The Safety of Bacteriophages in Treatment of Diseases Caused by Multidrug-Resistant Bacteria

1. Introduction

The re-emergence of bacteriophages (phages) for the treatment of chronic or difficult-to-treat infections and diseases has been extensively observed in recent years. Phages are viruses that specifically target and kill host bacteria. They serve as a possible alternative to antibiotics in the treatment of bacterial infections, especially in this era where there is a lack of new and effective antibiotics to combat the rise of multidrug-resistant (MDR) bacteria. The term “MDR” refers to organisms that are resistant to at least one antibiotic agent from three or more antibiotic classes [1]. Extensively drug-resistant (XDR) and pan-drug-resistant (PDR) bacteria are also used to categorize bacterial resistance, of which XDR bacteria are non-susceptible to at least one agent in all but two or fewer antibiotic categories, and PDR bacteria are resistant to an agent from all antibiotic classes [2].

The development of phage therapy as an alternative to traditional antibiotics has gained substantial interest over the years. However, its ultimate success in clinical use relies on evidence that proves phage therapy is safe and non-toxic for humans. A major safety concern is the disruption of the body’s microbiome, which is a key regulator of human health. Another concern is the impact of phage on the immune system, which may ultimately lead to chronic inflammation and other immune reactions. As phages are prepared by co-culturing with bacteria, it is crucial to consider the potential risk of endotoxin contamination that could trigger the inflammatory cytokine response, resulting in serious health issues such as toxic shock [3]. Additionally, the use of temperate phages may produce bacterial lysogens that are resistant to the same phage type, potentially increasing their virulence [4].

Recent studies have shown that phages are generally safe and do not produce any adverse effects when used in animals or humans [5,6,7,8]. Nevertheless, a few studies have reported transient adverse events or side effects during phage therapy, which include inflammation, flushing, hypotension, and fever [9,10,11]. The absence of a standard protocol to evaluate the safe usage and preparation of phages results in a lack of consistent, complete, and reliable data to conclude the safety aspect of phage therapy. Hence, a rigorous and detailed exploration of phage safety is required to guide treatment decisions.

In this review, we discuss the advancement, importance, and current applications of phages. Phage applications in clinical settings, the food and agricultural sector (e.g., prevention), and environmental control (e.g., biosensors) are reviewed. It also focuses on the safety concerns and challenges of translating phages from the bench to clinical bedside applications. The topics that are included are the disruption of the microbiome, immunological responses, induction of phage resistance in bacteria, lysogeny, and contaminants (e.g., endotoxins) associated with phage preparation. The environmental safety issue related to phage release is also briefly discussed.

2. The Era of Phages

2.1. An Alternative to Antibiotic

Ever since the discovery of the “wonder drug” penicillin, antibiotics have been the first line of defense against bacterial infections. Indeed, virtually everyone alive today has grown up in the antibiotic era. However, the overuse of antibiotics has inadvertently led to the emergence of MDR bacteria. For example, infections caused by Acinetobacter baumannii such as pneumonia, meningitis, and sepsis have traditionally been treated with beta-lactams [12,13]. However, MDR A. baumannii strains, including those resistant to beta-lactams, are increasingly reported; hence, last-line antibiotics such as polymyxins are prescribed for their treatment [14,15]. Thus, A. baumannii is listed by the World Health Organization (WHO) as a priority pathogen for which new antibiotics are urgently needed, along with other bacteria such as Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa, collectively referred to as the ‘ESKAPE’ pathogens [16]. As MDR bacteria become more prevalent among human populations, they pose a serious threat to clinical and public health, thus becoming a major global health issue. With only a handful of new antibiotics on the horizon [4], there is a growing need to explore alternative antimicrobial strategies, of which phage therapy has become increasingly apparent.

Phages are the most abundant and diverse biological entities that are present on Earth [17]. Phages are highly specific, and they are loosely categorized into monovalent or polyvalent phages depending on their host range. Monovalent phages are defined as phages that have a narrow host range spectrum specific to a single bacterial genus, whereas polyvalent phages are phages that have a broad host range specific to more than two genera [18]. For example, FAHEc1 is a monovalent phage that only targets Escherichia coli and can be used to reduce contamination in beef, whereas S5 and vB_EcoM_swi3 are polyvalent and target both Salmonella and E. coli [19,20,21]. Phages exhibit different life cycles, including the lytic cycle, chronic cycle, lysogenic cycle, and pseudolysogenic cycle [22]. Worth noting, lytic phages are often favored for phage therapy due to their ability to effectively lyse bacteria [15].

2.2. Current Phage Applications

Ever since the discovery of phages, researchers have taken advantage of their abundance and infection specificity to combat pathogenic bacteria, mainly for treating bacterial infections, preventing food contamination, and for environmental control. With the emergence of MDR bacteria, research examining phages as an alternative to antibiotics has once again begun in earnest, with the current application of phages against these “superbugs” briefly discussed below.

3. Safety Concerns and Challenges

Despite successful cases of treatment with phage therapy, the safety and potential side effects pose a significant challenge to its broader application, especially for clinical use. The concerns associated with the human body include the impact of phage on the microbiome, lysis-induced endotoxin release, immune activation, and increased bacterial resistance. Phage usage may also have environmental implications.

3.1. Human Body

3.2. Temperate Phages

Lytic phages are unanimously preferred over temperate phages for therapy purposes. The administration of temperate phages may not be favored due to their intrinsic nature, which favors the lysogenic cycle, in which their genomes are integrated into the bacterial genome and do not lead to immediate bacterial killing. Importantly, bacterial lysogens often exhibit resistance to subsequent infections by phages [4]. Superinfection exclusion and superinfection immunity are the mechanisms that prevent superinfecting phages from either entering the bacterial cell or blocking their infection cycle within the bacterial cell [66].

Temperate phages have the ability to obtain ARGs and virulence genes from the infected host and subsequently transfer them to other bacterial hosts. This process can inevitably lead to the widespread distribution of these factors among bacteria, contributing to the development of difficult-to-treat MDR bacteria. Hence, it is advisable to refrain from using temperate phages in phage treatment until more comprehensive research is available to guide their application. In fact, researchers have been exploring phage engineering techniques to modify temperate phages, making them safe and effective for use in phage therapy.

3.3. Induction of Phage-Resistant Bacteria

As phages are increasingly employed for the treatment of bacterial infections, it has unavoidably led to the emergence of phage-resistant bacteria. It has been reported that bacteria can develop phage resistance through various mechanisms, which include receptor alterations, abortive infection systems, bacteriophage exclusion (BREX), and quorum sensing defense [105]. An example of receptor alteration is observed in Bordetella spp. that prevents infection from phage BPP-1 by suppressing the expression of the phage receptor pertactin autotransporter (Prn) [106]. The abortive infection (Abi) system is a strategy that induces host cell death, thus limiting phage propagation. An example of Abi involves the toxin-antitoxin systems, of which Erwinia carotovora subspecies atrosepticawa was found to consist of a toxI gene that encodes for an antitoxin that neutralizes ToxN [107,108]. The BREX defense system is another mechanism that has been increasingly reported. Bacillus cereus consists of six-gene cassettes called BREX defense systems that are subject to substantial horizontal gene transfer and offer total phage resistance to a variety of phages, including lytic and temperate phages [105]. A summary of the mechanism of phage resistance in relation to the life cycle of phages is presented in Figure 1.

Figure 1. A schematic illustration of the mechanism of phage resistance in relation to the general lytic phage cycle. (1) Phages can attach to the surface of host bacteria using receptor-binding proteins (RBPs). Bacterial cells have various ways to disrupt this attachment process, such as by alternating, reducing, and/or masking their receptors on the surface of the cell. (2) During translocation, phage DNA is directly injected into the host cell’s cytoplasm. Certain bacterial strains can hinder this injection by employing proteins encoded by the host that interfere with the transfer of phage nucleic acid. (3) Once inside the host cytoplasm, phage DNA undergoes preparation for replication. Whether the phage DNA is modified or unmodified, it can be degraded by host-encoded proteins following its translocation into the host cytoplasm. Normally, replication, transcription, and translation of the phage DNA will proceed as usual. However, bacterial cells may be able to resist this action through the initiation of the Restriction–Modification system, the CRISPR system, the BREX system, or the abortive infection system. (4) Assembly and packaging are crucial steps in the production of new phage particles. Certain bacterial strains express proteins that interfere with the assembly or packaging process of the newly synthesized virions. These proteins disrupt the proper formation of the phage capsid or the packaging of phage DNA into the capsid. (5) If the lytic phages manage to pass through all the bacterial defenses, it will eventually lead to host cell lysis. Created with Biorender.com.

3.4. Environmental Impact

The application of phage therapy may directly or indirectly affect ecosystem biodiversity as phages are released into the environment; however, there is limited research on the environmental impact.

Research has been conducted to compare the disposal of therapeutic phages and broad-spectrum chemical antibiotics in the environment. There has been an increasing focus on antibiotic surveillance and investigations into strategies for appropriate antibiotic disposal [109]. The presence of antibiotic traces in the environment, such as surface and ocean waters, has resulted in increasing public concern due to the potential for promoting the emergence of MDR bacteria. Contrary to antibiotics, discarded therapeutic phages are said to only have a minimal effect on a small group of bacteria as they are often originally isolated from the environment. Furthermore, phages can be rapidly inactivated if they are not adapted to harsh environmental factors, such as extreme temperature, humidity, and UV light [66]. Worth mentioning is that phages are able to withstand a wide range of temperatures (generally 40–70 °C) [110], therefore making them more thermally stable in comparison to antibiotics.

Although phages are naturally present in the environment, the release of high phage concentrations as a result of phage therapy could potentially cause an imbalance in the ecosystem by disrupting the natural microbial balance [111]. Hence, proper waste management represents an essential area that should be put in place to protect the environment and safeguard public health.

4. Studies on Phage Safety

Several animal studies [6,8,83], case reports [5,7,10], and clinical trials [13] have been conducted to monitor the safety of phages in the treatment of MDR bacteria.

4.1. Animal Studies

Murine and sheep are often used as animal models for studying phage safety. The use of the sheep model provides an advantage over the more commonly used murine model as it is one of the most significant representations of human organ systems, providing a more accurate assessment of phage safety in humans.

Phage therapy has been demonstrated to be safe and effective in treating pathogenic E. coli, P. aeruginosa, S. aureus, and A. baumannii in sheep and mouse models [6,83]. Utilizing a murine model, phage 536_P1 successfully eradicated E. coli infection without inducing an innate inflammatory response [83]. In another study conducted by Yin et al. (2017), phage Abp1 was effective in eliminating MDR A. baumannii in mice without eliciting any cytotoxic effects [8]. Employing a sheep rhinosinusitis model, the administration of a phage cocktail locally at the sinus for treating P. aeruginosa infection resulted in no significant adverse effects, such as loss of appetite, fever, or other signs of systemic illness [6]. Similarly, the treatment of S. aureus-associated rhinosinusitis in sheep with the phage cocktail NOV012 was not associated with tissue damage or inflammatory infiltration [112]. Details for these animal studies are summarized in .

4.2. Clinical Cases

Multiple case studies have included phage safety monitoring. Liu et al. (2021) have conducted one of the first systematic literature reviews on phage therapy clinical cases where phage safety monitoring alongside treatment is included [113]. These case studies mostly involve patients with conditions such as cystic fibrosis, prosthetic knee infections (PKI), urinary tract infections (UTI), surgery/transplant-related wound infections, and abscesses.

As endotoxins are a major source of phage contamination that may lead to adverse effects during therapy, several case reports have reported the endotoxin level of the phage products used for clinical treatment. While most of the studies reported endotoxin levels within the FDA limits [10,114,115], dilutions were required by some phage products to achieve safe endotoxin levels [11,30,116]. The process of diluting phages to adhere to clinical endotoxin limits results in a reduced phage concentration, potentially compromising the effectiveness of therapy [94]. Due to the lack of standardization, some studies do not include this safety aspect in their research, and consequently, endotoxin levels are not reported [5,117].

In one study, inflammatory changes were assessed following IV and/or intraarticular (IA) administration of SaGR51Φ1, along with antibiotic administration. This study reported no significant inflammatory effect except for a transient, reversible transaminitis [10]. Most cases have reported little to no significant adverse reactions or that the effects were not phage-related . Of note, transient fever represents the most associated adverse effect reported; however, fever is a common physiological response to infection.

Overall, it is crucial that standardized therapeutic guidelines are made available to promote consistency and uniformity in monitoring the safety profile of phage therapy, enabling a more reliable conclusion to be drawn.

4.3. Clinical Trials

Clinical studies that evaluate the safety aspects of phage therapy are scarce. In a clinical trial to test the efficacy and safety of phage therapy for treating urinary tract infections caused by MDR uropathogens (Enterococcus spp., E. coli, Proteus mirabilis, P. aeruginosa, Staphylococcus spp., and Streptococcus spp.), patients were subjected to either receiving Pyo phage (intravesically), placebo, or antibiotics [134]. The lowest occurrence of adverse effects was demonstrated by the phage group (21%; 6/28) in comparison to the placebo (41%; 13/32) and antibiotic (30%; 11/37) groups. Another phage therapy clinical trial was conducted on patients with MRSA infections. The safety aspects that were considered in this study include pain and systemic adverse reactions [135]. When patients were treated with phage AB-SA01, no adverse events were reported, although there was a notable decrease in inflammation markers and an increase in cytokine interactions. In a clinical trial involving the treatment of chronic ear infections caused by antibiotic-resistant P. aeruginosa, Biophage-PA significantly reduced the bacterial load, and no phage-related adverse effects were observed [136]. The details of these clinical trials are shown in . The presented clinical studies were chosen based on the criteria that they are recent studies involving phage therapy, specifically related to MDR bacterial infections, and that they evaluate the safety aspect of phage therapy.

5. Challenges and Future Improvements

Difficulties arise when attempting to compare the data across published clinical cases and clinical trials, as different studies employ their own set of treatment and monitoring protocols [113]. In order to improve current practices, the establishment of a gold standard or standard operating procedure is of paramount importance to guide phage preparation, storage, and transport, as well as the monitoring criteria for determining the efficacy and safety of phage therapy. The purified phage lysate should also adhere to the Good Manufacturing Practice (GMP) guidelines to ensure safety [129].

When phage products are used for therapeutic purposes, information such as the phage genome, titer, purity, and endotoxin level should be made available. Insufficient and incomplete data regarding phage safety monitoring represents another limitation to fully understanding the safety profile of phage therapy. The safety endpoints that can be included are evaluation of the patient’s physical symptoms, chemical lab assessment (e.g., kidney and liver function tests, electrolytes, and inflammation markers), hematology lab assessment (e.g., complete blood count), and immunological response evaluation (e.g., antibodies) [113]. The availability of this comprehensive data would permit a more thorough safety assessment of phage therapy, thus facilitating policymakers’ efforts to establish a comprehensive regulatory framework for phage treatment [137].

Phages are often used in combination with antibiotics to achieve better antibacterial activity [5,87,117], achieved by phage-antibiotic synergy (PAS) [138]. For instance, Uchiyama et al. (2018) evaluated phage-antibiotic combinations against P. aeruginosa and observed that combining piperacillin and ceftazidime with P. aeruginosa phage KPP22 showed the strongest PAS [139]. Understanding the mechanisms underlying PAS is the key to designing phage-antibiotic therapy. Utilizing metabolomics, it was revealed that the combination of polymyxin B and phage pK8 caused a prolonged inhibition of the citrate cycle, pentose phosphate pathway, and amino acid and nucleotide metabolism of K. pneumoniae [140]. It should also be noted that antagonistic phage-antibiotic combinations are often overlooked. A recent study by Zuo et al. (2021) showed that replication of coliphage T3 was impeded by aminoglycoside antibiotics (e.g., neomycin and kanamycin), which inhibit protein synthesis [141]. Overall, careful consideration and more research are needed to inform appropriate concentrations, application timing, and optimal selection of phages and antibiotics based on patients’ diagnoses and medical histories.

In order to further advance the field of phage therapy, it is essential to establish comprehensive phage libraries consisting of a diverse array of phages that are known to be safe and effective against bacterial infections. By having such accessible repositories of phages, the potential for finding suitable phages can be significantly enhanced.

6. Conclusions

Since their discovery, phages have been extensively utilized in the agricultural and environmental sectors to ensure food safety and effective pathogen control. Phages have also re-emerged as an alternative to antibiotics due to the emergence of MDR bacteria. As phage therapy research against MDR bacteria advances quickly, ensuring its safety in clinical applications becomes an absolute priority.

The recent success of in vivo studies, case reports, and clinical trials has demonstrated that phages exhibit a relatively safe profile and are typically tolerable when administered to animals and humans. These encouraging findings solidify the foundation for the broader application of phage therapy as a safe and well-tolerated treatment modality. Given existing knowledge gaps and limited data on the potential health implications of phage therapy, it will be imperative to address and overcome the safety concerns discussed in this paper. It is also vital to establish and implement standardized safety assessments. By adhering to consistent and rigorous safety evaluation protocols, researchers can effectively address any uncertainties and validate the reliability of phage therapy, reinforcing its position as a trustworthy medical approach.

Nonetheless, ongoing research in the phage field enables researchers to enhance their comprehension of the safety aspects surrounding phage therapy for combating MDR bacteria. While there remains a considerable journey before phage therapy becomes an established standard of clinical care, it is crucial to continue expanding the knowledge base and facilitating the translatability of phages from bench-side to clinical bedside applications.

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