen and the host, much like appropriate antibiotic selection for antibiotic-sensitive organisms. However, researchers are exploring additional pathways that clinicians can learn more about including³:

• Combining antimicrobial medications and dressings (eg, hydrogels)
• Using biomaterials made of macromolecules
• Implementing evolving nanotechnology

Hydrogels

Hydrogel dressings are vital to the wound healing armamentarium owing to their numerous beneficial properties (ie, antimicrobial, adhesive, homeostatic, anti-inflammatory, and anti-oxidative activity) and their effect on substance delivery, response to stimuli, and conductivity.⁵ Wound care professionals may incorporate additional antimicrobial components to enhance action on drug-resistant infections.⁵

The bioactive properties of probiotics have been found to prevent bacterial adhesion as well as biofilm formation, release antimicrobial factors like organic acids and enzymes, and mediate the inflammatory response.⁶ Research has demonstrated the effectiveness of probiotics combined with hydrogels against multidrug-resistant organisms like against certain multidrug-resistant organisms.⁶ In in vitro studies, mechanical strength increased along with self-healing, good liquid-absorption abilities, and cyto- and blood cell compatibility. In vivo, hydrogel-probiotic combinations were shown to lessen infection and inflammation and promote reepithelialization and collagen activity, hastening full-thickness wound repair despite the presence of superbug bacteria.⁶ In a mouse model, supramolecular hydrogels containing hydroxypropyl chitosan and poly N-isopropyl acrylamide showed antimicrobial activity against S aureus. Most notably, efficient tissue remolding, collagen deposition, and decreased inflammation, outperforming film dressings.⁷

Phloroglucinol derivative carbomer hydrogels have been shown to accelerate healing in wounds infected with methicillin-resistant S aureus (MRSA) by lowering the number of skin bacteria, reducing inflammation, and upregulating keratinocyte proliferation marker and angiogenesis with no toxicity, or histopathological or hematological changes.⁸

Hydrogels for Fungal infections

A two-layer hydrogel has been shown to immobilize and kill Candida auris cells, offering a viable treatment option for challenging nosocomial wound fungal infections.⁹ Additionally, antimicrobial peptides that can compromise the structural integrity of an organism’s cell walls can be incorporated into hydrogels to offer safe antifungal treatment.⁹

Nanotechnology

Nanomaterials are substances measuring between 1 and 100 nm. Their use in wound care is expanding, owing to their high surface area-to-volume ratio and the variety of platforms in which they are available (nanoparticles, nanofibers, and nanocomposites). These platforms facilitate combining different antibacterial products (eg, zinc and aloe) and help extend the release of medications. Nanomaterials promote cell migration, proliferation, and differentiation, temper inflammation, and enhance angiogenesis.¹⁰ Antibiotics infused with nanoparticles may enhance a drug’s ability to bind and/or infiltrate cells at the wound site.³ They are known to be effective in treating biofilms and expediently diagnose MRSA via nanotheranostics.¹¹

 Nanotheranostics is when therapeutic and diagnostic tools are linked via nanoparticles into a single agent.¹² Noble metals such as silver, gold, and platinum are nanomaterials often used in wound healing. Their ease of incorporation, surface features, response to electromagnetic waves, photothermal and optoelectronic abilities, inertness, and biocompatibility may help expedite diagnosis and drug delivery, including when MRSA is present. The surface areas of nanoparticular zinc sulfide, cadmium sulfide, and zinc oxide aid in semiconduction. These nanoparticles all have demonstrated their ability to thwart infection and improve healing speed. Mesoporous silica has demonstrated success in therapeutic and diagnostic drug release.^10,11 Additionally, research has shown that dressings made of bacterial cellulose are effective in treating gram-negative organisms, E coli, and Pseudomonas aeruginosa.¹³

Natural Products

Natural products are an interesting area that warrants further high-level research. Manuka honey has shown inhibitory action on several bacterial species. A recent laboratory-based study¹ found non-manuka honey products may also have the capability to inhibit the growth of certain superbugs involved in wound infection.¹

Secondary plant metabolites may also exhibit some antibacterial efficacy that can extend to resistant organisms, as may some specific components of Ginko biloba, and aqueous and lime extracts of certain natural spices.¹

Conclusion

Recent research offers potential additional solutions to successfully contribute to treating superbugs that confound wound care. A combination of emerging technology and delivery methods may incorporate tried-and-true options to provide new and innovative thinking on how to approach these types of infections. Proper antimicrobial stewardship and appropriate management of all infections certainly remain a mainstay in preventing multidrug-resistant organisms. But when faced with the clinical challenge of superbugs, research is pointing the way to more pathways to address them.

References

1. Hewett SR, Crabtrey SD, Dodson EE, Rieth CA, Tarkka RM, Naylor K. Both Manuka and non-Manuka honey types inhibit antibiotic resistant wound-infecting bacteria. Antibiotics. 2022;11(8):1132; https://doi.org/10.3390/antibiotics11081132
2. Kaur T, Singh P. Prevalence of Bacterial Species in Traumatic, Burns and Post-Surgical Wounds: Focus on Emerging Drug Resistance. Microbiol Res J Int. 2023;33(5):26-34. https://adfawk3023.s3.ap-southeast-1.amazonaws.com/Singh3352023MRJI1036…
3. Parmanik A, Das S, Kar B, Bose A, Dwivedi GR, Pandey MM. Current treatment strategies against multidrug-resistant bacteria: a review. Curr Microbiol. 2022;79(12):388. doi: 10.1007/s00284-022-03061-7
4. Muzaheed MAA, Fatani AJ, Alosaimi M. Antimicrobial resistance, mechanisms and its clinical significance. Disease-a-Month. 2020;66(6).https://www.sciencedirect.com/science/article/pii/S001150292030033X
5. Liang Y, He J, Guo B. Functional hydrogels as wound dressing enhance wound healing. ACS Nano. 2021;15(8):12687–12722. https://doi.org/10.1021/acsnano.1c04206
6. Mei L, Zhang D, Shao H, et al. Injectable and self-healing probiotics-loaded hydrogel for promoting superbacteria-infected wound healing. ACS Appl Mater Interfaces. 2022;14(18):20538–20550. doi: 10.1021/acsami.1c23713
7. Zhu DY, Chen ZP, Hong ZP, et al. Injectable thermo-sensitive and wide-crack self-healing hydrogel loaded with antibacterial anti-inflammatory dipotassium glycyrrhizate for full-thickness skin wound repair. Acta Biomater. 2022;143:203–215. doi: 10.1016/j.actbio.2022.02.041
8. Huang X, Yang J, Zhang R, et al. Phloroglucinol derivative carbomer hydrogel accelerates MRSA-infected wounds’ healing. Int J Mol Sci. 2022;23(15):8682. doi: 10.3390/ijms23158682
9. Kubiczek D, Flaig C, Raber H, et al. A cerberus-inspired anti-infective multicomponent gatekeeper hydrogel against infections with the emerging “Superbug” yeast Candida auris. Macromol Biosci. 2020;20(4):e2000005. doi: 10.1002/mabi.202000005
10. Nandhini J, Karthikeyan E, Rajeshkumar S. Nanomaterials for wound healing: current status and futuristic frontier. Biomed Technol. 2024;6:26–45. https://doi.org/10.1016/j.bmt.2023.10.001
11. Mosselhy DA, Assad M, Sironen T, Elbarhiu M. Nanotheranostics: a possible solution for drug-resistant Staphylococcus aureus and their biofilms? Nanomaterials (Basel). 2021;11(1):82. doi: 10.3390/nano11010082
12. Ladju RB, Ulhaq ZS, Soraya GV. Nanotheranostics: A powerful next-generation solution to tackle hepatocellular carcinoma. World J Gastroenterol. 2022 Jan 14;28(2):176-187. doi: 10.3748/wjg.v28.i2.176. PMID: 35110943; PMCID: PMC8776531.
13. Li Y, Tian Y, Zheng W, et al. Composites of bacterial cellulose and small molecule-decorated gold nanoparticles for treating gram-negative bacteria-infected wounds. 2017;13(27). doi: 10.1002/smll.201700130