NRMJ_9_6_454-469

Introduction

The number of periprosthetic infections (PPIs) continues to grow steadily due to increase in the number of prosthetic joints (Izakovicova et al., 2019; Ashkenazi et al., 2023). By 2030, the number of hip and knee replacements is expected to increase by 174%. 673%, respectively (Bi et al., 2019; Flynn et al., 2024). Annual expenses for treatment of PPIs in the United States exceed $ 8.6 billion, and in Europe they amount to about 2 billion euros (Sukeik and Haddad, 2019; Barros et al., 2022; Sarantis et al., 2022). The average total cost of revision for total knee arthroplasty associated with PPIs is 75 thousand dollars (Leta et al., 2024). The average age of patients with PPIs is 60-66 years, and the 5-year mortality rate is 26% (Ivantsov et al., 2020; Nikolaev et al., 2021; Karczewski et al., 2023; Piuzzi et al., 2024). PPIs occur in 0.3-2.2% of cases with primary prosthetics, while recurrent PPIs occur in 23.2-31.5% of cases (Dobrovol’skaya et al., 2020). The objective of this study is to analyze the structure of the causative agents of periprosthetic infections.

Elderly people are most often susceptible to the occurrence of PPIs in presence of diseases leading to a decrease in bone strength and/or with a comorbid background (Flurin et al., 2019; Izakovicova et al., 2019; Karczewski et al., 2023). Risk factors for PPI include: Rheumatoid arthritis, diabetes mellitus, obesity and a history of multiple surgeries, post-traumatic osteoarthritis, prolonged use of immunosuppressores, and prolonged hospital stay, leading to the appearance of resistant microflora and subsequently to complications such as sepsis, systemic inflammatory reactions syndrome, and pulmonary embolism (Stewart and Bjarnsholt, 2020; Onorato et al., 2024). In addition, the risk of systemic inflammation increases with PPIs, if a substantial period of time has passed since the onset of inflammation (Izakovicova et al., 2019). Occurrence of PPI requires an integrated approach to the diagnosis and treatment of this disease with the participation of physicians of various specialties (Izakovicova et al., 2019).

Periprosthetic infections are caused by various types of microorganisms. The Gram-positive bacteria are the most common, while Gram-negative microorganisms are much less common, however, the infections caused by them are characterized by difficult treatments and unfavorable outcomes. In addition, PPIs caused by Gram-negative bacteria are more common in the form of mixed infections (Dandé et al., 2021; Tsiskarashvili et al., 2022). The epidemiology of pathogens differs in prosthetics of different joints (Flurin et al., 2019).

According to the TSUKAYAMA classification, PPIs are divided into 4 groups depending on the time of development; mainly (1) early acute, (2) early acute delayed, (3) late chronic, and (4) acute hematogenous infections (Flurin et al., 2019). The various types of PPI differ from each other in the main pathogens and the mechanism of infection; accordingly, the clinical course is extremely important for the clinician to take into account during treatment (Fink et al., 2019). Early acute ones occur within 4 weeks after prosthetics, late chronic ones after 4 weeks, and acute hematogenic ones occur after a year or more (Tsukayama et al., 1996; Murylev et al., 2022).

Pathogenesis

There are several mechanisms for penetration of microorganisms to the surface of prostheses. Firstly, wound contamination is possible during injury or during surgery, which usually leads to early and acute delayed infection (Renz et al., 2019). Secondly, there is a possibility of hematogenous and lymphogenic spread of the pathogen from foci of acute and chronic infection located in the respiratory tract, on the skin, soft tissues, the gastrointestinal tract, and the genitourinary system (Barros et al., 2022; Izakovicova et al., 2019). For example, in patients with caries and inflammatory diseases of the oral tissues caused by bacterial pathogens, the probability of occurrence of PPIs one year after prosthetics is 1.6 times higher than patients without caries (Gordon et al., 2024). Hematogenous spread is possible with daily oral hygiene, dysbiosis, and concomitant increased intestinal permeability, leading to the creation of a Trojan horse of phagocytic cells and bacteria that can penetrate to the joints (Charlotte Höfer et al., 2022; Piuzzi et al., 2024).

After penetration to the prosthesis, microorganisms need to gain a foothold on the surface. In turn, the following types of adhesion are distinguished, including passive reversible adhesion due to non-specific forces (i.e., electrostatic and acid-base interaction), active irreversible specific interaction of microorganisms, and soluble proteins trapped on the surface of the prosthesis. Later, some microorganisms form biofilms, which reduce the effectiveness of antibacterial treatment by 1000 times (Khatoon et al., 2018). The following microorganisms most often produce biofilms: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp., Cutibacterium acnes, Candida albicans, C. parapsilosis, C. glabrata, and C. tropicalis (Rienmüller and Borens, 2016). It should be emphasized that biofilms affect the host’s immune response; therefore, PPI can be considered as an immune dysregulation of the body. In addition, the process of horizontal gene transfer is much more active in biofilms, contributing to the widespread spread of antibiotic resistance (Arciola et al., 2018; Piuzzi et al., 2024).

Periprosthetic infection is a consequence of complex interaction among the implant, the microorganism, and the human body (Arciola et al., 2018). Not only microbial pathogens, but also prosthesis material itself is capable of causing local tissue reactions, including acute and chronic inflammation, granulation tissue formation, and fibrous encapsulation (Arciola et al., 2018; Izakovicova et al., 2019). The prosthesis material reduces local immunity, leading to an increased risk of developing PPIs (Arciola et al., 2018; Izakovicova et al., 2019). Colonization of the lacunar-canalicular network of osteocytes by microorganisms leads to long-term persistence, due to inaccessibility of this histological barrier to the immune system and antibiotics (de Mesy Bentley et al., 2017; Piuzzi et al., 2024).

The inflammatory process leads to the loss of a stable connection between the prosthesis and bone tissue and its failure, which requires one or more operations, including arthrodesis, amputation, exarticulation, and lethal outcomes are also possible (Gazendam et al., 2022; Gramlich and Parvizi, 2023).

Laboratory diagnostics of microorganisms

Identification of the pathogen is crucial for selecting the necessary treatment and prognosis for the patient (Gazendam et al., 2022). The cultural method is the gold standard in the diagnosis of PPI, but is characterized by a number of serious drawbacks (Azad et al., 2022). Firstly, isolation of the pathogen from a biofilm and bone tissue is complicated. Secondly, the culture method is characterized by low sensitivity. Thirdly, preoperative antibiotic therapy can affect the viability of microorganisms. Fourthly, traditional cultivation methods depend on the ability of bacteria to grow in a certain nutrient medium, so the proportion of PPIs with a negative result is about 40% (Gazendam et al., 2022; Tsikopoulos and Meroni, 2023). The timing of results is also important, which can take up to 2 weeks for seeding (Portillo and Sancho, 2023). The seeding material is preoperative synovial fluid samples, surgical materials, dispersed hard tissues, and samples obtained as a result of ultrasound treatment of prostheses (Vrancianu et al., 2023). In order to increase sensitivity and specificity, cultivation in commercial vials for hemocultures is possible (Li et al., 2019). The combined sensitivity of preoperative fluid, intraoperative tissue, and ultrasound fluid for the diagnosis of PPI are 0.63 (95%; 0.56–0.70), 0.71 (95%; 0.63–0.79), and 0,78 (95%; 0,68–0,85), whereas the specificity is 0,96 (95%; 0,93–0,98), 0,92 (95%; 0,86–0,96), and 0.91 (95%; 0.83–0.95), respectively (Watanabe et al., 2024). When using vials for hemocultures, the combined sensitivity is 0,70 (95%; 0,66–0,75), while specificity is 0.97 (95%; 0.95–0.98) (Li et al., 2019).

The indisputable advantage of this technique is the possibility of setting up phenotypic assays for antibiotics, and detecting small-colonial forms of bacteria that are common in chronic infections and require the appointment of intracellular antibiotics, which is impossible upon using the molecular genetic methods (Portillo and Sancho, 2023).

In an attempt to increase the accuracy of diagnosis, molecular genetic variants of pathogen identification have been proposed, namely various new generation sequencing and polymerase chain reaction (PCR) methods (Azad et al., 2022). PCR methods are divided into universal PCR, necessary for the detection of genes ubiquitously present in microorganisms, specific PCR; the task of which is to detect a specific microorganism or mechanism of resistance, multiplex PCR, which is performed to simultaneously detect multiple microorganisms and/or resistance mechanisms (Portillo and Sancho, 2023). Universal PCR without additional methods indicates only the presence of microorganisms, without precise species identification (Tkadlec et al., 2019). The results of sensitivity and specificity of different PCR methods differ considerably in different studies (Li et al., 2022; Subedi et al., 2024). Despite their high sensitivity and specificity, primers in specific PCR tests are single, which makes them difficult to screen for PPIs and limits their use in clinical practice (Higgins et al., 2022; Vrancianu et al., 2023). Multiplex PCR is characterized by its high efficiency, surpassing the results of traditional methods of culturing Cutibacterium spp. and coagulase-negative staphylococci; however, the ability to detect only those microorganisms targeted by primers creates problems in identifying rare pathogens (Zhou et al., 2024).

In the case of new generation sequencing (NGS) method, it raises the question of economic feasibility of this analysis, complexity of the formulation, impossibility of determining the sensitivity of a microorganism to antibiotics, and lack of standardization of analysis methods, which substantially limits the possibility of widespread use in routine clinical practice (Portillo and Sancho, 2023). The sensitivity and specificity of NGS method varies very widely depending on nature of the material, preanalytical stage, and method of performing the analysis (Portillo and Sancho, 2023). The main advantage of molecular genetic techniques is absence of the need for cultivation, which considerably reduces the study time (Auñón et al., 2022).

A common limitation of the aforementioned methods used in detection of mixed infections with draining inflammations is the difficulty of determining clinical significance of the detected microorganisms, since there is no clear understanding of the cause of infection, which turned out to be transient microflora (Arciola et al., 2018). However, diagnosis of chronic PPI is currently an urgent task (Portillo and Sancho, 2023).

Microorganisms causing PPIs

The Staphylococcaceae family

About 50% or more of bacterial infections are caused by Staphylococcus aureus and Staphylococcus epidermidis (Dobrovol’skaya et al., 2020; Tsiskarashvili et al., 2022). Staphylococcus aureus differs from other pathogens as it leads to early onset of the infectious process, early bacteremia, and frequent recurrence (Hersh et al., 2019; Guo et al., 2020; Klasan et al., 2021). There are also other species, including Staphylococcus capitis, Staphylococcus warneri, Staphylococcus hominis, and Staphylococcus haemolyticus (Hersh et al., 2019). Staphylococcus epidermidis is more likely to cause hip PPI, while Staphylococcus aureus causes both knee and hip PPI (Guo et al., 2020; Ivantsov et al., 2020). The resistance of Staphylococcus epidermidis and Staphylococcus aureus to methicillin increases every year. Moreover, the rates of development of methicillin-resistant Staphylococcus epidermidis strains amounted to 89% of the total number of Staphylococcus epidermidis. In PPIs, methicillin-resistant Staphylococcus aureus (MRSA) predominantly causes early infections, whereas methicillin-sensitive Staphylococcus aureus (MSSA) leads to delayed and late infections. The number of MSSA infections is approximately 2.5 times greater than that of MRSA infections (Arciola et al., 2018). These pathogens are highly sensitive to vancomycin, linezolid, amoxiclav, and ceftriaxone (Tsiskarashvili et al., 2022). An important feature characterizing these pathogens is their ability to form biofilms on the surface of the prosthesis (Dobrovol’skaya et al., 2020).

Periprosthetic infections are complicated by the ability of Staphylococcus spp. to form L-forms, characterized by slow growth, an aberrant colony shape, and unusual metabolic characteristics. These are in addition to the possibility of their persistence within phagocytes protected from the immune system of the microorganism and antimicrobial agents (Hersh et al., 2019). A number of scientists believe that it is most appropriate to use a two-stage replacement of the endoprosthesis as a treatment for PPIs (Ivanian et al., 2021). Staphylococcus aureus is the common causative agent of PPIs in the United States, while Staphylococcus epidermidis is more common in Europe (Arciola et al., 2018).

Staphylococcus epidermidis is characterized by numerous virulence factors. The protein autolysin (AtlE) plays an important role in biofilm formation, which also promotes lysis of host cells and release of extracellular DNA. Staphylococcus aureus has a similar protein with a similar function. Staphylococcus aureus and Staphylococcus epidermidis produce surface proteins able to recognize and bind collagen and fibronectin (Arciola et al., 2018).

The Streptococcaceae family

Periprosthetic infections caused by streptococci account for up to 10% of all cases (Dobrovol’skaya et al., 2020; Tsiskarashvili et al., 2022). The most common pathogenic species include Streptococcus agalactiae (34.4%), β-hemolytic streptococci with large colonies (26.2%), the viridans group of streptococci (18.6%), Streptococcus pyogenes (7.8%), Streptococcus anginosus group (6.9%), Streptococcus pneumoniae (4.5%), and other streptococci (1.5%) (Lora-Tamayo et al., 2017). PPIs caused by streptococci occur mainly with the hematogenous spread of infection from the gastrointestinal and genitourinary tracts. Streptococcus disgalactiae is mainly detected in the elderly persons (Lora-Tamayo et al., 2017; Erden et al., 2020).

Periprosthetic infections caused by Streptococcus bacteria are accompanied by a high percentage of unsuccessful treatment compared to those caused by bacteria of the genus Staphylococcus; with the worst treatment results recorded in patients with Streptococcus. agalactiae compared to other Streptococcus spp. There is an assumption that this bacterial pathogen spreads already as part of the biofilm and forms a biofilm faster on surface of the prosthesis. The Streptococcus agalactiae capsule that is rich in sialic acid protects the pathogen from phagocytosis. A key factor in the pathogenesis of Streptococcus agalactiae is β-hemolysin, enabling the pathogen to invade epithelial and endothelial cells (Cho et al., 2024).

The Enterococcaceae family

About 2-11% of PPIs are caused by enterococci. Despite low virulence of these pathogens; however, treatment of these infections is complicated by slow bactericidal action of antimicrobial agents and increasing antibiotic resistance (Haeberle et al., 2024; Hersh et al., 2019; Kheir et al., 2017a; Maurille et al., 2023; Renz et al., 2019). Enterococcus spp. are often found in combination with other microorganisms of different species in the same sample (Renz et al., 2019; Maurille et al., 2023). The most common pathogens among Enterococcus spp. are mainly; Enterococcus faecalis (89%), E. faecium (9%), and others (2%) (Renz et al., 2019).

Periprosthetic infections caused by Enterococcus spp. occurs in 54-55% of cases with hip replacement, 40% of cases with knee replacement, and 3% with elbow and shoulder joint replacement (Hersh et al., 2019; Renz et al., 2019). The intraoperative route of infection is most common (more than 80%); however, hematogenous one is much less common (17%) (Renz et al., 2019).

Enterococcus faecalis is a Gram-positive facultative anaerobic bacterium that occurs in the gastrointestinal tract and is a part of the human microbiota. This pathogen forms a biofilm and causes urinary tract infections (Cho et al., 2024; Haeberle et al., 2024).

The Pasteurellaceae family

PPI caused by Haemophilus parainfluenzae or Pasteurella multocida is rare because it has low pathogenic activity. H. parainfluenzae is a Gram-negative coccoid-like bacterium. This bacterium is a part of the normal microflora of the oral cavity and upper respiratory tract, less often isolated from the mucous membrane of the gastrointestinal tract, vagina, and urethra. However, under certain unfavorable conditions, this pathogen causes pneumonia, endocarditis, and other diseases. In most cases, H. parainfluenzae infection is preceded by invasive procedures, including those in the oral cavity (Sermet et al., 2021; Medel-Plaza et al., 2023).

The Mycoplasmataceae family

Representatives of the Mycoplasmataceae family are often the cause of lung and genitourinary infections, rarely lead to PPI; however, there are reported cases of knee and hip arthroplasty (Rieber et al., 2019; Cai et al., 2023). Ureaplasma urealyticum and Ureaplasma parvum are considered as difficult-to-grow pleomorphic bacteria that colonize mainly the genitourinary tract (Rieber et al., 2019; Muramatsu et al., 2022). An important morphological aspect is that they lack a cell wall, which must be taken into account when prescribing an empirical therapy. These pathogens differ in being difficult to isolate using standard cultivation methods. Gram staining and cultivation on culture plates give negative results; therefore, PCR with the determination of 16S rRNA sequencing is used to identify these pathogens (Rieber et al., 2019; Ball and Snape, 2021).

The Enterobacteriaceae family

The Enterobacteriaceae family accounts for about 8% of all PPIs (Zhou et al., 2021; Tsiskarashvili et al., 2022). Among them, Enterobacter cloacae accounts for 15.4% of PPIs, E. coli (42.6%), and Klebsiella pneumoniae (38.5%) (Zhou et al., 2021; Tsiskarashvili et al., 2022).

A recent study revealed that PPI caused by E. cloacae is more common after hip replacement than knee one, and has also reported that this pathogen is predominantly polymicrobial in nature, often associated with the family Staphylococcaceae, P. aeruginosa, E. faecalis, and K. pneumoniae. Of the 108 PPI cases reported in this study, 12 cases have been associated with E. cloacae, and have developed within 3 months after the endoprosthesis (Ashkenazi et al., 2023).

Serratia marcescens, being a Gram-negative anaerobic bacterium, leads to the appearance of PPIs in less than 1% of all reported PPIs cases, usually detected in the respiratory and urinary tracts (Karczewski et al., 2023). According to the literature data, a total of 14 cases of PPIs caused by S. marcescens have been described. The average age of patients is 66 years, and 75% of them are men (Karczewski et al., 2023). In four cases, coexistence with C. glabrata, Bacillus cereus, Proteus mirabilis, and Staphylococcus epidermidis has been observed. PPI associated with S. marcescens is characterized by poor prognosis of the patients as a result of frequent recurrence of infection (Karczewski et al., 2023).

Klebsiella pneumoniae is most often associated with hip joint damage. This pathogen is characterized by severe course of infections and patients high mortality rate (Cespedes Santana et al., 2022; Fischer et al., 2024). It exists in urinary tract, intra-abdominal, and pneumonia infecttions (Tosatto et al., 2020) K. pneumoniae is considered as a pathogen with a high level of natural resistance (Karczewski et al., 2023).

Salmonella spp. rarely cause PPIs; however, in 98% of detected cases of Salmonella spp., the causative agents are Salmonella enteritidis and Salmonella typhi. S. typhi is considered a very rare causative agent of PPIs. Bacteria of this genus can form biofilms. It is more often found in the hip joint than the knee one. It occurs in people with immunodeficiency (Rajgopal et al., 2017).

The Micrococcaceae family

Periprosthetic infections caused by Falsarthrobacter nasiphocae (Arthrobacter nasiphocae) is often detected as a mixed culture along with Corynebacterium phocae, P. aeruginosa, and Staphylococcus aureus. F. nasiphocae is resistant to ceftriaxone but sensitive to vancomycin, co-trimoxazole, doxycycline, penicillin, and ciprofloxacin. In treatment of PPI caused by F. nasiphocae, large doses of antibiotics are required, because F. nasiphocae is found in biofilms, allowing it to protect itself from the effects of antimicrobial drugs (Tay et al., 2023).

The Clostridiaceae family

Periprosthetic infections caused by pathogens of the Clostridiaceae family are rare (Karczewski et al., 2021). Clostridium difficile and C. perfringens are most often isolated (Hersh et al., 2019). Laboratory diagnosis of PPIs caused by Clostridium spp. is strictly dependent on tissue sampling and treatment. It can be complicated by the fact that Clostridium bacterium is more often detected in mixed infections.

Clostridium difficile refers to anaerobic spore-forming Gram-positive bacterium that produces a toxin. This pathogen usually leads to pseudomembranous colitis with manifestations of diarrhea and abdominal pain (Stokey et al., 2023; Deckey et al., 2024). According to literature data, a total of 5 cases of PPIs caused by C. difficile have been reported, two of which resulted in amputation. Only 1% of all C. difficile infections occurs outside the intestine (Stokey et al., 2023; Deckey et al., 2024).

The Mycobacteriaceae family

Periprosthetic infections caused by pathogens of the Mycobacteriaceae family occur in 0.6% of reported cases of all PPIs (Dasari et al., 2022; Liu et al., 2024). Non-tuberculous mycobacteria are considered atypical pathogens of PPI and are divided into two categories, mainly fast- and slow-growing. The first group includes Mycobacterium abscessus, M. chelonae, and M. fortuitum, while the slow-growing ones include M. kansasi,i and M. gordona (Maimaiti et al., 2023; Damronglerd et al., 2024). M. abscessus is a representative of non-tuberculous mycobacteria and includes 3 subspecies: M. abscessus subsp. abscessus, M. abscessus subsp. bolletti, and M. abscessus subsp. Massiliense. M. abscessus is capable of colonizing artificial surfaces and medical instruments, and is resistant to disinfectants (Kasimova et al., 2023). M. abscessus can affect the skin, soft tissues, bones, joints, lymph nodes, internal organs, and forms characteristic granulomas (Kasimova et al., 2023). Tendon sheaths, joints, and bones can become infected as a result of various injuries, surgical procedures, and/or invasive procedures. With ineffective treatment, relapses and complications may occur, fatal cases were also reported. This pathogen is characterized by high natural resistance to a wide range of antibacterial drugs; therefore, it is necessary to prescribe at least three antibiotics to which M. abscessus is sensitive (Genovese et al., 2021; Kasimova et al., 2023). M. houstonense is a fast-growing, acid-resistant Gram-positive bacterium that does not form spores. One case of PPI caused by M. houstonense has been officially registered (Li et al., 2023). M. kansasii is a non-tuberculous mycobacterium that rarely leads to PPIs. It often leads to infections of the respiratory system and skin (Dasari et al., 2022; Maimaiti et al., 2023). The most likely pathway of transmission of this pathogen is through the skin. M. tuberculosis causes PPIs with a frequency of 0.3%. It mainly affects large joints (Guan and Zeng, 2021; Dasari et al., 2022) M. fortuitum more often affects the knee joint, very rarely the hip one (Ramanathan and Ayoade, 2021).

The Pseudomonadaceae family

Pseudomonas aeruginosa occurs in 8% of cases of all PPI (Leggett et al., 2022; Tsiskarashvili et al., 2022). It is the most frequently isolated pathogen among representatives of Gram-negative bacteria (Hsieh et al., 2009). P. aeruginosa is included in the ESKAPE list (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.); a list of the most significant pathogens that account for most of the morbidity and mortality attributed to multidrug resistance (Kozlov et al., 2024). This microorganism is characterized by wide metabolic adaptability due to its large genome (Moyano et al., 2014). P. aeruginosa is one of the bacteria that can form biofilms on the surface of a prosthesis (Neut et al., 2005). The incidence of PII of the knee joint caused by P. aeruginosa is 4.4%, while of the hip joint is 3.7% (Barros et al., 2022).

The Moraxellaceae family

Acinetobacter baumannii is a widespread nosocomial pathogen included in the ESKAPE list (Kozlov et al., 2024). It accounts for 7.4% of all bacterial PPI (Tsiskarashvili et al., 2022). This pathogen is capable of forming biofilms on the surface of prosthesis (Neut et al., 2005). Mortality rate in the presence of this pathogen is about 30% (Canty et al., 2017). PPI caused by multi-drug resistant A. baumannii is one of the most difficult complications in orthopedic practice detected in the European population, with multidrug resistance observed in 36.8% of Acinetobacter strains.

The Propionibacteriaceae family

According to literature data, Propionibacterium granulosum rarely leads to PPI (Nikolaev et al., 2021). In PPI associated with Cutibacterium acnes, inflammatory markers are higher if the infectious process is localized in the knee and hip joint, compared to the shoulder joint. However, other studies have reported the opposite. Propionibacterium is a pathogen that is often found in infected arthroplasty of the shoulder, less often in infections of the knee or hip joint (Vasiliadis et al., 2021). Propionibacterium acnes is the most common cause of PPI of the shoulder joint because it is found mainly in the dermal and epidermal layers of the shoulder as a result of a large number of hair follicles and sebaceous glands (Paxton et al., 2019; Sewpaul et al., 2022; Nelson et al., 2023). In turn, Cutibacterium avidum more often leads to hip inflammation (Egglestone et al., 2019).

Periprosthetic infections caused by fungi

Fungal infections are atypical because they occur very rarely, representing 1-2% of all infections (Chisari et al., 2022; Fusini et al., 2023). The prognosis for fungal infections is not always favorable, since some fungal strains are resistant to modern drugs, leading to arthrodesis, lifelong spacer insertion, and/or even amputation (Azad et al., 2022; Fusini et al., 2023; Lin et al., 2022). In case of fungal infections, the prosthesis must necessarily be removed, because of high risk of infection recurrence (Tabliago et al., 2022).

It is believed that PPIs of fungal etiology are more common in people with a reduced immune response, resulting from malignant neoplasms, use of antitumor agents; corticosteroids, immunosuppressants, uncontrolled and improper use of antibiotics, in addition to tuberculosis, diabetes, use of narcotic substances, and acquired immunosuppressive diseases (Escolà-Vergé et al., 2021) Due to biofilm formation, fungi are capable of persistence and have antimicrobial resistance, leading to a greater risk of chronization and recurrence of infection, in contrast to bacterial aetiology (Lin et al., 2022; Fusini et al., 2023).

Fungal infections are most often induced by fungi of the genus Candida, causing approximately 80% of all fungal infections (Rienmüller and Borens, 2016; Dobrovol’skaya et al., 2020; Azad et al., 2022; Chisari et al., 2022). The most common species of these are C. albicans (55-65%) and C. parapsilosis (13-33%) (Bozhkova et al., 2019; Escolà-Vergé et al., 2021; Menotti et al., 2024). Cryptococcus neoformans, Pseudallescheria boydii, Candida lipolytica, Candida lusitaniae, Alternaria infectoria, Rhodotorula minuta, Aspergillus spp., Pithomyces spp., Aureobasidium spp., Hormonema spp. and Coccidioides spp. occur in 1-2% only of cases. However, in 15-20% of cases, PPIs caused by fungi occur with concomitant bacterial infections (Vasoo et al., 2014; Fusini et al., 2023). According to the major European and American reference centers, occurrence of a particular fungal species depends on geographical location, Thus, in Southeast Asia, the most common pathogens are C. albicans and C. parapsilosis (Vasoo et al., 2014). Unlike other species, C. albicans forms a larger and more complex biofilms (Menotti et al., 2024).

Acremonium spp. are very rare, they affect various organs and systems such as the eyes, lungs, and gastrointestinal tract. In a recent study, it was proved that Acremonium kiliense and Acremonium egyptiacum are involved in the occurrence of PPIs. They are sensitive to voriconazole (Chisari et al., 2022). Fungi of the genus Aspergillus, Aureobasidum, Talaromyces, Cryptococcus, Malassezia, and others are less common.

The clinical symptoms of fungal PPI are mild and not acute, which distinguish them from bacterial PPI. When treating PPI caused by fungi, a two-stage surgical intervention and a systemic antifungal therapy are effective. The first stage involves inserting a spacer with amphotericin B, and the second stage involves revision joint replacement (Escolà-Vergé et al., 2021; Fusini et al., 2023).

Periprosthetic infections of polymicrobial etiology

Polymicrobial infections are reported in about 15% of PPI cases, and no recommendations are accepted for management of such patients (Flurin et al., 2019). In case of mixed bacterial and fungal infections, combinations of sanitation and antimicrobial drugs are necessary for successful treatment of such infections. Specifically, patients with diabetes have an increased risk of polymicrobial infections (Ergin et al., 2024).

Conclusions and Recommendations

In the treatment and diagnosis of PPIs, it is necessary to take into account the complex relationships of micro- and macroorganisms, and the influence of the prosthesis. To reduce the likelihood of PPIs, careful preoperative preparation should be carried out, including treatment of foci of chronic infections, decolonization of Staphylococcus aureus in carriers, and compliance with aseptic and antiseptic rules. When creating orthopedic devices, it is necessary to create coatings that prevent the development of microorganisms and biofilms, while simultaneously capable of rapid bio-integration with host tissues. Studying the microbiological spectrum of the main causative agents of PPIs will allow us to create more accurate and faster laboratory tests, rationally approaching antibacterial therapy, and narrowing the range of used antibiotics.

Due to the fact that PPIs may be caused by wide range of various microorganisms, it is recommended to use modern high-tech laboratory diagnostic methods, including Matrix-activated laser desorption/ionization, time-of-flight mass spectrometry, and NGS methods for rapid and correct diagnosis. The use of these modern methods certainly contributes to making a more accurate and timely diagnosis and prescribing optimal therapy, which will reduce the complications and economic damages caused by PPIs.

Acknowledgement

The authors are very grateful to the rector, as well as Vice-Rector of research and innovation of Samara State Medical University for their support.

Novelty Statement

The novelty of this review is that it presents current data on pathogens that cause periprosthetic joint infection. It describes the main groups of microorganisms, including rare and atypical pathogens, which are identified using modern laboratory diagnostic methods, such as MALDI-ToF mass spectrometry and sequencing.

Author’s Contribution

Andrei Vladimirovich Kozlov: Conceptualization, data curation, supervision, writing review and editing, project administration.

Artem Viktorovich Lyamin: Conceptualization, writing review and editing, project administration. Araik Levikovich Misakyan and Aleksei Alekseevich Neilenko: Conceptualization, writing original draft, writing review editing.

Dmitry Sergeevich Kudashev: Conceptualization, writing review editing.

Maria Yur’yevna Sefedinova: Writing review editing.

Ethical approval

Non-applicable.

Funding source

This work was not funded by any source.

Generative AI and AI-assisted technology statement

The authors declare that no Generative AI was used in the creation of this manuscript.

Conflict of interests

The authors have declared no conflicts of interest.

References

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