Phage Therapy for Resistant Staphylococcus aureus Infections: Comparison
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The production and use of antibiotics increased significantly after the Second World War due to their effectiveness against bacterial infections. However, bacterial resistance also emerged and has now become an important global issue. Those most in need are typically high-risk and include individuals who experience burns and other wounds, as well as those with pulmonary infections caused by antibiotic-resistant bacteria, such as Pseudomonas aeruginosa, Acinetobacter sp, and Staphylococcus sp. With investment to develop new antibiotics waning, finding and developing alternative therapeutic strategies to tackle this issue is imperative. One option remerging in popularity is bacteriophage (phage) therapy. 

  • phage therapy
  • antibiotics resistant
  • S. aureus
  • biofilms
  • infection

1. Introduction

Bacteriophages (phages) are found in all habitats, and their interaction with bacteria has attracted greater attention from scientists for almost a decade [1]. Bacteriophage therapy or phage therapy (PT) that consists of specific virulent bacteriophages can be used for targeting multidrug-resistant bacteria and can mimic the action of an antibacterial agent [2]. Indeed, PT has currently been used to treat patients with methicillin-resistant Staphylococcus aureus (MRSA) infections [3][4][5][6]. According to the NCBI database, a total of 69 genomes of virulent staphylophages have been deposited, with 26 and 43 genomes belonging to the family of Podoviridae and Myoviridae phages, respectively [7]. The high efficiency of staphylophages in the therapeutic cocktail is attributed to its broad host range and high lytic capabilities [8].
Although various successful investigations have explored using singular or multiple phage types (phage cocktails), a definitive answer on their safety and efficacy as part of standard clinical care is still unknown [9].

2. Phage Therapy for Resistant Staphylococcus aureus Infections

2.1. Staphylococci

Staphylococci are frequently isolated as the causal agent of bacterial infections in humans, and its management remains challenging due to the advent of multidrug-resistant strains [10]. It commonly causes surgical wound infections and pneumonia and is the second most common cause of blood infections [11]. Importantly, S. aureus has been extremely efficient at developing resistance to the most recent antibiotic classes. Although methicillin-resistant S. aureus (MRSA) was quite rare between the 1960s and 1980s, the problem escalated in the mid-1990s when particular ‘epidemic’ strains became established in hospitals throughout the UK, which were caused by SCCmec type 1. Several antibiotics targeting methicillin-resistant S. aureus (MRSA) have been developed and approved for use, including linezolid, daptomycin, tigecycline, ceftobiprole, telavancin, ceftaroline, dalbavancin, oritavancin, and tedizolid [12]. However, they have reduced efficacy when staphylococci establish as biofilms, typically seen with device-associated infections and endocarditis [13].

2.2. Genetic Structure of Staphylococcus aureus

The S. aureus genome consists of a circular double-stranded chromosome as well as several plasmids. The number of complete and draft genomes has grown exponentially, with hundreds now available in the NCBI repository [14][15]. Upon examination, conservational similarities and differences are seen between methicillin-sensitive S. aureus (MSSA) and MRSA. For example, the genomic core (representing ~75% of the entire genome) is extremely conserved between both MRSA and MSSA isolates and contains genes associated with housekeeping and other metabolic functions [16]. In addition to the core genome, accessory genomes can be obtained from other bacterial species by lateral gene transfer [17]. This domain accounts for ~25% of the entire genome and consists of mobile genetic elements such as virulence factors, chromosome cassettes, genomic plasmids, transposons, and antibiotic resistance dynamics [18].

2.3. Staphylococcal Cassette Chromosome (SCC)

As an important basic mobile genetic element, the SCC serves as the motor vehicle for gene substitution among Staphylococcus species. It typically contains the mec gene (although not always present), which codes for methicillin resistance, regulatory genes, as well as the cassette chromosome recombinases (ccr), which enables the integration and cutting of SCCmec [19]. SCCmec typing enables structural determination of SCCmec and can assist in inferring the origins of particular MRSA strains [20]. Each SCCmec element integrates at the same site, which is a precise site at the 3‘ end of a unique ORF (open reading frame) of unknown function, designated orfX [21]. To date, 13 different types of SCCmec (I-XIII) have been defined according to their subparts, namely, the ccr and the mec complexes [22][23].

2.4. Update on Treatment of S. aureus Infections and Its Associated Challenges

Treatment agents currently available for S. aureus infections include cloxacillin, flucloxacillin, cefazolin, ceftaroline, ceftobiprole, vancomycin, daptomycin, linezolid, teicoplanin, tigecycline, co-trimoxazole, doxycycline, clindamycin, telavancin, dalbavancin, oritavancin, and others [24]. Several antibiotic guidelines for treating S. aureus infections have been established and regularly updated according to the epidemiological data of antibiotic resistance patterns, national and global surveillance of resistance, and efficacy data of newly anti-staphylococcal agents [25]. The guideline consists of recommended antibiotics (weak and strong recommendations) and therapy regimes (dosage and duration) used for specific types of infections such as skin and soft-tissue infections (SSTIs), urinary tract infections (UTI), bone and joint infections, bacteremia, endocarditis, pneumonia, and meningitis [26]. However, infections caused by MRSA deserve special attention as common antibiotics used for MSSA are no longer effective against them, and their propensity to rapidly spread, causing an outbreak, is very common [27][28]. Topical antiseptics such as hydrogen peroxide 1% cream remain an effective option for patients with uncomplicated impetigo due to MRSA [26]. Despite new anti-MRSA agents that have been officially licensed, there is no solid evidence to establish the optimal agent(s) for specific infections caused by MRSA. Retapamulin ointment 1%, an agent of the pleuromutilin class, is still inferior to oral linezolid in a clinical trial, thus, limiting its use for this condition [29]. Ceftobiprole, dalbavancin, and tedizolid are not recommended for the SSTIs caused by MRSA due to inconclusive evidence from the clinical trials [30][31][32]. In fact, major side effects, including thrombocytopenia and optic neuropathy, have been reported in patients treated with linezolid and tedizolid [33]. Limited data from clinical trials also suggested that complicated (non-catheter related) UTIs caused by MRSA should be treated with intravenous glycopeptides such as vancomycin or teicoplanin [26]. Similarly, intravenous glycopeptides are strongly recommended for treating necrotizing pneumonia due to Panton–Valentine leucocidin (PVL)-producing MRSA strains despite no recent update about the existing guideline in the UK since 2008 [34]. As for hospital-acquired pneumonia (HAP) caused by MRSA, a similar approach to therapy is not highly recommended due to a lack of data based on clinical trials [26].  Rifampicin is used as an adjunct therapy in patients with MRSA bone or joint infections for its ability to penetrate the biofilm [34]. There has been an increasing preference for using dalbavancin among clinicians for its long half-life and convenient dosing regimen [35]. Nonetheless, recent evidence from the clinical trials fails to support the use of these drugs for this condition. Instead, intravenous glycopeptides are highly recommended with proper therapeutic drug monitoring in view of the nephrotoxic effect associated with the prolonged use of vancomycin [26][36]. A similar recommendation is proposed for MRSA bacteremia except for the use of teicoplanin. Linezolid, telavancin, and ceftaroline can be used as alternative second-line drugs if vancomycin is contraindicated [37][38], although it is not highly recommended by the recent guidelines [26]. 

2.5. Resistance to Antimicrobial Therapy

A pathogen’s success in causing infection depends on two factors, (i) developing resistance to antibiotics and (ii) virulence factors. Resistance in S. aureus is obtained via the acquisition of mobile genetic elements (SCCmec) containing resistance genes such as mecA encoding a unique protein called penicillin-binding protein 2a (PBP2a). Its low affinity for β-lactam antibiotics thus enables it to substitute the biosynthetic functions of PBPs [39]. In addition to SCCmec, other mobile genetic elements involved in resistance acquisition include plasmids, transposons, insertion sequences, integrons, integrative-conjugative elements, and pathogenicity islands [40]. One staphylococcal conjugative plasmid (pGO1/pSK41) has been directly shown to have contributed to resistance to aminoglycosides, penicillin, trimethoprim, bleomycin, tetracycline, macrolides, lincosamide, streptogramin B, and more recently linezolid and vancomycin [41]. Furthermore, transposons, which themselves are a group of mobile genetic elements, can transfer resistance genes due to their ability to transfer between plasmids or from a DNA chromosome to a plasmid (or vice versa) [42]. Thus, antibiotic resistance emerges rapidly through the acquisition of antibiotic-resistance genes from other strains of S. aureus or even from other genera. The development of resistance due to antibiotic treatment failure results in outbreaks of multiple drug-resistant (MDR) strains, typically in hospital institutions as well as the general population [43].

2.6. Role of Biofilm Formation in S. aureus Infections

Microbial populations tend to adhere to surfaces by producing extracellular polymeric substances (EPS) and forming biofilms [44]. Bacterial cells growing in a biofilm are difficult to treat by antibiotics since the EPS matrix prevents them from reaching the bacteria via physical repulsion or limited diffusion [45]. It has been estimated that of all bacterial infections, ~80% involve biofilm formation [46], and these appear to be 10–1000-fold more resistant to antibiotics compared to their planktonic counterparts [47]. The challenge to eradicate bacterial biofilms via antibiotics is well documented, with evidence suggesting some variabilities between drugs. For example, oxacillin, cefotaxime, and vancomycin have shown limited penetration, whereas amikacin and ciprofloxacin are far more effective in this function [48]. However, eradication of biofilms is very challenging, especially in clinical settings, as high rates of recurrent or chronic bacterial infections have been observed due to biofilms [49]. The development of biofilm-related S. aureus infections is always associated with medical devices or procedures used as part of patients’ management, such as indwelling catheters or implants, and chronic conditions such as chronic lung infections, chronic wounds, endocarditis, and others [49].

2.7. Phage Therapy

The term “phage” is defined as a type of virus that can enter and destroy bacterial cells whose potential was appreciated early in history [50][51]. The morphological structure of a bacteriophage is unique as it consists of a head that is filled with DNA or RNA and a tail that is used for the introduction of the genome into the bacterial cells (Figure 41). It has limited receptors on eukaryotic cells; hence, it may not enter mammalian cells, making it the most promising alternative therapeutic option in humans [52][53].
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Figure 41.
Illustration of a bacteriophage with its structure and components.
Their bactericidal activity begins with the binding of the virion to specific bacterial cell-surface receptors via phage receptor binding proteins (RBP), followed by the adsorption of phage DNA into a bacterium. This then initiates various molecular mechanisms which promote phage propagation and resultant bactericidal activity [54]. Bacteriophage therapy has been actively implemented since the early twentieth century after its discovery by Twort [55] and D’Hérelle [56]. Since this period, its popularity diminished as antibiotic use became the preferred method of treating infections in western countries. However, with the advent of antibiotic resistance, several recent investigations have explored the efficacy of treating bacterial infections with phages in the human setting [57][58][59]. Chan and Abedon first suggested that treatment strategies could be categorized by the number of phage types used, with ‘monophage therapy’ exploiting a single phage type and ‘polyphage therapy’ involving multiple phage types [60]. Levin and Bull initially emphasized the importance of accurately matching pathogens with specific phages. Although usually assessed in vitro, phage activity in this setting is not always predictive of their efficacy in vivo [61]. It has also been identified that phage preparations should be purified by filtration and passed through specific columns or resins to remove endotoxins from the phage lysate to a level appropriate for use, and toxicity testing of formulations in vivo should be conducted [62][63][64]. As natural predators of bacteria, bacteriophages have several innate mechanisms to destroy biofilms (Figure 52). For example, degradation of the extracellular matrix is initiated by the induction of bacterial cells to produce exopolysaccharides (EPS)-degrading enzymes, which later break down the polysaccharides and proteins of the extracellular matrix (biofilms). Hence, this could facilitate the penetration of bacteriophages into the biofilms and later replicate in the bacterial cells and destroy them [65]. The phage can also express polysaccharide depolymerases, an enzyme that is able to degrade biofilms, as well as polysaccharide-forming capsules and lipopolysaccharides [66][67]. Interestingly, bacteriophages can enter the bacterial genome and integrate themselves, leading to “floating bacterial cells” that could interfere with the formation of biofilms [66].
/media/item_content/202303/6406f485c5c17antibiotics-12-00286-g005.png
Figure 52. Illustration of the disruptive mechanisms of bacteriophages in Staphylococcus aureus biofilms on abiotic and biotic surfaces by the (a) expression of polysaccharide depolymerases which degrade extracellular matrix, (b) induction of host cells to produce exopolysaccharides (EPS)-degrading enzymes, (c) diffusion via biofilm water channels for inner layer penetration, and (d) adsorption to bacteria for biofilm penetration. The role of each bacteriophage is depicted in various colors (dark yellow, orange, yellow, and white).
Phage therapy (PT) should also be carefully assessed in patients with chronic infections caused by polymicrobial agents. For example, anti-S. aureus PT failed to completely cure chronic polymicrobial biofilm infection of a bone allograft in a sarcoma patient. The scholars explained the possibility of incomplete coverage of anti-S. aureus PT against non-staphylococci bacteria [68]. In addition, a special precaution should be implemented when PT is used when treating infections in patients with cancers. Following the introduction of bacteriophages (T4 and M13) into prostate cancer cell lines (PC-3), overexpression of integrins was observed, which may be beneficial to prostate cancer cases [69]. However, it may be detrimental to other types of cancers, such as ovarian and breast cancers. Overexpression of selected integrins (ITGAV and ITGB3) would promote the survivability of these cancer cells and their proliferation [70]. Although there is a lack of phage receptors in mammalian cells, Bichet et al. [71] demonstrated the uptake of phages by several cell lines through micropinocytosis in vitro [71]. The uptake of phages and their internalization process across the cell lines are very heterogenous, and the scholars concluded that the type of cells and phages have no roles in their specificity. Interestingly, the viability of these phages was lost due to the inactivation process [71]. This finding could further compromise the accessibility of phages to the site of infection in the tissues or organs during phage therapy. Modifications in the shape of phages may reduce the sequestration issues related to cellular uptake during phage therapy. It has been shown that the elongated-shaped phages have lower uptake rates by the cells compared with the disc-shaped phages [72]. Tolerability and safety for patients are paramount but are affected by the solution formulations phages are stored in. Formulations need to be specifically designed in order to maintain phage stability in storage, which, when poorly formulated, would impact effectiveness during treatment [73]. On a similar note, an appropriate therapeutic regime (dosage, dosing interval, and timing) is also pivotal in ensuring the efficacy of phage therapy, as clearly explained by [1].

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