Antibiotic resistance is an immediate threat to global health. In fact, the twenty-first century has seen the emergence of pan-resistant strains, specifically among Gram-negative bacilli. This includes strains resistant even to colistin, which has long been considered the last resort treatment for infections caused by such Gram-negative bacteria. The scope of this threat is reflected in the designation by the Infectious Diseases Society of America (IDSA) of the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) based on their prominence as a cause of human infections and the diminishing availability of antibiotics to treat these infections. Similarly, the Centers for Disease Control (CDC) has designated an even larger group of bacterial pathogens as “concerning” (3 species), “serious” (12 species) or “urgent” threats (3 species). The problem of drug resistance is compounded by the fact that efforts to develop new antibiotics have dramatically decreased in recent years owing largely to economic considerations. An additional issue is the certainty that resistance to any new antibiotic will rapidly develop in direct accordance to the frequency of its use. Another feature of drug resistance is the capacity of many of the most concerning bacterial pathogens to form a biofilm, the presence of which confers a therapeutically relevant degree of intrinsic resistance to both conventional antibiotics and host defences. Such observations emphasise the urgent need for alternative therapeutic approaches to the treatment of infectious diseases.
Thus, it is with great pleasure that we introduce this special issue of the International Journal of Hyperthermia focused on the treatment of infectious diseases using heat. Although this theme has existed within the field of thermal medicine from its beginning, much of the content of this journal has historically been focused on applications in oncology. While this focus is clearly justified and has led to important applications of thermal medicine, we believe thermal medicine also offers a unique approach to the treatment of infectious diseases. Indeed, developing improved and highly targeted approaches to manage localised and systemic infections based on thermal therapy has the potential to tackle a major challenge facing global healthcare systems that in many regions rivals or even exceeds the burden of cancer in terms of incidence, mortality and cost.
Thermal medicine offers many unique characteristics that make it an attractive candidate for treating infectious diseases. For example, the body uses mild fever as its own defence mechanism against infection, so there is a pre-existing biological rationale for the use of heat. Another reason for considering thermal approaches in infectious disease is the ability to non-invasively deliver the energy required to generate the necessary heat. A third is that thermal approaches have the potential to result in the physical destruction of bacterial cells and thus retain their efficacy irrespective of the metabolic or even antibiotic resistance status of the offending pathogen. Thermal approaches also offer an opportunity to augment the efficacy of conventional antimicrobial agents. This is particularly true in localised infections like osteomyelitis and infections associated with indwelling medical devices, where a non-invasive means of augmenting existing antimicrobials would be particularly attractive. In oncology, the nature of most drugs is such that they can only be delivered in a single or limited number of doses due to the toxicity of the agents. However in infectious disease, the administration of antibiotics can occur over a prolonged period of days to weeks depending on the infection. This raises the opportunity to take advantage of ongoing heat-drug interactions to augment the effect of antimicrobials, especially if synergistic relationships are found to exist and can be exploited.
The application of heat in infectious diseases is certainly not without its challenges. First, many infectious diseases are systemic, and targeting such infections with heat is likely to prove difficult. Second, data from prior studies, including one in this issue, suggest that inactivation of bacteria requires greater temperatures for longer periods of time in comparison with eukaryotic cells. This raises questions about the safety of thermal treatment without adverse effects on surrounding tissues. Thirdly, the biological differences across the multiple species and strains of pathogens are much greater than the differences between normal and tumour cells, which suggest that a single unified model of thermal inactivation may be unlikely. At the same time, this diversity offers tremendous opportunities for highly specific targeting such that the desired therapeutic impact can be achieved without damage to surrounding host tissues or even the bacterial species that constitute the important normal flora of healthy humans.
At present, there is a paucity of data regarding the appropriate thermal thresholds required for inactivating pathogens in the body, the response of these pathogens to heat, and the interaction of heat with antimicrobials. These areas represent opportunities for our field to fill the knowledge gap and develop new strategies for treatment of infectious diseases. In this vein, this special issue is a “kick-off” of a new movement in the Society for Thermal Medicine. This effort expands the reach and application of heat to treat resource limited underserved populations. However, drug resistance knows no economic boundaries, as it is an important issue in developed countries as well.
This issue contains comprehensive reviews and primary manuscripts that address a wide range of topics that we trust you will find interesting. For example, Ibelli et al provide a review on prior studies that have explored the use of hyperthermia for bacterial infections, and Wang et al provide a review of heat inactivation models from the foodborne pathogen field. The topic of combining heat with nanoparticles to treat infections is addressed in a number of the articles in this issue. Cortie et al address this from a theoretical view, evaluating the energy requirements, opportunities and challenges in trying to utilise nanoparticles sensitive to light or magnetic fields for pathogens in the body. Nigatu et al and Munaweera et al explore the well-established temperature sensitive liposomes that have seen clinical translation in oncology for their applications in infectious disease. Meeker et al report on gold nanoparticles loaded with antibiotics for the treatment of biofilm-associated infectious. Ricker et al also explore the thermal sensitivity of Pseudomonas aeruginosa biofilms to heat shock, and Bucsek et al review the role of the immune system in responding to infectious disease.
We hope the reader finds the combined effect of the information presented in this special issue stimulating, and that it serves as a catalyst to attract many of the talented researchers in the field of thermal medicine to apply their tools and knowledge to this increasingly important medical problem.
Disclosure statement
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.