Infectious complications during large joint replacement are one of the significant medical and socio-economic problems. The incidence of infectious complications during total knee arthroplasty (TKA) is 0.4-4%, and during total hip arthroplasty (THA) - 0.3-2.2% [1]. According to forecasts, by 2030, infectious complications are expected to increase to 6.8 and 6.5%, respectively. Treatment of periprosthetic infection (PPI) poses a significant economic burden on healthcare [2]. Annual costs for revision arthroplasty for infectious complications in the United States increased from 2001 to 2009. from 320 to 566 million US dollars. These costs are expected to exceed US$1.62 billion by 2021 [3, 4].
The reason for the development of late chronic PJI, as a rule, is the transfer of pathogens from foci of acute and chronic infection (cellulitis, diabetic foot, skin, periodontal, respiratory and urinary tract infections) [2, 5]. The pathogenesis of PJI is based on the ability of microorganisms to form biofilms on the surface of implants. Pathogens of PJI in the form of a biofilm become resistant to immune defense factors, including phagocytosis, and the action of antimicrobial drugs [6–9].
The modern classification of PPI is based on the process of microbial biofilm development. Depending on the stage of its development, early PJI is distinguished with an immature biofilm, which appears during the first 4 weeks after implantation of the endoprosthesis, and chronic - with a mature biofilm, which appears more than 4 weeks after implantation [2]. Thus, in the case of chronic PJI, effective treatment is only possible if the infected implant is removed.
Drug of choice for the treatment of PJI caused by methicillin-resistant (MR) bacteria Staphylococcus aureus
(Staphylococcus aureus) and coagulase-negative staphylococci is vancomycin [10-13]. From 20 to 90% of intraoperatively created plasma concentrations of vancomycin (VV) can penetrate into the bone structure, depending on its vascularization and density [14]. When the drug is applied locally as part of a cement spacer1 (SP), the maximum amount of antibiotic is released during the first few days after implantation, then the elution slows down, continuing for several weeks and months [6, 14]. According to the literature, local use of vancomycin makes it possible to maintain its concentration in the implant area at a high level for several days after surgery [5, 6, 19].
A residual concentration of 15–20 μg/ml has been accepted as an effective therapeutic serum CV for the treatment of infections caused by MR Staphylococcus aureus [15]. For other pathogens, the serum concentration level should be several times higher than the minimum inhibitory concentrations (MICs) for isolated microbiological cultures of patients [6, 15]. Currently, there is no consensus on the clinically effective CV in periarticular fluid. According to clinical recommendations, depending on the type of staphylococcus, the MIC of vancomycin should be up to 4 μg/ml [16].
There are reports of studies of CV in biological fluids (blood serum, drainage and synovial fluid, bone tissue) in PJI. When using bone grafts impregnated with vancomycin, high levels of excreted antibiotic were found, which suppressed vancomycin-sensitive staphylococci throughout the entire 16-day observation period [17].
A group of authors [18] conducted a study of the concentrations of vancomycin and aztreonam in blood serum and synovial fluid using high-performance liquid chromatography in 46 patients with PJI after the first stage of revision arthroplasty with the installation of SP on cement, as well as those taken intraoperatively during the second stage. On the 1st day after SP installation, high levels of antibiotics were observed in the periarticular fluid (vancomycin 1538.0±243.6 μg/ml; aztreonam 1003.5±323.5 μg/ml). The concentration of antibiotics in the blood serum 1 day after surgery was low (vancomycin 0.58±0.2 μg/ml, aztreonam 0.46±0.3 μg/ml). 107 days after the first stage of re-endoprosthesis, the concentrations of antibiotics in the synovial fluid (second stage) were significantly higher than the MIC for the most common microorganisms.
The optimal level of local antibiotic concentration and the required duration of its maintenance in the treatment of PJI currently remain the subject of debate.
The purpose of the study was to evaluate the CV on days 1, 3, 7 in the blood serum and periarticular fluid in patients with PJI of the knee joint after installation of an articulating joint device with an antibiotic during intravenous antibiotic therapy.
Material and methods
We examined patients with PJI who were treated at the Federal State Budgetary Institution Federal Center for Emergency Surgery of the Ministry of Health of the Russian Federation. Barnaul. In the majority of patients (76.4%), staphylococci predominated: in 38% of cases S.
a ureus
, in 62% - coagulase-negative staphylococci. MR strains of staphylococci accounted for 40.5% [10].
The study included 17 patients (14 women, 3 men) diagnosed with chronic PJI of the knee joint. The diagnosis was established according to the accepted criteria for PJI [13, 20], the isolated pathogen was sensitive to vancomycin. Exclusion criteria were renal failure, individual intolerance to vancomycin, and superficial infection.
All patients underwent two-stage re-endoprosthesis with the use of a temporary articulating joint impregnated with vancomycin at the first stage. All studies and manipulations, including joint punctures, were carried out according to indications as part of the treatment process.
The patients were divided into two groups. Group 1 included 9 patients who received vancomycin intravenously and locally as part of the joint venture. S.
e pidermidis
(MRSE)
was isolated in 3 cases P. m agnus
and MR
S. aureus ,
microbiological culture growth was not obtained .
Group 2 included 8 patients who were prescribed 2 different antibiotics: intravenous amoxicillin/clavulanate, linezolid or cefoperazone/sulbactam, and local vancomycin as part of the joint venture. In patients of this group, MSSA was identified in 4 cases, streptococcus, streptococcus and Escherichia coli, MRSE were identified in one case each, and in another case, in the presence of clinical manifestations of infection, microbiological culture growth was not detected. After receiving the final results of microbiological studies in some patients, therapy was changed.
The production of the SP was carried out intraoperatively on the basis of the components of the knee joint endoprosthesis using a polyethylene liner and the femoral component of the endoprosthesis with preservation of the posterior cruciate ligament. Material collection (blood and periarticular fluid) was carried out on the 1st, 3rd and 7th days after surgery. Periarticular fluid was taken on the 1st and 3rd days using a drainage tube inserted into the wound, and on the 7th day by puncture of the joint. The material was drawn into a syringe in a volume of 3-5 ml. Blood for the study was taken from a peripheral vein of the forearm through an installed venous catheter into vacuum tubes VACUETTE, for serum - PREMIUM (Greiner Bio-One, Austria) in a volume of 5 ml before the next intravenous administration of an antibacterial drug.
Thus, the determination of CV was performed in parallel in blood serum and periarticular fluid at a minimum concentration (before drug administration). The blood was centrifuged for 15 minutes at g=1500. Serum was aliquoted and frozen at –20°C. The collected periarticular fluid from the syringe was placed into a similar vacuum tube. After delivery to the laboratory, the periarticular fluid was also centrifuged; if fibrin clots were present in the supernatant, the supernatant was subjected to repeated centrifugation. The resulting material was aliquoted and frozen at –20°C. Immediately before the study, samples of biological fluids were thawed and examined in one analytical series on the ADVIA CENTAUR CP immunochemical system (Siemens Healthcare GmbH, Germany) with ADVIA Centaur VANC MCM reagents (Siemens Healthcare GmbH, Germany) by direct immunochemiluminescent analysis.
Statistical processing was carried out using Microsoft Excel. Taking into account the fact that non-parametric methods of statistical analysis were used, the results are presented as median and interquartile range. For all statistical tests, a critical significance level of p
<0.05. Group comparisons were made using the Mann-Whitney test.
Paraprosthetic infection of the knee joint - diagnosis
Infection is one of the most common complications during endoprosthetics. With revision intervention, the number of victims of infection increases to 40%. And these numbers are increasing every year, as the number of people who have resorted to endoprosthetics is growing. Previously, these were elderly patients, but now young people are getting implants. Therefore, in the 21st century, endoprosthetics is literally on stream. The causes of paraprosthetic infection are different and not fully understood. Recently, publications have increasingly appeared on the connection between the pathogen and the material from which the prosthesis is made, as there is evidence of the ability of some microorganisms to adhere to certain types of implants.
The severity of symptoms of infection after endoprosthetics depends on the virulence of the pathogen, the source of infection, the condition of the patient and his age. In the first few days after implantation of a knee prosthesis, clinical data still do not clearly distinguish between postoperative tissue reaction and initial infection. Classic signs of inflammation (hyperthermia, redness, swelling, pain and dysfunction) may initially exist without the presence of infection, and their absence or severe delay during the first week should be a good reason for further monitoring.
Clinical data
Paraprosthetic inflammation manifests itself after installation of the endoprosthesis for several months; depending on the time of occurrence, it is distinguished:
- if symptoms appeared within 30 days after the intervention, they speak of an acute form;
- if signs of infection appear 30 days after placement of the implant or within a year after it, then we are talking about a chronic form;
- if complaints appear 12 months after surgery, then doctors talk about an acute hematogenous infection
Febrile body temperature, as an indication of infection, usually occurs three to six days after arthroplasty, more so in the case of a (super-)infected postoperative hematoma. However, the presence of persistent (sub-)febrile fever should, at the very least, be considered an alarm that requires enhanced monitoring. If systemic parameters of sepsis occur, postoperative wound infection should be excluded.
Sometimes the disease occurs latently without obvious signs. The presence of effusion without local or systemic signs of infection is usually nonspecific. It can be punctured under sterile conditions so that the punctate can be further examined microbiologically. The fistula form is characterized by the appearance of a fistula in the form of a pathological course from the prosthesis to the epidermis, through which pus is released.
The diagnosis is based on examination data, anamnesis, patient complaints and additional examination. Due to the vagueness of symptoms and the absence of specific examination results, making a diagnosis of parainfection is quite difficult and, first of all, depends on the experience and qualifications of the doctor.
Main complaints
People usually come to the doctor with complaints of swelling of the joint, limited functionality, low-grade fever (and sometimes fever), redness and swelling in the knee area.
But the classic signs of inflammation may be absent, and the main symptom of infection and the patient’s complaint will be constant pain in the knee, vaguely associated with movement and worsening at night. The pain can be aching or throbbing, local or radiating.
If the paraprosthetic process is deep, the muscles next to the implant are affected. Intoxication spreads throughout the body, the general condition worsens, the temperature remains high, the patient shudders, weakness is noted, and vomiting is possible.
The doctor clarifies with the patient the nature of the pain, its onset, the dynamics of the process, and finds out whether treatment was carried out (if complaints appeared outside the clinic)
If the infection is latent, there may be no pronounced complaints; the patient notes fatigue, aching pain, and slight swelling in the joint area.
Any complaint of pain in the area of the endoprosthesis, especially during the first three years after surgery, should be considered as an infectious complication. In addition to complaints, the doctor collects a thorough medical history, finding out:
- Do you have any joint diseases?
- whether the patient suffers from rheumatism;
- whether you took a long course of medications;
- were there any injuries or falls after the operation;
- what condition are the vessels in?
- do you have diabetes?
- do you have osteoporosis?
- what type of prosthesis and whether there were problems with the postoperative wound;
- whether there is cardiovascular insufficiency;
- Is there any pain in the area of the prosthesis, and when did it appear?
Patient examination
During a clinical examination, attention is drawn to an enlarged knee or limited swelling, a change in the color of the skin around the joint. The doctor determines whether there is a restriction of movement. Unambiguous confirmation of paraprosthetic infection are fistulous tracts. The edges of the wound may diverge, discharge appears from it, and sometimes areas of necrosis form.
On palpation - enlargement of the inguinal lymph nodes, increased local temperature, pain in the area of the projection of the joint space. Tachycardia (rapid heart rate) and rapid breathing are noted.
Laboratory research
Usually, blood is taken for clinical and biochemical analysis, and blood is donated for culture. Laboratory tests include, in particular, the determination of serum CRP [C-reactive protein], which currently represents the most important control parameter in addition to the white blood cell count in the blood picture. However, here the absolute values of the corresponding indicators are of less importance compared to the course of the disease. Immediately after surgery, CRP (C-reactive protein) values almost always increase and then begin to fall in the following days. The absence of a decrease in CRP or its continued increase, combined with clinical signs of infection, indicate the presence of infection until proven otherwise. In this context, erythrocyte sedimentation rate (ESR) is unlikely to play a role in the current clinical picture, except to provide indirect monitoring of the long-term course of the disease and the determination of chronic infection.
Regarding laboratory parameters, it should be noted that, for example, an infection such as Staphylococcus epidermidis usually does not cause a significant increase in CRP and clinical parameters are often very nonspecific.
For example, a change in the number of leukocytes may be observed, but the information content of this parameter of paraendoprosthetic infection is not significant. If the cultures of the synovium are sterile, this does not mean the absence of parainfection; it is necessary to repeat the examination of tissues for culture from different areas of the knee joint.
Instrumental studies
There is absolutely no doubt in the case of large soft tissue defects with visually distinguishable prosthetic components identified during instrumental examination.
- Sonography
Sonographic examination plays an important role when early infection is suspected, as it can be used to visualize periprosthetic effusion or hematoma and, if necessary, to perform sonographically guided puncture. The basis for diagnosis may be detected areas of hypoechogenicity.
- X-ray
A conventional x-ray image is unlikely to convey the target information in early parainfection, since there are very few specific x-ray signs. In contrast, with the late form there is a different situation: in this case, periprosthetic signs of weakening on the x-ray can be observed at two levels. The presence of infectious inflammation can be suggested by the periosteal reaction and signs of osteolysis revealed in the image. Regular x-ray monitoring is mandatory to see the dynamics of the process. If a fistula exists, then X-ray fistulography can provide evidence of the involvement of the prosthesis in the pathological process. An X-ray image of a fistula clarifies its localization, the branching of its passages, connection with organs and tissues, and finds purulent accumulations (leakage). In addition, if a fistula is present, a smear is taken for bacteriological examination, including a resistogram.
- CT and MRI
Due to the layering of the prosthesis when implanting, in most cases, steel components, computed tomography (CT) and magnetic resonance imaging (MRI) play virtually no role here (with the exception of titanium prostheses).
- Scintigraphy
In case of a long course of the disease, (three-stage) scintigraphy can also be used, with which the pathological metabolic activity of soft tissues and/or bone in the periprosthetic area can be proven.
- Biopsy
Tissue puncture in the area of the knee joint to obtain puncture is carried out under ultrasound control. The resulting contents are studied in the laboratory, where culture is carried out to identify the pathogen.
Only after interpreting the data obtained can the doctor develop the optimal treatment strategy.
Conclusion
Correct diagnosis will help answer many medical questions, find out the involvement of surrounding tissues and the design of the endoprosthesis in the inflammatory process, find out its prevalence, understand at what stage the blood circulation is impaired and, most importantly, develop optimal and effective treatment tactics. Treatment of paraprosthetic infection is lengthy, using expensive drugs and materials. Debate continues about the choice of optimal technologies that can restore joint function with minimal risk of re-infection, so it is very important to find a doctor with extensive experience in arthroplasty and a specialized clinic with modern equipment.
results
In group 1, the average CV in the blood serum on the 1st day after surgery was close to the therapeutic value - 16.8 [9.8; 16.9] mcg/ml, on the 3rd and 7th days it was 20.18 [16.6; 22.69] and 16.43 [13.2; 27.3] µg/ml. In the periarticular fluid on days 1 and 3, high CVs were found - 59.84 [57.3; 74.0] and 43.0 [36.53; 31.2] µg/ml, respectively, decreasing by the 7th day to 29.94 [21.44; 36.5] µg/ml, however, significantly exceeding the MIC of the isolated pathogens.
In patients of group 2, low CV was determined in the blood serum on days 1, 3, 7 - 2.86 [1.23; 3.9], 3.05 [1.25; 4.25], 3.14 [2.16; 3.47] µg/ml, respectively. In the periarticular fluid in the 2nd group on the 1st and 3rd days, the CV was high, as in the 1st group - 52.95 [20.4; 60.4] and 31.36 [22.6; 36.5] mcg/ml, respectively, and also gradually decreased by the 7th day - 11.09 [8.69; 17.15] µg/ml (Fig. 1,
Rice. 1. Distribution of K.V. in blood serum in both groups on days 1, 3, 7. 2
).
A significant difference in CV in the periarticular fluid in patients of groups 1 and 2 was obtained only on the 7th day after surgery ( U
em=7;
p
<0.01).
Rice. 2. Distribution of K.V. in the periarticular fluid in both groups on days 1, 3, and 7.
No pathological deviations in serum creatinine and glomerular filtration rate were detected in both groups of patients. All patients had no clinical signs of inflammation after the first stage. The level of C-reactive protein on day 1 was 118.6 [97.8; 123.4] mg/l and gradually decreased by the 7th day to 58.3 [41.7; 67.5] mg/l, which corresponded to the usual course of the postoperative period. The ESR level did not change significantly at all control points.
The second stage of endoprosthetics in all patients was performed on average after 11 [7; 12] weeks In patients of both groups after two-stage re-endoprosthetics, there were no signs of recurrent infection (average follow-up period 26.1 [17.2; 27.3] months).