Orthopedic Implant-Associated Infection: Clinical Guidelines

List of Abbreviations

ALT – alanine aminotransferase

AB - systemic antibacterial drug (ATC J01);

AT - antibacterial therapy;

ATC - Anatomical Therapeutic Chemical classification;

IV - intravenous;

IM - intramuscular;

DSSI - deep surgical site infection;

G(+) - Gram-positive microorganisms;

G(-) - Gram-negative microorganisms;

VED - vital and essential drugs;

IAI - implant-associated infection;

KS – knee joint;

INN – International Nonproprietary Name;

MO – medical organization;

MRI – magnetic resonance imaging;

NSAIDs – Nonsteroidal anti-inflammatory and antirheumatic drugs (M01A);

PAI – fracture-related infection

PCT – procalcitonin

PJI – periprosthetic joint infection;

DAIR – debridement, antibiotics, and implant retention;

revOS – revision osteosynthesis;

revJR – revision joint replacement;

SDE – surgical debridement;

SCT – spiral computed tomography;

SIRS – systemic inflammatory response syndrome;

PMMA – polymethylmethacrylate;

CRP – C-reactive protein;

ESR – erythrocyte sedimentation rate

HIP – hip joint;

DTEPs – difficult-to-eradicate pathogens;

ultrasound – ultrasound examination;

JR – joint replacement;

MRS – methicillin-resistant staphylococci;

MRSA – methicillin-resistant S. aureus;

MRSE – methicillin-resistant S. epidermidis;

MS – methicillin-sensitive;

MSSA – methicillin-sensitive S. aureus;

MSSE – methicillin-sensitive S. epidermidis;

VRE – vancomycin-resistant enterococcus.

Terms and Definitions

Implant-associated infection – an infection of the orthopedic implant surgical site, the risk of which persists throughout the entire period of its presence in the patient's body.

Fracture-related infection – an acute or chronic infectious process in the area of a bone fracture, elements of an osteosynthesis device (plate, rod, external fixation device, etc.), and surrounding tissues.

Infected non-union – an infectious process in the area of a bone fracture and surrounding tissues without clinical and radiological signs of fragment consolidation after 2 average bone healing periods following osteosynthesis.

Osteomyelitis – an acute or chronic infectious inflammation involving the bone and surrounding tissues to a varying extent with morphological and functional changes in other organs and systems of the body; it is a sequential stage in the development of chronic implant-associated infection in the absence of rational treatment and preservation of the infected hardware.

Periprosthetic joint infection – an acute or chronic surgical site infection that develops after joint arthroplasty; it represents a specific case of implant-associated infection.

Resolution of the infectious process – the absence of local and systemic signs of an infectious process following radical debridement surgery and a course of targeted antimicrobial therapy.

Implant retention and revision – a revision procedure involving radical surgical debridement of the infection focus while retaining well-fixed implants and, in cases of PJI, mandatory replacement of mobile arthroplasty components.

Single-stage revision procedure – a revision surgery involving simultaneous radical surgical debridement of the infection focus, thorough removal of all foreign bodies, including bone cement, and implantation of a new device.

Two-stage revision arthroplasty – surgical treatment of PJI in which radical (secondary) surgical debridement of the infection focus with removal of all arthroplasty components involves the placement of a temporary antimicrobial spacer, and the subsequent removal of the spacer and implantation of the permanent prosthesis are performed after resolution of the infectious process.

Two-stage revision osteosynthesis – surgical treatment of FRI in which the first stage involves radical surgical debridement of the infection focus with removal of the infected implant and stabilization of the operated limb segment (using an antibiotic-loaded bone cement spacer and/or an external fixation device), as well as plastic reconstruction of soft tissue defects if present, and the second stage restores the bone defect after resolution of the infectious process.

Spacer – an implant designed for the temporary replacement of a prosthesis or bone defect reconstruction during revision surgery for implant-associated infection and/or osteomyelitis. Most importantly, it is a custom-made (manually or using 3D printing) orthopedic device that may contain polymethylmethacrylate-based bone cement impregnated with antimicrobial agents for local sanitization of infected tissues and partial stabilization of the operated limb segment (bone defect and/or joint cavity); it comes in various sizes and configurations determined by the surgeon individually for each clinical case.

Articulating spacer – a temporary prosthesis whose components are fixed with bone cement additionally impregnated with antimicrobial agents, preserving the function of the affected joint.

Block spacer – a manually manufactured bone cement structure without articulating surfaces that provides a local antibacterial effect and partial stabilization of the operated limb segment; when implanted in the affected joint area, it does not preserve joint function.

Difficult-to-eradicate pathogens (DTEPs) – strains of microbial pathogens resistant to antibiotics with antibiofilm activity and causing chronic (recurrent) IAIs; these include strains of staphylococci resistant to rifampicin**, enterococci to ampicillin**, and gram-negative bacteria to ciprofloxacin**, as well as Candida species resistant to fluconazole**.

Difficult-to-treat periprosthetic joint infection – a chronic recurrent periprosthetic joint infection caused by difficult-to-eradicate pathogens.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Periprosthetic joint infection (PJI) – an acute or chronic surgical site infection that develops after joint arthroplasty; it represents a specific case of implant-associated infection. Synonyms: prosthetic joint infection, periprosthetic infection, deep surgical site infection following joint arthroplasty.

Fracture-related infection (FRI) – an acute or chronic infectious process in the area of a bone fracture, elements of an osteosynthesis device (plate, rod, external fixation device, etc.) and surrounding tissues; it represents a specific case of implant-associated infection. Synonyms: osteosynthesis-associated infection, infected pseudarthrosis, periprosthetic infection, postoperative osteomyelitis, post-traumatic osteomyelitis, surgical site infection following osteosynthesis.

Standard case definition of IAI as SSI

It is important to note existing discrepancies in terminology. The development of any IAI is essentially a specific case of SSI and, consequently, a healthcare-associated infection [1]. Current sanitary regulations (SanPiN 3.3686-21) determine that the incubation period for an SSI in the presence of an implant at the surgical site can be one year or more. According to the professional community of traumatologists and orthopedists in the Russian Federation, as well as in most countries, the standard definition of SSI in the presence of an implant as a postoperative complication establishes a timeframe of 90 days post-surgery [2,3]. At the same time, it is known that the majority of PJI cases are due to an endogenous route of infection, and the risk of developing any IAI persists for the entire lifetime of the implant; therefore, in the presence of an endoprosthesis, it persists for life.

Implant-associated infection (PJI and FRI)

I. Must meet the following criteria:

• is associated with a surgical intervention;

• is not a predictable progression of the underlying disease;

• if the infection develops up to 90 days, the infection is considered postoperative; after 90 days, endogenous (hematogenous, lymphogenous, contact, or via translocation);

• involves peri-implant tissues in the purulent process, involving bone tissue, fascial and muscle layers, subcutaneous fat, and rarely skin.

II. In addition, the patient has at least one of the following signs:

• a sinus tract communicating with the joint cavity;

• purulent drainage from a drain placed in the prosthetic joint cavity;

• isolation of microorganisms from fluid or tissue obtained aseptically from the prosthetic joint area by any method;

• additionally for PJI - leukocyte count >3000 /µL and/or neutrophil granulocyte percentage >70% in joint aspirate upon cytological examination;

  III. upon direct visual inspection during re-operation, or by microbiological, pathoanatomical, or radiological examination (fistulography), detection of signs of infection involving the prosthetic joint area or involving the fracture and/or osteosynthesis area.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The leading causative agents of implant-associated infections (IAIs) are staphylococci: Staphylococcus aureus and Staphylococcus epidermidis [1-4]. Possessing a scant set of virulence factors, S. epidermidis cannot cause infection in an immunocompetent organism; however, under conditions of trauma and surgical stress during joint arthroplasty and reconstructive bone surgeries, especially those accompanied by massive blood loss, immunoreactivity decreases, which facilitates the expression of virulence factors by opportunistic microorganisms, resulting in the development of pyogenic-septic infection. The most challenging infections to treat are those caused by methicillin-resistant (MR) strains of S. aureus (MRSA) and S. epidermidis (MRSE). The leading role of S. aureus and S. epidermidis in the etiology of orthopedic infections is largely due to their ability to rapidly form multi-layered microbial biofilms on the surface of artificial implants (joint endoprostheses, plates, rods, etc.) [5-7]. The existence of pathogens within biofilms complicates the diagnosis of IAIs and reduces the efficacy of antibacterial therapy, including drugs with high activity against MR-staphylococci [8,9]. It is also known that staphylococci are able to penetrate and colonize osteoblasts and immune cells such as macrophages and neutrophils [10], which complicates not only diagnosis but also treatment.

The proportion of other Gram-positive pathogens, streptococci and enterococci, averages 10% in the etiological structure of orthopedic infections. In 8–10% of cases, the causative agents of IAIs can be Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus spp., Enterobacter spp., Acinetobacter spp. [1,2,4]. Polymicrobial infection is the cause of IAIs in 16–32% of cases [13-15].

Successful treatment of most infectious diseases due to antibacterial therapy is still not typical for the treatment of bone and joint infections, including those following orthopedic surgeries [9]. The main reason for failures is considered to be the physiological and anatomical features of bones, as well as the involvement of microbial biofilms in the pathogenesis, which can form not only on implants but also on biological tissues, for example, on bone fragments and sequestra in the development of osteomyelitis. It should be noted that in the event of fracture-related infection (FRI), the presence of microorganisms in the fracture zone delays bone consolidation and stimulates bone resorption, which leads to the formation of pseudarthrosis and instability of the fixation device. These processes are caused by the accumulation in the infected fracture zone of the membrane protein RANKL (Receptor Activator of Nuclear Factor Kappa-B Ligand), which is a key factor in osteoclast differentiation and activation. The protein is expressed on T lymphocytes, the activation of which leads to cytokine production, increased osteoclastogenesis, and bone loss [16–18].

It is known that the etiology of IAIs significantly influences the choice of treatment tactics and the prognosis of its efficacy. Despite the minor proportion of Gram-negative bacteria in the overall spectrum of pathogens causing orthopedic infections, their involvement in the etiology significantly complicates the prognosis for recovery due to the worldwide growing resistance of this group of pathogens to antibiotics [5,19,20]. In addition, for the selection of surgical tactics and antimicrobial therapy, the identification of hard-to-eradicate pathogens causing difficult-to-treat (DTT) periprosthetic joint infection is significant. Problematic microbes include rifampicin-resistant staphylococci, fluoroquinolone-resistant Gram-negative bacteria, and fungi (Candida sp.). Currently, there are no systemic antibiotics active against these pathogens within a microbial biofilm, and therefore a long interval ($\ge$ 6 weeks) should be chosen between the debridement surgery with removal of the endoprosthesis and its re-implantation, or alternative surgical treatment methods should be used, such as resection hip arthroplasty with muscle transposition using a non-vascularized m. vastus lateralis muscle flap [21,22]. Rifampicin-susceptible** methicillin-resistant staphylococci are also currently not classified as problematic pathogens, since combination therapy, typically including vancomycin** or daptomycin** combined with rifampicin**, is effective against the biofilms they form.

1.3 Epidemiology of the Disease or Condition

Pyogenic-septic complications after fractures and surgeries on bones and joints, in particular periprosthetic joint infections (PJIs) and fracture-related infections (FRIs), create a significant burden on the patient, the attending physician, and the healthcare system as a whole [23]. Implanted foreign bodies are a serious lifelong risk factor for bacterial and fungal infections. Orthopedic implants are mainly used for bone fixation in fractures and for joint arthroplasty. The fundamental difference between these procedures is that internal fixators are needed only temporarily and can be removed after fracture union, whereas endoprosthesis components irreversibly replace the damaged joint [4].

The incidence of infectious complications after fracture osteosynthesis ranges from 1.8% to 27%, depending on the localization and type of fracture. Closed and Gustilo type I open fractures have the lowest infection rate (1.8%), while severe high-energy open lower extremity fractures are characterized by a high infection rate (27%), with the tibia being the most frequently affected bone [24]. The Orthopaedic Trauma Association open fracture classification (OTA-OFC, 2010), according to international experts, meets all modern requirements and allows for predicting probable complications [25]. Predisposing factors for the occurrence of infection after osteosynthesis include: diabetes mellitus, atherosclerosis, alcoholism, obesity, smoking, advanced age, and compromised skin integrity over the fracture [26–28].

Periprosthetic joint infection is the primary cause of revision surgery after total knee arthroplasty (TKA) and the third most common cause after total hip arthroplasty (THA), posing a serious threat to patient health and accounting for a significant proportion of healthcare institution expenditures [23]. According to the Russian Endoprosthesis Registry of the Vreden National Medical Research Center of Traumatology and Orthopedics, this pathology occupies a leading place among the causes of revision surgeries [29]. The diverse clinical manifestations of PJIs, the multitude of factors influencing the development of the infectious process and treatment efficacy, and the sparse data obtained from randomized controlled trials are the reasons why many issues regarding the treatment of this complication continue to remain a hot topic of discussion among specialists [30]. Currently, the main risk factors for PJI development are considered to be diabetes mellitus, urinary tract infection, HIV infection, oncological diseases, decompensated chronic kidney disease, obesity, and previous surgeries in the joint arthroplasty area [30].

Despite the relatively low incidence of PJI development after primary arthroplasty (0.3–2.2%), in cases of repeated (revision) surgeries, the risk of PJI development increases several fold, reaching 5.9–13.6%, while the recurrence rate in the treatment of already existing PJI is 23.2–31.5% [7, 15, 16]. The economic burden of PJI is steadily growing because the number of patients with joint prostheses is constantly increasing, and with a permanent implant in the body, the risk of hematogenous infection persists for life [9]. Despite the relatively low incidence, infectious complications significantly worsen the patient's condition, and the financial costs of their treatment remain enormous: in the USA, expenditures to combat periprosthetic infection increased from $320 million in 2001 to $566 million in 2009, and by 2020 their growth is projected to reach $1.620 billion [33].

1.4 Features of Coding the Disease or Condition

T84.5 – Infection and inflammatory reaction due to internal joint prosthesis

T84.6 – Infection and inflammatory reaction due to internal fixation device [any site];

T84.7 – Infection and inflammatory reaction due to other internal orthopedic prosthetic devices, implants and grafts;

Z96.6 – Presence of orthopedic joint implants.

1.5 Classification of the disease or condition

Any classification should be designed for the rational choice of tactics and determination of the patient's treatment prognosis. In addition, it is expected to serve as a reliable tool for comparing treatment outcomes of similar clinical cases across various independent patient groups. To date, there is no unified classification of either PJIs or FRIs that incorporates all the necessary features that the attending physician must take into account during treatment.

1.5.1 PJI Classification

According to the depth of the infectious process, PJIs, like any surgical site infection (SSI), can be divided into [1]:

• superficial – involving only the skin and subcutaneous tissue,

• deep – involves periprosthetic tissues in the infectious process, involving bone tissue, fascial, and muscle layers.

Currently, a number of researchers point to the absence of reliable differences between superficial and deep PJI in the case of implant-associated infection [6,34,35]. However, it seems premature to abandon the accumulated clinical experience in daily practice. Dividing PJI, including PJI, into superficial and deep allows in certain clinical cases to timely diagnose superficial PJI, reduce surgical intervention to the excision of affected soft tissues within the fascia, and abandon arthroplasty revision while preserving the functioning implant. Deep PJI always requires arthroplasty revision, with the surgical technique chosen individually in each specific case.

According to the infection pathway of the endoprosthesis by pathogenic microorganisms, exogenous and endogenous PJI are distinguished. The main pathway of exogenous pathogen penetration is intraoperative contamination of the wound and/or endoprosthesis, which is why this type of PJI is called postoperative. In most countries, this pathway of PJI development is considered the primary one within 90 days after surgery in the absence of other obvious sources of infection in the patient and is regarded as a complication of the surgery [1,2]. Endogenous infection is realized by the hematogenous or lymphogenous movement of pathogenic microorganisms from existing foci of chronic or acute infection in the patient, as well as their translocation from the intestinal lumen. The risk of developing endogenous PJI in a patient with a permanent orthopedic implant persists for life.

To date, a more rational classification seems to be one that takes into account the modern understanding of the pathogenesis of the infectious process [36], based on the division of PJI into acute and chronic proposed by Zimmerli W. (2014) [6]. This classification is quite simple to use and involves choosing the optimal surgical intervention depending on the degree of maturity of microbial biofilms on the implant, which is determined by the time of infection manifestation and the duration of symptoms (Table 1).

Table 1 Classification of periprosthetic joint infection according to Zimmerli W. (2014) [6] with additions by Li et al. (2018) [36]

Widespread use in routine clinical practice of D.T. Tsukayama's (1996) PJI classification, based on the time of symptom manifestation and the presumed mechanism of infection [37], has shown that the absence of the duration of infection from its manifestation to the provision of specialized care among the classification criteria does not allow for the selection of adequate surgical treatment tactics. This circumstance casts doubt on all potential advantages of this classification and makes its further clinical application incorrect within the orthopedic care system of the Russian Federation. The existing classification by McPherson E.J. et al. (2002) [38] also takes into account the patient's condition and the local status of soft tissues in the area of the upcoming surgery. However, the temporal characteristics of PJI in this classification do not correspond to the modern view of IAI pathogenesis, which does not allow recommending it for widespread use.

1.5.2 FRI Classification

Currently, the professional community has agreed to combine all infections developing as a result of trauma and/or their treatment into a single concept of fracture-related infection (FRI) (https://icmphilly.com/trauma/). Unfortunately, to date, there is no universally accepted consensus classification of FRI. However, we considered it necessary to outline below the most frequently encountered classification criteria for FRI in specialized publications.

By the depth of infection, it is advisable to divide FRI into superficial – involvement of the skin and soft tissues up to the fascia in the inflammatory process, and deep – subfascial involvement of soft tissues and bone [39].

The most widespread is the division of FRI by the time of manifestation into acute (up to 2 weeks postoperatively), delayed (3–10 weeks), and late infection (more than 10 weeks) [39–42]; however, distinguishing acute infection is of the greatest practical importance for choosing surgical tactics.

In addition, a significant role in determining treatment tactics is played by the type and stability of osteosynthesis: internal or external, stable or unstable, as well as whether fracture consolidation is determined or not – the presence of clinical and radiological signs of a bone callus (Romano et al. classification, 2011 [43]). Furthermore, critically important points are the local status of tissues in the area of osteosynthesis and the general condition of the patient, which is reflected in the still relevant Cierny-Mader chronic osteomyelitis classification (1985) [44]. All the above-mentioned characteristics of FRI allow the surgeon to obtain the most complete information about the emerging clinical situation and decide on the necessary treatment option [16,45,46].

1.6 Clinical presentation of the disease or condition

The clinical picture of IAI is largely determined by the type of infection. In the case of acute IAI development, classic clinical symptoms of inflammation are present, such as local tissue swelling, tenderness upon palpation, local temperature increase, skin hyperemia, functional impairment, combined with systemic signs of the infectious process: fever, elevated CRP, ESR, leukocytosis. In the case of chronic infection, the only nonspecific symptom of trouble may be pain. The most specific signs of IAI development are signs of deep tissue involvement: a sinus tract, purulent discharge, abscesses, and extensive necrosis.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnosis of periprosthetic and fracture-related infection, especially in its chronic course, requires vigilance and professionalism from the physician, as there may be no specific symptoms [47]. The diagnostic approach in patients with suspected IAI may vary across different medical organizations depending on physician experience, equipment availability, and local guidelines. However, the first stage is a clinical examination and laboratory blood tests along with radiography. The next stage in patients with a suspected infectious process is a puncture (much less frequently a biopsy) of a potential purulent focus with microbiological (culture) examination of wound (purulent) discharge in the case of FRI or synovial fluid in case of suspected PJI; in the latter case, a cytological examination of the obtained synovial fluid is also advisable.

2.1 Complaints and Anamnesis

The complaints of a patient with suspected PJI may vary significantly depending on the nature of the infectious process (acute or chronic), localization, and the type of implant. In acute presentations, patients may report fever, pain, edema, erythema, and local hyperthermia around the implant site. However, the most sensitive but least specific clinical symptom of PJI is pain in the area of the prosthetic joint [30] in the absence of other manifestations of the infectious process. Every case presenting with pain in the prosthetic joint area, especially within the first 2–3 years following implantation, should be considered a potential infectious complication until proven otherwise. In the early postoperative period following arthroplasty or fracture osteosynthesis, prolonged wound discharge may be the only sign of trouble. In a long-standing, previously undiagnosed infectious process, the patient may present with complaints of a sinus tract, purulent discharge, and necrosis in the area of the previous surgery. It should be borne in mind that in immunosuppressed patients, the clinical manifestations of the infection are often muted [49].

When taking the medical history in suspected IAI, it is advisable to find out the date of the preceding trauma/surgery, the presence of wound healing problems after implantation, the type of endoprosthesis, clarify the presence of infections in other locations, assess clinical symptoms upon presentation and their duration, drug tolerance, concomitant pathology, previous microbiological test results if available, and courses of antibiotic therapy received, including local antibacterial therapy [30,31].

Signs of deep tissue involvement are the most specific indicators. It is important to note that clinical outcomes vary significantly depending on the type of large joint involved, as well as the timing and manifestation of PJI (i.e., early postoperative, acute hematogenous, and chronic) [48]. When hematogenous PJI is suspected, it is necessary to search for potential remote sources of infection by examining the skin, periodontium, upper and lower respiratory tracts, and urinary tract. Risk factors such as immunosuppression due to underlying conditions or medications, rheumatic diseases, or previous hip surgery are of substantial importance. Unlike periprosthetic joint infection, fracture-related infection (FRI) lacks clear diagnostic criteria and a unified nosological definition among clinicians. This is due to the severity and diversity of skeletal trauma, as well as the variability of its surgical treatment options [22,28–31].

2.2 Physical Examination

• Trauma and orthopaedic surgeons or general surgeons are recommended to perform a general physical examination of patients with suspected BJI to identify classic systemic and local clinical symptoms of inflammation [23, 24].

LNC 5 LeC C

Comments: when examining a patient with suspected BJI, it is advisable to assess for signs of systemic inflammatory response syndrome (SIRS), characterized by the presence of at least two of the following four clinical criteria: 1) temperature above 38°C or below 36°C; 2) heart rate greater than 90 beats per minute; 3) respiratory rate greater than 20 breaths per minute; 4) leukocyte count above 12×10⁹ /L or below 4×10⁹ /L, or an immature neutrophil (band cell) count exceeding 10% [56]. The presence of SIRS generally requires emergency interventions to drain the purulent focus and the administration of antibacterial therapy to prevent further generalization of the infection. Although there are currently no studies evaluating the role of blood microbiological testing in the diagnosis of periprosthetic and fracture-related infections, given the frequent hematogenous origin of any BJI, it is advisable to perform blood cultures for sterility in febrile patients with suspected infection [115].

Performing a visual and palpatory assessment of the local status in the area of the previously placed implant allows for evaluation of the soft tissue condition [26,57]. The development of BJI may be accompanied by classic signs of inflammation: localized swelling, local tenderness, local tissue hyperthermia, skin hyperemia, functional impairment, wound dehiscence, and the presence of a sinus tract communicating with the bone and/or implant, as well as purulent discharge in the area of the fracture and/or implant placement The presence of a sinus tract communicating with the bone or implant, and/or purulent discharge in the area of the fracture, osteosynthesis, or joint arthroplasty without another known cause, is an absolute criterion for the presence of both periprosthetic and fracture-related infection [54]. A sinus tract can be characterized as: (1) a pathological channel in the soft tissues between the bone or joint arthroplasty and the external environment, which is definitively or presumptively colonized by bacteria; (2) its presence can be confirmed by direct visualization of the bone or prosthesis, communication with the external environment via fistulography, ultrasound, CT, or MRI [48]. Currently, there are no comparative studies proving that a sinus tract with purulent discharge is an absolute sign of PJI; however, given the natural skin colonization, bacteria undoubtedly colonize the exposed implant or bone. The significance of these criteria is evidenced by their inclusion in the diagnostic algorithms of all national professional medical societies providing care to patients with BJI [30,58–60].

• Patients with suspected FRI are recommended to undergo an examination of the adjacent joints of the fixated limb segment [39].

LNC 5 LeC C

Comments: The surgeon must take into account that infection of the fixation device may result in septic arthritis of adjacent joints, especially in cases of direct contact between the implant and anatomical structures of the joint.

2.3 Laboratory Diagnostics

2.3.1 Preoperative Diagnostics

• All patients admitted for elective revision joint arthroplasty are recommended to undergo screening for serum inflammatory markers: testing serum C-reactive protein levels and erythrocyte sedimentation rate [61–64].

LRE 1, GR A

• All patients with suspected BJI are recommended to undergo serum C-reactive protein (CRP) testing and erythrocyte sedimentation rate (ESR) testing [62,63,65].

Level of Evidence (LE) 3, Grade of Recommendation (GR) B

Comments: CRP and ESR are the most widely accepted screening tests in the diagnosis of PJI; they are well studied and have high sensitivity. Their combination demonstrates high diagnostic value for diagnosis and subsequent monitoring of treatment outcomes [61,63,66,67]. For diagnostic purposes, a threshold value of 10 mg/L for CRP and 30 mm/h for ESR is recommended [30,60]. At present, the reliability of these markers for PJI is limited, so the results obtained should be interpreted with caution. According to most experts, CRP is the most sensitive serum marker for the diagnosis of PJI [62,65]. Although both markers can be affected by numerous factors (neoplastic and inflammatory diseases, age, and technical details), if either marker exceeds the threshold value, further diagnostic tests should be performed to confirm or rule out PJI. It should also be noted that at present the diagnosis of PJI cannot be based solely on serologic tests [48], since normal values do not rule out its presence [59], while elevated values are not always indicative of an infectious process, for example, in patients with systemic diseases (rheumatoid arthritis, systemic lupus erythematosus, etc.).

• Patients with suspected PJI are not recommended to undergo blood procalcitonin (PCT) testing to confirm or rule out an infectious process [68–70].

LRE 1, GR A

Comments. Several studies, including a meta-analysis, have not established any advantage of PCT testing compared to CRP and/or interleukin-6 [68–70]. Determining PCT is justified when generalized infection is suspected in a patient with BJI (presence of SIRS signs) to rule out or confirm sepsis, as well as to assess the effectiveness of its treatment.

• Patients with suspected PJI are not recommended to use blood D-dimer concentration measurements to confirm or rule out an infectious process [71].

Level of Evidence (LE) 3, Grade of Recommendation (GR) B

Comments. Despite the emergence of publications suggesting with a number of limitations to consider D-dimer as one of the criteria for chronic hip or knee PJI [72], other studies fail to show its significance compared to traditional inflammatory markers (ESR and CRP) [71]. D-dimer increases in DIC syndrome, pulmonary embolism, venous thrombosis, heart disease, burns, extensive surgical interventions, pregnancy, the elderly, oncology, bedridden patients (with prolonged immobilization), and rheumatoid arthritis. In view of the above, it appears inappropriate to routinely use this parameter for BJI diagnosis.

• In patients with BJI who have open wounds and/or sinus tracts, it is not recommended to take wound (purulent) discharge samples with a swab for microbiological (culture) testing for aerobic and facultatively anaerobic microorganisms [73,74, 113].

LoE 2, GrB

Comments. This sampling method frequently identifies skin microflora colonizing the sinus tract or open wound, which can lead to misinterpretation of the results [54,74,113,114].

• All patients with suspected PJI, as well as those admitted for revision arthroplasty, are recommended to undergo joint aspiration to perform cytological and/or microbiological (culture) examination of the synovial fluid for aerobic and facultatively anaerobic microorganisms in order to confirm or rule out an infectious process [77, 79].

LoE 3, GrB

Comments. Currently, there are no clear contraindications to knee or hip joint aspiration performed as part of the evaluation of a patient with infection [30]. It appears appropriate to perform aspiration when acute PJI is suspected if the diagnosis is not clinically obvious; in patients with chronic pain in a joint arthroplasty; as well as in patients with elevated ESR and/or CRP levels or clinical signs of PJI. Cytological examination of synovial fluid should include leukocyte count and the proportion of neutrophils, which most studies and systematic reviews demonstrate to have high diagnostic significance [46,76–79]. A threshold value for leukocyte count of >3000 cells/µL (according to various authors, ranging from 1700 cells/µL to 5000 cells/µL) is considered justified, and a proportion of neutrophils >70% is a significant criterion for establishing the diagnosis of PJI (range 65–80%) [58]. Cytological examination of synovial fluid can be performed on an outpatient basis; unlike bacterial culture, its results are not affected by antimicrobial therapy [80]. It must be remembered that in patients with periprosthetic fractures and during the first 6 weeks after joint arthroplasty, as well as in patients with rheumatoid arthritis, periprosthetic fracture, or in the presence of a metal-on-metal bearing surface, cytological examination of synovial fluid may yield false-positive results [36,81].

Numerous studies and a published systematic review demonstrate moderate to high diagnostic sensitivity (43.5–100%) and high specificity (81.2–100%) for microbiological (culture) testing of synovial fluid [62,78,82–89]. The recommended incubation time for samples should be at least 7 days, with some studies recommending extending the incubation period to 2 weeks [67,74]. It should be noted that culture results may be false-negative due to prior antibiotic use, a low burden of microorganisms, use of an unsuitable culture medium, infection caused by fastidious microorganisms, dilution of synovial fluid with anesthetic, or violations of sample transport rules to the laboratory. It is known that the diagnostic sensitivity of culture testing is significantly reduced during antibacterial therapy [74,91,92]. Discontinuing antibacterial therapy at least 2 weeks before synovial fluid aspiration, as well as strict adherence to culture testing methodology and sample delivery rules to the laboratory, increases the likelihood of pathogen isolation.

In terms of establishing a microbiological diagnosis, molecular diagnostic methods (PCR) showed superiority over traditional culture only in cases of evaluating patients with infections caused by low-virulence pathogens [93,94]. In addition, in cases of evaluating patients with culture-negative PJI, a certain role is assigned to next-generation sequencing (NGS).

• In patients whose previous diagnostic workup has not yielded conclusive results for or against the presence of PJI, it is recommended to determine one of the inflammatory biomarkers in synovial fluid to confirm or exclude an infectious process: alpha-defensin [48,64–67], leukocyte esterase [97–100], IL-6 [90,96,101–104], D-lactate [105,106] and C-reactive protein [63,66,76,97,107,108].

LoE 1 GoR A

Comments. The determination of biomarkers is characterized by high diagnostic significance; however, it must be remembered that the presence of blood traces in the aspiration fluid can lead to false-positive results, while the presence of a sinus tract in the patient can lead to false-negative results. These markers are believed to be less affected by prior antimicrobial therapy than microbiological culture results. Most studies using alpha-defensin demonstrate high sensitivity and specificity (95.5–100% and 95–100%, respectively) of this method [48,64–67]; however, this test is expensive and may not be available in every medical organization. In addition, in infections caused by certain low-virulence bacteria, such as Cutibacterium acnes (formerly Propionibacterium acnes), an increase in alpha-defensin levels may not be observed [109].

Leukocyte esterase also demonstrates high diagnostic significance, with a sensitivity of 66–100% and specificity of 77–100% in several studies [97–100], along with low cost, ease of performance, and the ability to provide real-time results.

IL-6 showed better diagnostic significance when determined in synovial fluid than in blood serum. Several high-level studies have shown a sensitivity of 62.5–97% and a specificity of 85.7–100% for this marker [90,96,101–104]. However, this test is also characterized by a high cost. Another serological marker that can be used to diagnose PJI is D-lactate, an elevated amount of which in synovial fluid indicates the presence of a bacterial infection [105,106]. However, this test has not yet found widespread use.

CRP levels can be measured in blood serum and synovial fluid. Synovial fluid CRP demonstrated a diagnostic sensitivity of 70–97.3% and specificity of 78.6–100% in a number of high-level studies [63,66,76,97,107,108]. However, it must be remembered that a normal CRP level in synovial fluid does not exclude PJI, since CRP is produced in the liver rather than in the joints, and the results of physical examination and anamnesis should be taken into account, as CRP is a nonspecific marker of acute inflammation.

• In patients with fracture-related infection (FRI) or suspected FRI, it is recommended to perform a puncture of a potential purulent focus followed by microbiological (culture) examination of the wound (purulent) discharge for aerobic and facultatively anaerobic microorganisms [60, 110, 112].

Level of Evidence (LE) 5, Grade of Recommendation (GR) C

Comments. Currently, isolating the same microorganism twice from the fracture or osteosynthesis area is generally considered one of the absolute signs of FRI. If pathological exudate is present in the fracture zone and/or adjacent joint cavity, it must be punctured and sent for microbiological (culture) examination [39, 60, 110, 112].

• In patients with diagnosed implant-associated infection (IAI), it is recommended to perform laboratory testing before surgery and in the postoperative period during antibacterial therapy, including: complete blood count, blood serum CRP level test, ESR test, total blood protein test, blood creatinine level test, total blood bilirubin level test, blood glucose level test, as well as determination of alanine aminotransferase (ALT) activity in the blood [31].

LNC 5 LeC C

2.3.2 Intraoperative Diagnostics

• In patients with orthopedic implants undergoing revision surgery, including revision arthroplasty, when IAI is suspected, it is recommended, if available, to perform an urgent intraoperative pathomorphological examination of the surgical material (peri-implant tissues) to confirm or rule out the infectious process and potentially modify the surgical treatment strategy [116,117].

LE 2 GOR A

Comments. The presence of acute inflammation patterns during urgent pathomorphological examination of frozen periprosthetic tissue samples, described by a pathologist, highly likely indicates the presence of PJI. Currently, histological criteria have been developed to confirm the infectious process in tissues. Thus, according to the Feldman criterion, the detection of more than 5 neutrophils in at least 5 high-power fields at ×400 magnification indicates the presence of IAI [116,117]. In addition, pathomorphological examination of surgical material using specific staining methods allows for the identification of bacteria and fungi [118].

• In a patient with confirmed or suspected IAI, it is recommended to intraoperatively obtain at least three periprosthetic tissue samples, as well as the removed implants, for further microbiological (culture) examination of the purulent discharge for aerobic and facultatively anaerobic microorganisms [74,119,120].

Level of Evidence 2, Grade of Recommendation B

Comments. Culture of tissue samples and sonication fluid after ultrasonic treatment of removed implants is essential for differentiating contamination from infection. When culturing tissue biopsies in blood culture bottles, three biopsies are sufficient; using standard culture techniques requires at least four periprosthetic tissue samples [120]. Growth of a virulent microorganism (e.g., S. aureus, K. pneumoniae) in at least one biological sample (aspirate, tissue biopsy, removed component) is a diagnostic criterion for periprosthetic joint infection (PJI). Isolation of the same low-virulence microorganism (e.g., S. epidermidis, Propionibacterium acnes), indistinguishable based on standard laboratory tests, including genetic and specialized identification and antibiogram, from two or more tissue biopsies or from synovial fluid and one intraoperative tissue biopsy or removed implant (endoprosthesis component) confirms the presence of implant-associated infection (IAI) [32,39,54,74]. At the same time, the isolation of a low-virulence pathogen from a single biological sample or removed construct should not be regarded unequivocally as confirmation of IAI and must be evaluated in conjunction with other examination results. Culture of fluid after sonication of removed implants can improve the accuracy of microbiological diagnosis, including in patients receiving antimicrobial therapy [92,112,121,122]. The results obtained will make it possible to establish a definitive microbiological diagnosis in the early postoperative period and adjust antibacterial therapy [4].

• A patient with an orthopedic implant undergoing revision surgery for its replacement is recommended to have multiple periprosthetic tissue samples taken for subsequent pathomorphological examination of the surgical material [117,123–125].

Leveled Research Evidence (LE) 2 Grade of Recommendation (GR) B

Comments. In accordance with international criteria, pathomorphological examination of biopsy/surgical materials is an integral part of IAI diagnosis [50,60,123]. Among existing cell-counting techniques, the method for determining neutrophil granulocytes using various staining methods in several high-power fields (HPF) under high-magnification microscopy has demonstrated the greatest significance for diagnosing infection. A direct correlation between the number of neutrophil granulocytes and the presence of bacterial infection has now been proven, and diagnostic criteria have been established. PJI diagnosis is based on the method of counting neutrophil granulocytes in the SLIM (synovial-like interface membrane); according to the Krenn and Morawietz classification [125] the presence of type II (infectious) or type III (mixed) membrane indicates periprosthetic infection, even without any other clinical or laboratory manifestations [21,125].

2.4 Instrumental Diagnostics

• All patients with suspected IAI are recommended to undergo radiography of the affected skeletal segment (A06.03.057) with the installed implant [126,127].

LNC 5 LeC C

Comments. X-ray examination of the affected skeletal segment in the development of periprosthetic or fracture-associated infection in the early postoperative period is generally diagnostically insignificant, but may help exclude other joint disorders [19,21,25].

Currently, there is a limited number of studies on specific radiographic signs for the diagnosis of chronic implant-associated infection (IAI); during X-ray examination, attention should be paid to signs of osteolysis, implant migration, sequestration, lack of bone union, and periosteal reaction outside the fracture zone.

In chronic PJI, radiography may show loosening of endoprosthesis components; however, generally in the absence of osteomyelitis, it is very difficult to differentiate between the infectious process and aseptic loosening of endoprosthesis components based on a single X-ray image alone. Signs of endoprosthesis loosening detected in the early stages after prosthesis implantation may serve as an indirect sign of the infectious nature of the pathological process [48].

In fistulous forms of IAI and PJI, fistulography is a mandatory study method that allows clarifying the location of fistulous tracts, the localization of purulent fluid collections, and their connection with bone destruction foci by filling them with a contrast agent followed by radiography [32,54]. Based on contrast fistulography, differential diagnosis of superficial and deep forms of IAI is possible. Recommended indications for performing fistulography:

1. the need to determine the extent of fistulas and branching of the fistulous tract;

2. suspicion of a connection between the fistulous tract and organs or tissues;

3. the need to detect fluid collections in soft tissues.

Contraindications to the procedure include: the patient's severe general condition and intolerance to radiopaque agents. The contrast agents used in fistulography may be oily solutions of organic iodine compounds (iodolipol, lipiodol) or water-soluble compounds thereof (cardiotrast, urographin).

• For patients with suspected PJI in whom synovial fluid/wound discharge could not be obtained from the suspected infection focus, it is recommended to perform a repeat puncture of the synovial bursa and/or soft tissue puncture under ultrasound guidance to obtain synovial fluid and/or wound (purulent) discharge for subsequent microbiological (culture) examination for aerobic and facultatively anaerobic microorganisms [128,129]

Level of Evidence 2, Grade of Recommendation B

Comments. Performing a puncture of the suspected infection area under ultrasound guidance helps determine the location of the infected hematoma or abscess and obtain the necessary samples of pathological contents for microbiological examination and pathogen identification [54,124].

• For patients with suspected PJI, it is not recommended to routinely use spiral computed tomography (SCT) (A06.14.017 computed tomography of joint or A07.03.003 single-photon emission computed tomography of bones), magnetic resonance imaging (A05.04.001 magnetic resonance imaging of joints (single joint) or A05.03.001 magnetic resonance imaging of bone tissue (single region)), three-phase soft tissue and bone scintigraphy, multi-position tumor-seeking radiopharmaceutical scintigraphy, single-photon emission computed tomography with tumor-seeking radiopharmaceuticals, or positron emission tomography combined with computed tomography using contrast-enhanced tumor-seeking radiopharmaceuticals to detect the infectious process [54,81,130].

LNC 5 LeC C

Comments: A clear indication for SCT in PJI is a defect in the bones forming the acetabulum. When the acetabular component is displaced medially from Köhler's line, SCT in vascular mode is recommended to study the relative positioning of the endoprosthesis components and pelvic organs. SCT is necessary for surgical planning and provides detailed data on bone architecture, fracture patterns, signs of osteogenesis, osteonecrosis, and implant instability. Furthermore, SCT detects additional symptoms of PJI: cortical bone periosteal reaction, presence of sequestra, intraosseous fistula, or abscess formation in the bone or adjacent soft tissues [131–133].

Magnetic resonance imaging of the affected skeletal region is the method of choice, allows for the assessment of the localization and boundaries of soft tissue involvement, and provides additional information on the development of infectious inflammation within the medullary canal [41]. However, in the case of PJI, metal artifacts hinder data interpretation, while scars, postoperative edema, and post-traumatic bone defects can mimic infection [134].

Positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals with contrast enhancement – significantly expands diagnostic capabilities for the exact localization of PJI, indicates the boundary of infectious inflammation of bone and soft tissues, and allows for the assessment of fracture consolidation, bone remodeling, and tissue reaction to inflammation [135]. In addition to visual analysis (location of uptake zones, uptake cavities, degree of uptake), the method also provides semi-quantitative evaluation by measuring standardized uptake values during image reconstruction [136]. Systematic literature reviews have established wide ranges of sensitivity (28%–91%) and specificity (34%–97%), which is attributed to differences in study design and data interpretation criteria. Another limitation of the technique is the postoperative time period. Thus, performing this study less than one month after surgery was associated with a significant increase in false-positive results [136], which prevents a definitive conclusion regarding its role in the diagnosis of PJI, subject to further clarification [137–139].

Three-phase bone scintigraphy has until recently been most widely used as a screening diagnostic method for PJI. However, within 5 years following hip or knee arthroplasty, the diagnostic accuracy of scintigraphy in patients with suspected infection remains low, as the method does not differentiate between PJI and post-traumatic bone changes [140].

2.5 Other Procedures

Timely detection of signs of surgical site infection in a patient after orthopedic implant placement and subsequent therapeutic management in most cases preserves the implant, prevents the development of deep PJI, or halts the chronization of the infectious process.

• In patients with an established implant, it is recommended to consider the development of local and systemic clinical and laboratory signs of an infectious and inflammatory process in the early postoperative period, as well as wound discharge persisting for more than 72 hours after surgery, as a sign of incipient PJI [48].

LNC 5 LeC C

Comments: The development of local (hyperemia, edema, hyperthermia, functional impairment) and systemic (fever, surge in CRP after the 5th postoperative day, increasing leukocytosis, etc.) signs of an infectious and inflammatory process, if adequate treatment is delayed—including surgical revision of the postoperative wound when necessary—leads in a significant proportion of cases to the subsequent development of chronic PJI. These signs may be a manifestation not only of early postoperative infection, but also of acute hematogenous infection, provided their duration does not exceed 3 weeks [36].

• If a surgical site infection is suspected in the early postoperative period in a patient with an established orthopedic implant, it is recommended to perform a microbiological (culture) examination of purulent (wound) discharge and/or tissue biopsies of viable tissue for aerobic and facultatively anaerobic microorganisms [48].

Level of Evidence (LE) 5, Grade of Recommendation (GR) C

Comments. Biomaterial must be collected prior to the initiation of antimicrobial therapy or immediately before administering the next dose of antibiotic [1]. The absence of microbial growth does not rule out infection. At the same time, the mere detection of bacteria in the wound cannot serve as confirmation of wound infection. The most important criterion for the presence of an infectious process in the wound is the clinical picture. The isolation of a microorganism (or association) against the background of edema, hyperemia, and pain in the acute wound supports its etiological significance. The isolation of bacteria from a wound during an active reparative process indicates only colonization or contamination of the wound surface [1].

• In patients who have undergone arthroplasty within the first 6 weeks postoperatively, it is not recommended to perform synovial fluid cytological analysis to confirm or exclude PJI [142].

Level of Evidence (LE) 3, Grade of Recommendation (GR) B

Comments. Performing leukocyte counts within the first 6 weeks after arthroplasty will lead to unreliable results [142].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The final decision on the treatment option should be made by an orthopedic traumatologist, and in complex cases, in conjunction with other specialists (e.g., plastic surgeon, clinical pharmacologist, infectious disease specialist). Successful treatment of PJI involves a combination of appropriate surgical tactics and antimicrobial therapy active against the causative agents of the given infectious process. The choice of incorrect surgical tactics and/or irrational use of antibiotics are the most common causes of the persistent and recurrent nature of the infectious process. To a large extent, the choice of treatment tactics is determined by the pathogenesis of PJI, namely the maturity stage of the microbial biofilm, as discussed previously. It should be noted that there are a number of fundamental differences between prosthetic joint infection (PJI) and fracture-related infection (FRI) that influence treatment tactics. Currently, there are no universally accepted criteria and standard approaches for the treatment of FRI. Moreover, compared to PJI, fracture-related infection is typically characterized by:

• poorer condition of perifocal tissues, as determined by the nature and severity of the trauma,

• the need for repeat surgeries to correct fixation, close soft-tissue defects, etc.,

• the need to ensure biomechanical stability of the damaged limb segment,

• more frequent prescription of initial empiric antibiotic therapy, due to the pathogen being isolated in most cases only from intraoperatively harvested samples.

A significant advantage compared to PJI is that internal and fixation devices in FRI can be removed once bone healing is achieved.

3.1 Conservative Treatment

Conservative treatment at the preoperative stage should aim at pain relief using NSAIDs and/or paracetamol** depending on the severity, or opioid analgesics if those are ineffective, as well as preparing the patient for major surgery, which implies optimization of concomitant pathology [49, 54]. Following revision surgeries for bone and joint infections of the lower extremities and spine, as in any major orthopedic surgery on the musculoskeletal system, the patient requires pharmacological prophylaxis of venous thromboembolism using antithrombotic agents (ATC B01A) [111], as well as supportive therapy including adequate pain control, nutritional support, iron preparations, and systemic antibacterial therapy [203], infusion therapy to correct circulating blood volume and electrolyte disturbances, and, if necessary, medications for comorbid conditions.

• In patients with hypoproteinemia and/or compromised nutritional status, it is recommended to correct these abnormalities to reduce the risk of an unfavorable treatment outcome [143, 144].

Level of Evidence (LE) 5, Grade of Recommendation (GR) C

Comments: Currently, it is an irrefutable fact that impaired nutritional status, including hypoalbuminemia, is an unfavorable prognostic sign for the outcome of revision surgeries [143, 144], which provides the rationale for prescribing nutritional support (ATC B05BA01 Amino acids**, ATC B05AA01 Albumin**) and parenteral iron preparations (ATC B03AC) to such patients.

• In all patients with moderate to severe pain syndrome after revision surgeries on the musculoskeletal system, it is recommended to prescribe analgesics: NSAIDs, paracetamol**, opioid analgesics [145];

Level of Evidence (LE) 2, Grade of Recommendation (GR) A

Comments. Multimodal analgesia, defined as the use of various analgesic drugs and techniques targeting different mechanisms of action in the peripheral and/or central nervous system, can provide additive or synergistic effects and more effective pain relief compared to single-modality methods. Various multimodal combinations and regimens are possible for each specific situation, depending on the scope of the specific surgery and the patient's individual characteristics. Systemic therapy can be combined with local administration of local anesthetics, as well as regional or neuraxial anesthesia, especially to prevent intense pain in the early postoperative period. Systemic opioids are not required for all patients [145].

• In patients with PJI, in the absence of contraindications, it is recommended to prescribe prolonged combination high-dose antibiotic therapy (for at least 6 weeks) to enhance the antimicrobial effect and activity against microbial biofilms and intracellularly located pathogens [146–155].

Level of Evidence (LE) 2, Grade of Recommendation (GR) A

• In patients with joint and bone infections during the postoperative period who show positive clinical and laboratory dynamics against the background of a course of parenteral antibacterial therapy, it is recommended to switch to oral systemic antibacterial drugs with high bioavailability [156].

Leveled Research Evidence (LE) 2 Grade of Recommendation (GR) B

• For patients in whom joint and bone infection is caused by multidrug-resistant strains of pathogens, with a recurrent course of infection, as well as in the presence of contraindications or the development of adverse events when taking antibacterial drugs, it is recommended to consult an antimicrobial chemotherapy specialist (a clinical pharmacologist or infectious disease specialist) [157].

Level of Evidence (LE) 5, Grade of Recommendation (GR) C

Comments. The basis of antibacterial therapy for joint and bone infections is inpatient intravenous administration (lasting 7–14 days) of medications, followed by a switch to oral administration of predominantly bactericidal antibiotics with good bioavailability [158]. For patients with PJI who underwent debridement and implant retention or single-stage revision, a course of treatment extended up to 3 months is recommended [155,319]. This duration of combination therapy showed similar efficacy compared to a 6-month course of therapy in patients with knee or hip arthroplasty retention in several clinical studies, including randomized ones [147,148,151]. In the case of two-stage PJI treatment, the standard duration of the antibiotic therapy course is 6–8 weeks after each stage, depending on the nature of the infectious process [21,54,159]. Based on our own developments [4,21,54] and the recommendations of European colleagues [159], lists of drugs for targeted antibacterial therapy have been formed (Appendix A3.1), compiled taking into account current knowledge on PJI pathogenesis, results of monitoring the antibiotic sensitivity of joint and bone infection pathogens, and known methods of affecting microbial biofilms.

There are no comparative studies defining the duration of antibacterial treatment for PJI. Expert consensus guidelines recommend prescribing antibiotic therapy for 6 weeks during implant removal and osteomyelitis treatment, and for 12 weeks during one- or two-stage implant exchange [158,159]. In patients with delayed infection, the duration of the antibiotic course is individualized and may continue throughout the entire fracture healing period and for 1–2 weeks after the orthopedic fixation system is removed [158]. Bone consolidation must be regularly evaluated and the implant removed after fracture healing, which can significantly shorten the course of antibiotic therapy. In addition to the antibacterial activity of the drug against the identified causative agent of the infection, patient-related factors must be taken into account: a history of drug intolerance, renal and hepatic function, and the ability to take the drug orally. To prevent antibiotic-associated colitis, it is advisable to consider prescribing antidiarrheal microbial drugs.

During long courses of antibacterial therapy, periodic monitoring of their efficacy (blood ESR testing, serum CRP level) and safety (performing serum creatinine tests and/or ALT activity determination depending on the chosen drugs, as well as a complete blood count) is indicated for the timely detection of adverse reactions affecting the kidneys, liver, or bone marrow [32,54].

• Patients with joint and bone infections are recommended to receive broad-spectrum initial empiric antibacterial therapy covering methicillin-resistant staphylococci, taking into account the results of preoperative microbiological (culture) examination of synovial fluid and/or wound (purulent) discharge, with subsequent correction after obtaining the results of microbiological (culture) examination of bone tissue for aerobic and facultatively anaerobic microorganisms and, if applicable, the removed implant [160].

LE 4 GSR C

Comments: Antibacterial therapy can be empirical or etiotropic. Empirical antibiotic therapy is carried out with drugs active against major Gram-positive and Gram-negative causative agents of bone and joint infections, the list of which is determined based on local microbiological monitoring in medical organizations. However, given the leading role of staphylococci in the etiology of orthopedic infection and the prevalence of methicillin-resistant strains, it is advisable to include drugs active against these pathogens in empirical therapy. Currently, a decrease in the clinical efficacy of vancomycin** is noted, therefore it is necessary to consider the possibility of prescribing alternative drugs with anti-MRS activity, for example, #daptomycin** (at a dose of 8–10 mg/kg/day intravenously [150,151] or #linezolid** (at a dose of 600 mg twice daily intravenously) [161,162]. Despite the fact that none of them has an approved indication for the treatment of bone and joint infections, practical experience in their use for treating specialized patients has already been accumulated. These drugs demonstrate good penetration into bone tissue and efficacy when prescribed as part of combination therapy, for example, with rifampicin** [149–152]. However, bone and joint infections usually require prolonged treatment, and therefore the use of #linezolid** for more than 4 weeks remains controversial, as serious side effects with its long-term intake must be taken into account: peripheral neuropathy, optic neuritis, and bone marrow suppression. As for #daptomycin** (at a dose of 8–10 mg/kg/day intravenously [150,151], there is currently insufficient clinical data to definitively evaluate its role in the treatment of bone and joint infections. Available data indicate treatment regimens with doses ranging from 8 mg/kg to 10 mg/kg once daily in combination with rifampicin** [12], but monitoring for its serious adverse effects is required.

Regarding gram-negative pathogens of joint and bone infections, cefoperazone + [sulbactam]** and carbapenem drugs exhibit the highest activity [5,7,48]. After obtaining the results of tissue biopsy cultures and removed hardware, antibiotic therapy is adjusted, switching from empiric to targeted. Due to the frequent isolation of microbial associations specifically from tissue biopsies, the etiology of the infection should be considered definitively established only after receiving the results of their intraoperative cultures.

An oral antibacterial drug highly active against staphylococcal biofilms is rifampicin**, which, due to the rapid development of resistance to it, must (according to the instructions for use) be prescribed only as part of combination therapy. The most active combination of oral drugs for staphylococcal joint and bone infection is rifampicin** combined with fluoroquinolones [163]: #levofloxacin** (at a dose of 0.5 g twice daily or 0.75 g once daily orally [21, 146, 283]) or #moxifloxacin** (at a dose of 400 mg once daily orally [164]). Bacteriostatic antibacterial drugs such as clindamycin** in PJI should be avoided if medications with a bactericidal action can be prescribed.

The use of high doses of antibacterial drugs is another feature of antibacterial therapy for joint and bone infections, which is associated with the necessity of creating concentrations of drugs at the infection site that are active not only against planktonic, but also sessile forms of bacteria within biofilms. During prolonged high-dose antibacterial therapy, monitoring of liver and/or kidney function is recommended for the timely detection of adverse effects both at the inpatient and outpatient stages.

Due to the formation of microbial biofilms and the transition of bacteria into a sessile phase with reduced metabolism, only a limited list of antibacterial drugs with antibiofilm activity can be effective in the treatment of implant-associated infections (IAI). Currently, this list includes: rifampicin** (active against staphylococci), fluoroquinolones (against Gram-negative bacteria), and #fosfomycin**, which exhibits high efficacy in enterococcal infections. Strains resistant to these drugs are currently classified as difficult-to-eradicate pathogens (DTE pathogens). At the current stage of medical development, there are no drugs highly active against biofilms formed by these pathogens [21,159]. The greatest challenge is the selection of drugs for antimicrobial therapy of IAI caused by fluoroquinolone-resistant strains of Gram-negative pathogens (members of the Enterobacteriaceae family, *P. aeruginosa*, *Acinetobacter* spp., etc.) or microbial associations involving them. The reason for this is the impossibility of prescribing etiotropic oral prolonged antimicrobial therapy at the outpatient stage [5]. This accounts for the lower treatment efficacy of infections caused by these pathogens [5,48,165–167]. In patients with recurrent IAI caused by multidrug-resistant (including carbapenem-resistant) and pandrug-resistant strains, it is advisable to consider including alternative antimicrobial drugs active against the isolated pathogens in the treatment regimen, or a combination of 2–3 drugs at the maximum possible doses whose activity spectrum includes the isolated pathogens to overcome their resistance mechanisms (Appendix A3.1) [5,168]

• During the debridement and sanitation of the purulent focus in a patient with IAI, it is recommended to initiate antimicrobial therapy intraoperatively after taking samples of clinical material and removed hardware for microbiological (culture) examination, unless the patient's condition requires immediate initiation of therapy [7,48,54].

Level of Evidence (LE) 5, Grade of Recommendation (GR) C

• In a patient with IAI, in the absence of a severe course of infection with the risk of process generalization and the development of systemic inflammatory response or sepsis, it is not recommended to prescribe antimicrobial therapy before the sanitizing surgery and taking samples of biomaterial and removed implants for microbiological (culture) examination [7,48,54].

Level of Evidence (LE) 5, Grade of Recommendation (GR) C

Comments. Conservative treatment of implant-associated infections (IAI), in the absence of adequate debridement of the infection focus, fails to resolve the infectious process. Without removal of the infected implant, antibiotic therapy should be prescribed only to patients with chronic PJI and fracture-related infection (FRI) who are at high risk of systemic dissemination, or who cannot tolerate surgery (septic status and/or severe comorbidities, etc.) until their condition stabilizes, or on a long-term, sometimes lifelong basis. Antibiotic therapy may also be prescribed in cases of FRI where the implant provides stable fracture fixation and bone healing is possible despite the infectious process controlled by antibiotics [159]. During the reimplantation stage of a two-stage PJI treatment, antibiotic administration should be initiated 30–40 minutes before the incision, in accordance with the principles of surgical infection prophylaxis. The choice of drugs must be based on the previously identified pathogen [32,53,154].

• For patients with severe comorbid conditions who may not tolerate surgery, it is recommended to prescribe continuous suppressive oral antimicrobial therapy (ranging from several months to lifelong) without performing radical surgery, upon the decision of a multidisciplinary specialist team [170–172].

LE 4 GSR C

Comments: The decision to choose this treatment method should be made by a multidisciplinary team of physicians when, in a patient with severe decompensated comorbidities, radical surgical intervention cannot be performed [36,173]. The main objectives of this approach are to reduce the symptoms of the acute infectious process, prevent generalization of the infection, and maintain joint function. The efficacy of suppressive antibacterial therapy without surgical debridement of the purulent focus does not exceed 25%. In cases where surgical debridement of the PJI focus with retention of the endoprosthesis was performed, followed by a prolonged (several weeks) course of parenteral antibacterial therapy with a switch to oral combination therapy with rifampicin**, and only thereafter the prescription of chronic suppressive therapy, treatment outcomes were more encouraging [174]. Another approach may be the formation of a permanent fistulous tract with continuous administration of low-dose antibacterial agents; however, it should be understood that in 80% of cases, infection recurs after antibiotic discontinuation [173]. This technique is described in more detail in Section 3.2.1. Surgical treatment of PJI.

This approach can be recommended only under the following conditions:

• the patient has no signs of systemic infection;

• adequate sanitation of the purulent focus with removal of the infected endoprosthesis is impossible due to the patient's debilitated condition;

• the prosthesis is stable;

• the etiology of the infection is caused by a low-virulence pathogen with good susceptibility to oral antimicrobial drugs;

• an agreement has been reached between the physician and the patient, who is willing to take the recommended medications for a prolonged period.

The use of suppressive therapy in young patients is controversial, and indications for treatment must be determined individually in each specific case. When prescribing continuous antimicrobial therapy, the physician must consider the potential toxicity of the drugs with prolonged use and the risk of selecting resistant microorganisms in the event of a recurrence.

The drugs of choice for this strategy are beta-lactam antimicrobials, fluoroquinolones, tetracyclines, or co-trimoxazole**, and clindamycin**, depending on the pathogen's susceptibility and the patient's drug tolerance [170–172]. It is not recommended to use #linezolid**, rifampicin**, and fusidic acid for suppressive antimicrobial monotherapy. This is due, on the one hand, to the high risk of adverse reactions (use of #linezolid** for more than 4 weeks significantly increases the risk of reversible myelosuppression in 40% of cases and irreversible peripheral neuropathy in 5% of cases). On the other hand, monotherapy with rifampicin** or fusidic acid leads to the rapid development of resistance in pathogens to these drugs.

• For patients with IAI, as part of complex IAI treatment, it is recommended to use local antimicrobial therapy in order to achieve effective concentrations of antibacterial drugs in the area of the purulent focus within the bone tissue [175, 178].

LE 3 GSR C

• When impregnating bone cement intended for the fixation of components of a permanent endoprosthesis, it is not recommended to use more than 5 wt% of a systemic antimicrobial drug [48,54,176].

Level of Evidence (LE) 5, Grade of Recommendation (GR) C

Comments. It is known that the minimum concentrations of antibiotics required for biofilm eradication exceed the minimum inhibitory concentrations (MICs) for planktonic forms of bacteria by thousands of times [177], and therefore eradication of pathogens in the focus of osteomyelitis can only be achieved by a combination of systemic and local antibacterial therapy. It is believed that an antibiotic released directly into the focus of infection at a concentration exceeding the MIC for a specific microorganism directly destroys planktonic forms of bacteria and additionally damages microbial biofilms, thereby increasing the overall efficacy of antibacterial therapy. High local concentration allows the drugs to penetrate into necrotic tissues and areas with poor blood supply via diffusion. In PJI, the standard technique is impregnation of bone cement with antimicrobials to place an antimicrobial spacer; in osteomyelitis, including after PAI, calcium sulfate- or calcium phosphate-based bioceramics and hydroxyapatite are used in some cases. When choosing an antimicrobial for use in bone cement, it is necessary to consider the results of preoperative microbiological examination of synovial fluid (aspirate) or the suspected pathogen profile (Appendix A3.3). For instance, in PJI caused by MSSA, #cefuroxime** can be used for mixing with bone cement, whereas in the case of MRSA, #vancomycin** is used. Currently, several groups of bone-substitute materials are distinguished that can be used in the focus of PJI: non-absorbable materials (polymethyl methacrylate-based cements) and biodegradable materials (bone grafts, demineralized bone matrix, bioceramic-based materials, natural and synthetic polymers, combined delivery systems for antimicrobials)[48,176,178].

3.2 Surgical Treatment

• If persistent wound discharge continues for 72 hours in a patient after surgery involving orthopedic implant placement, it is recommended to perform a sequential course of conservative and, if necessary, surgical treatment [144, 179, 202].

LNC 4 LeC C

Comments. To date, there is no validated definition of "persistent wound discharge". In the absence of such data, the international expert consensus on PJI management defines persistent discharge as any ongoing fluid leakage from the surgical site lasting more than 72 hours postoperatively [48]. The management of wounds with persistent discharge after orthopedic implant placement consists of two main stages: non-surgical and surgical. Non-surgical measures include modification of venous thromboembolism (VTE) prophylaxis, local measures (such as negative pressure wound therapy), and immobilization. If discharge continues for more than 3-7 days after the initiation of non-surgical measures, surgical intervention must be considered. Depending on the clinical situation, this may include irrigation and debridement, synovectomy, exchange of mobile arthroplasty components, or, if required, single-stage revision arthroplasty. In some situations, superficial wound irrigation alone may be indicated. In most cases, timely surgical revision of the surgical site in the early postoperative period allows for implant retention and prevents chronicity of the infectious process [179, 202].

• In patients with severe acute symptoms of an infectious and inflammatory process in the setting of PJI when radical surgical intervention cannot be performed in full, to reduce the risk of infection generalization, it is recommended to perform opening and drainage of the synovial bursa/phlegmon (abscess) in any surgical department, prescribe antibacterial therapy, and subsequently refer the patient to a specialized trauma and orthopedic hospital [180].

Level of Evidence (LE) 5, Grade of Recommendation (GR) C

• In patients with PJI requiring emergency medical care due to the risk of infection generalization, when radical surgical intervention cannot be performed in full, conservative treatment alone is not recommended [181].

Comments. Currently, there are no publications on the provision of care to patients with PJI in non-specialized departments. However, the involvement of microbial biofilms in the pathogenesis of PJI definitively dictates the impossibility of resolving the infectious process solely through antibacterial therapy in the absence of surgical debridement of the purulent focus in a patient with an implant [7, 48, 54]. The inability to perform radical surgical intervention in a patient with PJI may be due to technical limitations (lack of material and technical equipment and/or qualified medical personnel at the medical facility where the patient resides), as well as the patient's condition, which may preclude major surgery (septic state and/or severe decompensation of concomitant pathology, etc.). The most rational tactic in such cases is opening and drainage of the purulent focus to reduce the microbial load on the body, with a short course of antibacterial therapy until the acute process subsides, followed by referral of the patient to a specialized hospital.

3.2.1 Surgical Treatment of PJI

• In patients with acute postoperative (<4 weeks post-surgery) or acute hematogenous (<3 weeks from manifestation) PJI, it is recommended to perform debridement, antibiotics, and implant retention (DAIR) and prolonged antibacterial therapy if they meet the following criteria [182–184]:

• the endoprosthesis components are stable;

• there is no uncontained soft tissue infection/inflammation (cellulitis, fasciitis, etc.);

• there is no pathogen resistant to oral antimicrobial drugs;

• a prolonged (up to 3 months) course of antibiotic therapy is feasible.

LE 2 GSR A

• Patients with periprosthetic joint infection who do not meet the criteria above, but for whom alternative surgical strategies are unacceptable or carry a high life-threatening risk, may also be recommended surgical debridement with retention of the endoprosthesis, though relapse is more likely [185–187].

Level of Evidence 2, Grade of Recommendation B

Comments. A recent study showed similar efficacy of DAIR (debridement, antibiotics, and implant retention) in the treatment of early postoperative infection (85%) and acute hematogenous infection (79%) [185]. Strict adherence to the recommended criteria is extremely important for the efficacy of DAIR. To date, the maturation period of the microbial biofilm in the human body has not been clearly established, and a period of 3-4 weeks from the time of surgery or symptom manifestation is defined as the most optimal in most specialized publications and guidelines. However, some researchers believe that DAIR can be considered the procedure of choice only in patients with symptoms of infection lasting less than 5 days [186]. A number of systematic reviews have demonstrated that DAIR for acute postoperative and hematogenous infections should be performed promptly and aggressively (with exchange of modular components), since each additional day of delay reduces the chances of a successful outcome [187–190]. The most significant factors for a successful outcome after DAIR include a time period from symptom onset to revision arthroplasty of up to 7 days, exchange of modular components of the endoprosthesis (141740 Liner for acetabular component of hip joint endoprosthesis, non-constrained, polyethylene***, 218470 Liner for acetabular component of hip joint endoprosthesis, ceramic***, 241970 Unicondylar liner for knee joint endoprosthesis***, 290010 Liner for acetabular component of hip joint endoprosthesis, constrained, polyethylene***)[48,187], as well as the absence of severe comorbid pathology in the patient [185] and preoperative anemia [191]. The nature of the pathogen also has a significant effect, and therefore performing DAIR in patients with periprosthetic joint infection caused by multidrug-resistant pathogen strains (MRSA and MRSE, especially rifampicin**-resistant strains, fluoroquinolone-resistant gram-negative rods, vancomycin-resistant enterococcus (VRE), etc.) is characterized by extremely low efficacy [189,192–194] .

It must be taken into account that acute hematogenous infection may be a manifestation of the patient's poor overall health status, as nearly half of them suffer from severe comorbidities, which can not only predispose to the development of infection but also lead to a high risk of sepsis and a mortality rate of about 20% within 2 years of surgery [195,196].

• For patients with chronic PJI presenting with good soft-tissue condition at the infection site, a preoperatively identified pathogen susceptible to oral antibiotics with high bioavailability, one-stage revision arthroplasty is recommended provided that hospital logistical and medical staff qualification capabilities allow [197,198].

LE 2 GSR A

• For patients with culture-negative chronic PJI presenting with good soft-tissue condition at the infection site, one-stage revision arthroplasty is recommended provided that hospital logistical and medical staff qualification capabilities allow [262].

Leveled Research Evidence (LE) 2 Grade of Recommendation (GR) B

Comments:One-stage exchange arthroplasty (107830 Knee joint endoprosthesis lengthening stem***, 109390 Knee joint endoprosthesis wedge***, 114100 Hip joint endoprosthesis acetabular component plug***, 114130 Hip joint endoprosthesis acetabular component shell***, 128870 Hip joint endoprosthesis femoral component uncoated, modular***, 128880 Knee joint endoprosthesis tibial component uncoated, polyethylene***, 128910 Knee joint endoprosthesis femoral component uncoated***, 128940 Ankle joint endoprosthesis tibial component uncoated***, 128950 Elbow joint endoprosthesis humeral component uncoated***, 128960 Knee joint endoprosthesis tibial component uncoated, metallic***, 128990 Ankle joint endoprosthesis talar component uncoated***, 129010 Hip joint endoprosthesis femoral component uncoated, single-component***, 129080 Knee joint endoprosthesis tibial component uncoated with insert***, 129120 Knee joint endoprosthesis tibial unicompartmental component uncoated, metallic***, 141740 Hip joint endoprosthesis acetabular component insert, non-constrained, polyethylene***, 151960 Knee joint endoprosthesis femoral trabecular component***, 151980 Knee joint endoprosthesis tibial trabecular component with insert***, 152030 Elbow joint humeral component endoprosthesis coated***, 152060 Hip joint endoprosthesis femoral component, coated, modular***, 152110 Knee joint endoprosthesis femoral component, coated***, 152120 Knee joint endoprosthesis tibial component coated***, 152130 Knee joint endoprosthesis tibial component coated with insert***, 152350 Elbow joint endoprosthesis total hinged***, 152390 Knee joint endoprosthesis femoral unicompartmental component coated***, 161180 Knee joint endoprosthesis total posterior-stabilized***, 165410 Hip joint endoprosthesis acetabular component polyethylene***, 165420 Elbow joint endoprosthesis ulnar polyethylene component***, 178660 Knee joint endoprosthesis femoral superficial partial component***, 178800 Knee joint endoprosthesis total cruciate-retaining***, 206730 Shoulder joint endoprosthesis total***, 207700 Elbow joint endoprosthesis ulnar component with metallic coating***, 208890 Shoulder joint endoprosthesis glenoid component***, 210090 Knee joint endoprosthesis total with mobile bearing***, 214680 Hip joint endoprosthesis total with metal-on-polyethylene bearing surface***, 214690 Hip joint endoprosthesis total with metal-on-metal bearing surface***, 218470 Hip joint endoprosthesis acetabular component insert ceramic***, 218500 Hip joint endoprosthesis total with ceramic-on-ceramic bearing surface***, 218510 Hip joint endoprosthesis total with ceramic-on-polyethylene bearing surface***, 218520 Hip joint endoprosthesis total with ceramic-on-metal bearing surface***, 221510 Knee joint endoprosthesis two-component***, 54990 Shoulder joint endoprosthesis head with anchor fixation type***, 269390 Shoulder joint endoprosthesis total reverse***, 269420 Reverse shoulder joint endoprosthesis polyethylene cup***, 269440 Reverse shoulder joint endoprosthesis head***, 272800 Hip joint endoprosthesis femoral component with press-fit fixation, modular***, 272810 Hip joint endoprosthesis femoral component with press-fit fixation, single-component***, 273600 Hip joint endoprosthesis femoral revision component coated***, 273730 Hip joint endoprosthesis femoral revision component uncoated***, 284590 Knee joint endoprosthesis total hinged***, 290010 Hip joint acetabular component endoprosthesis insert constrained polyethylene***, 320760 Reverse shoulder joint endoprosthesis body***, 321740 Hip joint endoprosthesis acetabular component made of combined material***, 321750 Hip joint endoprosthesis acetabular component metallic***, 321760 Hip joint acetabular component endoprosthesis ceramic***, 322360 Reverse shoulder joint endoprosthesis metal cup***)includes radical debridement of soft tissues, meticulous removal of bone cement and all other foreign bodies, creation of a local antibiotic depot, implantation of a new prosthesis, as well as prolonged postoperative antibiotic therapy (up to 3 months)[32,48,54]. As a rule, one-stage revision arthroplasty is performed with cemented fixation of components and the use of antibiotic-loaded bone cement***. It is also possible to use antibiotic-impregnated bone matrix (bone matrix implant, composite***, synthetic antibacterial***, animal*** or human origin***) or intra-articular catheters for local antibiotic therapy, which ensure successful outcomes of one-stage revision arthroplasty in up to 92% of cases[200,201].

Contraindications to one-stage revision arthroplasty include: unconfined infectious soft tissue inflammation (cellulitis, fasciitis, purulent tracts into soft tissues, pelvic cavity, and neurovascular bundles); systemic inflammatory response syndrome (SIRS); insufficient soft tissue coverage to close the surgical wound; bone defects and poor bone quality (sclerosis/osteoporosis) precluding implantation of standard prosthetic designs; the presence of other unmanaged foci of infection (trophic ulcers, genitourinary infection, oral cavity infection, etc.); a patient history of revision surgeries, including for PJI, and/or antibiotic courses for PJI; inability to undergo prolonged (up to 3 months) oral antibiotic therapy [202–208]. Furthermore, patients with recurrent PJI following one-stage revision arthroplasty are not candidates for repeat one-stage revision arthroplasty [209]. Two meta-analyses demonstrate that one-stage revision arthroplasty achieves a risk of reinfection statistically comparable to that of a two-stage procedure, regardless of infection localization in the hip or knee joints [197,198]. With meticulous patient selection, the success rate of one-stage revision arthroplasty reached 100% [210]. A recent meta-analysis showed no significant differences in treatment efficacy when comparing 1- and 2-stage techniques in patients with culture-negative PJI [199, 262].

• For patients with chronic, including recurrent, PJI caused by resistant pathogens, as well as with acute PJI when contraindications to other types of surgical intervention are present, two-stage revision arthroplasty is recommended provided that the patient's general health status allows enduring multiple surgical procedures with a predictably satisfactory functional outcome [211–213].

LE 2 GSR A

Comments. Two-stage exchange remains the most common surgical management method for chronic PJI [159,203,211]. The main indications for two-stage revision arthroplasty are: chronic postoperative (symptom duration >4 weeks) or hematogenous (symptom duration >3 weeks), including recurrent PJI; acute periprosthetic soft tissue inflammation; presence of other unmanaged foci of infection; high antimicrobial resistance profile of pathogens, as well as the impossibility of performing other types of surgery in acute PJI [32,54]. Contraindications to two-stage revision arthroplasty include: decompensation of comorbidities; infectious soft tissue inflammation not confined by natural barriers (acute necrotizing fasciitis, purulent tracts into fascial spaces, toward neurovascular bundles, etc.); soft tissue deficiency insufficient for surgical wound closure; extensive bone defects precluding subsequent implantation of a permanent endoprosthesis; multiple (>3) PJI recurrences after revision arthroplasty for infectious complications; pan-drug-resistant pathogens; patient refusal of staged surgery [32,54].

The goal of the first stage is infection eradication and, where feasible, preservation (restoration) of lower limb function. There is no single universal standard for performing the debridement stage of two-stage revision arthroplasty, as the course of the operation largely depends on the anatomical extent of the infectious process, the patient's general condition, the status of periprosthetic soft tissues, etc. [48,203]. Mandatory requirements of the first stage include: total resection of affected bone, necrotomy; submission of bone tissue for microbiological (culture) examination for aerobic and facultatively anaerobic microorganisms (3–5 specimens) and histopathological examination of surgical material, as well as sending explanted prosthetic components for microbiological (culture) examination; wound irrigation with a significant volume of antiseptics (up to 10–12 L) using dedicated surgical debridement lavage systems; filling tissue defects with temporary devices (spacers) fashioned from drug-containing bone cement***, followed by layered tissue closure and postoperative hematoma prevention [31].

Depending on the reconstruction of the lower limb biomechanical chain, two options of bone cement spacers are available: articulating and non-articulating (block-type). The choice of spacer type, weighing the pros and cons for each specific case, is made by the operating orthopedic surgeon [214–220]. When fabricating spacers, it is advisable to add an additional antibiotic to the drug-containing bone cement*** based on the preoperative antibiogram—for example, cefuroxime** in MSSA infection. A list of antibacterial agents and their doses that may be incorporated into bone cement is provided in Appendix A3.3. Temporary hip joint prostheses***, as well as cemented endoprosthetic components of the affected joint (107830 Extension stem for knee joint prosthesis***, Uncoated modular femoral hip joint prosthesis component***, 128910 Uncoated femoral knee joint prosthesis component***, 128940 Uncoated tibial ankle joint prosthesis component***, 128950 Uncoated humeral elbow joint prosthesis component***, 128960 Uncoated metallic tibial knee joint prosthesis component***, 128990 Uncoated talar ankle joint prosthesis component***, 129010 Uncoated monoblock femoral hip joint prosthesis component***, 273730 Uncoated revision femoral hip joint prosthesis component***) can also be used as spacers. General principles of local antibacterial therapy are detailed in Section 3.1 "Conservative Treatment" and Appendix A3.3. An all-cement antimicrobial spacer remains active for a limited duration and must be removed [203,221–223].

In exceptional cases during revision surgery involving the removal of well-fixed endoprosthesis components—especially custom-made devices and oncological megaprostheses—performing an osteotomy can lead to massive bone defects, which subsequently causes technical difficulties in achieving stable fixation of the endoprosthesis components during reimplantation and may ultimately result in permanent impairment of limb function [224–226]. When treating this category of patients in specialized centers with a multidisciplinary team of physicians managing periprosthetic joint infection (PJI), it may be possible to consider incomplete (subtotal) removal of the endoprosthesis [224,225,227–229]. If instability of the endoprosthesis components is detected by any means (radiographically, via CT, or visually intraoperatively), in the presence of a sinus tract, conditions leading to immunosuppression (diabetes mellitus, rheumatoid arthritis, etc.), as well as when the causative agent of the infection is not identified preoperatively or is resistant to antibiotics with antibiofilm activity [224], performing incomplete endoprosthesis removal is strictly contraindicated. Strict adherence to selection criteria results in the extremely rare use of this technique, yet it makes it possible to achieve infection eradication in the vast majority of cases: in series of 18, 15, and 5 observations, respectively, in 84% [224], 93.3% [229], and 100% of cases [225].

Currently, there are no definitive guidelines regarding the optimal time interval between the stages of revision joint replacement[48,203]. At the same time, the orthopedic community has accumulated decades of successful experience with reimplantation of an arthroplasty(107830 Knee joint endoprosthesis lengthening stem***, 109390 Knee joint endoprosthesis wedge***, 114100 Hip joint endoprosthesis acetabular component plug***, 114130 Hip joint endoprosthesis acetabular component shell***, 128870 Hip joint endoprosthesis femoral component uncoated, modular***, 128880 Knee joint endoprosthesis tibial component uncoated, polyethylene***, 128910 Knee joint endoprosthesis femoral component uncoated***, 128940 Ankle joint endoprosthesis tibial component uncoated***, 128950 Elbow joint endoprosthesis humeral component uncoated***, 128960 Knee joint endoprosthesis tibial component uncoated, metallic***, 128990 Ankle joint endoprosthesis talar component uncoated***, 129010 Hip joint endoprosthesis femoral component uncoated, single-component***, 129080 Knee joint endoprosthesis tibial component uncoated with insert***, 129120 Knee joint endoprosthesis tibial unicompartmental component uncoated, metallic***, 141740 Hip joint endoprosthesis acetabular component insert, non-constrained, polyethylene***, 151960 Knee joint endoprosthesis femoral trabecular component***, 151980 Knee joint endoprosthesis tibial trabecular component with insert***, 152030 Elbow joint humeral component endoprosthesis coated***, 152060 Hip joint endoprosthesis femoral component, coated, modular***, 152110 Knee joint endoprosthesis femoral component, coated***, 152120 Knee joint endoprosthesis tibial component coated***, 152130 Knee joint endoprosthesis tibial component coated with insert***, 152350 Elbow joint endoprosthesis total hinged***, 152390 Knee joint endoprosthesis femoral unicompartmental component coated***, 161180 Knee joint endoprosthesis total posterior-stabilized***, 165410 Hip joint endoprosthesis acetabular component polyethylene***, 165420 Elbow joint endoprosthesis ulnar polyethylene component***, 178660 Knee joint endoprosthesis femoral superficial partial component***, 178800 Knee joint endoprosthesis total cruciate-retaining***, 206730 Shoulder joint endoprosthesis total***, 207700 Elbow joint endoprosthesis ulnar component with metallic coating***, 208890 Shoulder joint endoprosthesis glenoid component***, 210090 Knee joint endoprosthesis total with mobile bearing***, 214680 Hip joint endoprosthesis total with metal-on-polyethylene bearing surface***, 214690 Hip joint endoprosthesis total with metal-on-metal bearing surface***, 218470 Hip joint endoprosthesis acetabular component insert ceramic***, 218500 Hip joint endoprosthesis total with ceramic-on-ceramic bearing surface***, 218510 Hip joint endoprosthesis total with ceramic-on-polyethylene bearing surface***, 218520 Hip joint endoprosthesis total with ceramic-on-metal bearing surface***, 221510 Knee joint endoprosthesis two-component***, 54990 Shoulder joint endoprosthesis head with anchor fixation type***, 269390 Shoulder joint endoprosthesis total reverse***, 269420 Reverse shoulder joint endoprosthesis polyethylene cup***, 269440 Reverse shoulder joint endoprosthesis head***, 272800 Hip joint endoprosthesis femoral component with press-fit fixation, modular***, 272810 Hip joint endoprosthesis femoral component with press-fit fixation, single-component***, 273600 Hip joint endoprosthesis femoral revision component coated***, 273730 Hip joint endoprosthesis femoral revision component uncoated***, 284590 Knee joint endoprosthesis total hinged***, 290010 Hip joint acetabular component endoprosthesis insert constrained polyethylene***, 320760 Reverse shoulder joint endoprosthesis body***, 321740 Hip joint endoprosthesis acetabular component made of combined material***, 321750 Hip joint endoprosthesis acetabular component metallic***, 321760 Hip joint acetabular component endoprosthesis ceramic***, 322360 Reverse shoulder joint endoprosthesis metal cup***)of the affected joint 2–12 months after implant removal[203,230–232]. However, a prolonged wait for the second stage increases the period of patient disability, functional impairment, and treatment cost. In addition to mechanical complications arising from untimely replacement of the temporary device with a permanent joint prosthesis, rare cases of renal impairment have been described in scientific literature following the placement of spacers impregnated with high doses of nephrotoxic ABPs, specifically vancomycin**[233–235]. Currently, in the absence of periparticular tissue defects and if the identified pathogen is susceptible to oral antibiotics, shortening the interval between treatment stages to 2–3 weeks is considered feasible due to the effective use of targeted antibiotic therapy[236–238].

During the second stage of revision joint arthroplasty, cemented or cementless fixation constructs may be used [54,203,239,240]. During the surgery, repeat surgical debridement is performed, and 3–5 tissue samples of bone tissue are taken for microbiological (culture) testing for aerobic and facultatively anaerobic microorganisms, as well as samples for pathomorphological examination of the surgical material. The removed spacer is also sent for microbiological testing [32,54]. On average, the use of this technique achieves infection control in 75–80% of cases [241,242], but may drop to 30–50% in patients with severe comorbidities and in infections caused by resistant pathogens [167,243,244].

• In patients with chronic recurrent hip PJI when other treatment methods are ineffective, particularly in cases of infection caused by difficult-to-eradicate pathogens, it is recommended to perform resection arthroplasty, including muscle flap transfer using a pedicled muscle flap, which, if anatomical options are preserved, should be considered as a debridement stage prior to potential joint replacement implantation once sustained remission of the infectious process is achieved [22,245].

Level of Evidence (LE) 3, Grade of Recommendation (GR) C

Comments.: to date, there is no consensus on the management strategy for patients with recurrent PJI, including those caused by difficult pathogens; in such cases, surgeons temporarily or permanently refuse to perform revision arthroplasty. Resection arthroplasty should be considered the method of choice for treating this category of patients. Indications for resection arthroplasty include: soft tissue deficiency preventing closure of the surgical wound following revision arthroplasty (greater than 100 cm²); repeated (≥ 3) PJI recurrences; chronic secondary osteomyelitis of the bones forming the joint; contraindications to antibiotic therapy (multiorgan failure, polyvalent allergy, etc.); PJI etiology involving difficult-to-treat pathogens (DTP) [32,54]. DTPs currently include rifampicin-resistant staphylococci and/or ampicillin-resistant enterococci and/or ciprofloxacin-resistant gram-negative bacteria and/or fluconazole-resistant Candida species** [21].

The goal of resection arthroplasty is to reconstruct the soft tissue defect in the joint area, compensate for severe comorbidities, treat chronic osteomyelitis, and eradicate pathogenic microflora. The essence of the surgical intervention consists of plasty of the bone or soft tissue defect using a pedicled muscle flap or covering with local tissues and drainage of the postoperative wound (for example, the Girdlestone procedure). Spacers are not used in this approach. The use of hip resection arthroplasty combined with pedicled muscle flap transfer (Patent RU 2735651 C1) makes it possible to achieve sustained PJI remission in more than 90% of observations, despite the prolonged and severe course of infection caused by difficult-to-treat pathogens [22,245]. This is largely due to the fact that pedicled muscle flap transfer guarantees a high blood supply to the transplanted muscle tissue fragment, facilitating good delivery of leukocytes, oxygen, and antibiotics to the infection focus [246]. All of this allows this type of surgical intervention to be considered the procedure of choice in the event of a recurrence of intractable PJI, with the potential subsequent performance of revision joint replacement against the background of sustained remission of infectious inflammation. However, potential and fairly frequent complications developing in the early postoperative period must be taken into account: formation of culture-negative hematomas, recurrence of infection, and partial or complete necrosis of the muscle flap [22]. Furthermore, if resection arthroplasty is performed as the definitive treatment stage, the majority of patients report long-term complaints of joint pain during movement, joint instability, and the need for permanent external fixation and additional support when walking [247].

• In patients with chronic multiply recurrent knee PJI, it is recommended to perform knee arthrodesis if indications for further staged joint replacement implantation are absent and there is an opportunity to preserve some limb function by immobilizing the joint in a functionally convenient position [248–250].

LRE 1, GR A

Comments. Among patients who have undergone one- or two-stage revision TKA, 22.7-39.7% require repeat revision surgery for recurrent PJI [242,251]. In immunocompromised patients or in infection caused by multidrug-resistant pathogens, this rate reaches 50-75% [243,244]. Under these circumstances, performing knee arthrodesis allows a painless weight-bearing limb to be achieved in most patients [247, 249], provides infection control in 78-89% of patients [241,252,253], and yields better social adaptation and lower mortality compared with outcomes of amputation and limb reprosthetics [254–256]. Indications for arthrodesis include: defect of the joint capsule, ligaments, or extensor mechanism; deficiency of the periarticular soft tissues precluding closure of the surgical wound after revision TKA; severe comorbidities or immunosuppression precluding further surgical treatment; chronic secondary osteomyelitis of the bones forming the joint; pathogens difficult to eradicate; and the patient's categorical refusal of further arthroplasty. Contraindications to arthrodesis are severe pathology of adjacent joints and significant defects of the articulating bone ends. It should be kept in mind that even after good consolidation of the bone fragments and a functional limb position, some patients remain dissatisfied with the loss of joint motion [257].

• In patients with a life-threatening course of chronic recurrent PJI when all other treatment modalities have been exhausted, it is recommended to perform limb amputation/exarticulation aimed at saving the patient's life or facilitating patient care [258, 259].

LNC 4 LeC C

Comments. Following multiple unsuccessful revision surgeries in severe infectious inflammation and the development of SIRS (sepsis), surgery is performed for life-saving indications [247,259]. In other cases, indications for amputation (exarticulation) include: a recurrent course of chronic PJI that has led to complete loss of limb function and patient disability; necrotizing fasciitis resistant to aggressive surgical debridement; progressive multiorgan failure as a result of an exacerbation of chronic recurrent PJI; vascular complications threatening the patient's life; soft tissue and/or bone defects not amenable to orthopedic correction and restoration of limb function; severe intractable pain causing intolerable suffering to the patient; and the patient's insistent demand to cease further surgical treatment attempts.

The level of amputation (exarticulation) is determined by the need to resect the area of infectious inflammation and ensure subsequent prosthetics [247], which is essential for the further restoration of limb function [256]. Currently, in certain cases, amputation for PJI of the knee joint followed by prosthetics with modern high-tech prostheses may surpass arthrodesis in terms of restoring limb function and the patient's quality of life [253]. Except for emergency cases, amputations are recommended to be performed in multidisciplinary surgical hospitals close to the patient's residence, following a conclusion regarding the necessity of this surgery by an interdisciplinary team of specialists from a specialized center with experience in treating PJI.

• In patients with the development of SIRS or sepsis against the background of PJI, parenteral antibacterial therapy and surgical intervention aimed at reducing the microbial load are recommended, based on the patient's condition, local status, and the feasibility of subsequent staged treatment [48].

LNC 4 LeC C

Comments. The development of SIRS and/or sepsis against the background of PJI significantly worsens the treatment prognosis and increases the mortality risk [260–263]. Considering the need to reduce microbial load, assess the patient's ability to withstand a specific volume of surgical intervention, and evaluate the prospects for future joint prosthesis implantation, it is possible to perform opening and drainage or secondary surgical debridement of the purulent focus while preserving the implants or removing its components (if indicated and safe for the patient), or to perform amputation (exarticulation) for life-saving indications [48]. A mandatory component must be empirical or etiotropic antibiotic therapy, which is initiated immediately after the detection of SIRS or sepsis [264].

• In patients with chronic recurrent PJI in cases where other surgical treatment methods are contraindicated according to the conclusion of an interdisciplinary team of physicians, the creation of a permanent fistula (PF) and the subsequent prescription of long-term or lifelong suppressive oral antibiotic therapy are recommended (see Section 3.1) [173,265,266].

Level of Evidence (LE) 3, Grade of Recommendation (GR) C

Comments. The main indications for suppressive oral antibiotic therapy and its specific features are described in Section 3.1 Conservative treatment. To form a permanent fistulous tract, a short incision is made along the old postoperative scar to access the joint cavity and the EP; a drainage tube is inserted into the joint cavity (Redon drain, or a semi-tube with a diameter of 10 mm, or other); the drainage tube is brought out of the joint cavity distal to the lower corner of the wound and sutured to the skin with a non-absorbable surgical suture [173]. It is preferable to keep the drainage tube in the wound for life, or it can be removed no earlier than 6 weeks after epithelialization of the fistulous tract walls, but on average, after the formation of a permanent fistulous tract, up to 3 revision surgeries are performed to restore its function [173].

• Patients with chronic PJI are recommended to undergo surgical treatment requiring the removal or replacement of endoprosthesis components in hospitals and departments whose staffing, equipment, and material resources allow for revision arthroplasty, and which are staffed by a multidisciplinary team of specialists [48,157,267,268].

LNC 4 LeC C

Comments. Despite the lack of scientific publications on the provision of care to patients with PJI in non-specialized departments, it is obvious that the removal of well-fixed endoprosthesis components and the cement mantle requires specialized instruments that are unavailable in general surgery hospitals and departments, as well as a specialist—an orthopedic trauma surgeon skilled in revision arthroplasty techniques. As stated above, general surgery departments may perform opening and drainage of a purulent focus in the event of an acute condition with a short course of antibiotic therapy until the acute process subsides, followed by referral of the PJI patient to a specialized institution, as well as amputation or disarticulation for vital or elective indications. The presence of a team of specialists in various fields in addition to orthopedic trauma surgeons specializing in the treatment of PJI (intensivists, medical microbiologists, clinical pharmacologists, plastic surgeons, clinical laboratory diagnosticians, etc.) significantly improves treatment outcomes for specialized patients intensivists, medical microbiologists, clinical pharmacologists, plastic surgeons, clinical laboratory diagnosticians, etc.), significantly improves treatment outcomes for specialized patients [156,157,267,268].

3.2.2 Surgical Treatment of FRI

The choice of surgical intervention for fracture-related infection (FRI) depends on several factors: the type of infection (acute or chronic), fracture union, quality of fragment reduction, implant stability, soft tissue condition, pathogen profile, and the patient's ability to tolerate surgery [274]. Today, it is advisable to consider the type of osteomyelitis at the time of the intervention using the Cierny and Mader classification (1984) when choosing the treatment method for FRI. This classification system suggests choosing an osteomyelitis treatment strategy depending on the type of bone lesion, the nature of the spread of the purulent process (medullary, superficial, localized, or diffuse), as well as the patient's somatic status and immune system condition [44,286].

• Patients with acute FRI (manifestation within less than 2 weeks) in the absence of fracture union, with satisfactory fragment reduction, provided the implant is stable, soft tissue condition is satisfactory, and the pathogen is identified and sensitive to oral drugs for prolonged antibiotic therapy, are recommended radical surgical debridement of the wound or infected tissue with implant retention, replacement of generated bone defects with an antimicrobial spacer, and prolonged antibiotic therapy [269–271].

Level of Evidence (LE) 5, Grade of Recommendation (GR) C

Comments. When performing revision with implant retention, it is extremely critical to thoroughly remove necrotic tissues and poorly vascularized bone fragments, using a pulsating lavage wound treatment system (with a fluid volume of at least 6–9 liters) [28,270].

• Patients with acute or chronic FRI in the absence of fracture union and clinical-radiological signs of osteosynthesis instability, provided there is a sufficient volume of soft tissue for primary wound closure and the pathogen is identified and sensitive to oral drugs for prolonged antibiotic therapy, are recommended single-stage revision osteosynthesis (rOS) with bone and soft tissue defect reconstruction, removal of the internal fixation device and installation of an external fixation device (fixation conversion) if necessary, as well as prolonged antibiotic therapy [269,271–273].

LE 3 GSR C

Comments. In this clinical situation, simultaneous replacement (partial in cases of external fixation devices) of K-wires and pins in the external fixation device, radical surgical debridement of the wound or infected tissue, necroectomy, and copious wound irrigation with antiseptic solutions (fluid volume of at least 6–9 liters) are performed [270]. For re-osteosynthesis, a non-absorbable orthopedic bone nail*** is often used, which is inserted intramedullary, pre-coated with antibiotic-loaded bone cement***, or an external fixation device is applied [16,272,273]. An intramedullary nail with a cement mantle provides a local sanitizing effect and also stabilizes the fracture zone. This type of fixation can be definitive until complete fracture healing. It must be remembered that a significant disadvantage of internal osteosynthesis methods (nails, plates) in the treatment of fracture-associated infection (FAI) is that they remain within the sanitized infection focus. Radical surgical debridement of the wound or infected tissue does not ensure complete sterility of the operated tissues. Small bacterial colonies can re-contaminate the implant surface, subsequently leading to biofilm formation.

An alternative option to the cement nail is external fixation devices (monolateral and circular). Their main advantage lies in the external fixation of bone fragments (outside the inflammation zone); the possibility of early full weight-bearing on the operated limb; and the correction of the limb axis in the postoperative period. However, prolonged wear of the external fixation device can be complicated by soft tissue inflammation around the wires and/or pins, as well as contractures of adjacent joints [273].

Having considered the indications and specific features of single-stage revision, it should be noted that orthopedic trauma surgeons are often forced to resort to significant resections of non-viable bone fragments to achieve adequate debridement [276]. Such complex clinical situations are practically impossible to resolve without limb shortening when using the single-stage treatment method.

• For patients with acute or chronic FAI with a widespread focus of the pathological process, unhealed fracture with unsatisfactory fragment alignment, significant bone destruction requiring resection and reconstruction of the post-resection defect, insufficient soft tissue volume to cover the postoperative wound, and a multidrug-resistant pathogen, it is recommended to perform a two-stage re-osteosynthesis with bone and soft tissue defect reconstruction, with conversion of the fixation method and antibiotic therapy if necessary [16,45,271,274,277,278].

Leveled Research Evidence (LE) 2 Grade of Recommendation (GR) B

Comments. Two-stage revision osteosynthesis (reOS) is the most widespread technique for treating PJI. The primary objective of the first stage is to arrest the infection process by removing the infected implant, resecting non-viable bone fragments, irrigating the tissues with antiseptic solutions and stabilizing the operated limb segment (using an antibiotic-loaded cement spacer and/or external fixation device), as well as plastic closure of soft tissue defects if present. The second stage of surgical treatment is performed in a delayed manner, after 2-10 weeks. Its objective is to reconstruct the post-resection bone defect using auto- or allograft bone (Masquelet technique and its modifications) or other bone matrix implants (composite***, synthetic antibacterial***, of animal*** or human origin***), or an osteotomized bone fragment using the Ilizarov technique [16,45,271,274,277–280].

There are also hybrid options of osteosynthesis, when components of external orthopedic fixation systems are used during the period of distraction of the osteotomized fragment, after which external fixation is replaced by internal fixation – placement of an intramedullary nail (111890 Intramedullary tibial nail, non-sterile***, 111880 Intramedullary tibial nail, sterile***, 328090 Uncoated femoral/tibial endoprosthesis lengthening nail***, 258660 Intramedullary femoral nail, non-sterile***, 258670 Intramedullary femoral nail, sterile***, 318410 Intramedullary arthrodesis nail, non-sterile***, 267030 Intramedullary arthrodesis nail, sterile***, 270050 Intramedullary humeral nail, non-sterile***, 270030 Intramedullary humeral nail, sterile***, 245700 Non-absorbable orthopedic bone nail***) [281,282].

• For patients with FAI, unhealed fracture, and contraindications to revision osteosynthesis with an identified pathogen sensitive to oral drugs, it is recommended to perform surgical debridement of the purulent focus followed by the creation of a permanent fistula and administration of suppressive antibiotic therapy [271,275].

Level of Evidence (LE) 3, Grade of Recommendation (GR) C

Comments. If there are contraindications to revision osteosynthesis, it is advisable to perform a radical (whenever possible) surgical debridement of the infection focus while preserving the stable implant; tissue irrigation using ultrasonic cavitation and a pulsatile jet with a total fluid volume of at least 9 liters; targeted oral antibiotic therapy for the entire period until clinical and radiological signs of bone fragment consolidation appear. This treatment option does not involve the use of additional implants (PMMA, bone grafts, and osteoconductive/osteoinductive materials) and, in essence, is aimed at preventing (or warding off) the patient's septic condition and reducing bacterial contamination of the fracture zone until the healing of the injured bone. After stabilization of comorbidities and achievement of bone union, removal of the internal fixation device is possible [26,28,45,284,285].

• For patients with FAI and consolidated fracture, it is recommended to remove the internal fixation device and, if necessary, treat osteomyelitis with surgery, the scope of which depends on the specific clinical situation, combined with pathogen-directed antibiotic therapy [283].

LNC 5 LeC C

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• For patients with implant-associated infection (IAI), after performing debridement surgery, to prevent complications associated with pulmonary congestion, it is recommended to train them in drainage breathing exercises [31,49].

LNC 5 LeC C

Rehabilitation and physical therapy techniques are not widely used in the routine surgical treatment of periprosthetic and fracture-associated infections. Additionally, patients may be prescribed medical chest massage also to prevent complications associated with pulmonary congestion [31,49]. Furthermore, the non-pharmacological VTE prophylaxis program includes elastic compression of the lower extremities in the form of stockings, knee-highs, elastic bandages, and pneumatic splints, which are put on the patient after major surgery on the bones and joints of the lower extremities. The duration of compression knitwear use is until limb muscle tone is restored, i.e., as long as the patient uses auxiliary mobility aids or immobilization.

Restoration of muscle tone and range of motion should begin after the reduction of pain syndrome, stabilization of the patient's general condition, and, as a rule, removal of the urinary catheter and drains from the postoperative wound. It is known that joint stiffness and, consequently, impaired limb function are the most common complications after surgery. This is particularly relevant when implementing the two-stage treatment technique. A compromise must be sought in each case of periprosthetic joint infection (PJI), between patient immobilization with structural limb defects and the need for range-of-motion exercises and restoration of self-care ability.

The rehabilitation program for PJI is tailored according to the surgery performed. In the case of implantation of an articulating or preformed spacer (the kinematic chain in the joint is preserved), it does not differ from standard post-arthroplasty rehabilitation. The use of static spacers does not allow for functional loading and is accompanied by a significant persistent limb length discrepancy. However, in all cases after spacer implantation (temporary constructs), functional loading must be restricted.

As a rule, in the early postoperative period, rehabilitation measures are limited to early mobilization of the patient. In patients with PJI, graduated load-bearing on the limb is determined depending on the specifics of the surgery, soft tissue and bone defects, the presence of allografts, as well as the type of implant (spacer, arthroplasty component). Following surgery for hip PJI, active rehabilitation is possible in the absence of soft tissue deficits, with acetabular and femoral defect classifications up to Paprosky 2, and the implantation of cemented fixation constructs. It is recommended to develop an individualized rehabilitation treatment plan for each patient in every case. Its formulation depends on the severity of soft tissue damage, bone defect, presence of infectious inflammation, osteomyelitis, and various specific circumstances related to the patient's personality.

Rehabilitation measures for patients after radical treatment of fracture-related infection (FRI) depend on the type of osteosynthesis performed and include a set of measures aimed at restoring limb weight-bearing capacity and the function of adjacent joints using therapeutic exercise for joint diseases and injuries, massage, physiotherapeutic procedures, sanatorium-resort treatment, and various orthopedic appliances: insoles, footwear, splints, orthoses, prostheses [287]. However, overheating or hypothermia of the affected area can lead to exacerbation and recurrence of the purulent process; therefore, all types of thermal procedures directly affecting the affected limb are contraindicated during the remission period. Following surgical treatment, patients with PJI can be referred to balneotherapy and climatotherapy health resorts—Sochi, Pyatigorsk, Khmelnik, Mironovka, Lipetsk, Pushchino (Moscow Region), and others—no earlier than 6 months after surgery. Work must be carried out using the provisions of Order of the Russian Ministry of Health No. 281n dated May 5, 2016, "On Approval of the Lists of Medical Indications and Contraindications for Sanatorium-Resort Treatment" (Registered with the Russian Ministry of Justice on May 27, 2016, No. 42304) regarding bone infections, since in most cases PJI is accompanied by the development of osteomyelitis (Table 6). According to this Order, medical contraindications for sanatorium-resort treatment include acute and subacute stage diseases, including acute infectious diseases until the end of the isolation period, and chronic diseases in the acute stage.

5. Prevention and Dispensary Observation

• In patients undergoing surgery involving metal implants (arthroplasty, fracture osteosynthesis, etc.), it is recommended to administer perioperative antibiotic prophylaxis for surgical site infections [288–290].

LRE 1, GR A

• In patients undergoing elective large joint arthroplasty, it is not recommended to use local systemic antibacterial agents for the prevention of surgical site infections [291].

LVE 3 GCR A

Comments. Joint arthroplasty is classified as a clean surgery in which the development of complications is associated with a high risk of harm to the patient's health and life. It is recommended that the choice of antimicrobial drugs for perioperative antibiotic prophylaxis (PAP) be based on their activity against the most likely causative agents of surgical site infections (SSI) in a specific procedure. The main drugs for PAP in orthopedic surgery are cefazolin** or cefuroxime**; in case of cephalosporin intolerance, #clindamycin** or vancomycin** [1,288] should be used. The latter is also the drug of choice when there is a risk of infection caused by MRSA. In cases of a high risk of infectious complications (immunocompromised patient, history of infections, course of antibiotic therapy within 2 months prior to surgery, etc.), it is advisable to consult a clinical pharmacologist if available in the hospital. All specifics of perioperative antibiotic prophylaxis in elective arthroplasty are detailed in the methodological recommendations "Prevention of Surgical Site Infections" [1].

In open fractures, prophylactic administration of antibacterial drugs (ABD) is effective in preventing early infection. The drug of choice is cefazolin**, which should be administered as soon as possible after the injury. However, in patients with type III open fractures according to Gustilo and Anderson [292] (diaphyseal fractures with displacement and segmental loss; major vascular injury; heavily contaminated wounds; high-energy kinetic trauma), it is advisable to expand the activity spectrum of the prescribed antibiotic therapy to include agents active against Gram-negative pathogens. In such cases, it is advisable to consider adding #gentamicin** to cefazolin** [293–295] or monotherapy with #ampicillin+[sulbactam]** (at a dose of 3.0 g every 8 hours for 3 days) [296], with the latter being especially relevant in case of a risk of clostridial infection. According to the majority of researchers, in type III open fractures according to Gustilo and Anderson, antibiotic therapy should not be continued for more than 72 hours after soft tissue wound closure [297].

Following the completion of treatment and endoprosthesis reimplantation, dynamic follow-up by an orthopedic trauma surgeon is advisable for 3 years: every 3 months for the first six months, then at 6 months, and thereafter once a year [32,54]. The dispensary follow-up examination includes radiography of the affected skeletal part, complete (general) blood count, blood C-reactive protein (CRP) level testing, and a consultation with an orthopedic trauma surgeon.

Despite the lifelong persistent risk of PJI in patients with joint endoprostheses, the use of antibiotic prophylaxis during dental procedures, colonoscopy, and other invasive procedures should be individualized and carried out taking into account the patient's risk factors and the complexity of the invasive procedure itself. Risk groups include patients with systemic diseases (rheumatoid arthritis, SLE, and others), immunosuppression (drug-induced, radiation-induced), type 1 diabetes mellitus, hemophilia, and infections of other organs [48,247,298].

The development of early postoperative superficial or deep suppuration following surgery in patients with PJI can hardly be called a complication of surgical treatment. The consequences of such an outcome may include difficulties in selecting etiotropic antibacterial therapy due to pathogen resistance or patient intolerance, the inability to perform thorough surgical debridement of the purulent focus due to technical difficulties and/or the patient's condition, the choice of inadequate treatment tactics, or the patient's immunocompromised state (due to comorbid pathology, multiple previous surgeries, advanced age, etc.). PJI recurrence may also be caused by severe osteoporosis, extensive infectious damage, and trophic soft tissue changes around the joint, with limited plastic tissue resources in the immediate vicinity of the focus. However, recurrence may also be a result of the patient's careless attitude toward their own health and non-compliance with the prescribed treatment (violation of the therapeutic regimen, interruption of the antibiotic therapy course, etc.).

6. Organization of Medical Care

Type of care

Despite the planning of diagnostic and therapeutic measures for patients with implant-associated infection, care is of an emergency nature. Delaying the initiation of treatment or violating the timeline of treatment stages leads to a decrease in treatment efficacy rates in these patients and worsens the prognosis for successful infection resolution in a given patient, and in some cases, with generalization of the infectious process, can lead to a fatal outcome.

Conditions for the provision of medical services

Diagnostic measures at the stage of diagnosis and between treatment stages can be carried out on an outpatient basis. The stages of surgical treatment require inpatient care, including anesthetic management, antibacterial, infusion, and other supportive therapy. The working group recommends providing care to patients with periprosthesis and fracture-related infections in specialized inpatient hospital departments by orthopedic trauma surgeons proficient in large joint arthroplasty and osteosynthesis techniques.

7. Additional Information

The current absence of clinical guidelines and algorithms for the treatment of implant-associated infection (IAI) with a high level of evidence and conviction is largely due to the lack of a robust evidence base for selecting a particular treatment method, which is determined by the difficulty of selecting representative patient groups with this pathology. A significant role in the treatment outcome of this complication is played by the validity of the chosen surgical technique, the radicality of the performed surgery, the ability to prescribe rational antibiotic therapy with drugs active against the pathogen, at appropriate dosages and for the necessary duration. The development and clinical course of IAI, as well as the efficacy of its treatment, depend on numerous factors, such as the nature of the pathogen and its level of antibiotic resistance, the time of manifestation and duration of the infectious process, the condition of bones and soft tissues and, consequently, the scope of the debridement procedure, the patient's condition, and the severity of comorbid pathology, including nutritional status. Despite the fact that a prolonged chronic infectious process—which periprosthetic joint infection (PJI) and fracture-related infection (FRI) essentially represent—involves accelerated breakdown (hypercatabolism) and increased consumption of amino acids, fats, and carbohydrates (hypermetabolism), due attention has not been paid to the issues of nutritional support for patients with PJI to date. It is known that the rational replenishment of patients' energy expenditures helps accelerate recovery, reduce the length of hospital stay, and leads to significant financial savings [299], for which purpose local protocols for patient nutritional support must be developed. It must be remembered that even properly administered treatment for IAI does not guarantee success in all cases, and despite the advances in modern orthopedics, the recurrence rate of IAI remains high—averaging 15–35%, and reaching 60–75% when highly resistant pathogens are involved, especially within microbial associations [165, 167, 203].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Svetlana A. Bozhkova (Saint Petersburg) – Doctor of Medical Sciences, Associate Professor, Head of the Research Department for Prevention and Treatment of Wound Infection and Department of Clinical Pharmacology, Professor at the Department of Traumatology and Orthopedics, Vreden National Medical Research Center of Traumatology and Orthopedics of the Russian Ministry of Health; Russian delegate to the EBJIS committee, member of the Scientific Committee of the World Association against Infection in Orthopedics and Trauma (WAIOT), member of ISAR; no conflict of interest.

2. Rashid M. Tikilov (Saint Petersburg) – Corresponding Member of the RAS, Doctor of Medical Sciences, Professor, Director of the Vreden National Medical Research Center of Traumatology and Orthopedics of the Russian Ministry of Health, Chief Traumatologist-Orthopedist of the Healthcare Committee of Saint Petersburg, Vice-President of the Association of Traumatologists-Orthopedists of Russia (ATOR), member of the European Hip Society, member of the International Hip Society; no conflict of interest.

3. Vasily A. Artyukh (Saint Petersburg) – Doctor of Medical Sciences, Head of the Purulent Surgery Department, Vreden National Medical Research Center of Traumatology and Orthopedics of the Russian Ministry of Health, member of EBJIS and WAIOT; no conflict of interest.

4. Aleksandr V. Burtsev (Kurgan) — Doctor of Medical Sciences, Director of the Ilizarov National Medical Research Center for Traumatology and Orthopedics of the Russian Ministry of Health, Chief freelance traumatologist-orthopedist of the Ural Federal District, member of ASAMI and ATOR; no conflict of interest.

5. Artem M. Ermakov (Kurgan) - Doctor of Medical Sciences, Head of the Bone and Joint Infection Clinic, Ilizarov National Medical Research Center for Traumatology and Orthopedics of the Russian Ministry of Health, Researcher at the Laboratory of the Bone and Joint Infection Clinic (Purulent Osteology), physician of the 1st category at the Purulent Traumatology and Orthopedics Department No. 1, member of ATOR, EJBIS, ASAMI; no conflict of interest.

6. Alina R. Kasimova (Saint Petersburg) – Candidate of Medical Sciences, Clinical Pharmacologist at the Department of Clinical Pharmacology, Vreden National Medical Research Center of Traumatology and Orthopedics of the Russian Ministry of Health; Associate Professor at the Department of Clinical Pharmacology and Evidence-Based Medicine, Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health; no conflict of interest.

7. Andrey N. Koyushkov (Kurgan) - highest-category physician at the Purulent Traumatology and Orthopedics Department No. 1, Ilizarov National Medical Research Center for Traumatology and Orthopedics of the Russian Ministry of Health, member of ATOR.

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. traumatologists-orthopedists

2. surgeons

3. clinical pharmacologists

4. infectious disease specialists

5. healthcare administrators

6. medical university students, residents, postgraduate students

Methods used for evidence collection/selection:

1. Search in domestic and international electronic databases: eLibrary, MedLine, PubMed, Cochrane Library, Elsevier publications. Search depth – 20 years.

2. Materials from domestic and international guidelines and consensus statements on the prevention and care of periprosthetic and fracture-related infection [1,2,39,48,54,130,139,287,298,300].

In these clinical guidelines, all information is ranked by the level of certainty (evidence) depending on the quantity and quality of studies on the issue. The group used the methodology for assessing the level of recommendation validity and degree of evidence certainty in accordance with Appendix 2 to the Requirements for the Structure of Clinical Guidelines, Composition and Scientific Validity of Information Included in Clinical Guidelines, approved by Order of the Russian Ministry of Health No. 1034 dated February 28, 2019.

Table P1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table P2. Scale for assessing levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table P3. Scale for determining the levels of recommendation validity

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1. Antibacterial drugs for targeted therapy of IAI

Compiled on the basis of monitoring results of the spectrum of leading pathogens of orthopedic infection and their antibiotic susceptibility for the period 2012–2018 [5,54] and scientific publications [21,159].

Notes hereafter:

** – drug included in the List of Vital and Essential Drugs for medical use for 2023 (Appendix No. 1 to Order of the Government of the Russian Federation No. 2406-r dated December 24, 2022)

# – bone and joint infection is not listed as an approved indication in the drug's summary of product characteristics.

^a – in case of allergy to β-lactam antibiotics;

¹ – to enhance activity against biofilms (especially in the presence of an implant) and intracellular bacteria, in combination with rifampicin**; if rifampicin is unavailable or the pathogen is resistant, consider a combination with co-trimoxazole** or #doxycycline** or fusidic acid or fosfomycin**;

² – possibly in combination with gentamicin** or amikacin**;

³ – combining vancomycin** with gentamicin** increases nephrotoxicity, requiring continuous renal function monitoring;

⁴– when carbapenem-resistant strains are isolated, see Appendix A3.2.

Appendix A3.2. Provisional list of antibacterial drugs and their combinations for the treatment of implant-associated infections (IAI) caused by high-resistance pathogens

Compiled on the basis of scientific publications

Appendix A3.3. List of antimicrobial agents for bone cement impregnation during spacer formation

The list is based on the results of our own studies [315–318] and recommendations of foreign experts [48,298].

# - the official product labeling does not include the route of administration as a component of bone cement

Appendix B. Physician Action Algorithms

Name of Algorithm 1 in the clinical guidelines "Implant-Associated Infection": 1. Algorithm for choosing the treatment strategy in patients with periprosthetic joint infection with implant retention

Name of Algorithm 2 in the clinical guidelines "Implant-Associated Infection": 2. Algorithm for choosing the surgical treatment strategy in patients with periprosthetic joint infection with implant removal

Name of Algorithm 3 in the clinical guidelines "Implant-Associated Infection": 3. Algorithm for choosing the surgical treatment strategy in patients with fracture-related infection

Appendix C. Patient Information

Following treatment for periprosthetic or fracture-related infection and return home, the following should be avoided:

• sharp temperature fluctuations – hypothermia (dressing and wearing shoes appropriately for the season), overheating (steam rooms, saunas, sunbathing),

• excessive or especially constant physical exertion, impacts, bruises, and vibration.

Patients after successful surgical treatment of PJI or FRI and resolution of the infectious process may visit balneotherapy and climatotherapy health resorts no earlier than 6 months after surgery. A calm, measured lifestyle, moderate feasible psychophysical exertion, avoidance of alcohol and smoking, outdoor walks, and healthy food constitute the lifestyle of patients with PJI. Following the physician's recommendations for pharmacotherapy, physical therapy, and therapeutic exercise in the postoperative period is of great importance for a successful outcome.

Medication therapy includes taking antibacterial drugs recommended by the physician, analgesics, antithrombotic drugs, nutritional support, as well as prevention of peptic ulcer disease and, if necessary, laxatives. The treatment efficacy must be monitored regularly, every 2-3 weeks. The patient should monitor body temperature and perform blood and urine tests. The patient must be informed about the importance of timely treatment and prevention of chronic infection foci on the skin surface, in the oral cavity, and elsewhere.

Orthopedic pillows are widely used to prevent spacer dislocation, helping to maintain the limbs in a functionally comfortable position. The patient must follow the rules of safe behavior in everyday life and proper limb positioning. For example, in hip surgery, one must not cross the legs, sit on low chairs, bend forward deeply, or flex the hip more than 90 degrees. Additional information on the rules of protective motor and load regimens is provided to the patient by the attending physician or a hospital rehabilitation department staff member. After the surgical wound heals and the satisfactory condition of organs and systems is restored, measures must be taken to combat overweight or underweight. By the time of the next orthopedic intervention, the patient's body mass should be close to the physiological norm.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

No