**Abstract**

Antimicrobial resistance (AMR) and its relevant health consequences have been explicitly framed as a shared global problem and are estimated to be one of the largest causes of death worldwide by 2050. Antimicrobial photodynamic therapy (aPDT) proposes an alternative treatment for localized infections in response to AMR's ever-growing problem. This technique combines molecular oxygen, a nontoxic photoactivatable photosensitizer (PS), and light of appropriate wavelength, leading to the formation of cytotoxic reactive oxygen species. Besides the ability to inactivate resistant pathogens via a non-selective approach (multiple targets), a relevant advantage of aPDT resides in the fact that no evidence of microorganism resistance has ever been reported to it. In this chapter, we address some efforts to use this technology to kill bacteria in the respiratory tract, from *in vitro* to clinical applications. We put forward three focuses: pharyngotonsillitis, pneumonia, and preventing secondary infections during the use of a photosensitizer-functionalized endotracheal tube. The results here presented offer a foundation for what may become a much larger clinical approach to treat respiratory tract infections.

**Keywords:** antimicrobial resistance, antimicrobial photodynamic therapy, photochemotherapy, infections of the respiratory tract, endotracheal tube

### **1. Introduction**

The increasing use of antibiotics has an important impact on human health by introducing the emergence of resistant bacterial strains, both in humans treated in an indiscriminate manner, and in two other situations as worrying as, which are the presence of these molecules in drinking water and abusive use in agriculture. This has all resulted in the phenomenon of antimicrobial resistance (AMR) [1].

Each year worldwide, 700,000 deaths occur, approximately, due to diseases that had antimicrobial resistance as responsible for the deaths. By 2050, these deaths could reach the terrifying 10 million mark [1].

One of the biggest barriers to antibiotic-resistant infections is that they add significant costs to the any nation's already overburdened health system [2].

Thus, the paths have been opened for other ways to fight infections and photodynamic therapy (PDT) has stood out with the aim of inactivating not only bacteria, but also fungi, protozoa, and viruses. It is a promising technique, including the treatment of diseases that already have antimicrobial resistance.

In this chapter we will address the theme of advances in research involving microbiological control with photodynamic action, more specifically in the treatment or prevention of diseases of the respiratory tract.

#### **1.1 Antimicrobial resistance**

The bacteria have developed several mechanisms to fight against antibiotics action. An important molecular mechanism involves the horizontal transfer of genes from the efflux pumps when the organism acquires a gene that confers the ability to eliminate antibiotics from the intracellular environment [3]. A well-known example is the acquisition of the β-lactamase gene from antibiotic inactivating enzymes, which inactivates β-lactam antibiotics, such as penicillin and cephalosporins [3], where bacteria acquire the ability to inactivate antibiotics through an enzymatic mechanism.

Two interesting aspects are related to cell wall morphology and the ability of bacterial colonies to form biofilms, and interestingly, these aspects are directly related to the cell wall structure of Gram-positive bacteria. The cell-wall glycopolymers from Gram-positive bacteria present an essential role in host-cell adhesion, the first step towards forming a bacterial biofilm. In contrast to Gram-negative, Grampositive bacteria have a thicker cell wall structure with multiple layers of peptidoglycan. In addition, many Gram-positive bacteria have protective surface structures, typically with glycopolymers bound to peptidoglycan or membrane lipids. These structures include glycopolymers of teicoic acids and branched mycobacterial polymers [4]. Infections caused by Gram-positive bacteria are important for human health and it is worrying that these bacteria are becoming increasingly resistant to existing antibiotics. The teicoic acids wall has multiple functional roles in Grampositive bacteria including resistance to cationic antimicrobial peptides, such as the vancomycin, a glycopeptide antibiotic. Other cellular processes influenced by this wall include autolysis, cell division, the location of penicillin-binding protein, survival at higher temperatures, biofilm formation and epithelial cell adhesion [5].

Biofilms have an important impact on bacterial infections and also on bacterial resistance. Organisms structured in biofilms exhibit up to 1,000 times more resistance to antibiotics than planktonic cells.

#### **1.2 Mechanisms of antibiotic resistance**

Pathogenic bacteria resistant to antibiotics are prevalent in different populations of the environment such as from the soil and water containing encode genes with resistance mechanisms [6], which can be mobilized for new hosts, including humans [7] and, depending on genic expression, may result in significant public health problems [8]. If the microbial mutations are for its benefice, such as antibiotic resistance, they are predominant in the species and transmitted for subsequent generations, making the bacteria predominant antibiotic-resistant [9]. The mechanisms of an antimicrobial resistance may be intrinsic to the microorganisms or even acquired through the transmission of the genetic material or by mutation (which may occur during replication) during the bacterial evolution, whether induced or spontaneous, by mutation mechanisms in a chromosome or transfer genes loci,

#### *Antimicrobial Photodynamic Therapy of the Respiratory Tract: From the Proof of Principles… DOI: http://dx.doi.org/10.5772/intechopen.95602*

which can encode inactivate enzymes in antibiotics or even reducing their permeability in cells [10]. The bacterial mutations that can occur are replacement (transition and transversion); deletion (macrodelection and microdeletion); insertion (macroinsertion and microinsection) and inversion, with exchange of pyrimidine or purine, removal of nucleotides, the inclusion of nucleotides, and removal or insertion of DNA, respectively.

Strains resistant to antibiotics can be transmitted between patients in healthcare units, often through healthcare professionals' contaminated hands, medical-surgical equipment, or inanimate objects from the hospital environment [11]. This type of spread is generally clonal, involving the transmission of a single resistant strain. Outbreaks caused by the clonal spread of an antibiotic-resistant organism have been commonly reported in *S. aureus* MRSA strains [12]. Patients' transmission can be clonal in multiple species of strains with different prevalence according to the geographic region [13].

### **1.3 The worldwide impact of antimicrobial resistance**

Infectious diseases are a major cause of human deaths. According to the World Health Organization (WHO), on the top ten global causes of death (2016), chronic obstructive pulmonary disease and lower respiratory infections are occupying the third and fourth places, respectively, behind ischemic heart disease and stroke [14]. It is relevant to note that infectious diseases outperform all types of cancer in terms of mortality, according to WHO data. Figures reported in 2016 indicate that there were 3.190 million deaths due to respiratory infections, with a mortality rate of 43/100,000. Analyzing again the top ten global causes of death but now, in low-income countries (2016), lower respiratory infections were among the leading causes of death across all income groups [14].

It is essential to discover and invest in the development of new antibiotic molecules, following the growing global need. But just as importantly, research into new non-antibiotic approaches for the prevention and protection against infectious diseases is needed and should be encouraged and a high priority research and development project [15].

In the US, the Centers for Disease Control and Prevention (CDC) estimated that antibiotic-resistant infections are responsible for \$20 billion a year in additional health care costs, and \$35 billion a due to loss of productivity [16]. Thus, a deeper understanding of the mechanisms of resistance to antibiotics is relevant in terms of human health, that is, it saves human lives, but it also reduces an important economic burden for public and private health systems.

Penicillin, discovered by Fleming in 1928, was first tested for the treatment of infectious diseases in the 1930s and became a widespread drug in the 1940s. β-lactam antibiotics, the group to which penicillin belongs, are effectively drugs of choice for the treatment of community-based respiratory diseases, for example, which are usually caused by Gram-positive bacteria, such as *Staphylococcus* and *Streptococcus*.

The introduction of new antibiotics in clinical use was quickly followed by the clinical observation of resistant strains and the time between clinical use and resistance has become shorter and shorter. For example, sulfonamides were introduced for clinical use in 1930 and resistant strains appeared in the 1940s. Vancomycin was introduced in 1956 and resistant strains were first reported in 1988. However, for newer antibiotics, such as daptomycin, fidaxomycin and linezolid, resistance was observed in the same year in which clinical use began [17].
