Matthew Whittaker

Delftia is a genus of gram negative, aerobic, rod-shaped bacteria commonly found as an environmental microbe^[1]. Although human infection with Delftia spp. is rare and primarily limited to immunocompromised individuals, there is an increasing prevalence in Delftia infections of both immunocompromised and immunocompetent patients reported in literature, with some cases resulting in death of the patient ^[2][3]. Delftia isolated from these infections often exhibit antimicrobial, specifically multidrug resistance, suggesting a need for therapies alternative to antimicrobial compounds in successfully combating these infections (Table 1). One alternative to conventional antimicrobial therapy is the use of bacteriophage therapy. Bacteriophages demonstrate the ability to disrupt biofilms, are effective at reducing populations of antimicrobial-resistant bacteria, and are not currently known to pose any significant health risks in patients receiving therapy ^[4]. This review focuses on Delftia spp. reported in clinical literature, including their antimicrobial resistance and biofilm formation, as well as the reported efficacy of bacteriophage in infecting and reducing Delftia populations in studies.

A major public health concern of increasing importance is the evolution of bacterial pathogens that are resistant to conventional antimicrobial agents, such as antibiotics and disinfectants. Antimicrobials are widely employed on a global scale, and excessive or inappropriate application of antimicrobials can contribute to the development of antimicrobial-resistant bacteria, or ARBs ^[5][6]. With the rise of antimicrobial resistance, an increasing number of conventional antibiotics are becoming obsolete in treating bacterial infections, and some bacterial infections have been documented that are resistant to most or all conventional antimicrobial agents and thereby untreatable via current methods^[7].  These antimicrobial-resistant infections are expected to claim 10 million lives and 100 trillion US dollars annually by the year 2050, while reducing the ability of healthcare professionals to perform surgery or administer chemotherapy, due to the high associated risks of infection ^[8]. Thus, alternate strategies to treat and prevent infections with antimicrobial-resistant bacteria are of immense value to the maintenance of public health in the modern era.

Recent literature has reported Delftia spp. as infectious agents in numerous clinical settings with human patients. Delftia infections typically occur in immunocompromised patients, especially those with indwelling devices such as catheters that present a risk for bacterial growth and biofilm formation and a breach in primary defense that allows for entry of environmental pathogens ^{[9][10][11][12][13][14]}. However, an increasing number of articles present Delftia infections in immunocompetent individuals with no indwelling devices or adverse health history (Table 1). These Delftia infections may become severe, with multiple cases resulting in the death of the patient ^[15][16]. The severity of these infections can be compounded by the antimicrobial resistance of reported Delftia pathotypes, which delays the ability of healthcare professionals to promptly administer antibiotics that are effective against the species and pathotype involved ^[17]. In addition, as Delftia spp. commonly form biofilms, especially in regards to infections resulting from the use of indwelling devices, antimicrobial resistance in these populations may be significantly heightened ^[18].

Biofilms are aggregations of surface-associated microbial cells that are enclosed in an extracellular polymeric substance matrix, typically of polysaccharides ^[19]. The formation of biofilms in pathogenic organisms is one of the greatest challenges to modern public health, as biofilms allow for: increased horizontal transmission of antibiotic resistance factors in comparison to planktonic bacteria, a significant reduction in susceptibility to antimicrobial compounds, prolongation of the time required for antimicrobial treatments to successfully cure infections, and the development of systemic infections when biofilm cells detach and enter the bloodstream or urinary tract ^[20]. Delftia bacteria are known to form biofilms on the surfaces of catheters, endotracheal tubes, and chemotherapeutic ports ^{[21][22][23][24]}. These biofilms demonstrate resistance to multiple classes of antimicrobial compounds, including antibiotics such as beta-lactams, aminoglycosides and quinolones, and disinfectants such as chlorhexidine and commercial contact lens solutions ^[25][26]. In addition, the formation of biofilms in Delftia spp. can promote the horizontal transmission of resistance factors, such as the class III integrons isolated from environmental strains D. acidovorans C17 and D. tsuruhatensis A90 ^[27]. As these integrons are known to encode for genes conferring resistance to antimicrobials such as beta-lactams and aminoglycosides, it is possible that rapid dissemination of resistance genes among Delftia spp. could be facilitated by biofilm formation in clinical settings ^[28].

It is apparent, especially with the prevalence of antimicrobial-resistant strains of Delftia and biofilm formation in clinical settings, that conventional antimicrobial approaches to combating Delftia infection may be limited in their scope and effectiveness in the future. A primary focus of current research in the treatment of multidrug-resistant bacterial infections is in the use of bacteriophages to treat bacterial infections, known as bacteriophage therapy. Bacteriophage therapy has been demonstrated to be effective in treating numerous infections in humans, including those of Klebsiella pneumoniae, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, with the success rates of bacteriophage treatment typically higher than the use of antibiotics or antibiotics alone ^[29]. In addition, bacteriophage therapy presents numerous benefits when compared to traditional antimicrobial compounds: bacteriophages are highly selective in lysing bacteria and therefore present a reduced risk of disrupting natural microbiota, cannot infect host cells and are therefore safe in human use, and experience a naturally high “evolution rate” to adapt to new strains of pathogenic bacteria ^[30].

Lytic bacteriophages, those capable of causing bacterial cell lysis and death that are the primary focus of bacteriophage therapy, have been reported for numerous strains of Delftia in literature ^{[31][32][33][34]}. Additionally, Delftia-specific bacteriophage RG-2014 has demonstrated the effective disruption of multidrug-resistant D. tsuruhatensis ARB-1 biofilms and the lysis of ARB-1 bacterial cells^[35][36]. To our best knowledge, only two phages have currently been reported in literature that are known to infect Delftia spp.: Delftia tsuruhatensis ARB-1 phage RG-2014 and Delftia acidovorans ATCC 9355 phage phiW-14. Both are capable of cellular lysis: RG-2014 is strongly implicated as a virulent phage, and phiW-14 is a lytic bacteriophage that can enter into a carrier state with its host ^[37][38].

Although the literature on phiW-14 is relatively limited, this phage possesses many unique properties that carry important implications in the study of bacteriophage-host interactions and potential medical or industrial use. PhiW-14, first isolated in 1967, is a member of the bacteriophage family Myoviridae, with a 157kb genome specifying 236 proteins ^[39]. PhiW-14 extensively modifies its DNA by substituting thymidine (T) with alpha-putrescinylthymidine (PutT) through specialized enzymatic pathways ^[40]. This substitution has been demonstrated to confer multiple advantages to PhiW-14: DNA resistance to 68.8% of Type II restriction endonucleases, reduced rate of exonuclease degradation when compared to similarly hypermodified DNA, resistance to digestion by DNA glycosylase (hSMUG1) and AP endonuclease (VIII), and improved packaging of DNA into the viral capsid ^[41]. However, the specific means by which this molecular hypermodification confers an advantage to phiW-14 are poorly understood, and represent a unique opportunity to better illuminate the mechanisms involved in bacteriophage-host interactions. In addition, understanding the ability of phage phiW-14 to resist, unlike other hypermodified phages, certain degradation mechanisms could prove valuable in studying and developing resistant bacteriophages for use in industry and healthcare settings, and could lead to improved effectiveness of bacteriophage products and treatments.

As discussed, antimicrobial resistance in bacteria presents a growing threat to public health. The increasing incidence of antimicrobial- or multidrug-resistant bacteria in human disease contributes to a decrease in effectiveness of conventional antimicrobials that serve as the main defense of infection in modern healthcare systems. This effectiveness may be further decreased by the ability of many bacteria to form biofilms, drastically decreasing their susceptibility to antimicrobial compounds, enhancing the transmission of genetic resistance factors, and facilitating the entry and spread of bacteria into the body. One promising area of research in combating antimicrobial-resistant microbes is the use of bacteriophage therapy, demonstrated to be successful in treating human infections of several widespread pathogens important to clinical research. One bacterial genus of increasing importance in clinical settings is Delftia, a generally harmless group of bacteria ubiquitous in water and soil environments. These bacteria, once believed to only infect immunocompromised patients, are increasingly linked to infections in immunocompetent individuals, and many strains reported in literature are both resistant to broad classes of antimicrobials and capable of forming biofilms. As scientific literature has demonstrated the effectiveness of bacteriophages in lysing antimicrobial-resistant Delftia and disrupting Delftia biofilms, it is possible that bacteriophage therapy could present a safe and effective remedy to Delftia infections in the future, especially in cases where antimicrobial use is ineffective or risky. In addition, Delftia bacteriophage phiW-14 presents a unique opportunity to study phage resistance to bacterial defenses, which could prove valuable to the development of more effective industrial products and medicinal treatments.

Table 1. A selection of clinical cases of Delftia infection reported in literature, including reported antimicrobial resistance, health history of the patient, and treatment outcome.