Abstract
Lower respiratory tract infections (LRTIs) present a significant global health burden, exacerbated by the rise in antimicrobial resistance (AMR). The persistence and evolution of multidrug-resistant bacteria intensifies the urgency for alternative treatments. This review explores bacteriophage (phage) therapy as an innovative solution to combat bacterial LRTIs. Phages, abundant in nature, demonstrate specificity towards bacteria, minimal eukaryotic toxicity, and the ability to penetrate and disrupt bacterial biofilms, offering a targeted approach to infection control. The article synthesises evidence from systematic literature reviews spanning 2000–2023, in vitro and in vivo studies, case reports and ongoing clinical trials. It highlights the synergistic potential of phage therapy with antibiotics, the immunophage synergy in animal models, and the pharmacodynamics and pharmacokinetics critical for clinical application. Despite promising results, the article acknowledges that phage therapy is at a nascent stage in clinical settings, the challenges of phage-resistant bacteria, and the lack of comprehensive cost-effectiveness studies. It stresses the need for further research to optimise phage therapy protocols and navigate the complexities of phage–host interactions, particularly in vulnerable populations such as the elderly and immunocompromised. We call for regulatory adjustments to facilitate the exploration of the long-term effects of phage therapy, aiming to incorporate this old-yet-new therapy into mainstream clinical practice to tackle the looming AMR crisis.
Shareable abstract
Phage therapy, at its youth, shows advantages tackling lower tract respiratory infections, especially when antibiotics are ineffective; however, its application, indications and safety measures need to be regulated. https://bit.ly/3xZobbq
Introduction
Lower respiratory tract infection (LRTI) is a broad term encompassing various diseases, such as acute bronchitis, pneumonia and acute exacerbation of chronic respiratory diseases such as COPD or bronchiectasis [1]. LRTIs are among the most impactful and widespread health challenges faced by the global population, resulting in substantial morbidity and mortality. In 2016 alone, LRTIs were responsible for >2.3 million deaths, placing them among the leading causes of years of life lost worldwide [2]. Mortality rates from LRTIs have been declining overall, but the number of deaths among the elderly population has increased significantly [3], underscoring the growing burden of these infections as global demographics shift toward an ageing population.
Enterococcus faecium, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae (ESKAPE) cause most bacterial LRTIs [4]. The management of LRTIs faces additional complexities due to the significant increase in antimicrobial resistance (AMR) arises from the improper use of antibiotics [5–7]. This issue has become a major public health concern, and is amplified by the growth of the ESKAPE pathogens known for their ability to resist conventional antibiotics [8]. The emergence of multidrug-resistant (MDR) bacterial infections poses a great threat, not only by elevating mortality risks, but also by imposing severe economic burdens on healthcare systems [9]. With global antibiotic use projected to increase dramatically, AMR is expected to be responsible for millions of deaths, particularly attributing to the LRTI burden [10, 11].
Faced with this disastrous scenario, the medical community is urgently seeking innovative therapies to counteract the escalating problem of AMR [12–14]. Bacteriophages (phages), the natural pathogens of bacteria, are being revisited as a potential solution in this era of AMR [15]. Phage therapy, which utilises the bacteria-specific lytic action of phages, offers a promising approach, particularly against MDR pathogens. Despite its promise, the deployment of phage therapy in clinical settings is in its infancy, with much to be learned about the optimal use of this biotherapeutic approach.
This article discusses the growing field of phage therapy, with a focus on its application in the treatment of LRTIs, a pressing concern given the rise of AMR. It presents a comprehensive review of the current state of phage therapy research, its potential to address the AMR crisis, and the challenges that lie ahead in translating this therapy from bench to bedside. Through rigorous scientific investigation and clinical trials, it seeks to chart a course for the future of phage therapy in combating LRTIs, offering hope for a new arsenal against the persistent threat of bacterial infections.
Phages: from environment to bed as biocontrol agent
Phages are numerous on the planet and considered “the viral dark matter” [16]. Phages are found in soil, water, air, plants and animals, maintaining healthy microbial communities. From the perspective of bacteria, phages are perceived as invaders that infect and ultimately lead to the demise of the bacteria [17, 18]. Phages exhibit two distinct life cycles when they interact with their host: the lytic cycle (virulent phage) and the lysogenic cycle (temperate phage). During the lysogenic cycle, the phage merges its genetic material with the host's and replicates along with the bacteria until the lytic cycle begins. In the lytic cycle, the phage compels the bacterial metabolic activities to generate more phage particles, eventually leading to the lysis or destruction of the bacteria [19].
Their host specificity, lack of harm or toxicity toward eukaryotic cells or microbiota, low required dosage, rapid life cycle and proliferation, and their status as natural micro-organisms facilitate their isolation, development and application of new phages. Furthermore, they are suitable for treating infections that are difficult to reach, as they actively seek out and infect their host bacteria [20, 21]. They can prevent the formation of bacterial biofilms and disrupt pre-existing ones [22]. Some phages are able to produce polysaccharide depolymerases which enable them to penetrate biofilms [23]. They also possess the capability to destroy bacteria and multiply during treatment and provide “autodosing” at the site of infection [24]. Despite some limitations, such as the time-consuming process of isolation and characterisation of lytic phages, developing phage cocktails [25], and evolution of phage-resistant bacteria [26], phage therapy holds high value and is one of the few options which is still available to control the AMR crisis.
Combining antibiotics and phages (phage–antibiotic synergy) in the context of phage therapy can enhance treatment efficacy while minimising bacterial resistance [27]. However, selection of the phages and antibiotics, as well as their mixing ratios, must be considered carefully for this dual antibacterial strategy [28–30]. Our current understanding of how phages behave and their effectiveness in vivo and in human clinical trials is still developing. Therefore, it is too early to make definitive conclusions about their overall effectiveness or the potential for the development of phage resistance.
Recent studies have shown that phages are generally safe [31] and do not cause adverse events when used in animals or humans [32]. In research exploring phage therapy for acute pneumonia caused by MDR P. aeruginosa in mice, successful therapy was observed to rely on a critical synergy between phage lysis and host's immune defences, notably involving neutrophils, termed “immunophage synergy”. Importantly, phages were well tolerated by the immune system and were not significantly neutralised in the lungs during the study [33]. Phage particles are recognised by the immune system, leading to their uptake by macrophages [34]. The development of phage-neutralising antibodies might vary depending on the route of administration, with stronger responses observed in parenteral application compared to topical or enteral routes [35]. However, it is noteworthy that while phage therapy may lead to the development of antibodies, it doesn't seem to trigger inflammatory responses. The possibility of future use of the same phage or other types and their impact on the immune response needs further investigation.
The interaction between phages and their host organisms is complex and influenced by several factors. The speed of phage reproduction at the infection site, the number of vulnerable bacterial hosts and the growth rate of these hosts in human tissues all contribute to the complex dynamics of how phages interact with their hosts. These aspects are fundamental to understand the pharmacodynamics and pharmacokinetics of phage–host interactions [36]. Phage pharmacodynamics involves understanding how the concentration of phages relates to their effectiveness in eliminating bacterial infections. Phage pharmacokinetics pose unique challenges compared to antibiotics, primarily due to their quantities and individual morphologies, leading to anticipated differences in their pharmacokinetics profiles. Their diverse routes of administration, including intravenous, intraperitoneal, oral and inhaled, among others, contribute to the complexity of phage pharmacokinetics. Understanding how pharmacokinetics and phage therapy affect bacterial load, immune responses and the long-term implications of phage-specific immune reactions is crucial for optimising the safety and efficacy of phage therapy in clinical applications.
Methodology for literature review
To comprehensively understand the current state of phage therapy in treating pulmonary infections, a systematic literature search was conducted. The time frame for this search was set from 2000 to 2023, aiming to capture the most relevant and recent developments in the field. The databases PubMed, Embase and the Cochrane Library were meticulously searched using a combination of specific keywords and phrases. The primary search terms included “phage therapy”, “pulmonary infections”, “bacteriophage” and “respiratory diseases”. These terms were cross-referenced with additional keywords such as “clinical trials”, “mechanisms of action”, “efficacy”, “safety” and “antibiotic resistance” to ensure a comprehensive coverage of the topic.
Initially, the search focused on identifying titles that directly related to the use of phage therapy in the context of pulmonary infections. Then the abstracts of the identified articles were carefully reviewed to determine their relevance to the research question.
In addition to database searches, the reference lists of all selected studies were manually examined. This hand-searching process aimed to uncover additional relevant studies that may not have been captured through the initial database search due to variations in terminology or indexing. All articles included in this review were peer-reviewed. The selection process involved the exclusion of studies that did not directly address the use of phage therapy in pulmonary infections, as well as those that lacked empirical evidence or were not relevant to the current clinical and research context. This methodology is designed to ensure a thorough and unbiased review of the existing literature, providing a comprehensive understanding of the role and effectiveness of phage therapy in treating pulmonary infections, particularly LRTIs.
LTRIs and different respiratory diseases
Data regarding the safety and efficacy of phage therapy in LRTIs primarily stems from in vitro studies, in vivo experiments and case reports. There exists a correlation between the efficacy observed in in vitro and in vivo settings, particularly when the phage is isolated directly targeting the specific host bacterium [37]. However, substantial supporting evidence from clinical trials is currently lacking. Notably, there are two ongoing randomised controlled trials (RCTs) investigating the impact of phage on P. aeruginosa infections in patients with cystic fibrosis (CF) (clinicaltrials.gov identifiers NCT04596319 and NCT04684641). However, at the present time, the results of these two RCTs have not yet been published. It is important to note that, to the best of our knowledge, no published RCT has yet investigated the effects of phage therapy, specifically in lower respiratory infections.
Presently, the existing data from human studies predominantly rely on case reports. phage therapy has been administered to patients with various respiratory conditions, including cystic fibrosis (CF), pneumonia, COPD and lung transplant recipients. These case reports form the basis of understanding the application and potential effectiveness of phage therapy in treating pulmonary diseases. The subsequent subsections delve into reviewing distinct aspects of phage therapy in pulmonary diseases, dissecting and analysing its applications within each specific condition separately. Table 1 demonstrates details of pulmonary cases that received phage therapy.
Studies of phage therapy in lower respiratory tract infections
Cystic fibrosis
CF patients experiencing chronic colonisation of MDR P. aeruginosa and biofilm formation which make a barrier against immune system and antibiotics [60, 61]. Various methods have been suggested to manage Pseudomonas infections, categorised into antivirulence or antiresistance strategies [62]. Antivirulence strategies aim to prevents bacterial pathogenesis by targeting its virulence traits, without directly killing the bacteria [63]. Conversely, antiresistance strategies target the mechanisms employed by bacteria to resist antibiotics [64]. Phage therapy, a method of growing interest within the CF community, shows promise as an antiresistance strategy. It can penetrate biofilms, proliferate at the site of colonisation and break through these barriers. Based on the results of case reports discussed later, notable improvements include a reduction in bacterial density within the lungs, overall enhancement of patient health and extended intervals without infection. Additionally, there has been a decrease in the production of sputum, a common complication in CF. Early observations also suggest that phage therapy may lead to short-term improvements in pulmonary function for individuals with CF [65].
While no clinical trials in CF patients have been published yet, published studies encompass in vitro, in vivo and compassionate use of phage therapy in individuals before or after lung transplant. Our team has recently discovered and sequenced the genome of five lytic phages targeting P. aeruginosa [66–69] for future studies on CF. In vitro studies targeting Pseudomonas strains from CF patients have shown promise in lysing colonies, preventing biofilm formation and destroying existing biofilms [70–75]. Animal studies involving mice infected with MDR P. aeruginosa demonstrated higher survival rates and increased bacterial clearance after administration of a single phage dose [76, 77]. In addition, phage therapy reduced bacterial burden and inflammation in a CF zebrafish infected with P. aeruginosa [78].
Consistent with laboratory findings, case reports affirm the efficacy of phage therapy. For instance, a study documented a 26-year-old CF patient who developed pneumonia due to an infection with MDR P. aeruginosa. The patient received a combination of systemic antibiotics and phage therapy. The treatment led to a successful resolution of the infection, with no clinical or laboratory adverse events. Additionally, the patient experienced no recurrence of the infection and enjoyed an exacerbation-free period of 100 days [38]. Two case reports from the Elivia Institute (Tbilisi, Georgia) described treating a 5-year-old and a 7-year-old CF patient complicated with P. aeruginosa and S. aureus. Both patients showed improvement clinically and a decrease in bacterial density [39, 40]. Custom phages could be an option for patients who show AMR. Zaldastanishvili et al. [41] reported two cases of CF and primary ciliary dyskinesia who were offered and applied individualised phage therapy. In 3 years of follow-up, both patients replaced antibiotic suppressive therapy with phage therapy. However, the patients were closely monitored, to substitute a new phage when bacterial strains became resistance to the old one. In a case of Kartagener syndrome, personalised phage therapy could replace antibiotic suppressive therapy after ∼3 years of concomitant on–off use of phage and antibiotics [42].
Another emerging nosocomial pathogen in CF patients is Achromobacter xylosoxidans [79, 80], a highly antibiotic-resistant Gram-negative bacterium [81]. Hoyle et al. [43] reported a CF patient presenting chronic infection with MDR A. xylosoxidans. The patient, a 17-year-old female, had suffered from persistent lung infections caused by various pathogens over 6 years, most recently battling an infection with Achromobacter. She underwent a treatment regimen consisting of daily nebulisation of Achromobacter-specific phage cocktail plus oral administration twice daily for 20 days, which was repeated four times. Following this therapy, the patient reported subjective improvements in her health; objective measures also noted significant enhancement in pulmonary function, with her forced expiratory volume in 1 s increasing from 1.83 L to 3.33 L. Additionally, her dyspnoea was alleviated, and the frequency of coughing episodes decreased. In another case of Achromobacter, concomitant therapy of cefiderocol, meropenem/vaborbactam and phage for two separate sessions led to enhanced lung function and negative sputum culture 8 and 16 weeks after the treatment courses [44]. Achromobacter responded successfully to phage therapy in a 12-year-old CF patient after lung transplant without any recurrence through the 2 years of follow-up [45]. Metagenome analysis of blood and sputum in a patient with CF who underwent phage therapy showed a 92% and 86% decrease, respectively, in Achromobacter DNA sequence with improvement of lung function at 1-month follow-up [46].
Engineered phages, designed to target specific pathogens, have demonstrated potential as a therapeutic option for treating infections that occur after lung transplant in patients with CF [82]. After undergoing a lung transplant, a patient with CF, who had a medical history of infections caused by P. aeruginosa and Mycobacterium abscessus received phage therapy; The treatment involved the i.v. administration of a customised cocktail containing three engineered phages, every 12 h for 32 weeks. During the 6-month follow-up, the patient showed clinical improvement, which included better lung function. The phage therapy was well tolerated by the patient, although an immune response was observed, indicated by the presence of antibodies in the patient's serum [47].
Pneumonia
Acute and chronic pneumonia with MDR pathogens improved significantly in animal models using phage therapy [83–85]. In an animal study, mice were infected with pneumococcal bacteria to induce pneumonia, then treated with an aerosolised single dose of the phage-derived enzyme, endolysin Cpl-1. Following administration of Cpl-1, a rapid increase in anti-inflammatory cytokines was observed, which facilitated a swift recovery and led to an 80% reduction in mortality rates among the treated mice [86]. The effectiveness of phage therapy is significantly influenced by the timing of its administration. For instance, administering phage therapy to mice 24 h prior to bacterial exposure has been shown to effectively prevent the onset of lung infections [87], indicating that the earlier administration could lead to more favourable treatment outcomes [88, 89].
Maddocks et al. [48] described the treatment of a 77-year-old woman who was suffering from pneumonia caused by P. aeruginosa resistant to meropenem, imipenem and piperacillin-tazobactam. After 23 days of receiving i.v. antibiotics without sufficient improvement, a supplementary phage therapy regimen was applied. This consisted of a combination of four different lytic phages, delivered both i.v. and as a nebulised treatment twice daily for 7 days. The patient tolerated the phage therapy well, with no adverse events reported. Notably, her oxygenation levels improved within 3 days of starting phage therapy, and she was subsequently discharged from the hospital after a total of 11 weeks. Similarly, Rao et al. [49] reported the case of a 52-year-old male diagnosed with ventilator-associated pneumonia (VAP) caused by carbapenem-resistant A. baumannii (CRAB) and P. aeruginosa. The patient's condition deteriorated despite treatment with various antibiotics based on antimicrobial susceptibility testing. Phage therapy was initiated on day 19, administered i.v. twice daily. Notably, Acinetobacter disappeared from sputum culture after 5 days of phage therapy; however, it reappeared with a reduced burden again after 9 days. With a 7-day gap in phage therapy, treatment continued with nebulisation twice daily. Subsequently, the patient exhibited clinical improvement, with two consecutive negative cultures for CRAB, and was successfully weaned off mechanical ventilation. Petrovic Fabijan et al. [50] reported results of a single-arm trial on 13 S. aureus infected patients. One of these patients suffered from septic shock and pneumonia. The phage therapy continued for 3 days for this patient with no response. The treatment stopped as the results of in vitro analysis showed that the bacteria was not lysed and was not susceptible to the phage.
COPD
Patients with COPD commonly experience exacerbations that necessitate hospitalisation, and these episodes are often precipitated by infections. The pattern of recurrent hospital stays, along with the repeated use of antibiotics, may lead to the development of MDR infections in these patients. A case report detailed the administration of phage therapy to an 88-year-old patient with COPD, who had developed respiratory failure as a result of an infection with CRAB. The patient, who also had diabetes, had a history of recurrent lung infections leading to multiple hospital admissions and the need for mechanical ventilation. Phage therapy was administered every 12 h for 16 days using a vibrating mesh nebuliser, with a progressively increasing dose. Concurrent antibiotic therapy was maintained for the first 10 days of the phage therapy. Notably, on day 7, the patient's bronchoalveolar lavage (BAL) culture yielded no growth, suggesting a clear improvement. There was also an observed enhancement in lung function, indicating a beneficial response to phage therapy [51]. This case demonstrates the potential efficacy of phage therapy as a treatment for infections caused by MDR bacteria, even in complex and challenging cases such as those observed in elderly COPD patients with a history of recurrent lung infections.
Lung transplant recipients
In the context of lung transplant recipients facing life-threatening MDR infections, Aslam et al. [52] investigated the application of phage therapy in three patients. The phage therapy was administered concurrently with antibiotic treatment under an emergency investigational new drug application. Two of the patients dealing with P. aeruginosa pneumonia displayed positive clinical responses to the phage therapy. They exhibited improvements in their conditions following the administration of phage therapy alongside antibiotics. The third patient had been experiencing recurrent infections caused by Burkholderia dolosa. Initially, there was an improvement observed in consolidative opacities indicative of a positive response to the therapy. However, despite the initial positive signs, the infection relapsed and led to the patient's death. Throughout the treatment process, phage therapy was well tolerated in all three patients, and no adverse events related to the phage therapy was reported. Recently, another case of lung transplant has been reported by Haidar et al. [53]. The patient was a 32-year-old female with CF who underwent lung transplant in 2017. In the first 3 years following transplant patient was hospitalised three times for respiratory tract infection, treated with various antibiotics. The last hospitalisation was complicated with respiratory failure and multifocal pneumonia; phage therapy was applied to the patient due to persistent bacteriaemia. The patient showed improvement at first; however, her condition deteriorated on day 5 and she died on day 8. Another case of MDR P. aeruginosa was reported recently in a patient after lung transplant. The patient suffered from bronchiectasis secondary to common variable immunodeficiency disease. After the lung transplant, the patient was hospitalised several times due to bronchopulmonary infection, resulted in wide application of antibiotics and emergence of MDR P. aeruginosa. The patient received phage therapy and improved after the first episode. However, his condition deteriorated into respiratory failure and multiorgan failure, and lead to the death of the patient despite clearance of BAL, bronchial aspiration and rectal smear from bacteria [54]. These results underscore the complexity of using phage therapy, necessitating further studies with refined protocols to better understand the efficacy and limitations of phage therapy, especially in such challenging clinical scenarios.
Nontuberculous mycobacteria
Nontuberculous mycobacteria (NTM) infection is an emerging respiratory disease; NTM were considered harmless environmental organisms and were believed to pose a threat only to immunocompromised patients. However, NTM infections are now increasingly common among seemingly healthy individuals, primarily through pulmonary infection [90]. M. abscessus is a category of NTM known for inducing severe and persistent infections, becoming resistant to antibiotics and causing a public health challenge. Recent studies underscore the potential effectiveness of phage therapy in addressing MDR M. abscessus. However, despite these promising results, challenges persist in phage therapy for M. abscessus, including absence of lytic phages capable of targeting all strains and subspecies within M. abscessus, as well as the risk of bacterial resistance development against phages during treatment [91, 92]. An immunocompetent 81-year-old patient with bronchiectasis and refractory M. abscessus received a cocktail of three phages for 6 months. After the first month the bacterial load decreased 10-fold; however, due to an increase in neutralising antibody, the load of M. abscessus reversed [55]. The failure observed in this case was in contrast to the previous case who received the same phage cocktail with successful response and resolution of the infection [47]. However, in the previous case, who was a CF patient with disseminated M. abscessus post lung transplant, no evidence of neutralising antibodies was observed which could be related to the immune system status of the patient. A case of CF and bronchiectasis with chronic M. abscessus infection was reported by Nick et al. [57]. The patient received phage therapy and responded with negative culture. The patient received lung transplant after 1 year of therapy with no evidence of recurrent infection afterwards. Dedrick et al. [56] recently published a study of compassionate use of phage in 20 mycobacterial induced infections, of which 18 were respiratory infections. Mycobacterium avium complex was isolated in one patient. The other patients had refractory drug-resistant M. abscessus. Nine out of 18 patients with respiratory infections improved clinically or microbiologically. Negative treatment response in four cases was related to neutralising antibodies in serum. No adverse events or resistance to phage were reported in any of the patients regardless of the pathogen, phage, route of delivery or treatment response. Three patients out of 18 were also reported separately [47, 55, 57].
Other respiratory infections
Rubalskii et al. [58] published an article on critical infections after cardiothoracic surgery. They reported eight patients, two of them complicated with respiratory-related infections after surgery. The first patient was a 40-year-old male with lung infection due to K. pneumoniae after heart transplant. The patient received a phage cocktail adjuvant to antibiotics. The BAL changed to negative for bacteria after the treatment. Stool samples remained positive, but showed susceptibility to antibiotics. The second patient was a 62-year-old male with fulminant pleural empyema after left ventricular assisted device implantation. The wound swab was positive for S. aureus. Phage therapy was administered locally via drainage for 7 days concomitant with daptomycin. Cultures from wound swabs changed to negative after the treatment. This patient died after 20 months of phage therapy due to transplant failure, which is unlikely to be related to the phage therapy.
Another respiratory infection reported to be treated with phages is VAP. Four cases of VAP secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were reported by Wu et al. [59]. The pathological agent in all three cases was carbapenem-resistant A. baumannii. The phage therapy was applied through the inhalation route. In one patient, a wet compress with phage was added locally to the skin wounds. Two of the patients improved substantially and were discharged on days 9 and 30. The other two patients died at day 10 due to Klebsiella infection and at day 40 due to respiratory failure. In one patient, interleukin (IL)-6 and IL-8 storm was observed a few hours after the application of the phage.
Coronavirus disease 2019: viruses against viruses
The SARS-CoV-2 pandemic, the latest public health challenge, involved all countries and frustrated healthcare systems and communities. Although phage therapy has primarily focused on combating bacterial pathogens, expansion of knowledge about phage immunobiology has sparked a revived interest in repurposing phage therapy to combat viral infections, such as coronavirus disease 2019 (COVID-19). A review published in 2005 [93] suggested that phages could potentially interfere with eukaryotic viruses, both in vitro and in vivo. The antiviral properties of phages might arise from various mechanisms, including the induction of interferon production by phages, competition between phages and eukaryotic viruses for cellular receptors, and the development of antiviral antibodies that cross-react with pathogenic viruses (figure 1). It is hypothesised that phages might compete with SARS-CoV-2 in binding to receptors, potentially interfering with the virus's ability to infect host cells, as well as inducing antiviral cytokines which enhance immunity [94]. During viral infection, activation of NF-κB is vital for the virus to survive within the host cell. Unlike viruses, phages restrict and even stop the activation of NF-κB, which might result in enhancing immunity against viral pathogens [95]. The clinical course of COVID-19 often involves an inflammatory response within the body. In this context, phages might serve a therapeutic role by potentially mitigating excessive inflammatory reactions. They could achieve this by inhibiting the activation of NF-κB and reactive oxygen species production, thereby helping to regulate the inflammatory response associated with the disease [96, 97]. The application of phages in virology holds promise, especially considering the scarcity of effective antiviral options. Recent advancements in comprehending phage antibacterial functions suggest a potential avenue for their application against viruses as well. However, this field is relatively nascent, requiring further in vivo and in vitro studies to comprehensively understand the mechanisms involved. These studies are essential to prepare phages for combating viral infections effectively.
The three potential mechanisms to apply engineered phages in the fight against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: competition with the SARS-CoV-2 virus for angiotensin-converting enzyme (ACE) receptors; the enhancement of intracellular killing via the type I interferon (IFN) pathway; and the stimulation of B-cells to produce antibodies against the SARS-CoV-2 receptor binding domain (RBD).
Phage therapy options
Considering that phages are not as broad-spectrum as certain antibiotics, the time-consuming processes of isolation, characterisation and laboratory workups may cause delays in treatment if specific phages are not available in phage banks [98, 99]. Their host specificity could also impede swift use, as time is needed to precisely identify the causative agent [100]. Consequently, the administration of phage therapy for acute infections could be challenging. One potential solution is the use of phage cocktails consisting of different phages [39, 101, 102]. These cocktails have shown promise in reducing bacterial load, inflammation and pathological injuries more effectively than individual phages. Compared to broad-spectrum antibiotics that may induce resistance, wide-spectrum phage cocktails have demonstrated the potential to avoid such resistance while effectively combatting bacterial infections [59, 103].
Several animal and in vitro studies have been conducted to explore various aspects of administering phage therapy, including the optimal route of administration, dosage and best combination with antibiotics [104–110]. An ongoing open-label single-arm trial is proposing a standardised protocol for phage therapy, primarily targeting patients who have no other viable treatment options. The trial aims to enrol 50–100 patients over a period of 5 years. The focus of the trial includes comprehensive safety assessments, evaluation of long-term safety, feasibility of treatment, clinical responses, measures related to the quality of life, analysis of phage kinetics, assessment of host immune responses and analysis of microbiome. In this proposed protocol, phage therapy will be administered for a duration of 14 days, following which patients will be monitored for up to 6 months. A pivotal aspect introduced in this protocol is the concept of therapeutic phage monitoring, which plays a crucial role in overseeing and ensuring the safety of phage therapy throughout the treatment process [111]. This approach is geared towards establishing a structured framework for the application of phage therapy, allowing for comprehensive evaluation and monitoring of its safety, efficacy and various associated parameters. However, there still remains a knowledge gap in this field, underscoring the need for RCTs to answer these questions.
There are several options that may be tailored to different clinical scenarios (supplementary figure S1).
Suppressive therapy: this approach is particularly suitable for chronic infections where continuous bacterial suppression is desired. It is often indicated for conditions such as CF and bronchiectasis, where the goal is to maintain a manageable level of bacterial load, preventing exacerbations and preserving lung function over time.
Combination therapy with antibiotics: for patients with pneumonia who are immunocompromised, the strategy of phage therapy coupled with antibiotics is advisable. The synergistic effect of both treatments can enhance bacterial eradication, potentially reduce the development of resistance, and provide a broad-spectrum approach that can be critical for these vulnerable patients.
Phage therapy in MDR infections: with the rising concern of AMR, phage therapy offers a viable alternative, particularly in MDR pathogens. It is a promising option for patients with pneumonia and COPD, where traditional antibiotics may no longer be effective. The specificity of phages to their bacterial targets means that they can be used to target these resistant strains without affecting the rest of the microbiota.
Each option has its own merits and is best chosen based on the patient's specific needs, the pathogen's profile, and the clinical context.
Cost-effectiveness of phage therapy
Cost-effectiveness analysis stands as a fundamental tool in assessing the viability of any health technology. Yet, in the nascent era of phage therapy, there remains a notable absence of comprehensive cost-effectiveness analysis studies evaluating its application. To the best of our knowledge, there is currently no specific study addressing the cost effectiveness of phage therapy in comparison to conventional treatment for various infections. However, when considering the diverse aspects of phage therapy discussed earlier, such as its specificity toward the target bacteria, reduced impact on the patient's microbiome, and ability to use different approaches, it becomes evident that phage therapy holds promise as an innovative and potentially effective approach to combat infections, especially MDRs. In contrast to conventional antibiotic production, the cost of isolating and developing phages is minimal [112]. The potential of phage to self-replicate and auto-dosing at the site of infection makes it possible to use fewer or even single dosage [113]. Moreover, establishment of locally isolated and pre-characterised phages as national or regional phage banks could decrease the isolation cost and represents as a proactive and strategic approach [114]. Additionally, in the absence of overarching regulations, the utilisation of phage therapy requires specific approval, which is time-consuming. Therefore, the time and effort involved must be regarded as a cost. Despite the absence of formal cost-effectiveness studies, these unique characteristics suggest that phage therapy could offer considerable economic benefits in the treatment of infectious diseases.
Regulatory challenges and concerns about phage therapy
Perhaps one of the most important challenges in the integration of phage therapy into clinical practice is the establishment of overarching regulations specifically tailored for phage products. These regulations need to define safety, quality and efficacy criteria for phage products, outline formal procedure for administration and specify corresponding responsibilities [115]. Bacteriophages are classified as medicinal products in the European Union (EU) and as drugs in the United States, based on their intended use for treating or preventing disease. This classification subject's bacteriophage products to the same regulatory requirements as antibiotics, including manufacturing standards, clinical trials and marketing authorisations [116]. In the United States, the Food and Drug Administration (FDA) has not yet approved phages for clinical use; therefore, submission of an investigational new drug application is necessary before administration of phage therapy to patients [117]. Another route is to submit the FDA form 3926 for compassionate use in a life-threatening condition with no alternative option [118]. Both applications include safety and adverse event monitoring data and plans. Specific factors that must be included are the source of phages, whole-genome sequencing, concentration, level of endotoxins, sterility and results of preparation-effectiveness tests [119]. In Eastern Europe, phage therapy has historically been widely utilised as part of clinical care. In contrast, its application in Western Europe is relatively limited. To address regulatory issues surrounding the use of bacteriophages, the EU introduced a new regulatory chapter titled “Phage therapy active substances and medicinal products for human and veterinary use” in 2021 [120]. Among other European countries, Belgium established an innovative regulatory framework for phage therapy, allowing pharmacists to produce tailored medicinal products for individual patients based on physician prescriptions. This magistral preparation approach ensures compliance with pharmaceutical standards and allows for customised therapy while ensuring quality control through government-approved laboratories [121].
Considering the limited research available on phage therapy, there are concerns about its experimental use, especially regarding its potential long-term effects (supplementary figure S2). There are potential impacts of phage therapy on human microbiome alteration, metabolic reprogramming within the host post-phage therapy, the effects of phage therapy on quorum sensing and the risk of phage therapy contributing to the transduction of antibiotic resistance genes [122], not all of them included in current regulations. Therefore, we suggest the modification of current regulations to include investigation into the long-term effects of phage therapy. This change will allow scientists to better understand and mitigate long-term risks associated with phage therapy, ensuring that any therapeutic applications of phages are as safe and effective as possible.
Conclusions
In conclusion, phage therapy presents a promising personalised approach that could minimise evolutionary pressures on bacterial populations. Nevertheless, concerns regarding the long-term effects of phage therapy, the immune system's response to phages and the probability of their elimination upon repeated use, posing limitations on their administration. Addressing these concerns and exploring the full potential of phage therapy requires extensive clinical trials, patient registries and systematic monitoring. These efforts are crucial to comprehensively understand various aspects of phage behaviour, tissue distribution and interactions with bacteria and the human body during treatment.
Keeping these challenges in mind, available data strongly suggest that phage therapy holds the potential to deliver positive clinical outcomes for a considerable number of patients with acute or chronic respiratory bacterial infections. Continued research, robust clinical investigations, and meticulous monitoring are essential to unlock the full therapeutic potential of phage therapy while ensuring its safety and efficacy in clinical settings.
Supplementary material
Supplementary Material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary figures S1 and S2 ERR-0029-2024.SUPPLEMENT
Footnotes
Provenance: Submitted article, peer reviewed.
Conflict of interest: G. Ebrahimi and S. Rezvankhah are employees of Phageolytix Inc. A. Hashemi Shahraki and M. Mirsaeidi are shareholders of Phageolytix Inc. The other authors declare no conflict of interest.
- Received February 15, 2024.
- Accepted April 16, 2024.
- Copyright ©The authors 2024
This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions{at}ersnet.org
References
Jump To
- Article
- Abstract
- Shareable abstract
- Introduction
- Phages: from environment to bed as biocontrol agent
- Methodology for literature review
- LTRIs and different respiratory diseases
- Phage therapy options
- Cost-effectiveness of phage therapy
- Regulatory challenges and concerns about phage therapy
- Conclusions
- Supplementary material
- Footnotes
- References
- Figures & Data
- Info & Metrics