1 Introduction

The aim of this review is to describe why antimicrobial Photodynamic therapy (aPDT) has become an important component in the treatment of human infection and to discuss what future guidelines for its clinical application might include. The emergence of antibiotic resistance has been considered, as have vertical and horizontal infection control strategies [1], and a range of technologies effective in eradicating microbes without building up new resistance. The mechanism of action of these technologies is described and examples of their clinical use summarised. Finally, national and international clinical guidelines on the manifestations of microbial infection and the use of PDT have been studied, including their research recommendations. While consensus on the use of antimicrobial PDT in humans is the ultimate focus of this review, it is first acknowledged that: the methods were developed in the laboratory; [2] many of the basic science investigations were done on murine cohorts; [3] current veterinary indications for PDT are broad ranging and include bacterial infection in domestic animals [4].

Antibiotics were clinically introduced during the Second World War and the emergence of resistant strains of bacteria was described as early as 1959 [5] followed by a detailed study of the underpinning mechanisms revealing several modes of resistance. Innate immunity to specific antibiotics exists in microbes because of impenetrable cell membranes, active cell efflux, and/or the presence of certain gene alleles in specific positions on the chromosome creating a resistant phenotype [6]. These mechanisms pre-date the use of antibiotic drugs [6]. Extrinsic resistance is an acquired property evolving via mutation, or during experimental recombination [7], when antibiotics are used at subinhibitory concentrations causing recombination [8], or via horizontal transfer of r-genes [9].

Methods of tracing the evolution of microbial strains have been described including phylogenetic trees [10]—retrospective by nature—and prospective in-vivo measurements of the natural course of the nosocomial bacterial infection becoming resistant to a series of antibiotics [11]. Nanotheranostics offers additional insights by allowing observation of microbes in-situ, [12] and during treatment.

During the Covid-19 pandemic, infection prevention and control in public places and healthcare has been enhanced [13,14,15,16] to minimise the proliferation of the virus. However, antimicrobial stewardship has diminished [17, 18] with the net effect likely to be a worldwide increase in microbial resistance. In their 2010 paper, Davies and Davies [19] highlight the presence of multidrug-resistant bacteria in the biosphere with consequences aggravated by civil unrest, violence, famine, natural disaster and poor hospital practices; and so the net long-term effects of Covid-19 on bacteria, and indeed other microbes, has yet to be realised. Multiple and extreme (a lack of susceptibility to four or more drugs) antibiotic resistance has necessitated the use of alternative treatment methods for microbial infection including electroporation [20]; antimicrobial peptides (AMPs) [21]; photodynamic therapy (PDT) [22]; photothermal therapy [23]; nitrous oxide (NO) releasing nanoparticles [24]; cannabidiol [25]; or combinations of therapies. Electroporation is a technique where 30–100 V pulses are used for a fraction of a second to create local aqueous permeable regions in between lipid membranes by destabilisation [26], however, its clinical importance have yet to be tested. Accessibility and limitations on sensitivity and specificity of PDT has been addressed by conjugation of known photosensitisers to cationic molecules, AMPs, antibodies, targeted antibiotics or nanomaterials [27,28,98] and antibiotics [31]; with adjunct illumination to modulate antibiotic function or monitor progress in bacterial eradication [12]; simultaneous PDT, PTT and bioluminescence [99]; the management of sepsis [100]. Conventional PDT will undoubtedly play a part given its large evidence base and existing healthcare facilities and infrastructure—It may be the only treatment necessary for some cases of Acne vulgaris and related scarring. Daylight PDT and the use of ambulatory devices could become more popular in regions where resources are limited, with a broader scope than just CL and Acne Vulgaris—subject to high-quality evidence. In theory, the resistance of microbes to antibiotics is reversible, and in practice it is possible that new resistance could at least be halted by the use of supplementary drugs. Antibiotics are therefore unlikely to become obsolete.