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Jamil Allen G. Fortaleza Senior High School Department, NU Fairview Incorporated, Quezon City, 1118, Philippines
National University, Philippines, Sampaloc, Manila, 1008, Philippines

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Christian Joseph N. Ong Department of Biology, College of Science, De La Salle University, Manila, Philippines

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Rener De Jesus Department of Biology, College of Science, United Arab Emirates University, Al Ain 15551, United Arab Emirates

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Abstract

Staphylococcus aureus infections have already presented a substantial public health challenge, encompassing different clinical manifestations, ranging from bacteremia to sepsis and multi-organ failures. Among these infections, methicillin-resistant S. aureus (MRSA) is particularly alarming due to its well-documented resistance to multiple classes of antibiotics, contributing significantly to global mortality rates. Consequently, the urgent need for effective treatment options has prompted a growing interest in exploring phage therapy as a potential non-antibiotic treatment against MRSA infections. Phages represent a class of highly specific bacterial viruses known for their ability to infect certain bacterial strains. This review paper explores the clinical potential of phages as a treatment for MRSA infections due to their low toxicity and auto-dosing capabilities. The paper also discusses the synergistic effect of phage-antibiotic combination (PAC) and the promising results from in vitro and animal model studies, which could lead to extensive human clinical trials. However, clinicians need to establish and adhere to standard protocols governing phage administration and implementation. Prominent clinical trials are needed to develop and advance phage therapy as a non-antibiotic therapy intervention, meeting regulatory guidelines, logistical requirements, and ethical considerations, potentially revolutionizing the treatment of MRSA infections.

Abstract

Staphylococcus aureus infections have already presented a substantial public health challenge, encompassing different clinical manifestations, ranging from bacteremia to sepsis and multi-organ failures. Among these infections, methicillin-resistant S. aureus (MRSA) is particularly alarming due to its well-documented resistance to multiple classes of antibiotics, contributing significantly to global mortality rates. Consequently, the urgent need for effective treatment options has prompted a growing interest in exploring phage therapy as a potential non-antibiotic treatment against MRSA infections. Phages represent a class of highly specific bacterial viruses known for their ability to infect certain bacterial strains. This review paper explores the clinical potential of phages as a treatment for MRSA infections due to their low toxicity and auto-dosing capabilities. The paper also discusses the synergistic effect of phage-antibiotic combination (PAC) and the promising results from in vitro and animal model studies, which could lead to extensive human clinical trials. However, clinicians need to establish and adhere to standard protocols governing phage administration and implementation. Prominent clinical trials are needed to develop and advance phage therapy as a non-antibiotic therapy intervention, meeting regulatory guidelines, logistical requirements, and ethical considerations, potentially revolutionizing the treatment of MRSA infections.

Introduction

Staphylococcus aureus is a prominent commensal pathogen found in both humans and animals. It has the potential to cause a wide array of severe infections affecting various body systems, including the skin, soft tissues, bones, joints, heart, and lungs [1–6]. Antimicrobial resistance poses a major global health threat, directly causing about 1.27 million deaths and contributing to nearly 4.95 million more in 2019 [7]. Furthermore, it is projected that this number could exceed 10 million deaths by the year 2050, potentially exceeding global cancer mortality rates [8]. This alarming trend is largely attributed to the increasing and occasionally inappropriate use of antibiotics, which has imposed selective pressure on pathogenic bacteria like S. aureus, leading to the development of antibiotic resistance [9]. Despite ongoing efforts to develop new antibiotics and therapeutic approaches, certain bacterial strains remain a significant and persistent human health threat as shown in Table 1.

Table 1.

Examples of antibiotic resistant bacterial strains and their characteristics

Bacterial strainKnown for resistance againstHighlights
Methicillin-resistant Staphylococcus aureus (MRSA)Methicillin,

Vancomycin
Common in hospitals, can cause severe infections like sepsis. Alters penicillin-binding proteins to confer resistance.
Vancomycin-resistant Enterococci (VRE)VancomycinOften found in healthcare settings, can cause urinary tract and blood stream infections. Resistant due to altered target sites [10].
Multi-drug-resistant Mycobacterium tuberculosis (MDR-TB)Isoniazid,

Rifampicin
Causes tuberculosis, challenging to treat due to resistance to first-line TB drugs [11, 12]
Carbapenem-resistant Enterobacteriaceae (CRE)CarbapenemHighly resistant, can cause various infections; resistance often due to carbapenemases [13]
Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-producing)Penicillins,

Cephalosporins
Common in urinary tract infections; produce enzymes that breakdown β-lactam antibiotics [14]
Multidrug-resistant Pseudomonas aeruginosaCarbapenems,

Aminoglycosides
Often infects wounds, lungs; resistance mechanisms include efflux pumps and enzyme production [1516].
Multidrug-resistant Acinetobacter baumaniiCarbapenemsAssociated with hospital-acquired infections; survival capabilities in hospital environment. [93]
Neisseria gonorrhoeae (drug-resistant)Cefixime,

Ceftriaxone
Causes gonorrhea; resistance complicates treatment options.
Clostridioides difficileFluoroquinolones,

Clindamycin
Causes gastrointestinal issues; resistance leads to recurrent infections.

The methicillin-resistant S. aureus (MRSA) is a bacterium particularly notable for its resistance to many antibiotics. This resistance makes treating infections caused by MRSA particularly challenging. Historically, vancomycin has been an effective treatment against MRSA, as this bacterium remained susceptible to it [17]. However, MRSA strains are increasingly exhibiting resistance to vancomycin [18], making it a concern in treating infections. Vancomycin resistance in MRSA is linked to acquiring the vanA gene cluster that initiates resistance mechanism and alters bacterial cell wall structure resulting in vancomycin affinity reduction [19]. This emerging resistance is a significant concern because it exacerbates the risk of treatment failure and leads to higher rates of mortality and morbidity associated with MRSA infections. In response to this urgent and concerning situation, the World Health Organization has issued a call to action, urging researchers and the medical community to pioneer innovative therapeutic strategies against MRSA infections [20]. This includes the development of new antibiotics, alternative therapeutic methods, and enhanced preventive measure.

Bacteriophages are omnipresent in the environment, representing the most abundant form of biomass on Earth [21, 22]. These viral agents possess the unique ability to identify and target specific bacterial cells precisely for replication [23]. This precision is achieved through adsorption, a process where they recognize and attach to certain bacteria using specific proteins. For instance, the classic bacteriophage T4 attached to Escherichia coli cells using its long tail fibers, which recognize and bind to lipopolysaccharides and OmpC on the cell surface [24]. This specific interaction allows the T4 phage to inject its genetic material into the bacterium, initiating replication. The specificity of these phages opens up promising avenues for their use in therapeutic applications [25, 26]. The development of phage therapy represents a significant advancement in medical intervention, particularly in its speed of treatment compared to traditional antibiotics. While the discovery and approval of new antibiotics can be a lengthy and costly process, often taking years, the isolation and selection of new bacteriophages can be accomplished in a much rapid, shorter time frame [27]. This rapid turnaround is crucial in responding to emerging antibiotic-resistant infections.

Furthermore, another distinct advantage of phages over antibiotics is their ability to target and disrupt biofilms. Biofilms are intricate bacterial communities that adhere to any surface and are encased in a protective layer known as exopolysaccharides [28, 29]. These biofilms are notoriously resistant to conventional antibiotics, presenting a significant challenge in treating infections. For instance, the biofilm of Pseudomonas aeruginosa hinders antibiotic penetration, while its diverse microenvironments modify bacterial metabolic states that diminish antibiotic effectiveness, and the reduced bacterial growth rate within the biofilms contributes to the resistance of persisted cells [30, 31]. Several studies have demonstrated bacteriophages for their ability to penetrate biofilms by effectively reducing and dispersing the bacterial communities [32–35]. This capability is particularly relevant for treating infections caused by MRSA, which are often characterized by the formation of resilient biofilms [36]. This review aims to delve into the potential therapeutic application of phage therapy in administering infections caused by MRSA. It also discusses the complex mechanisms by which bacteriophages and their endolysins target MRSA, their effectiveness in overcoming biofilm-related challenges, and the potential for integrating phage-antibiotic approaches into clinical treatment protocols. By examining the latest research and advancements in the field, this review seeks to provide a comprehensive understanding of how phage therapy could revolutionize the approach to treating various MRSA infections, offering a promising avenue in the fight against antibiotic resistance.

Microbiology of MRSA

Methicillin-resistant S. aureus (MRSA) was first studied in 1961 [37]. This was shortly after the antibiotic methicillin was introduced in 1959. MRSA is a Gram-positive, facultative anaerobic bacterium, characterized by its spherical shape in grape-like clusters. As a member of the Staphylococcus genus, MRSA possesses a thick peptidoglycan cell wall, which is integral to its structural integrity and resistance to osmotic pressure. The cell wall features teichoic acid, contributing to its virulence by mediating adhesion to host tissues and evading immune responses [38–40]. A pivotal element in the MRSA resistance to methicillin and related β-lactam antibiotics is the mecA gene. This gene, carried on the staphylococcal cassette chromosome mec (SCCmec) that encodes for the penicillin-binding protein 2a (PBP2a) [41]. This protein has a low affinity for β-lactam antibiotics enabling MRSA to circumvent the bactericidal action of these drugs [42].

The virulence of MRSA is further augmented by an array of toxins and enzymes, including Panton-Valentine leukocidin (PVL) [43], α-hemolysin [44], and various extracellular proteases [45], which contribute to tissue invasion and immune system evasion. The capacity of MRSA for biofilm formation is another critical factor in its pathogenicity, particularly in the context of indwelling medical devices [46]. Furthermore, the epidemiology of MRSA has evolved, with strains now classified into hospital-associated MRSA (HA-MRSA) and community-associated MRSA (CA-MRSA), each exhibiting distinct genetic and phenotypic profiles [47]. The HA-MRSA strains are often associated with multi-drug resistance (MDR), whereas CA-MRSA strains are typically more virulent but may be susceptible to a broader range of antibiotics (e.g., oxacillin, nafcillin, amoxicillin, and certain cephalosporins). This dichotomy underscores the necessity for ongoing surveillance and tailored antimicrobial strategies in managing MRSA infections.

Clinical impact of MRSA

Due to its resistance to standard antibiotic regimens, MRSA poses a formidable challenge in clinical settings. This bacterium is a leading causative agent of healthcare-associated infections (HAIs), including bloodstream infections [48], surgical site infections and pneumonia [49, 50], and urinary tract infections [51]. The adaptability and resilience of MRSA in hospital settings exacerbate the risk of nosocomial transmissions [52], often necessitating more aggressive and costly therapeutic interventions. Moreover, the clinical management of MRSA infections is further complicated by their ability to colonize patients asymptomatically, serving as a reservoir for transmission and complicating infection control measures [53]. The virulence of MRSA is multifaceted, which is attributed to the types of toxins and enzymes mentioned earlier. In addition to its inherent resistance to β-lactam antibiotics, MRSA strains often exhibit resistance to other antibiotic classes, including macrolides, tetracyclines, aminoglycosides, and fluoroquinolone, a phenomenon known as multi-drug resistance (MDR) [54, 55]. This resistance profile significantly narrows therapeutic options, often leading to the use of more potent antibiotics like vancomycin and linezolid, which can have more severe side effects and contribute to further antibiotic resistance development [56, 57].

Moreover, the impact of MRSA extends beyond the immediate healthcare costs and treatment challenges. The pathogen is associated with increased morbidity and mortality rates compared to methicillin-sensitive S. aureus (MSSA) infections [58, 59]. Patients with MRSA infections often experience longer hospital stays, increased risk of treatment failure, and higher healthcare-associated expenses. In severe cases, MRSA can lead to systemic infections, such as sepsis [60] or endocarditis [59], which are challenging to treat and can result in serious patient morbidity and mortality. On the other hand, the CA-MRSA strains have emerged as a public health concern, with infections occurring in individuals without traditional healthcare-associated risk factors. These strains often carry genes (lukS-PV and lukF-PV) encoding for PVL [43, 61] that is associated with skin and soft tissue infections or sometimes more severe necrotizing pneumonia [62]. The emergence of CA-MRSA emphasizes the need for vigilant surveillance, both in healthcare settings and the community, to monitor the evolving epidemiology and resistance patterns of MRSA. Thus, the clinical impact of MRSA is substantial, encompassing both healthcare-associated and community settings. The resistance of the bacterium to multiple antibiotics, coupled with its virulence and ability to cause a wide range of infections, underscores the urgent need for continued research into novel therapeutic agents and strategies, as well as robust infection control practices to mitigate its spread and impact.

Bacteriophages: an overview

Bacteriophages, also called phages, are viruses that specifically target and infect bacteria influencing the evolution and behavior of bacterial populations [63]. They display a variety of structures, but typically, they consist of a genetic material core, either DNA or RNA, encapsulated within a protein coat known as capsid [64]. Some phages also possess a tail structure, which facilitates the attachment to and penetration of bacterial cell walls. Phages primarily follow two types of life cycles: the lytic cycle and the lysogenic cycle. In the lytic cycle, a phage infects a bacterial cell, replicates within it, and eventually causes the cell to lyse, releasing new phage particles. In the selection of phage, lytic activity is one of the criteria for the potential therapeutic application. In contrast, during the lysogenic cycle, the phage integrates its genome into the host DNA, replicating passively with the host cell until triggered to enter the lytic cycle.

Bacteriophages can be found and isolated from various environments [65, 66], as they are adapted to infect bacterial hosts in nearly all ecosystems, such as soil [67], water bodies [68], animal and human bodies [69], extreme environments [70], wastewater [71], and sewage [72]. In the field of biotechnology and medicine, phages are harnessed for numerous applications. For instance, Phage therapy explores the use of bacteriophages as an alternative to antibiotics for treating bacterial infections, particularly those resistant to conventional treatments like MRSA. Most of the reported phages that have conceivable clinical applications were isolated from sewages, such as VB_SauS_SH-St 15644 [73], P509 [74], PB1-like, phiKZ-like, and LUZ24-like viruses [75], PE1 [76], and SLPW [77].

Phage against MRSA: a new frontier in antibiotic resistance

Phage therapy is gaining attention as a potential treatment for antibiotic-resistant infections, such as those caused by MRSA. Also, phages can be engineered to specifically target MRSA bypassing the resistance mechanisms that the bacteria have developed against antibiotics. For example, the integration of CRISPR/Cas9 system into a temperate phage genome that focuses the S. aureus nuc gene was successfully developed [78]. This engineered phage (φSaBov-Cas9-nuc) demonstrated high efficacy in killing S. aureus in both in vitro and in vivo assays. Importantly, to enhance safety, major virulence genes were removed from the host S. aureus strain used to propagate the phage, reducing the risk of spreading harmful bacterial genes. The host range of φSaBov was expanded by complementing the phage with a tail fiber protein (Tif) gene from another phage (φ11), improving its ability to target different S. aureus strains, including the MRSA [78]. Hence, this study demonstrates a significant advancement in the use of CRISPR/Cas9 for antimicrobial therapy against S. aureus, including drug-resistant strains.

Phage endolysins as alternative to antibiotics

As an alternative to traditional antibiotics, phages offer a promising approach in managing MRSA infections. Central to this approach is the enzymatic action of phage endolysins. Phages are capable of producing a variety of enzymes that are essential for their life cycles, including lytic enzymes, integrases, depolymerases, replication enzymes, and those involved in modifying host functions [79–82]. Endolysins are one of the enzymes that are synthesized during the latter stage of the phage replication cycle. These enzymes exhibit remarkable specificity in targeting and degrading the peptidoglycan layer of bacterial cell walls. This targeted action enables them to lyse and destroy bacterial cells with high efficiency while leaving human cells unharmed. Several studies have demonstrated the specificity of phage endolysins on targeting Gardnerella vaginalis [83], Enterococcus faecalis [84], Acinetobacter baumannii, P. aeruginosa [85], and S. aureus [86, 87]. Endolysins also exhibited biofilm eradication. For example, an endolysin LysP108 revealed antibacterial potential against MRSA with a rate of approximately 90% and destroyed bacterial biofilms [88]. Table 2 shows previous studies indicating the efficacy and potential clinical application of various phage endolysins against MRSA strains. Thus, endolysins hold immense promise as a novel antibacterial class. Their development and application in clinical settings are a testament to the innovative approaches being pursued in modern medical science to address the growing challenge of treating MRSA infections.

Table 2.

Phage-derived endolysins against MRSA and their potential clinical applications

EndolysinOrigin (Phage name)Targeted MRSA strainsResultsPotential clinical applicationsReferences
LysKStaphylococcal bacteriophage KUSA300 (NARSA NRS384)The C-His-tagged variant of LysK demonstrated a higher efficacy against MRSA (MIC = 32.85 ± 4.87 mg mL−1). Antibacterial activity was improved in combination with lysostaphin.The enzyme could be formulated into topical creams or ointments, wound cleaning solutions, medical device coatings, surgical prophylactic measures, and other related clinical applications.[88]
MR-10Phage-derived lysinMRSA ATCC 33591

MRSA ATCC 43300
Sequential treatment of MRSA biofilms with minocycline followed by endolysin MR-10 showed significant decreases in biofilm cell counts, indicating that this combination therapy can effectively target both young and mature biofilms formed by MRSA.Treating infections caused by MRSA involving biofilms. Potentially be used to treat chronic infections or to prevent the formation of biofilms on medical devices and implants.[89]
CHAP_KStaphylococcal bacteriophage KMRSA252Combination of CHAP_K and lysostaphin, when released from thermally responsive PNIPAM nanoparticles, is effective against MRSA. This combination showed synergistic behavior, with CHAP_K contributing to rapid bacterial cell lysis.Could be particularly useful in chronic wound infections, potentially being incorporated into dressings or bandages.[90]
LysRODIphilPLA-RODIClinical MRSA isolatesThe MRSA isolates showed varying degrees of susceptibility to LysRODI.Could be developed for topical formulations for skin and soft tissues. Could be used in hospital settings to combat nosocomial infections.[91]
SAL200Staphylococcus-specific bacteriophage SAP-1LAC

ATCC 33591

ATCC B1707
SAL200 with standard-of-care (SOC) antibiotics decrease S. aureus counts of >2 log10 CFU mL−1. SAL200 lowered blood bacterial density within 1 h by > 10 log10 CFU mL−1 in bacteremic mice.Reduction of bacteremia and metastatic S. aureus infection suggesting that SAL200 could be useful as an adjunctive therapy in the treatment of difficult-to-treat- S. aureus.[92]
LysP108P108XN108The antibacterial rate of LysP108 is ∼90%. Can also inhibit and destroy bacterial biofilms. In combination with vancomycin (8 μg mL−1), the growth of bacteria could be inhibited.Could be used to treat infections, such as osteomyelitis, periodontitis, and chronic rhinosinusitis.[93]

Phage action against MRSA biofilms

Biofilms produce an extracellular matrix that enhances their tolerance and protects them from antibiotic treatment. Biofilm formation begins when environmental stress and pressure trigger specific bacteria to adhere to a surface, which can be either abiotic or biotic [92]. Biofilms have received significant attention due to the human diseases caused by bacterial biofilms-associated infections including catheter infection, endocarditis, and some nosocomial infections. There have been reports that antimicrobial resistance occurs due to the biofilm formation ability of several microorganisms. Initially, antibiotic-susceptible bacteria tend to form stronger biofilms compared to resistant strains [93] to survive in environments with the presence of antibiotics. However, the exact mechanisms governing the balance between biofilm formation and antibiotic resistance, and how resistant strains achieve high levels of biofilm-specific resistance despite producing weaker biofilms, require further investigation. Also, biofilm-antibiotic resistance developed rapidly over time, while traditional antibiotic resistance remained stable in planktonic cultures [94]. This suggests that biofilm formation significantly contributes to increased antibiotic resistance. In the case of MRSA, a significant proportion of biofilm-producing MRSA strains (43.3%) showed a higher incidence of antibiotic resistance compared to non-biofilm producers [95]. To address this phenomenon, phages as biocontrol agents against MRSA biofilms were studied. Two phages, UPMK_1 and UPMK_2, showed abilities to degrade MRSA biofilms in vitro. UPKM_1 showed a gradual reduction in biofilm biomass at a maximum rate of 52% after 6 h. While UPKM_2 demonstrated a more rapid biofilm degradation by 51% reduction after phage inoculation and more than 58% of the biomass was eliminated after 8 h of treatment [96].

Furthermore, phages demonstrate a versatile ability to adhere in different biofilm layers that leads to biofilm matrix destruction [97, 98]. The elimination of the biofilm matrix causes the release of bacterial cells as planktonic cells and afterward attacked by the bacteriophage [99]. It also plays a role in delaying the treatment of severe infections due to the increased prevalence of antibiotic resistance in S. aureus [100–102]. Therefore, the application of phages demonstrated an improved range of virulence in S. aureus and has a strong effect on MRSA biofilm dispersion.

Phage-antibiotic combination (PAC) approach against MRSA

The continuous problem in the antibiotic resistance crisis has led to the use of combination or multidrug therapies that involve the administration of two or more antibiotics together. Instead of replacing antibiotics, combining both types of antibiotics and phages against bacterial infection results in enhanced performance shown in Table 3. The PAC therapy capitalizes on the strengths of both phages and antibiotics. While phages provide a targeted approach by specifically infecting MRSA strains and overcoming host specificity issues than antibiotics can disrupt bacterial cell walls, rendering MRSA more susceptible to phage attack. This synergy can enhance the overall treatment efficacy [107, 108]. Yet, there are limited proposals and studies about the mechanism of PAC for bacterial infection. In the study of Li et al. [109], sublethal concentration increases phage production and enhances the release of the progeny phages from bacterial cells. The synergistic effects of combining both antibiotics and phages are being investigated to avoid the evolution of bacterial resistance to both. Significantly, the synergistic action of the PAC is an alternative that not only works against bacterial infections but also helps to reduce antibiotic resistance. In addition, few studies found that the human immune system can sometimes neutralize phages [110–112], thus reducing their effectiveness. Also, the interaction between phages, antibiotics, and bacteria is complex and not fully understood, which can affect the predictability and reliability of treatment outcomes. And lastly, phages may have difficulties in penetrating and distributing evenly within biofilms resulting in phage ‘delay’. This process limits phage propagation, resulting in decreased efficacy for treatment [113].

Table 3.

Successful administration of PAC in treating MRSA for animal models

Infection typeAnimal modelPhage strainCombinationHighlighted resultsReferences
Joint infectionMiceMR-5 phageLinezolid with biopolymerMice treated with phage and linezolid coated wires showed significant improvement in locomotion and motor function, correlating with a decrease in inflammation. Dual coated wire (phage + linezolid) group showed fastest recovery in locomotor activity and balancing act, with minimal inflammatory cell infiltration and maximum healing of the affected joint tissue.[103]
Diabetic foot infectionMiceMR-10 phageLinezolidA single injection of phage MR-10 resulted in a significant reduction in bacterial load and resolved the infection within 5 days, compared to 15 days in untreated mice. The combination of MR-10 and linezolid was found to be more effective in controlling the infection process compared to either agent used alone.[104]
Implant related osteomyelitisRatsSb-1 phageTeicoplaninThis combination therapy reduced the CFUs of treated group (20 mg/kg/day) to 5,000 compared to control group (50,586 CFU). This combined approach was the only treatment that completely eradicated biofilm in the MRSA group.[105]
Nasal colonizationPigPhage K*710 and P68MupirocinNo significant reduction in MRSA numbers was observed following bacteriophage treatment. But a reduction in MRSA nasal colonization was only observed when mupirocin was applied.[106]

Clinical studies on phage therapy against MRSA

The exploration of phage therapy against MRSA has been advanced through a variety of clinical studies, each employing distinct methodologies to assess efficacy and safety. These studies encompass a range of designs including in vitro analyses, animal model testing, and human clinical trials. In vitro studies have been pivotal in understanding the basic interactions between phages and MRSA bacteria. For example, a virulent bacteriophage SLPW demonstrated strong lytic activity in vitro and showed a broad host range targeting a variety of S. aureus strains, including MRSA, and the burst size was determined to be approximately 95.3 plaque-forming units (PFU) per infected cell [77]. A phage VB_SauS_SH-St 15644 showed MRSA inhibition in vitro in a murine skin infection model with 80% of the phage approximately adsorbed by MRSA in 4 min resulting in an estimated burst size of 13 PFU per infected cell [73]. Meanwhile, animal models have provided insights into the therapeutic potential and safety profile of phage therapy in a living organism.

These animal models include mice, rabbits, rats, and pigs. A study demonstrated the potential of phage therapy in treating both acute and chronic osteomyelitis caused by MRSA in rabbits [114]. The animal models were treated with a cocktail of seven virulent bacteriophages, which were previously characterized for their antibacterial activity against MRSA [23]. The rabbits treated with phage therapy showed significant clinical, microbiological, radiological, and histopathological improvements. Also, PAC approaches using animal models were applied as previously listed in Table 3. Phages with linezolid were utilized in mice to treat joint infection [103] and diabetic foot infection [104]. Linezolid is an antibiotic used to treat certain serious bacterial infections caused by Gram-positive bacteria, including those caused by MRSA. The mode of action of linezolid is to inhibit bacterial protein synthesis by binding to the ribosome preventing the formation of a functional 70S initiation complex, which leads to the cessation of bacterial growth and replication [115].

Another effective antibiotic against most Gram-positive bacteria is teicoplanin. Teicoplanin belongs to the glycopeptide class of antibiotics, which also includes the well-known antibiotic vancomycin. Teicoplanin inhibits bacterial cell wall synthesis by binding to the D-alanyl-D-alanine terminus of the cell wall precursors, preventing the incorporation of these precursor molecules into the cell wall and thus inhibiting cell wall synthesis [116]. This action eventually leads to the death of the bacterial cell. This antibiotic was used in combination therapy with the Sb-1 phage in rats to treat implant-related osteomyelitis [105]. The treatment showed approximately 90% reduction rate and completely eradicated MRSA biofilm as well. Unlike animal models, humans present a unique set of physiological and immunological responses, making human clinical trials the most relevant for understanding how phage therapy works in treating MRSA infections. Despite their significance, human clinical trials of phage therapy against MRSA are relatively rare. This could be attributed to the multifaceted challenges associated with conducting such trials, encompassing regulatory, logistical, and ethical considerations.

The clinical application of bacteriophage represents a chapter in medical history, rooted in the early 20th century. The discovery of phages by Frederick Twort in 1915 and later by Félix d’Herelle in 1917 marked the emergence of these viruses as potential therapeutic agents against bacterial infections [117, 118]. D'Herelle was notably the first to propose the idea of using phages to treat diseases caused by bacterial infection, a concept he put into practice in 1919 to treat dysentery in Paris [119]. The subsequent years saw the rise of phage therapy, particularly in Eastern Europe and the Soviet Union, where it was extensively used in the 1930s and 1940s, most notably at the Eliava Institute in Georgia [120, 121]. This period was characterized by an empirical approach, with phages being applied to treat various bacterial infections like cholera, typhoid, and bacterial dysentery, often with reported success [121] However, the advent of antibiotics in the 1940s, particularly penicillin, led to a decline in phage therapy research and use in the Western world, owing to the broad-spectrum and ease of use of antibiotics [118]. Before the end of the 20th century, with the alarming rise in antibiotic-resistant bacteria, there was a renewed interest in phage therapy. This resurgence is driven by the specificity of phages to their bacterial targets and their potential to combat antibiotic-resistant strains, making them a promising alternative or in combination with traditional antibiotic therapies [122].

Conducting clinical trials for phage therapy against MRSA involves a complex regulatory setting. Since phage therapy is considered a relatively new and innovative treatment in the frame of modern medicine in the Western world, regulatory guidelines may not have been fully established, leading to uncertainties in the approval process. This is especially pertinent in the case of genetically modified phages in human populations, where different countries may have varying regulations. For instance, Eastern Europe (Georgia and Russia) allows easier access to phage products, while Western countries including the European Union (EU) and the United Kingdom (UK), are still developing, and refining regulatory guidelines for this innovative treatment [123, 124]. Additionally, ensuring compliance with these evolving regulations is crucial to maintain the validity and credibility of the trials. The challenge is compounded by the need to harmonize these regulations across different regions if the trial is international in scope. Similarly, the logistics of conducting phage therapy trials present several challenges. Recruitment and retention of participants are major hurdles, particularly finding individuals with MRSA infections who meet the specific criteria for phage therapy. The experimental nature of the treatment might also make patient recruitment more difficult, as potential participants may be hesitant to join a trial that uses a relatively unknown method [123, 125]. The specificity of phages adds complexity to the trial design and necessitates careful planning in terms of phage selection and patient matching. Managing data effectively is another logistical challenge, given the need for detailed analysis of phage-bacteria interactions and patient outcomes [125, 126].

Moreover, financial constraints may be a critical factor, as phage therapy might not acquire the same level of investment as conventional pharmaceutical approaches [123, 125]. Finally, ethical concerns are crucial in phage therapy trials for MRSA to ensure the safety and rights of participants. This ethical conduct of clinical trials is grounded in several key documents and guidelines, including The Declaration of Helsinki (https://www.wma.net/), The Belmont Report (https://www.hhs.gov/), and Good Clinical Practice Guidelines (https://www.ema.europa.eu). Informed consent is essential, where participants are fully briefed about the potential risks and benefits of the therapy. The ethical dilemma is vastly impacted by the severity of MRSA infections, which can be life-threatening, thus raising questions about the balance between urgent needs and patient safety. Additionally, ensuring a diverse patient population in the trials is not only a logistical but also an ethical requirement [127], to ensure the generalizability of the results and equity in healthcare advancements. The consistent monitoring of participants is also an ethical necessity to determine any delayed side effects of the development of resistance to the phages. Hence, conducting phage therapy trials against MRSA requires careful consideration of a range of regulatory, logistical, and ethical factors. Each of these aspects plays a crucial role in ensuring the trials are conducted in a manner that is safe, scientifically valid, and ethically sound.

Discussion

Animal models have been widely used in testing and have been extensively studied for phage efficacy in treating infections in vivo shown in Table 3. The health problems for animals and humans that arise due to MRSA, are limited to skin infection but can trigger septicemia and severe illnesses [128]. Nevertheless, the use of phage for treatment shows a promising report. In the study of Oduor et al. [129], phage therapy was assessed in MRSA using a mice model and provided evidence that, even at the fatal sepsis stage, it was shown to be 100% effective against MRSA infection for 72 h post-infection. It is also reported the effectiveness and efficacy of phage therapy in the treatment of ventilator-associated pneumonia caused by MRSA [130].

The major concern of phage therapy is the lack of protocol needed for treatment. Furthermore, an insufficient number of clinical trials hinder the development of phages in clinical settings. There have been no randomized double-blind trials conducted. The treatments available are based on case reports or small clinical trial series (Table 3). Besides, despite the understanding of phage's antimicrobial properties in vitro, there is only limited data on their activities in vivo, particularly generated in clinical trials, and more data is required for their use in healthcare settings.

Furthermore, the development of phage resistance by bacteria may limit the success of the phage therapy. The initial step of infection is phage adsorption to cell receptors, and some bacterial strains have developed mechanisms to prevent this critical process [131]. Bacterial resistance to phages can be reduced by using phage cocktails and administering a higher initial phage inoculum, or PAC [132]. For phage therapy to progress, clinical studies and trials must systematically assess the development of resistance [133]. Furthermore, extensive research, monitoring, and prevention strategies are necessary to ensure the long-term success of phage therapy. This suggests that research, monitoring, and prevention strategies are necessary to ensure the long-term effectivity of phage therapy.

Future directives and perspectives

The advancement of phage therapy against MRSA infections stands at a pivotal juncture, presenting a promising alternative in the context of escalating antibiotic resistance. The specificity of bacteriophages to their bacterial hosts offers an innovative approach to targeted therapy, minimizing the impact on the human microbiome and reducing the emergence of broad-spectrum antibiotic resistance [134, 135]. Future studies should pivot towards enhancing the understanding of phage-host dynamics, with a focus on the development of phage libraries and the optimization of phage cocktail formulations to circumvent bacterial resistance mechanisms. Additionally, the exploration of advanced phage engineering techniques, such as CRISPR-Cas systems, could significantly amplify the efficacy and specificity of phage therapeutics.

An additional critical area of focus is the development of rapid and precise diagnostic tools for bacterial strain identification, which is essential for the timely and effective deployment of phage therapy [136]. Bridging the gap between in vitro efficacy and clinical applicability remains a significant concern, necessitating concerted efforts to translate laboratory success into tangible clinical outcomes. The future of phage therapy against MRSA thus lies in a multidisciplinary approach, integrating molecular biology, clinical medicine, and regulatory science to fully harness the therapeutic potential of bacteriophages.

Conclusion

This review has clearly demonstrated the remarkable potential of phage therapy in the treatment of MRSA infections. This therapeutic approach not only highlights exceptional promise but also offers several distinct advantages and presents itself as a compelling alternative to traditional antibiotic treatments. A particularly noteworthy aspect of phage therapy is its capacity to combat infections and biofilm, a challenging aspect of MRSA infections that conventional antibiotics often struggle to address effectively. However, it is crucial to acknowledge certain disadvantages and considerations associated with phage therapy. Clinicians and researchers must be aware of the challenges and the imperative need for well-designed clinical trials to translate this promising approach into effective treatments for MRSA infections. Bacteriophages are poised to play a pivotal role in the ongoing fight against antibiotic-resistant bacterial pathogens, and further research and clinical exploration are warranted to fully harness their therapeutic potential.

Funding

None.

Author contribution

JAGF conceptualize the manuscript. JAF and CJNO wrote the original draft. JAGF, CJNO, and RDJ revised the original draft. JAGF, CJNO, and RDJ wrote, reviewed, and edited the manuscript. CJNO and RDJ performed supervision. All authors read and approved the final manuscript for publication.

Conflict of interest

The authors declare that no conflict of interest exists.

Acknowledgement

The authors would like to express their sincere gratitude to Dr. Esperanza C. Cabrera of De La Salle University (DLSU) Manila and Dr. Pierangeli G. Vital of Biological Research and Services Laboratory (BRSL) for their approach, guidance and content review of the manuscript. Also, to Ms. Erika Gin Constantino-Bacuyag of NU Fairview Incorporated for her meticulous attention to detail, keen grammatical insights, and unwavering commitment to ensuring the highest standards of written expression.

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