Antimicrobial Photodynamic Therapy – A new treatment approach for infectious diseases

The context of emerging antibiotics resistance and our first human study on Malaria patients

This article was initially published on the substack "Light and Equanimity". Click the link below to read more of the substack´s content and subscribe:

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Summary

In times of emerging antibiotic resistance, antimicrobial photodynamic therapy might be a promising treatment alternative for infectious diseases. I describe its advantages toward antibiotics; how it is currently used but also limited; and how it might have more widespread application in the future. In this context, I summarize our recent study in which the Weber Medical Endolaser system was used to treated Malaria patients with antimicrobial photodynamic therapy, demonstrating both the safety and efficacy of our protocol.

Antimicrobial Photodynamic Therapy

In my last substack, I highlighted how Photodynamic Therapy is different from “normal” Photobiomodulation, and explained its mechanisms that we can use to treat viral, bacterial, fungal, and parasitic infections.

Let´s now put this in the context of a major challenge in global public health; the development of antibiotic resistance, i.e. the ability of pathogens to grow despite exposure to antibiotics.

Sir Alexander Fleming initially discovered the first antibiotic penicillin in 1928, but widespread use of it only peaked in the mid-1950s. Antibiotics have been a great success story for many decades, but natural microbial selection mechanisms in combination with inappropriate use are increasingly leading to multi-resistant pathogen strains. Treatment failures and subsequently higher rates of morbidity and mortality, longer hospitalization, as well as increased healthcare costs are natural consequences. Here is a good publication if you want to read more about the molecular mechanisms of antibiotic resistance:

The need to develop treatment alternatives to conventional antibiotics is urgent and this is an offer to look in detail into one such alternative – antimicrobial photodynamic therapy (aPDT). A quick reminder – aPDT is based on the usage of “photosensitizers” (such as Riboflavin, as we will read a bit later) which bind to and thereby “mark” specific targets. The photosensitizers are then activated by light of specific wavelengths, according to their respective absorption bands. In the presence of oxygen, photochemical processes generate reactive oxygen species, resulting in the death of the microorganisms through the oxidation of genetic material, as well as cell membranes and other crucial cell components. Surrounding tissue is not damaged if photosensitizers with appropriate selectivity are used.

The method has several advantages to antibiotics:

- it also works on antibiotic-resistant pathogens, due to its multi-target mechanism of action.

- it can be used to treat many different kinds of pathogens, incl. bacteria, fungi, viruses, and parasites. A list was provided by Alves et al. in their review.

- its effects unfold on the order of seconds, whereas antibiotics take hours or even days to work.

- because the effects unfold in different ways and so quickly, pathogens seem to be unable to develop resistances against aPDT, at least to our current knowledge.

Sounds pretty good, doesn´t it? So why is aPDT still relatively unknown and not widely used then?

Well, that is mainly because aPDT-photosensitizers need a specific site to which they can bind and to which light with appropriate wavelength and dosage can be delivered. Naturally, this is much easier for superficial and localized infections, such as chronic wounds, chronic sinusitis, and infections on the skin and in the oral cavity. These applications of aPDT are pretty well recognized. However, it is sometimes described as inapplicable against systemic infections, mainly for two reasons:

- it is much more complicated to identify the right location to which the therapy should be targeted.

- sophisticated technology is required to deliver the light to these locations (which are, potentially, multiple locations across the body) or systemically. Keep in mind that the vast majority of PBM devices facilitate external, but not invasive light application.

Put simply, while the principle of aPDT is widely recognized and accepted, its practical in vivo application has so far been limited to mostly superficial and localized infections.

Our study on Malaria patients: Antimicrobial Photodynamic Therapy for malaria is safe and induced a significant reduction of parasite counts

This is the context of the study I recently co-published with Dr. Michael Weber, Robert Weber, Dr. Habeeb Ali, and Dr. Matthias Wojcik. We used an aPDT-protocol with Riboflavin (Vit B2) as a photosensitizer to treat the most severe form of Malaria – a systemic infection caused by plasmodium falciparum, a unicellular protozoan parasite. The study was designed as both a safety and proof-of-concept study. Riboflavin is free (“generally recognized as safe” by the US FDA), inexpensive, and at the same time a very potent photosensitizer. To anticipate the results, we were very happy to see that the protocol was efficient and fully safe.

But before we look into the details, let´s reflect on why Plasmodium falciparum caused Malaria is a suitable target for the aPDT protocol. On one hand, there is strong lab data that shows that the aPDT principle works well on this particular type of pathogen. The MIRASOL system I already mentioned in my last post could, for example, be used to reduce the percentage of parasitemia from 0.97 before treatment to <0.0005% after treatment. You can find links to other studies that concluded similar results on purifying blood samples from Plasmodium falciparum in the literature section below.

Part two of why Malaria is a suitable target for the aPDT protocol, despite being an internal systemic infection, is that Plasmodium falciparum has a development stage within mature red blood cells. Thus, our logic was to treat the disease during that stage, whereby Riboflavin (our photosensitizer) binds to the parasites while they are mostly located within red blood cells. The photoactivation can then be achieved via the intravenous application of ultraviolet and blue light (facilitated by the Weberneedle Endolaser system), as these are the wavelengths required for the photodynamic activation of Riboflavin. The sophisticated application technology is crucial at this point.

I am not going to write too much about the details of our study – you can find them all here:

https://www.jclinmedcasereports.com/articles/OJCMCR-2111.pdf

The quick summary is that we used White Blood Cell Counts and the Packed Cell Volume Test (a general blood screening done to diagnose dehydration, or abnormally low or high levels of red blood cells) to test for the safety of the protocol. To assess the efficacy of the protocol, we conducted parasite counts and let the patients report their symptom development quantitatively. The findings of our study group were compared to a control group that received standard Artemisinin-based combination therapies (ACTs).

You find an overview of the parasite count values in both groups below. It is important to highlight that ACTs deliver good and quick results in most cases. Seeing that our aPDT-protocol delivered even faster parasite clearance was super encouraging for us. Likewise, symptoms improved on average a bit faster in the aPDT group than in the control group. There were no significant changes in packed cell volume and white blood counts detectable. A very much desired outcome, we can say.

Can we use this protocol to treat all kinds of infections?

It is certainly too early to make such a statement, but what we understand so far suggests that the protocol can effectively be used against a variety of pathogens. However, we also understand some aspects that influence how well patients will likely respond to the protocol. As mentioned before, the course of the disease must somehow offer an appropriate spatial treatment side, which is not always the case for systemic diseases. Furthermore, microbial barriers, i.e. microbial cell walls and biofilms, play a crucial role. In general, Gram-positive bacteria are more susceptible to aPDT compared to Gram-negative bacteria and fungi. Akin to antibiotics, photosensitizers cannot effectively penetrate biofilms, making “biofilm-protected pathogen communities” less susceptible to aPDT. However, nano-material-packed photosensitizers (and of course other “delivery solutions”) can be used to deal with such delivery issues. As usual, I offer you a good read to dive deeper into this.

I believe that antimicrobial PDT can play an important role in how we treat infectious diseases in the future. The results of our study were very encouraging but, undoubtedly, a lot more research is required.

By Martin Junggebauer

https://www.linkedin.com/in/martin-junggebauer-3892b566/