Authors:
Vincent A. Eiselt Gastrointestinal Microbiology Research Group, Institute of Microbiology, Infectious Diseases and Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

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Stefan Bereswill Gastrointestinal Microbiology Research Group, Institute of Microbiology, Infectious Diseases and Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

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Markus M. Heimesaat Gastrointestinal Microbiology Research Group, Institute of Microbiology, Infectious Diseases and Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

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Abstract

Prosthetic joint infections (PJIs) are dreaded arthroplasty complications often caused by Staphylococcus aureus. Due to methicillin-resistant S. aureus (MRSA) strains or biofilm formation, successful treatment remains difficult. Currently, two-stage revision surgery constitutes the gold standard therapy of PJIs, sometimes replaced or supplemented by debridement, antibiotics, and implant retention (DAIR). Given the dire consequences of therapeutic failure, bacteriophage therapy might be another treatment option. Here we provide a comprehensive literature review addressing the efficacy of phages applied against S. aureus as causative agent of PJIs. The included 17 publications had in common that the applied phages proved to be effective against various S. aureus isolates including MRSA even in biofilms. Experiments with mice, rats, rabbits, and moth larvae confirmed favorable features of phage preparations in PJI treatment in vivo; including its synergistic with antibiotics. Case reports of PJI patients unanimously described the bacterial eradication following, alongside other measures, intravenous and intra-articular phage administration. Generally, no major side effects occurred, but in some cases elevated liver transaminases were observed. To conclude, our review compiled promising evidence suggesting the safety and suitability of phage therapy as an adjuvant to DAIR in S. aureus PJIs, and thus, underscores the significance of further research.

Abstract

Prosthetic joint infections (PJIs) are dreaded arthroplasty complications often caused by Staphylococcus aureus. Due to methicillin-resistant S. aureus (MRSA) strains or biofilm formation, successful treatment remains difficult. Currently, two-stage revision surgery constitutes the gold standard therapy of PJIs, sometimes replaced or supplemented by debridement, antibiotics, and implant retention (DAIR). Given the dire consequences of therapeutic failure, bacteriophage therapy might be another treatment option. Here we provide a comprehensive literature review addressing the efficacy of phages applied against S. aureus as causative agent of PJIs. The included 17 publications had in common that the applied phages proved to be effective against various S. aureus isolates including MRSA even in biofilms. Experiments with mice, rats, rabbits, and moth larvae confirmed favorable features of phage preparations in PJI treatment in vivo; including its synergistic with antibiotics. Case reports of PJI patients unanimously described the bacterial eradication following, alongside other measures, intravenous and intra-articular phage administration. Generally, no major side effects occurred, but in some cases elevated liver transaminases were observed. To conclude, our review compiled promising evidence suggesting the safety and suitability of phage therapy as an adjuvant to DAIR in S. aureus PJIs, and thus, underscores the significance of further research.

Introduction

Epidemiological burden

Although joint replacements enable millions of patients to live with greater mobility at less pain year after year, it is suspected that nearly seven out of a thousand US-American patients who received a hip or knee prostheses will be affected by an infection with various symptomatic manifestations [13] (Fig. 1).

Fig. 1.
Fig. 1.

Core symptoms of a prosthetic joint infection and the principle of phage therapy

The quarter-split circle illustrating core symptoms comprises alluding depictions of (starting from upper left in clockwise direction) reduced mobility, fistula with purulent discharge, prosthesis loosening, and substantial pain. In the box below, an outline of the principle of phage therapy from both the clinical perspective (administration through joint injection) and the molecular perspective (phage enters bacterial cell and causes its lysis) is given.

Citation: European Journal of Microbiology and Immunology 14, 2; 10.1556/1886.2024.00010

Such prosthetic joint infections (PJIs) are responsible for approximately 25% and 15% of revision surgeries following total knee and hip arthroplasties, respectively [46]. Moreover, a five-year mortality in PJI patients of over 20% was described in one study [7]. Given these consequences, including functional restrictions, PJIs are deemed as the worst complication of arthroplasty [8, 9]. All in all, healthcare costs in the amount of 1.62 billion dollars were expected for the US health care system in 2020 due to treatment procedures [10]. Unfortunately, this number is likely to rise even further, as the number of primary arthroplasties is projected to experience a significant increase by 2030 [11].

Properties of Staphylococcus aureus

Around 63% of PJIs are caused by S. aureus, which is simultaneously regarded as the most virulent pathogen in PJIs [12, 13]. The species name of the Gram-positive cocci stems from its clustered appearance under the microscope and gold pigmentation of colonies on solid growth media [14]. Not only is it known as causative agent of severe infections like endocarditis, osteomyelitis, or arthritis, for instance, but it is also found on the skin and nasal mucosa in approximately 30% of healthy adults [14, 15]. Mainly its ability to form biofilms, i. e. bacterial conglomerates encased in a glycocalyx matrix on prostheses and devitalized bones, makes it a difficult-to-treat pathogen in PJIs [1619]. This is due to a biofilm-mediated antimicrobial resistance further promoted by a maturation process in biofilm-encased bacteria involving an alteration in bacterial metabolism and transcriptome [20, 21]. It is estimated that biofilm-encasement of bacteria increases the antibiotic dosage required for anti-infective treatment by one thousand fold [22]. It is noteworthy that biofilm-encased bacteria are preceded by so called “planktonic” bacteria which are referred to as being in a “free-living” state because they do not form part of the biofilm matrix.

Besides pan-penicillin-resistance in methicillin-resistant variants of S. aureus (MRSA), two other features compounding the clinical predicament are persister cells and small-colony variants formed by S. aureus in deep-tissue or bone infections. While persister cells are bacteria which temporarily resist antibiotic effects until their normal state is restored as soon as antibiotic pressure ceased, small-colony variants exhibit various stable and continuous differences in the phenotype resulting in differing virulence and growth [23].

Conventional therapy of PJIs

The gold standard therapy of PJIs is two-stage revision surgery, in which the prosthesis is removed for mechanical eradication of biofilms and reimplanted after six weeks of antibiotic treatment, with vancomycin being the first choice in case of methicillin-resistant S. aureus (MRSA) [92426]. Considering its success rate of roughly 85%, failure of two-stage revision surgery in association with risk factors like obesity or immunosuppression is common [2728]. In elderly patients and other patients in whom two-stage revision surgery was either not advisable in the first place or ultimately unsuccessful, another therapeutic scheme is usually employed: debridement, antibiotics, and implant retention (DAIR) having a minimum success rate of as low as 21% is then followed by suppressive antibiotic treatment (SAT), which still does not provide an adequate rate of therapeutic success, as relapses remain probable [29, 30].

Phage therapy as an adjunct

To forestall dire conditions and improve the overall outcome, concomitant phage therapy could be a promising treatment option [31, 32] (Fig. 1). Bacteriophages are viruses which target solely bacteria and undergo genetic propagation by chromosomal integration in a temperent state. If phages are produced at large scale in the lytic cycle the hosting bacteria are killed by phage-derived lysins [31]. In case of S. aureus phages, teichoic acid is considered a common receptor for attachment [33]. Particularly, synergetic effects of such bacteriotropic viruses with antibiotics underscore the potential suitability for patients suffering from PJI [34]. Even the application of phage-derived lysins like peptidoglycan hydrolases alone demonstrated broad efficacy against antibiotic-resistant and biofilm-forming S. aureus [35, 36].

Generally speaking, phage therapy entails favorable properties like high host specificity, low interference with the resident commensal microbiota, self-regulated dose through lytic replication, pharmacological harmlessness, and versatility in terms of administration [37]. For example, both intra-articular (IA) and intravenous (IV) injection as well as the use of multiple phages together (a phage cocktail) are possible treatment modalities [31].

Objective

The primary objective of this literature review is to cast a light on the general issue of phage therapy in PJIs caused by S. aureus. For that purpose, we bring together a multitude of published results and try to elucidate mutual insights. Lastly, we strive to reach conclusions about the evidence on its suitability and safety itself.

Methods

Inclusion and exclusion criteria

Meeting recency and general availability, we included only original publications in English being not older than ten years. Dealing with the manageable quantity of publications, we included all contributing to the general topic of phage therapy in S. aureus-associated PJI without setting further requirements beforehand. Thus, in vitro and in vivo experiments, for instance, were considered. Naturally, case reports received special appreciation. Nevertheless, we excluded publications solely mentioning S. aureus en passant while focusing on other species of the genus Staphylococcus. Articles concerning genetic properties without sufficient overall relevance were excluded as well.

Search strategy and data retrieval

Employing the “Advanced Search Builder” of the search engine “PubMed” by the United States National Library of Medicine, multiple queries structured our eventual search being based on the input concisely presented in Table 1. On the 10th of July 2023, 20 search results were obtained in the MEDLINE database. Following individual examination with regard to our criteria, three publications were excluded with the remaining 17 publications constituting the studies under investigation of the review at hand.

Table 1.

Systematic queries using tags, Boolean operators, and filters in PubMed's advanced search builder

TagTitle/AbstractPublication type
Boolean operatorsANDNOT
ORStaphylococcus aureusPhagePJIReview
Staph aureusPhage therapyProsthetic joint infectionSystematic review
MRSABacteriophagePeriprosthetic joint infection
Methicillin-resistant S. aureusBacteriophage therapy
S. aureus
Filters: in the last 10 years, English

Results

Effects of phages under various conditions

Doub et al. briefly reported the results of an experiment with phenotypic variants of S. aureus with regard to their sensitivity towards applied phages [38]. First of all, the authors recovered S. aureus from an arthrocentesis culture and three up to five deep tissue cultures from each one of three PJI patients. Testing these cultures against a library of 56 phages, it was shown that the phages' efficacy in bacterial killing varied considerably. For instance, appropriate lytic capacity was considered when the duration of growth inhibition after the addition of a phage in vitro was ascertained to be greater than 12 h. In general, pronounced heterogeneity as well as a substantial disparity were observed. Remarkably, some phages capable of inhibiting S. aureus from an arthrocentesis culture for 46 h tended to do poorly in case of respective deep tissue cultures of two patients. However, three of five phages exhibiting strong activity against the arthrocentesis culture also had a comparable or at least sufficient activity against all deep tissue cultures of the third patient. With respect to such phages that inhibited all S. aureus isolates regardless of their intrapatient origin, it became apparent that they did not necessarily achieve this in other patients. Based on their findings, the authors recommended the individual selection of phages as a treatment to S. aureus-associated PJIs taking both arthrocentesis and deep tissue cultures into account in order to address the varying glycosylation patterns of the teichoic acids depending on the in vivo environment and, thus, providing broad enough effectiveness [38].

DePalma et al. conducted an in vitro study on a 15-phages-group's activity against 15 MRSA and 14 methicillin-susceptible S. aureus (MSSA) clinical isolates originating from hip and knee PJIs [39]. Observing bacterial growth within the course of 48 h, an adequate (i.e., for 12 or more hours) inhibition of prevailing planktonic colonies was accomplished in all but one of the 29 S. aureus samples by at least one phage in each case. Of note, four MRSA and three MSSA isolates comprised additional colonies exhibiting a smaller size as well as slower growth. Due to the unavailability of the remaining two samples, only five of these seven isolates with secondary morphology colonies (all four MRSA, only one of the three MSSA) were subject to further investigation. As it turned out, all small colonies' growth remained unimpaired by all phages except for one particular phage, which possessed an internally stronger activity against bacteria in biofilms. Indeed, only phage SaMD07FSΦ1 was capable of an adequate reduction in bacterial growth in leastwise 80% of such secondary colonies, impeding also the accompanying planktonic colonies of the same sample. The general phenomenon was attributed to an assumed difference in attachment receptors between the colony variants. As a consequence, the necessity of in vitro testing in respect of planktonic and stationary biofilm encased colonies prior to approaching a PJI with phages as a treatment was concluded, in order to attain the highest possible probability of therapeutic success [39].

Morris et al. explored the in vitro anti-biofilm capacity of a phage cocktail against 30 strains of S. aureus [40]. The bacteria were, then, probed against a library of 31 specific phages, revealing five distinct phages (StaPh_1, StaPh_3, StaPh_4, StaPh_11, and StaPh_16) that exhibited lytic activity against more than 90% of the tested S. aureus strains. Subsequently, these phages were united within a “StaPhage” cocktail, which caused an inhibition of bacterial growth instantaneously following inoculation by more than 98% within eight hours as long as multiplicity of infection (MOI) of phages to bacteria was above a 1:1-relation. Beyond that, a substantial reduction in viable bacteria encased in biofilm on titanium surfaces was noted as a consequence of the phage cocktail's administration. In contrast, not even a 100-fold of the minimum inhibitory concentration (MIC) of cefazolin was capable of a substantial reduction in biofilms. Hereby dismissing a universal approach, the authors advocated for an individualized phage cocktail based on precedent susceptibility testing as a treatment for PJI [40].

Totten et Patel studied the lytic capacity of seven phages against planktonic and biofilm phenotypes of S. aureus from 122 PJI isolates in vitro [41]. To begin with, susceptibility towards phages was found in up to 73% of clinical isolates, with all planktonic isolates experiencing a substantial destruction of biofilms due to usage of phages. Additionally, no corroboration of differences in phage susceptibility between small and non-small colony variants was possible on the basis of the study's results. While a correlation of planktonic susceptibility to the phage ATCC 11988-B1 with oxacillin susceptibility was identified, the testing of possible correlations between biofilm susceptibility and susceptibility to linezolid, daptomycin, rifampin, clindamycin, and levofloxacin did not reveal considerable coherences. Consequently, the authors considered the phage sensitivity of antibiotic-resistant S. aureus to be equivalent to that of S. aureus being susceptible to antibiotics [41].

Shinde et al. examined the effect of 10% human plasma on the lytic efficacy of two phages (Staphylococcal phage 1 and 3) against multiple S. aureus isolates in vitro [42]. It was found out that human plasma diminished the phages' infectivity substantially. In case of two MRSA isolates separately targeted by the same phage (Staphylococcal phage 1), a reduction in the infectivity of 48% and 81% compared to absence of human plasma was detected. While another phage's (Staphylococcal phage 3) infectivity in terms of a third MRSA isolate was downscaled by even 98%, no inhibition of infectivity at all was reached through human plasma regarding a specific phage (Enterococcus phage 1) addressing an isolate of Enterococcus faecalis. These comparative observations led the authors to the hypothetical conclusion that human plasma proteins stick on surface proteins of S. aureus and, thus, prevent phages from attaching to and entering the bacterial cell, causing the reduced lytic activity. Therefore, the surgical removal of synovial fluid containing plasma protein aggregates was hold in contemplation as a means of improving phage therapy of staphylococcal PJIs [42].

Totten et al. performed pharmacokinetic research in a single-dose, single-phage design with the phage K (ATCC 19685-B1) against S. aureus after IV and IA application in a rabbit model [43]. Their main finding was that phages were widely distributed within the course of 24 h independent of the administration route. Nevertheless, lower phage concentrations in synovial fluid and blood were detected after IV and IA administration, respectively. Furthermore, diminished phage loads in synovial fluid were recognized in case of a knee inflammation modeled by an induced osteoarthritis, leading to the assumption that longer dosing intervals of an IA administration should be considered under the circumstances of a PJI. Given constantly negative scores on the North American Science Associates, Inc. Comprehensive Histopathology Scoring System for Biomaterial Implants independent of various tissues and administration routes, a possible impairment of host tissues through low-endotoxin phage preparations was denied. In addition, no abnormalities were found in hematologic studies. However, transvascular dissemination of inflammatory cells and papillary proliferation of bronchial epithelium were discovered in phage-treated rabbits, being otherwise healthy. The authors called for further studies dealing with the pharmacokinetic effects of iterated phage administration and declared demand for a better understanding of the production of neutralizing antibodies dependent on the administration route [43].

Combination of phages with antibiotics

Sosa et al. comprehensively surveyed the phage-derived lysin PlySs2 in multiple tests against the MSSA strain Xen36 [44]. Firstly, an in vitro destruction of one-day biofilm of 77% and 75% was ascertained after application of PlySs2 for four hours in comparison to growth media control and vancomycin, respectively. Moreover, a destruction of 30% and 44% of five-day biofilm occurred, again if compared to growth media control and vancomycin. Even in high concentrations of Xen36, PlySs2 succeeded in terminating the bacteria, as shown by a reduction of absorbance by more than 50% in the first 15 min. In contrast, vancomycin impeded bacterial growth only after five hours post-treatment, involving an 80% plus of bacteria compared to the initiation of exposure. In another experiment, prevention of bacterial colonization on polyethylene surfaces was mediated by PlySs2 as well as vancomycin, each on their own, as indicated by a two to three log-fold diminution. Employing a DAIR model for acute PJI in mice, S. aureus biofilms on the surface of a tibial implant experienced an in vivo reduction in colony-forming units by more than three orders of magnitude due to PlySs2 in comparison to vancomycin. However, also a combination of the lysin and antibiotic was tested. While the mean MIC against Xen36 of PlySs2 alone was 64 μg mL−1, the MIC of PlySs2 and vancomycin together against Xen36, underpinning a synergistic relation, came down to as low as 8 μg mL−1. On top of this, the combination fostered bacterial clearance in soft tissues and on the implant of the murine model as well. Given these results the authors assumed an enhanced therapeutic effect of DAIR with the addition of phage-derived lysins [44].

Kaur et al. investigated a plethora of aspects with regard to the phage MR-5 specifically targeted at S. aureus ATCC 43300 (MRSA) in mice [45]. The authors' main interest centered on the exploration of conditions and circumstances of phage and linezolid coated implants as a treatment of respective PJIs. Generally, the wires were planted in the intra-medullary canal of the murine femur, prior to bacterial infection. While an expanding edema developed after a naked wire was implanted, only an insignificant and comparably faster subsiding edema arose in mice provided with a dual coated implant. Best functional healing (in terms of locomotor activity and the rotarod test) compared to naked, polymer, phage-only or linezolid-only coated wires was found in mice with dual coated implants. On a related note, a pronounced correlation between the extent of a developed edema and a limited physical activity was conceded. A maximum bacterial burden on naked wires was detected by day 3, representing an increase of roughly six order of magnitude, whereas lowest values of bacterial adherence was constantly found in mice treated with a dual coated wire implant. Similarly, bacterial growth occurred in joint tissues in case of the naked wire group, whereas a substantial decline in bacterial loads was noted for mice from the dual coated wire group. Moreover, favorable observations in terms of dual coated wires were reported in view of procalcitonin and cytokines values. In particular, the peak concentrations of procalcitonin amounted to as much as 600 pg mL−1 and only slightly more than 300 pg mL−1 for the naked and dual coated wire mice, respectively. Likewise, pro-inflammatory cytokine levels (i.e., IL-1β and TNF-α) recorded mounting highs in mice with naked wire with, again, lowest levels found in mice with dual coated wire. Also worth mentioning is that no resistant mutants regarding phage and linezolid coated implants occurred. Ultimately, histopathological examinations revealed mitigated degrees of tissue infiltration by lymphocytes and plasma cells in the general case of coated wires, compared to the tissues of naked wire mice [45].

A study of Taha et al. tested the efficacy of a phage called vB_SauM_Remus together with vancomycin against biofilm-like aggregates of the MRSA strain BP043 cultivated in 78% synovial fluid. In principle, it has been demonstrated that synovial fluid is not crucially detrimental to both the bacteria and the phages, as observed in even facilitated aggregate-formation as well as still feasible propagation in aggregates, respectively. Remus alone exhibited a dose-dependent effect against planktonic BP043 in a virulence essay, showing most distinct anti-bacterial activity at higher MOIs of 10 to 0.01, which led to a killing that began after four hours and lasted for another 44 h. Phage concentrations of 109 and 108 plaque-forming units (PFU) mL−1 proved to be most efficacious in lowering synovial aggregates of BP043 built up in advance. Besides, no emergence of S. aureus resistant to Remus was encountered at any time. Considering an in vitro stand-alone setting, vancomycin (500 μg mL−1) and Remus (108 PFU mL−1) achieved a 20% and 68% diminution in bacterial viability, respectively. However, even a 97% diminution in bacterial viability was made possible through an initial administration of Remus combined with a subsequent use of vancomycin. An established coefficient of drug interaction of 0.0028 was ascertained, pointing towards considerable synergistic relation between Remus and vancomycin. Those general observations were further corroborated in vivo. While Galleria mellonella larvae infected with BP043 had a survival rate of only 3% as early as 24 h without any treatment, larvae which received a combinatory therapy comprising Remus and vancomycin experienced a survival rate of still 37% at even 96 h [46].

Morris et al. addressed the suitability of concomitant phage therapy for PJIs with S. aureus as causative agent. In line with this, rats were infected with the MSSA clinical isolate OR16_C02N [47]. Then, a phage cocktail comprising the following five phages was prepared: StaPh_1, StaPh_3, StaPh_4, StaPh_11, and StaPh_16. Compared to a control group, the separate administration of phages and vancomycin, each alone, entailed 5-fold and 6.2-fold diminutions in bacterial burden in tissues surrounding the implant, respectively. The combination of the phage cocktail with vancomycin resulted in a 22.5-fold diminution in bacterial load of joint tissues, again in comparison to a control group. This also led to a mitigated swelling in the implanted knee as well as attenuated inflammatory responses. Furthermore, no occurrence of resistance to the five phages was observed. All in all, the authors postulated safety and efficacy of phage therapy in PJIs caused by S. aureus [47].

Clinical experiences

A total of seven publications addressed clinical experience with phage therapy in nine cases of PJIs with S. aureus as causal agent. Ferry et al. reported the use of the Defensive Antibacterial Coating (DAC®) hydrogel as a means of carrier for a phage cocktail comprising the two phages PP1493 and PP1815 to tackle, along with other measures, a recurring knee megaprosthesis infection with S. aureus [48]. The hydrogel was intended to counteract bacterial attachment and allow the local delivery of anti-bacterial substances. Observing the phage titers in a dilution of DAC® powder and phage suspension over time, the authors concluded a fast release and stability for a minimum of six hours. While the phage PP1493 exhibited pronounced efficiency against the patient's strain in vitro, PP1815 revealed only minor lytic activity in general. Moreover, full impairment of bacterial proliferation was noted at all concentrations of PP1493, whereas the same effect was achieved by PP1815 in the highest applied dosage only. Still, both phages were used together in order to prevent the emergence of resistances. The myocardial infarction suffered by the patient was not attributed to phage therapy, especially since previously unknown atherosclerosis was detected. When a transfemoral amputation was ultimately carried out one year after the application of phages, an infection with various bacteria was found, including S. aureus. However, this strain showed no genetic relationship to the original isolate [48].

Schoeffel et al. outlined a case of an MRSA infection of the knee and hip, which experienced treatment success only after the administration of the phage SaWIQ0488ø1. After common procedures involving antibiotics and revision surgeries had been shown to be ineffective, phage therapy was repeatedly performed as an adjuvant. To extend the therapeutic effect to sites not reachable by IA received phages, like cortical canaliculi or distal bones, the pages were also IV applied. On the first postoperative day, a slight increase in transaminases was detected while phage therapy was maintained. Regardless, no aggravation occurred and the liver enzymes normalized three days after phage therapy was finished. Despite of this, careful monitoring of liver function was advocated for [49].

Ramirez-Sanchez et al. described a partially self-administrable phage therapy in two cycles for a lengthy case of prosthetic knee infection with S. aureus [50]. Originally, a phage cocktail, named AB-SA01, containing the phages J-Sa36, Sa83, and Sa87 was used IA and IV. Subsequently, only a particular phage, called SaGR51ø1, was employed. Antibiotics were applied concomitantly in both phases of phage therapy. Side effects of phage therapy were not observed at any time point, especially liver function tests did not reveal abnormalities. Nevertheless, C-reactive protein (CRP) continued to be at a high level, when the first cycle of phage therapy was stopped prematurely owing to lack of phage supply by the manufacturer. In the further course, the patient's CRP values fell significantly and cultures, ultimately, were S. aureus-negative. Since above-knee amputation was considered by other physicians as a last resort, the authors declared a resounding success of phage therapy. Yet, they discussed, learning from the first round of phage therapy, longer duration and higher dosage as possible means of improvement and credited the removal of hardware as well as the cleaning of visibly infected sites between the two cycles with making an important contribution. Lastly, research on the immune response to phages was called for, albeit neutralizing antibodies did not interfere in the case of monotherapy. As multiple phages in question can be traced to a common phage, phage cocktails were not deemed superior in general [50].

Ferry et al. published a case report of a prolonged S. aureus prosthetic hip infection involving, among other bacteria, originally assumed MDR Pseudomonas aeruginosa [51]. Cocktails of three phages each were used against S. aureus and P. aeruginosa, respectively. While the phages targeting P. aeruginosa were chosen based on phagogram results, the combination of phages destined for the treatment of the S. aureus infection component was based only on their spectra due to the strain's unavailability at that time. Both cocktails were then locally injected prior to joint closure. In the course of this, the presence of other infectious agents was discovered and, thus, antibiotic therapy was provided. Eventually, S. aureus was overcome without side effects, indicating success and safety of phage therapy. It was also speculated that biofilm control was a supporting feature. A subsequently undertaken killing assay with the patient's strain of S. aureus revealed that the phages 1493 and 1815 exhibited specific capacity of lysis, whereas the phage 1957, completing the cocktail, did not. This led the authors to emphasize the importance of sensitivity testing in advance [51].

Doub et al. delineated a phage therapy temporarily brought to a premature end in a case of chronic prosthetic knee infection with MRSA [52]. While liver function stayed unsuspicious on antibiotics, elevated transaminases were noticed after a few days of administrating the phage SaGR51φ1. Hepatomegaly was revealed upon investigation, but tests for other infectious agents led to negative results. However, the original infection was cleared, as cultures showed weeks later. Further surgeries and phage therapies were conducted, but no return of elevated transaminases appeared following the decline after the initial phage therapy was stopped. Given that the patient was freed from the recalcitrant infection and could leave the hospital maintaining his lower limb, the phages proved to be an effective cure. As for the side effect, it was speculated that a steatosis possibly resulted in vulnerability, albeit the IV application was also a considered cause, since the IA route was not associated with elevated transaminases. This set of facts prompted a call for cautious monitoring of liver function as well as further studies investigating the human cytokine responses [52].

Doub et al. reported results from a treatment of a prolonged MRSA prosthetic knee infection with the phage Mallokai [53]. The authors pointed out that a testing of the phage prior to therapeutic application indicated the absence of endotoxins. Nonetheless, a small amount of staphylococcal enterotoxin A was measured during an afterwards carried out examination of the amplified phage. The authors pondered this observation as the potential reason for the rise in transaminases also seen over the course of phage therapy, apart from the earlier discussed involvement of cytokines. Hence, they strongly suggested the assurance of purity to avoid undesirable consequences. Another finding was that differing colony morphologies of MRSA were encountered in the knee and at the proximal end of the femoral lateral plate, respectively. Growth inhibition assays confirmed the lytic killing by the same phage as independent of the particular morphology. Still, it is highlighted that the possibility of multiple colony morphologies should be met with the verification of broad enough efficacy of the phages [53].

Ferry et al. gave a collective report on three similar cases of prolonged prosthetic knee MSSA infection handled with, as they put it, the “PhagoDAIR procedure” [54]. The involved phages (PP1493, PP1815, and PP1957) were chosen based on their target spectra against S. aureus using a reference panel. Seeking to benefit from complementary activity and looking to address the issue of resistance emergence, PP1957 was used together with the other two phages as a cocktail, even though it turned out to have comparably inferior lytic capacity in experiments with phagograms. While a repeat DAIR was all it took for patient 1, phagoDAIR procedure followed by antimicrobial therapy including rifampicin was not sufficient in curing patient 3 of the persistent discharge of synovial fluid. Indeed, the latter patient was, as it is speculated, perioperatively infected by two strains of S. aureus differing in agr type with the result of varying sensitivity. However, results from cultures as well as PCR were negative. The residual inflammation (observed in the form of elevated CRP levels) alone did not justify renewed phage therapy. Apart from the aforementioned, the overall outcome was seen as beneficial, notably as the infection abated fully in each case, leaving all three patients with the ability to walk without pain. Hence, the authors emphasized the necessity for a prospective multicentric clinical trial [54]. The following Table 2 briefly summarizes general aspects of the included case reports for the purpose of better comparability.

Table 2.

Comparative summary of case reports

PatientHistory/ConditionInterventionOutcomeReference
49y/m
  • Recurring knee megaprosthesis infection

  • No loosening, but exposition of the prosthesis

  • DAIR

  • Phage cocktail in DAC® hydrogel

  • Free flap for covering of soft tissue

  • Myocardial infarction with re-exposition of the prosthesis

  • Elimination of strain

  • Transfemoral amputation

Ferry et al. [48]
64y/f
  • Prosthetic knee and hip infection with MRSA

  • Unsuccessful use of antibiotics and surgeries

  • IV antibiotics

  • Implant exchange

  • DAIR

  • IV and IA phage

  • therapy

  • Therapeutic success, both from a microbiological and clinical perspective

  • No relapses, ambulation possible

Schoeffel et al. [49]
61y/f
  • Prosthetic knee infection, recurring for multiple years

  • (two-stage) TKA

  • Antibiotics and surgeries failed

  • Two-cycle phage therapy; first as a cocktail, then one phage alone

  • Antibiotics

  • Removal of infected implants

  • Initial execution allowed only clinical improvement

  • No relapse of Staphylococcus aureus infection for 20 months after second course

Ramirez-Sanchez et al. [50]
80y/f
  • Chronic infection of prosthetic hip

  • No loosening

  • Other bacteria like Pseudomonas aeruginosa involved

  • Multiple DAIR

  • Antibiotics

  • Phage cocktails injected, active against S. aureus and P. aeruginosa

  • P. aeruginosa was not confirmed in operative sampling

  • S. aureus eradicated without subsequent antibiotic treatment

Ferry et al. [51]
72y/m
  • Chronic infection of a prosthetic knee with MRSA

  • Loosening of prosthesis (later)

  • Failure of therapy

  • Amputation was turned down

  • Phage therapy was given IV and IA

  • DAIR, further use of antibiotics

  • Implantation of distal femoral megaprosthesis

  • Temporary end of phage therapy due to transaminitis

  • Prosthesis could not be preserved

  • Infection was finally overcome, patient left for rehabilitation

Doub et al. [52]
70y/f
  • Prolonged MRSA prosthetic knee infection with involvement of femoral lateral plate

  • Loose prosthesis

  • Explantation and reconstruction

  • Implant exchange

  • Intraoperative and IV phage therapy

  • Antibiotics

  • No hardware salvage

  • Neither signs of infection nor S. aureus remained

  • Rehabilitation was scheduled to improve mobility

Doub et al. [53]
P1

80y/m
  • Relapsing infection of prosthetic knee

  • Loosening of prosthesis (x-ray)

  • Intra-articular phage cocktail

  • DAIR

  • Suppressive antibiotic therapy

  • Infection subsided

  • Unspecific synovitis remained, ultimately negative CRP

  • Painless ambulation

Ferry et al. [54]
P2

84y/m
  • Prosthetic knee Infection with S. aureus also in blood culture

  • No loosening

  • DAIR

  • Phage cocktail was applied after joint closure

  • Antibiotics

  • Rapid basic recovery

  • Neither infection nor inflammation noted after seven months

  • Painless ambulation

P3

83y/f
  • Prosthetic knee infection with S. aureus of two different types

  • No loosening

  • DAIR, antibiotics

  • Coverage of soft tissue with flap

  • Phage cocktail after joint closure

  • Got better soon

  • Absence of S. aureus

  • Painless ambulation

  • Continuing discharge of synovial fluid

Abbreviations: CRP = C-reactive protein; DAC® = Defensive Antibacterial Coating; DAIR = Debridement, Antibiotics, and Implant Retention; IV = intravenous; IA = intraarticular; MRSA = methicillin-resistant Staphylococcus aureus; P1 = Patient 1; P2 = Patient 2; P3 = Patient 3; P. aeruginosa = Pseudomonas aeruginosa; S. aureus = Staphylococcus aureus; TKA = total knee arthroplasty.

Notably, the reviewed case reports had one aspect convincingly in common: The initial clinical condition of the patient following standard therapeutic schemes resembled a dead end and phage therapy, as shown by clinical success, proved to be rather a salvage therapy [4854]. In some cases, even amputation was originally taken into consideration, but could be principally avoided through compassionate or emergency use of phage therapy after a second opinion was obtained [48, 50, 52]. Complicating the matter, the patients occasionally had a variety of pre-existing conditions including diabetes, hyperlipidemia, hypertension, or lymphedema [5154]. Finally, just as a personalized approach was generally adopted [49, 53, 54], phage therapy was found to be safe also as a magistral preparation originating in a research and development laboratory instead of a good manufacturing practice laboratory [51].

Discussion

Main findings

Proof of concept: staphylococcal challenges overcome

Lytic killing and staphylococcal growth inhibition with high efficacy were demonstrated for distinct phages (summarized in Fig. 2). The results were generated in several in vitro studies, albeit with distinct heterogeneity due to varying sensitivities of S. aureus isolates [3842, 46, 48, 51]. Moreover, in vivo studies revealed that phages substantially contributed to both the alleviation of symptoms and the attenuation of pro-inflammatory host responses [45, 47]. Even a phage-derived lysin single-handedly featured strong antibacterial activity in vitro and in vivo, which also involved a preventative effect concerning bacterial colonization on polyethylene surfaces [44]. Despite underlying (multi-morbid) medical conditions and advanced age, the eradication of S. aureus was rendered feasible in patients with refractory prosthetic hip and/or knee infection following concomitantly administered phage therapy [4854]. An anti-biofilm effect of phages and a phage-derived lysin proved to be another favorable feature corroborating their principal suitability for the treatment of S. aureus-associated PJIs [3941, 44]. This became apparent, for example, in the form of the elimination of biofilm-coated bacteria or the destruction of the biofilm itself [40, 41, 44]. Beyond that, several publications described a lytic efficacy of phages also extending to MRSA, with case reports suggesting further confirmation in a clinical context [39, 42, 45, 46, 49, 52, 53]. Colony variants of S. aureus, meanwhile, turned out to be capable of posing a challenge to phages, albeit an occasionally insignificant one [39, 41, 53].

Fig. 2.
Fig. 2.

Collective chart of investigated phages

Exemplaric names of phages used within the summarized studies are shown. For more information about the respective phage see also the main text of the results section.

Citation: European Journal of Microbiology and Immunology 14, 2; 10.1556/1886.2024.00010

Synergetic effect with antibiotics

Phages as well as a phage-derived lysin alone exhibited superior anti-staphylococcal activity over compared antibiotics in varying clinical settings [40, 44, 46]. Moreover, it was the addition of phage therapy as an adjuvant against S. aureus which ultimately made therapeutic success in seriously compromized PJI patients a reality after common procedures involving antibiotics failed to do so, as described in numerous case reports [4854]. But still, improved results with best overall outcome in respective experiments were invariably achieved when phages or a phage-derived lysin were concomitantly with antibiotics tested against S. aureus [44–47]. This included without limitation a lower MIC (as a combination) in vitro, enhanced bacterial clearance of tissues in mice and rats, and a highly increased survival rate of moth larvae [4446, 47]. Remarkably, findings of one experiment suggested that the bacterial resistance to phages was independent of antibiotic resistance [41].

Safety, side effects, and resistance

Safety and the absence of adverse side effects of any kind directly attributable to phage therapy were explicitly declared in various reports [4750, 51]. Additionally, considerable emergence of bacterial resistance to the applied phages was reported by none of the included publications. While, regardless of respective tissues or administration route, neither histopathological nor hematologic examinations revealed any evidence of host tissue impairment through low-endotoxin phages, investigated rabbits did exhibit inflammation-associated changes after exclusive application of phages in one study [43]. In contrast, the multiple times observed increase in liver transaminases following phage therapy in humans suffering from S. aureus-associated PJIs was particularly striking as it led in one also hepatomegaly involving case to phage therapy discontinuation [49, 52, 53]. Thus, comprehensive monitoring of liver function was recommended [49, 52].

Modalities of clinical application

The diverse scope of included publications did not only elucidate the principle suitability of phage therapy but also its versatility. In this way, clinicians have a choice between using only one phage or a phage cocktail as an adjuvant to treat S. aureus-associated PJIs [48–54]. Sensitivity testing for the purpose of individualized phage selection should be carried out beforehand [40, 51], taking further into account, if relevant, secondary morphology colonies or bacterial cultures of different intrapatient origins [38, 39, 53]. As dose-dependency became evident [46, 48, 50], dosage requires careful consideration just like duration and other treatment parameters do [43, 49, 50]. Not only IA and IV administration led to therapeutic success [5254], but also special use cases like a carrier hydrogel or a coated implant were associated with promising results [45, 48]. On a related note, even a prophylactical potential of phages and a phage-derived lysin was shown in laboratory experiments, however, clinical confirmation is pending [44, 45].

Limitations

As a matter of fact, errors or inaccuracies remain an improbable, yet possible flaw of this review, especially due to only one person being solely responsible for search and selection of studies as well as collection and compilation of data. In addition, incompleteness regarding the objective can be assumed, since only PubMed was employed as scientific search engine, while its Medical Subject Headings were not. Also, the range of original articles as basis of this literature review is likely to be unnecessarily limited due to the disuse of specific terms within the search like “prosthetic knee infection” or “prosthetic hip infection”. A nonobservance of most recent studies is further conceivable, because publications released in the meantime were not considered. Nevertheless, a large majority of the publications which we did consider was indeed not even older than five years, so that a distinct currency is to be acknowledged.

While not all kinds of prosthetic joints which could be principally affected by infection (elbow or shoulder, for instance) were addressed by the publications, the most common (i.e., prosthetic hip and knee infection) were, albeit a considerable dominance of the prosthetic knee infection in the available literature was noticed. Considering the obvious diversity in key aspects of the studies and reports, e.g., experimental settings or modalities of phage therapy, a restricted comparability is given. In terms of the credibility of published results, it should be kept in mind that some authors are represented more than once, giving those individuals much weight, or were associated with companies, which naturally entail a conflict of interest between pursuit of profit and thirst for knowledge.

Lastly, half of all publications referring to laboratory experiments reported primarily on in vitro-only studies, while the other half was made up of 60% in vivo-focused studies as well as 40% of studies were conducted both in vitro and in vivo. Clinical experience involving a total of only nine patients was described in seven case reports. Taking these numbers into account, it can be said that the level of evidence is still too low to draw definitive conclusions, no matter how promising certain results of research may appear to be. Hence, caution and curiosity in terms of the translational potential and further extrapolations is indicated. The main features of our review article are summarized in Fig. 3.

Fig. 3.
Fig. 3.

Summary of the main features of the review article

Citation: European Journal of Microbiology and Immunology 14, 2; 10.1556/1886.2024.00010

Conclusions

Our review of the identified literature emphasized the anti-staphylococcal capacity and suitability for therapeutic use of phages and a phage-derived lysin in patients suffering from S. aureus-associated PJI. Especially favorable was their distinct effectiveness against both biofilms and MRSA. Apart from isolated reports of elevated liver enzymes such as transaminases, phages appear to be harmless in terms of adverse drug reactions. Accordingly, phage therapy may represent a potent addition to the conventional DAIR regimen as also synergetic effects with antibiotics were described. However, the status quo is rather to be considered an incentive for further research including prospective clinical trials, because ambiguities based on divisive findings subsist and questions regarding rare or long-term side effects as well as interaction details remain insufficiently answered.

Conflict of interest

SB and MMH are editorial board members, therefore they did not take part in the review process in any capacity and the submission was handled by a different member of the editorial board.

Acknowledgments

The figures were created with BioRender.com.

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  • 1.

    McConoughey SJ, Howlin R, Granger JF, Manring MM, Calhoun JH, Shirtlif M, et al. Biofilms in periprosthetic orthopedic infections. Future Microbiol. 2014;9(8):9871007.

    • Search Google Scholar
    • Export Citation
  • 2.

    Wolford H, Hatfield K, Paul P, Yi SH, Slayton RB. The projected burden of complex surgical site infections following hip and knee arthroplasty among adults in the United States, 2020 through 2030. Infect Control Hosp Epidemiol. 2018;39(10):118995.

    • Search Google Scholar
    • Export Citation
  • 3.

    Tande AJ, Patel R. Prosthetic joint infection. Clin Microbiol Rev. 2014;27(2):30245.

  • 4.

    Bozic KJ, Kurtz SM, Lau E, Ong K, Vail TP, Berry DJ. The epidemiology of revision total hip arthroplasty in the United States. J Bone Joint Surg. 2009;91(1):12833.

    • Search Google Scholar
    • Export Citation
  • 5.

    Bozic KJ, Kurtz SM, Lau E, Ong K, Chiu V, Vail TP, et al. The Epidemiology of revision total knee arthroplasty in the United States. Clin Orthopaedics Relat Research®. 2010;468(1):4551.

    • Search Google Scholar
    • Export Citation
  • 6.

    Pitta M, Esposito CI, Li Z, Lee Y-Y, Wright TM, Padgett DE. Failure after modern total knee arthroplasty: a prospective study of 18,065 knees. J Arthroplasty. 2017;33(2):40714.

    • Search Google Scholar
    • Export Citation
  • 7.

    Natsuhara KM, Shelton TJ, Meehan JP, Lum ZC. Mortality during total hip periprosthetic joint infection. J Arthroplasty. 2018;34(7):S337S42.

    • Search Google Scholar
    • Export Citation
  • 8.

    Osmon DR, Berbari EF, Berendt AR, Lew D, Zimmerli W, Steckelberg JM, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the infectious diseases society of America. Clin Infect Dis. 2012;56(1):e1e25.

    • Search Google Scholar
    • Export Citation
  • 9.

    Premkumar A, Kolin DA, Farley KX, Wilson JM, McLawhorn AS, Cross MB, et al. Projected economic burden of periprosthetic joint infection of the hip and knee in the United States. J Arthroplasty. 2020;36(5):14849.

    • Search Google Scholar
    • Export Citation
  • 10.

    Kurtz SM, Lau E, Watson H, Schmier JK, Parvizi J. Economic burden of periprosthetic joint infection in the United States. J Arthroplasty. 2012;27(8).

    • Search Google Scholar
    • Export Citation
  • 11.

    Sloan M, Premkumar A, Sheth NP. Projected volume of primary total joint arthroplasty in the U.S., 2014 to 2030. J Bone Joint Surg. 2018;100(17):145560.

    • Search Google Scholar
    • Export Citation
  • 12.

    Weiser MC, Moucha CS. The current state of screening and decolonization for the prevention of Staphylococcus aureus surgical site infection after total hip and knee arthroplasty. J Bone Joint Surg. 2015;97(17):144958.

    • Search Google Scholar
    • Export Citation
  • 13.

    Byren I, Bejon P, Atkins BL, Angus B, Masters S, McLardy-Smith P, et al. One hundred and twelve infected arthroplasties treated with ‘DAIR’ (debridement, antibiotics and implant retention): antibiotic duration and outcome. J Antimicrob Chemother. 2009;63(6):126471.

    • Search Google Scholar
    • Export Citation
  • 14.

    Lowy FD. Staphylococcus aureus infections. New Engl J Med. 1998;339(8):52032.

  • 15.

    Wertheim HF, Melles DC, Vos MC, Leeuwen WV, Belkum AV, Verbrugh HA, et al. The role of nasal carriage in Staphylococcus aureus infections. The Lancet Infect Dis. 2005;5(12):75162.

    • Search Google Scholar
    • Export Citation
  • 16.

    Saeed K, McLaren AC, Schwarz EM, Antoci V, Arnold WV, Chen AF, et al. 2018 international consensus meeting on Musculoskeletal infection: summary from the biofilm workgroup and consensus on biofilm related Musculoskeletal infections. J Orthopaedic Res. 2019;37(5):100717.

    • Search Google Scholar
    • Export Citation
  • 17.

    Gristina AG, Costerton JW. Bacterial adherence to biomaterials and tissue. The significance of its role in clinical sepsis. J Bone Joint Surg. 1985;67(2):26473.

    • Search Google Scholar
    • Export Citation
  • 18.

    Drilling A, Morales S, Jardeleza C, Vreugde S, Speck P, Wormald P-J. Bacteriophage reduces biofilm of Staphylococcus aureus ex vivo isolates from chronic Rhinosinusitis patients. Am J Rhinology Allergy. 2014;28(1):311.

    • Search Google Scholar
    • Export Citation
  • 19.

    Arciola CR, Campoccia D, Montanaro L. Implant infections: adhesion, biofilm formation and immune evasion. Nat Rev Microbiol. 2018;16:397409.

    • Search Google Scholar
    • Export Citation
  • 20.

    Goswami K, Cho J, Foltz C, Manrique J, Tan TL, Fillingham Y, et al. Polymyxin and Bacitracin in the irrigation solution provide no benefit for bacterial killing in vitro. J Bone Joint Surg. 2019;101(18):168997.

    • Search Google Scholar
    • Export Citation
  • 21.

    Urish KL, DeMuth PW, Craft DW, Haider H, Cavis CM III. Pulse lavage is inadequate at removal of biofilm from the surface of total knee arthroplasty materials. J Arthroplasty. 2014;29(6):112832.

    • Search Google Scholar
    • Export Citation
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    Mah T-FC, O'Toole GA. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol. 2001;9(1):349.

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Senior editors

Editor(s)-in-Chief: Dunay, Ildiko Rita, Prof. Dr. Pharm, Dr. rer. nat., University of Magdeburg, Germany

Editor(s)-in-Chief: Heimesaat, Markus M., Prof. Dr. med., Charité - University Medicine Berlin, Germany

Editorial Board

  • Berit Bangoura, Dr. DVM. PhD,  University of Wyoming, USA
  • Stefan Bereswill, Prof. Dr. rer. nat., Charité - University Medicine Berlin, Germany
  • Dunja Bruder, Prof. Dr. rer. nat., University of Magdeburg, Germany
  • Jan Buer, Prof. Dr. med., University of Duisburg, Germany
  • Edit Buzas, Prof. Dr. med., Semmelweis University, Hungary
  • Renato Damatta, Prof. PhD, UENF, Brazil
  • Maria Deli, MD, PhD, DSc, Biological Research Center, HAS, Hungary
  • Olgica Djurković-Djaković, Prof. Phd, University of Belgrade, Serbia
  • Jean-Dennis Docquier, Prof. Dr. med., University of Siena, Italy
  • Zsuzsanna Fabry, Prof. Phd, University of Washington, USA
  • Ralf Ignatius, Prof. Dr. med., Charité - University Medicine Berlin, Germany
  • Achim Kaasch, Prof. Dr. med., Otto von Guericke University Magdeburg, Germany
  • Oliver Liesenfeld, Prof. Dr. med., Inflammatix, USA
  • Matyas Sandor, Prof. PhD, University of Wisconsin, USA
  • Ulrich Steinhoff, Prof. PhD, University of Marburg, Germany
  • Michal Toborek, Prof. PhD, University of Miami, USA
  • Susanne A. Wolf, PhD, MDC-Berlin, Germany

 

Dr. Dunay, Ildiko Rita
Magdeburg, Germany
E-mail: ildiko.dunay@med.ovgu.de

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2023  
Web of Science  
Total Cites
WoS
674
Journal Impact Factor 3.3
Rank by Impact Factor

Q2

Impact Factor
without
Journal Self Cites
3.1
5 Year
Impact Factor
3.2
Scimago  
Scimago
H-index
15
Scimago
Journal Rank
0.601
Scimago Quartile Score Microbiology (medical) (Q2)
Microbiology (Q3)
Immunology and Allergy (Q3)
Immunology (Q3)
Scopus  
Scopus
Cite Score
5.0
Scopus
CIte Score Rank
Microbiology (medical) Q2
Scopus
SNIP
0.832

 

European Journal of Microbiology and Immunology
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European Journal of Microbiology and Immunology
Language English
Size A4
Year of
Foundation
2011
Volumes
per Year
1
Issues
per Year
4
Founder Akadémiai Kiadó
Founder's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Publisher Akadémiai Kiadó
Publisher's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Responsible
Publisher
Chief Executive Officer, Akadémiai Kiadó
ISSN 2062-509X (Print)
ISSN 2062-8633 (Online)

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