Predictive Factors for Risk of Reinfection in Septic Two-Stage Revision of Total Hip and Knee Arthroplasties
1
Department of Trauma and Reconstructive Surgery, BG Klinik, University of Tübingen, Schnarrenbergstraße 95, 72076 Tübingen, Germany
2
Department of Joint Replacement, General and Rheumatic Orthopaedics, Orthopaedic Clinic Markgröningen gGmbH, Kurt-Lindemann-Weg 10, 71706 Markgröningen, Germany
3
Department of Orthopaedics and Traumatology, Paracelsus Medical University, Prof. Ernst Nathan Strasse 1, 90419 Nuremberg, Germany
4
Orthopaedic Department, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
*
Author to whom correspondence should be addressed.
Antibiotics 2025, 14(2), 167; https://doi.org/10.3390/antibiotics14020167
Submission received: 10 January 2025
/
Revised: 4 February 2025
/
Accepted: 5 February 2025
/
Published: 8 February 2025
(This article belongs to the Special Issue Prevention, Diagnostic and Antibiotic Treatment of Periprosthetic Joint and Fracture Related Infection, 2nd Edition)
Abstract
:Background: The two-stage septic exchange is the most common therapy concept in the treatment of periprosthetic hip and knee infections. However, before the second-stage reimplantation can be carried out, the physician has to assess whether or not the eradication of the periprosthetic joint infection (PJI) has been successful. Therefore, the aim of this study was to evaluate possible predictive parameters for the successful treatment of PJI before and at the time of reimplantation. Methods: This study investigated a total of 145 patients with periprosthetic hip infection and 93 patients with periprosthetic knee infection, who all underwent a two-stage septic exchange between 2017 and 2021. In order to identify possible risk factors for reinfections, the patients underwent preoperative examination of serological inflammatory parameters, microbiological and histological examination of the periprosthetic membrane at the time of reimplantation, as well as postoperative evaluations at regular intervals for a period of at least 24 months. Results: During the follow-up period, reinfection occurred in 11.3% of cases after the two-stage septic revision. None of the serological, microbiological, or histological parameters were able to significantly predict the risk of reinfection. Risk factors associated with reinfection were BMI and previous revision surgery. Conclusions: Currently, there is no reliable predictive factor indicating the risk of reinfection at the time of reimplantation. New diagnostic methods need to be developed to evaluate the possibility and timing of endoprosthesis reimplantation.
1. Introduction
Periprosthetic infections are one of the most serious complications following hip and knee prosthesis implantation. A general distinction is made between early infections shortly after implantation and late infections, with the boundary between the two usually being drawn at 4 weeks after implantation [1,2,3]. While in early infections there is a realistic chance of leaving the implant in place and controlling the infection by means of so-called DAIR (debridement, antibiotics, and implant retention), in cases of periprosthetic late infections, the implant and all foreign material must be removed [3]. The so-called two-stage septic exchange is the most common treatment concept in which, after removal of all foreign material, either an antibiotic-releasing spacer is inserted for usually from 6 to 12 weeks or, in the case of the hip, a so-called Girdlestone situation, without a spacer, is created for the same period [3]. If the infection appears to be under control, a new prosthesis is then implanted. Prior to reimplantation, assessing whether an infection has been eradicated or not presents considerable problems for the surgeon. In several studies, our working group and others have shown that the serological inflammation parameters assayed prior to reimplantation have no predictive value [4,5,6,7,8]. Straub et al. [8] were also able to show that the histological processing of the spacer membrane and synovial membrane has no predictive value. It is, therefore, unclear whether there is a predictive factor at all that can give the treating physician an indication as to whether the infection has been controlled—and the new prosthesis can be implanted—or whether debridement and possibly a spacer exchange should be performed again.
The aim of this study was, therefore, to analyze whether any of the usual infection parameters (serological parameters, histological examination of the synovium and the spacer membrane, and bacteriological examination of this tissue) can provide information about the probability of reinfection and act as a predictor for possible reinfection.
2. Results
Reinfection occurred in 27 patients (11.3%) during the follow-up period of the two-stage septic revision.
In 17 cases (63.0%), a pathogen shift was observed (Table 1). Identical pathogens were detected in four patients with reinfection (14.8%, Table 2). In four cases (14.8%), a culture-negative infection was initially identified, and, upon reinfection, a pathogen was detected. After an initial pathogen detection, culture-negative reinfection occurred in two cases (7.4%, Table 3).
Of the possible predictive and influencing factors, the following six factors had a p-value of <0.30 (Table 4). The possible predictive and influencing factors are shown in Table 5, Table 6 and Table 7. No serological, microbiological, or histological factors were predictive with any level of significance. Only BMI and previous revision had a significant predictive value for reinfection. If revision had been performed before, the risk of reinfection was increased 8-fold. However, the p-value was not significant if two of the five microbiological samples were positive, even though the risk of reinfection was increased 4-fold. Similarly, if Krenn type II or III was seen in the histology, the risk was doubled, but there was no significant predictive value.
3. Discussion
This study shows that neither the serological parameters nor the bacteriological and histological examination of the synovial and spacer membrane can provide a clear indication of whether there is a risk of reinfection and, therefore, whether reimplantation can be performed at the second stage of the septic two-stage exchange. Thus, these data are unable to identify a factor that can predict whether reimplantation can be performed or not. It was only shown that patients with a previous septic or aseptic exchange operation had an 8-fold increased risk of reinfection after a two-stage septic exchange. Furthermore, patients with a high BMI had a significantly higher risk of reinfection, although this is not helpful in determining the optimal time for reimplantation. Prior revision was also found to be a risk factor for reinfection in the studies by Logroscino et al. [9] and Wang et al. [10] and obesity in the studies by Jhan et al. [11] and Logroscino et al. [9].
In other studies, neither serological parameters [4,5,6,7] nor histological parameters [8] were found to have a significant predictive value. There are several explanations for this. Firstly, a distinction must be made as to whether there is a reinfection with the same pathogen or with a different pathogen. The former can be explained by the presence of osteitis, in which bacteria may be present intracellularly and so would not necessarily be affected during the first stage of treatment. If the immune system is subsequently weakened, this could then lead to an exacerbation of the infection and, thus, reinfection with the same pathogen that caused the first periprosthetic infection [12]. This view is substantiated by the significantly higher risk of reinfection in patients who have already undergone septic replacement surgery. In the present study, 14.8% of patients with reinfection had the same pathogen as in the first septic revision.
Secondly, it is also possible for a new infection caused by other bacteria to develop later, after the successful treatment of the first infection. The patient’s general risk factors and comorbidities for infections play a decisive role here. Reinfection with a different bacterium was seen in 17 cases (63.0%) in our study.
Chen et al. considered intraoperative positive culture as a significant risk factor for reinfection [13]. In our study, the risk of reinfection was increased 4-fold when bacteria were detected in two of the five samples, but this association was not significant in our study.
This study has some strengths and weaknesses. The strength is that a standardized treatment regimen was used in all patients, which has shown success rates of between 92% and 100% in previous studies [3,14,15]. The retrospective evaluation, which does not rule out a certain bias, can be seen as a weakness. A higher number of cases could possibly increase the statistical power due to the higher number of reinfections. However, it seems unlikely that different results can then be expected.
4. Materials and Methods
The study design is retrospective: First, the patient data were captured prospectively in the database of the hospital information system. For the current study, the data were retrospectively analyzed. All reviewed patients had received two-stage revision surgery following confirmed PJI of their THA or TKA between 2017 and 2021 in the Orthopaedic Clinic Markgröningen, Germany. Periprosthetic joint infection was diagnosed preoperatively in all cases according to the criteria of the Musculoskeletal Infection Society (MSIS) and the International Consensus on Musculoskeletal Infection (ICM) 2018 [16,17]. Patients with a follow-up of fewer than 24 months and cases with histopathological examination without classification of the periprosthetic membrane, according to Krenn and Morawietz, at the time of reimplantation, were excluded. The medical records of all patients were reviewed for sex, age, body mass index (BMI), time from primary implantation to revision, American Society of Anesthesiologists (ASA) score, Charlson Comorbidity Index (CCI) score, comorbidities, prior revision surgeries (septic, aseptic), type of infection (monobacterial or polybacterial), type of pathogen (easy-to-treat, difficult-to-treat (according to published reports), or methicillin-resistant staphylococci), histopathological examination (neutrophil granulocytes per high-power field, classification of the periprosthetic membrane according to Krenn and Morawietz), microbiological examination, laboratory parameters (white blood cell count, C-reactive protein), and follow-up and outcome (later reinfection or no reinfection).
The groups no reinfection and reinfection were subdivided and then compared according to the predetermined objectives. Statistical analyses were performed as described in Section 4.5.
4.1. Characteristics of the Patient Cohort
This study investigated 145 patients (60.9%) with periprosthetic infection in total hip arthroplasty and 93 patients (39.1%) with periprosthetic infection in total knee arthroplasty. The mean age of the 135 male (56.7%) and 103 female (43.3%) patients was 69.4 ± 11.4 (27.8–96.8) years. The body mass index (BMI) of the patient cohort averaged 30.2 ± 6.8 (17.7–60.6) kg/m2. Concerning the American Society of Anesthesiologists (ASA) risk classification, 6 patients (2.5%) were classified as ASA I, 102 patients (42.9%) as ASA II, 124 patients (52.1%) as ASA III, and 6 patients (2.5%) as ASA IV [18,19].
Regarding the Charlson Comorbidity Index (CCI), 12 patients (5.0%) were categorized as CCI 0, 15 patients (6.3%) as CCI 1, 41 patients (17.2%) as CCI 2, 47 patients (19.7%) as CCI 3, 48 patients (20.2%) as CCI 4, 36 patients (15.1%) as CCI 5, 24 patients (10.1%) as CCI 6, 8 patients (3.4%) as CCI 7, 3 patients (1.3%) as CCI 8, 2 patients (0.8%) as CCI 9, 1 patient (0.4%) as CCI 10 and 1 patient (0.4%) as CCI 11. In terms of secondary diseases potentially relevant to the development of PJI, 11 patients (4.6%) had a rheumatic disease and 50 patients (21.0%) had diabetes mellitus [19,20].
The average time between the primary implantation and the subsequent two-stage septic revision was 95.9 ± 85.407 (2–500) months. The septic revision was carried out in 70 patients (29.4%), and 13 patients (5.5%) had aseptic revision prior to the analyzed two-stage septic revision.
4.2. Characteristics of the Periprosthetic Joint Infections
The periprosthetic joint infections were monobacterial in 201 cases (84.5%) and polybacterial in 37 cases (15.5%). Easy-to-treat (ETT) pathogens were found in 191 infections (80.3%), difficult-to-treat (DTT) pathogens in 21 infections (8.8%), and methicillin-resistant staphylococci (MRS) in 26 infections (10.9%). In 172 cases (72.3%), the histopathological samples obtained during spacer explantation and endoprosthesis reimplantation did not show any evidence of a persisting periprosthetic joint infection: histopathologically, the periprosthetic membrane was classified, in 145 cases (60.9%), as type IV according to Krenn and Morawietz (indifferent type) and, in 27 cases (11.3%), as type I according to Krenn and Morawietz (wear particle type) [21]. A histopathological correlate of a persisting periprosthetic joint infection was identified in 66 cases (27.7%): the periprosthetic membrane showed, in 52 cases (21.8%), type II according to Krenn and Morawietz (infectious type) and, in 14 cases (5.9%), type III according to Krenn and Morawietz (combined type).
Evidence of a persisting periprosthetic joint infection in the microbiological samples from spacer explantation and endoprosthesis reimplantation (identical pathogen detection in at least two out of five microbiological samples) was found in eight patients (3.4%). The average number of neutrophil granulocytes per high-power field detected at the histopathological examination was 6.0 ± 16.2 (0–100).
The preoperative white blood cell (WBC) count averaged 6.4 ± 1.9 (3.1–12.7) 103/µL. The preoperative C-reactive protein (CRP) average was 13.7 ± 15.7 (0–89) mg/L.
4.3. Treatment Protocol
The diagnosis of a periprosthetic infection was determined according to the MSIS and ICM criteria with joint aspiration and/or joint biopsy performed prior to any revision endoprosthetic procedure.
A two-stage septic exchange procedure was performed in cases of periprosthetic joint infection. In the stage-one surgery, explantation of the infected endoprothesis, radical debridement, and the implantation of spacer components were performed. Furthermore, samples for microbiological and histological examination were taken intraoperatively. The Krenn and Morowitz type classification [21] was used for the histological examination of the spacer membrane. The spacer consisted of a hip stem coated with an individualized multiantibiotic-loaded bone cement, as previously described [3,14,15]. The bone cement was tailored according to the resistance profile of the pathogen isolated preoperatively (Table 7).
The postoperative antibiotic therapy was also in accordance with the antibiogram and the recommendation of a microbiological consultant. An initial parenteral antibiotic therapy for two weeks was followed by an oral antibiotic therapy for four weeks (Table 8 and Table 9).
The stage-two surgery took place after an interim period of 6 weeks and included explantation of the spacer components, repeated radical debridement, and reimplantation of the endoprothesis. The implant fixation in total hip revision arthroplasty was always performed as a cementless procedure. Cementless fixation was chosen because the typically sclerotic and smooth bone following spacer explantation exhibits impaired cement interdigitation [3,14]. However, solely cementless fixation in total knee arthroplasty revision is not successful at the second-stage surgery, so fixation with cement was chosen for reimplantation of knee prostheses [3]. The cemented fixation was performed with the same mixture of multiantibiotic-loaded bone cement used in the previous stage-one surgery. The antibiotic treatment protocol after the step-two surgery was identical to the preceding antibiotic therapy during the interim phase: two weeks of parenteral antibiotic therapy were followed by oral administration for four weeks.
4.4. Laboratory Parameters
The measurement of WBC count (/µL) was performed using a completely automated hematology analyzer (UniCel DxH 800; Beckman Coulter, Pasadena, Calefornia, USA) that utilizes impedance technology and light scatter for cell identification. CRP levels (mg/L) were quantified by the principle of particle-enhanced turbidimetric immunoassay (Cobas C303; Roche, Basel, Switzerland). The recommendations of the manufacturers of UniCel DxH 800 and Cobas C303 were followed exactly.
The measurement of WBC count (/µL) and CRP levels (mg/L) was carried out preoperatively, especially prior to the stage-two revision surgery. The internal threshold value for diagnosing an infection was set at >10 mg/L for the CRP level and at >9000/μL for the WBC count. The Cobas C303 immunoassay does not differentiate CRP levels within the normal range and displays them as <5 mg/L. For the purposes of statistical analysis, the CRP levels in cases with normal values were virtually set at 0 mg/L.
4.5. Tests at Second Stage Revision Surgery
During revision surgery, samples for microbiological examination were extracted from five distinct areas close to the prosthesis (periprosthetic tissue and synovium). Additionally, five samples from the synovium and periprosthetic connective tissue membrane associated with the loosened prosthesis were procured for histological evaluation. To prevent the distortion of microbiological results, the administration of perioperative antibiotics took place after the sample collection. The samples for microbiological analysis were placed in sterile sample tubes and were sent to the microbiological institute within a one-hour timeframe. The same procedure was used for synovial fluid samples obtained pre-operatively.
The microbiological samples were inoculated onto blood agar and into nutrient broth specific for anaerobic pathogens. The incubation period was 14 days [22].
The pathogens were categorized into three groups according to Faschingbauer et al. [23]. Group 1 consists of difficult-to-treat (DTT) pathogens, encompassing rifampicin-resistant staphylococcus, quinolone-resistant Gram-negative bacteria, enterococcus, and candida. Methicillin-resistant staphylococci (MRS), including methicillin-resistant staphylococcus aureus (MRSA) and methicillin-resistant staphylococcus epidermidis (MRSE), are classed as group 2. Group 3 consists of easy-to-treat (ETT) pathogens, encompassing any remaining pathogen and culture-negative periprosthetic joint infections.
In histological analysis, the classification system of Morawietz and Krenn et al. was used to categorize the periprosthetic tissue [21,24,25]. The periprosthetic tissue was differentiated into four types: the particle type (I), the infection type (II), the combined type (III), and the indeterminate type (IV). The histopathologist also assessed the number of polymorphonuclear leukocytes per high-power microscope field.
The microbiological assessment of the tissue samples and aspiration fluids was carried out according to the ICM criteria [16,17]: this means that, if the cumulative diagnostic score was equal to or greater than 6, a periprosthetic joint infection (PJI) was diagnosed.
Table 10 summarizes the histological, microbiological, and clinical chemistry results.
4.6. Follow-Up Examinations
The follow-up examinations were conducted at regular intervals for a period of at least 24 months. First, the patient data were captured prospectively in the database of the hospital information system. In the second step, the data were retrospectively analyzed. The average follow-up period was 56.2 ± 19.8 (24–112) months.
A successfully treated periprosthetic joint infection was defined according to the criteria of Diaz-Ledezma et al. [26]: The patients were classified as free of reinfection if there was clinical absence of PJI for at least 24 months, microbiological absence of PJI for at least 24 months, no subsequent surgical revision because of reinfection and no PJI-related mortality. We employed the MSIS criteria 2014 and the ICM criteria 2018 for the identification of periprosthetic joint reinfection. The internal threshold of the CRP value for detecting a periprosthetic infection was defined at >10 mg/L [26].
Periprosthetic joint reinfections were treated again by a two-step-septic procedure including local antibiotic therapy (bone cement) and systemic antibiotic therapy which was administered intravenously for two weeks and orally for four weeks. Both occurred in accordance with the antibiogram and the recommendation of the microbiological consultant.
4.7. Statistical Analyses
IBM SPSS Statistics for Windows (version 24, IBM Crop., Armonk, NY) was used for statistical analysis. To calculate the cumulative survival, the Kaplan–Meier method was utilized. The survival curve is illustrated by a Kaplan–Meier plot. A multivariable binary logistic regression using the all-enter method was performed, with 15 potential predictors for the primary endpoint of re-infection. The sample size was adequate for the performed multivariate regression analysis [27].
The model was then pared down to include only important predictors, removing variables where p > 0.300. Odds ratios (ORs) and 95% CIs (confidence intervals) are presented.
Unless otherwise stated, data are presented as mean ± standard deviation (and range) or number (percentage). The significance level was set at p < 0.05.
The research was performed following the guidelines of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Landesärztekammer Badenwürttemberg (committee’s reference number F-2023-115).
5. Conclusions
In conclusion, this study shows that, currently, there is no clinical chemistry, microbiological, or histological factor that can predict the risk of reinfection and, thus, the optimal time of reimplantation in two-stage septic replacement operations of hip and knee prostheses. A previous replacement operation and a high BMI alone indicate a higher risk of reinfection but have no influence on determining the time of reimplantation. This means that the timing of reimplantation is still determined by the specifications for the various concepts of two-stage septic prosthesis replacement. Future comparative studies will have to show whether it makes sense to carry out longer antibiotic therapies in patients with a higher risk of reinfection.
Author Contributions
Conceptualization, B.F. and B.P.B.; methodology, B.F. and B.P.B.; formal analysis, P.S.; investigation B.P.B. and F.H.S.; data curation, B.P.B. and F.H.S.; writing—original draft preparation, B.F. and B.P.B.; writing—review and editing, B.F. and B.P.B.; supervision, B.F.; project administration, B.F.; funding acquisition, B.F. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
This study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Landesärztekammer Badenwürttemberg (committee’s reference number F-2023-115).
Informed Consent Statement
Informed consent was obtained from all subjects involved in this study.
Data Availability Statement
We do not wish to share our data because some of the patient’s data relate to individual privacy and, according to the policy of our hospital, these data may not be shared with others without permission.
Acknowledgments
Special thanks are extended to Julia-Stefanie Frick from MVZ-Labor Ludwigsburg for performing the microbiological analyses and to Irina Berger from the Pathological Institute, Klinikum Kassel for conducting the histopathological analyses of the synovial tissue.
Conflicts of Interest
Authors Florian Hubert Sax, Philipp Schuster and Bernd Fink were employed by the Orthopaedic Clinic Markgröningen gGmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflicts of Interest.
References
- Coventry, M.B. Treatment of Infections Occurring in Total Hip Surgery. Orthop. Clin. N. Am. 1975, 6, 991–1003. [Google Scholar] [CrossRef]
- Tsukayama, D.T.; Estrada, R.; Gustilo, R.B. Infection after Total Hip Arthroplasty. A Study of the Treatment of One Hundred and Six Infections. J. Bone Jt. Surg. 1996, 78, 512–523. [Google Scholar] [CrossRef]
- Fink, B. Revision of late periprosthetic infections of total hip endoprostheses: Pros and cons of different concepts. Int. J. Med. Sci. 2009, 6, 287–295. [Google Scholar] [CrossRef] [PubMed]
- Bian, T.; Shao, H.; Zhou, Y.; Huang, Y.; Song, Y. Tests for predicting reimplantation success of two-stage revision for periprosthetic joint infection: A systematic review and meta-analysis. Orthop. Traumatol. Surg. Res. 2018, 104, 1115–1123. [Google Scholar] [CrossRef]
- Hoell, S.; Borgers, L.; Gosheger, G.; Dieckmann, R.; Schulz, D.; Gerss, J.; Hardes, J. Interleukin-6 in two-stage revision arthroplasty. Bone Jt. J. 2015, 97, 71–75. [Google Scholar] [CrossRef] [PubMed]
- Khury, F.; Oltmanns, M.; Fuchs, M.; Leiprecht, J.; Reichel, H.; Faschingbauer, M. Against the Norm: Do Not Rely on Serum C-Reactive Protein and White Blood Cell Count Only When Assessing Eradication of Periprosthetic Joint Infection. Antibiotics 2022, 11, 1174. [Google Scholar] [CrossRef]
- Kusuma, S.K.; Ward, J.; Jacofsky, M.; Sporer, S.M.; Della Valle, C.J. What is the Role of Serological Testing Between Stages of Two-stage Reconstruction of the Infected Prosthetic Knee? Clin. Orthop. Relat. Res. 2010, 469, 1002–1008. [Google Scholar] [CrossRef] [PubMed]
- Straub, J.; Staats, K.; Vertesich, K.; Kowalscheck, L.; Windhager, R.; Böhler, C. Two-stage revision for periprosthetic joint infection after hip and knee arthroplasty. Bone Jt. J. 2024, 106, 372–379. [Google Scholar] [CrossRef] [PubMed]
- Logroscino, G.; Campana, V.; Pagano, S.; Taccari, F.; Fantoni, M.; Saracco, M. Risk Factors for Failure of Two-stage Revision Arthroplasty for Infected Hip Prosthesis: Review of the Literature and Single Centre Cohort Analysis. Eur. Rev. Med. Pharmacol. Sci. 2019, 23 (Suppl. 2), 65–75. Available online: https://www.europeanreview.org/wp/wp-content/uploads/065-075.pdf (accessed on 4 February 2025). [PubMed]
- Wang, Q.; Huang, J.; Chen, X.; Jin, Y. Risk factors of reinfection after prosthesis removal and antibiotic bone cement spacer implantation for the treatment of periprosthetic joint infection. BMC Infect. Dis. 2022, 22, 905. [Google Scholar] [CrossRef]
- Jhan, S.-W.; Lu, Y.-D.; Lee, M.S.; Lee, C.-H.; Wang, J.-W.; Kuo, F.-C. The risk factors of failed reimplantation arthroplasty for periprosthetic hip infection. BMC Musculoskelet. Disord. 2017, 18, 255. [Google Scholar] [CrossRef] [PubMed]
- Gresham, H.D.; Lowrance, J.H.; Caver, T.E.; Wilson, B.S.; Cheung, A.L.; Lindberg, F.P. Survival of Staphylococcus aureus Inside Neutrophils Contributes to Infection. J. Immunol. 2000, 164, 3713–3722. [Google Scholar] [CrossRef] [PubMed]
- Chen, Y.-C.; Lin, Y.-C.; Chang, C.-H.; Lee, S.-H.; Chang, Y. Risk Factors for Treatment Failure in Patients Who Have Knee Periprosthetic Joint Infection Treated with Two-Stage Exchange Arthroplasty as Well as Their Fate. J. Arthroplast. 2022, 38, 355–360. [Google Scholar] [CrossRef] [PubMed]
- Fink, B.; Grossmann, A.; Fuerst, M.; Schäfer, P.; Frommelt, L. Two-stage Cementless Revision of Infected Hip Endoprostheses. Clin. Orthop. Relat. Res. 2008, 467, 1848–1858. [Google Scholar] [CrossRef]
- Fink, B.; Oremek, D. The Transfemoral Approach for Removal of Well-Fixed Femoral Stems in 2-Stage Septic Hip Revision. J. Arthroplast. 2015, 31, 1065–1071. [Google Scholar] [CrossRef] [PubMed]
- Parvizi, J.; Zmistowski, B.; Berbari, E.F.; Bauer, T.W.; Springer, B.D.; Della Valle, C.J.; Garvin, K.L.; Mont, M.A.; Wongworawat, M.D.; Zalavras, C.G. New Definition for Periprosthetic Joint Infection: From the Workgroup of the Musculoskeletal Infection Society. Clin. Orthop. Relat. Res. 2011, 469, 2992–2994. [Google Scholar] [CrossRef] [PubMed]
- Parvizi, J.; Tan, T.L.; Goswami, K.; Higuera, C.; Della Valle, C.; Chen, A.F.; Shohat, N. The 2018 Definition of Periprosthetic Hip and Knee Infection: An Evidence-Based and Validated Criteria. J. Arthroplast. 2018, 33, 1309–1314.e2. [Google Scholar] [CrossRef]
- Teves, J.; Holc, F.; Lalín, A.C.; García-Mansilla, A.; Vildoza, S.; Brandariz, R.; Carbó, L.; Costantini, J. Are frailty scores superior to the ASA score in predicting complications, hospital stay, and readmissions in total knee replacement? A comparative study between octogenarian and septuagenarian patients. Rev. Española Cirugía Ortopédica Traumatol. 2023, 68, T128–T133. [Google Scholar] [CrossRef]
- Quach, L.H.; Jayamaha, S.; Whitehouse, S.L.; Crawford, R.; Pulle, C.R.; Bell, J.J. Comparison of the Charlson Comorbidity Index with the ASA score for predicting 12-month mortality in acute hip fracture. Injury 2020, 51, 1004–1010. [Google Scholar] [CrossRef] [PubMed]
- Glasheen, W.P.; Cordier, T.; Gumpina, R.; Haugh, G.; Davis, J.; Renda, A. Charlson Comorbidity Index: ICD-9 Update and ICD-10 Translation. PubMed 2019, 12, 188–197. [Google Scholar]
- Krenn, V.; Morawietz, L.; Perino, G.; Kienapfel, H.; Ascherl, R.; Hassenpflug, G.J.; Thomsen, M.; Thomas, P.; Huber, M.; Kendoff, D.; et al. Revised histopathological consensus classification of joint implant related pathology. Pathol. Res. Pract. 2014, 210, 779–786. [Google Scholar] [CrossRef] [PubMed]
- Schäfer, P.; Fink, B.; Sandow, D.; Margull, A.; Berger, I.; Frommelt, L. Prolonged Bacterial Culture to Identify Late Periprosthetic Joint Infection: A Promising Strategy. Clin. Infect. Dis. 2008, 47, 1403–1409. [Google Scholar] [CrossRef] [PubMed]
- Faschingbauer, M.; Bieger, R.; Kappe, T.; Weiner, C.; Freitag, T.; Reichel, H. Difficult to treat: Are there organism-dependent differences and overall risk factors in success rates for two-stage knee revision? Arch. Orthop. Trauma Surg. 2020, 140, 1595–1602. [Google Scholar] [CrossRef] [PubMed]
- Krenn, V.; Otto, M.; Morawietz, L.; Hopf, T.; Jakobs, M.; Klauser, W.; Schwantes, B.; Gehrke, T. Histopathologic diagnostics in endoprosthetics: Periprosthetic neosynovialitis, hypersensitivity reaction, and arthrofibrosis. Der. Orthopäde 2009, 38, 520–530. [Google Scholar] [CrossRef] [PubMed]
- Müller, M.; Morawietz, L.; Hasart, O.; Strube, P.; Perka, C.; Tohtz, S. Histopathological diagnosis of periprosthetic joint infection following total hip arthroplasty. Der. Orthopäde 2009, 38, 1087–1096. [Google Scholar] [CrossRef]
- Diaz-Ledezma, C.; Higuera, C.A.; Parvizi, J. Success After Treatment of Periprosthetic Joint Infection: A Delphi-based International Multidisciplinary Consensus. Clin. Orthop. Relat. Res. 2013, 471, 2374–2382. [Google Scholar] [CrossRef]
- Khamis, H.J.; Kepler, M. Sample Size in Multiple Regression: 20 + 5k. J. Appl. Stat. Sci. 2010, 17, 505–517. [Google Scholar]
Table 1.
Cases of reinfection with a pathogen shift.
| Microorganism One (First Septic Revision) | Microorganism Two (First Septic Revision) | Two or More Samples Positive (of 5) at Time of Re-Implantation | Membrane Type 2 or 3 (Krenn) at Time of Re-Implantation | Microorganism One (Second Septic Revision) | Microorganism Two (Second Septic Revision) | |
|---|---|---|---|---|---|---|
| 1 | Streptococcus agalactiae (ETT) | no | yes (type II, 7/HPF) | Staphylococcus aureus (ETT) | ||
| 2 | Staphylococcus aureus (ETT) | no | yes (type II, 11/HPF) | Enterococcus faecalis (DTT) | Citrobacter koseri (ETT) | |
| 3 | Streptococcus mitis (ETT) | Streptococcus oralis (ETT) | no | no (type I, 4/HPF) | Staphylococcus epidermidis (MRS) | |
| 4 | Staphylococcus epidermidis, rifampicin-resistant staphylococcus (DTT) | no | yes (type III, 6/HPF) | Enterobacter cloacae (ETT) | ||
| 5 | Pseudomonas aeruginosa (ETT) | no | yes (type II, 16/HPF) | Staphylococcus epidermidis (MRS) | Candida albicans (DTT) | |
| 6 | Streptococcus gordonii (ETT) | no | no (type I, 0/HPF) | Streptococcus mutans (ETT) | ||
| 7 | Streptococcus mitis (ETT) | no | no (type I, 1/HPF) | Staphylococcus epidermidis (MRS) | ||
| 8 | Staphylococcus capitis (ETT) | Staphylococcus epidermidis (ETT) | no | no (type I, 2/HPF) | Staphylococcus lugdunensis (ETT) | |
| 9 | Staphylococcus aureus (ETT) | no | yes (type II, 13/HPF) | Raouletta planticola (ETT) | ||
| 10 | Staphylococcus aureus (ETT) | no | no (type IV, 0/HPF) | Staphylococcus epidermidis, rifampicin-resistant staphylococcus (DTT) | ||
| 11 | Staphylococcus capitis (ETT) | no | no (type IV, 0/HPF) | Corynebacterium urealyticum (ETT) | Cutibacterium acnes (ETT) | |
| 12 | Cutibacterium acnes (ETT) | no | yes (type II, 20/HPF) | Cutibacterium granulosum (ETT) | ||
| 13 | Staphylococcus capitis (ETT) | Cutibacterium acnes (ETT) | no | yes (type II, 5/HPF) | Staphylococcus epidermidis, rifampicin-resistant staphylococcus (DTT) | |
| 14 | Staphylococcus epidermidis (MRS) | no | no (type IV, 0/HPF) | Cutibacterium acnes (ETT) | ||
| 15 | Cutibacterium acnes (ETT) | no | yes (type IV, 1/HPF) | Staphylococcus capitis (ETT) | ||
| 16 | Cutibacterium acnes (ETT) | no | no (type II, 50/HPF) | Staphylococcus aureus (ETT) | ||
| 17 | Candida albicans (DTT) | no | no (type IV, 1/HPF) | Staphylococcus epidermidis (MRS) |
Table 2.
Cases of reinfection with identical pathogens.
| Microorganism One (First Septic Revision) | Microorganism Two (First Septic Revision) | Two or More Samples Positive (of 5) at Time of Re-Implantation | Membrane Type 2 or 3 (Krenn) at Time of Re-Implantation | Microorganism (Second Septic Revision) | |
|---|---|---|---|---|---|
| 1 | Staphylococcus aureus (ETT) | Finegoldia magna (ETT) | No | yes (type III, 5/HPF) | Staphylococcus aureus (ETT) |
| 2 | Staphylococcus aureus (ETT) | No | no (type IV, 1/HPF) | Staphylococcus aureus (ETT) | |
| 3 | Staphylococcus aureus (ETT) | Yes | no (type IV, 1/HPF) | Staphylococcus aureus (ETT) | |
| 4 | Eschericia coli, quinolone-resistant Gram-negative bacteria (DTT) | No | no (type IV, 0/HPF) | Eschericia coli, quinolone-resistant Gram-negative bacteria (DTT) |
Table 3.
Cases of reinfection with culture-negative infection in first or second septic revision.
| Microorganism One (First Septic Revision) | Two or More Samples Positive (of 5) at Time of Re-Implantation | Membrane Type 2 or 3 (Krenn) at Time of Re-Implantation | Microorganism One (Second Septic Revision) | |
|---|---|---|---|---|
| 1 | No pathogen detectable | yes | no (type IV, 1/HPF) | Pseudomonas aeruginosa (ETT) |
| 2 | No pathogen detectable | no | yes (type II, 25-30/HPF) | Staphylococcus aureus (ETT) |
| 3 | No pathogen detectable | no | no (type IV, 0/HPF) | Staphylococcus aureus (MRS) |
| 4 | No pathogen detectable | no | no (type IV, 0/HPF) | Streptococcus dysgalacticae (ETT) |
| 5 | Cutibacterium acnes (ETT) | no | yes (type II, >100/HPF) | No pathogen detectable |
| 6 | Enterococcus faecalis (DTT) | no | no (type IV, 0/HPF) | No pathogen detectable |
Table 4.
Predictors of reinfection after paring down the model using p < 0.300 *.
| Predictor Variable | Odds Ratio | 95%-CI | p-Value | |
|---|---|---|---|---|
| Sex | 2.30 | 0.796 | 6.625 | 0.124 |
| BMI | 1.01 | 1.013 | 1.163 | 0.020 |
| ASA | 1.85 | 0.654 | 5.248 | 0.246 |
| Any revision before | 8.05 | 2.898 | 22.336 | 0.001 |
| Krenn Type II or III at time of revision | 2.52 | 0.780 | 8.116 | 0.122 |
| ≥2 of 5 microbiological samples positive at time of re-implantation | 4.21 | 0.447 | 39.750 | 0.209 |
* Sex included as male vs. female; effect of BMI per increase of one; effect of ASA increase of one category; other factors included as dichotomous variables (yes/no). BMI: body mass index.
Table 5.
Characteristics of patient cohort.
| Cases | 238 |
|---|---|
| Sex | |
| Male | 135 (56.7%) |
| Female | 103 (43.3%) |
| Age [years] | 69.4 ± 11.4 (27.8–96.8) |
| BMI (kg/m2) | 30.2 ± 6.8 (17.7–60.6) |
| Time from primary implantation to revision [months] | 95.9 ± 85.407 (2–500) |
| Joint | |
| Knee | 93 (39.1%) |
| Hip | 145 (60.9%) |
| ASA | |
| I | 6 (2.5%) |
| II | 102 (42.9%) |
| III | 124 (52.1%) |
| IV | 6 (2.5%) |
| CCI | |
| 0 | 12 (5.0%) |
| 1 | 15 (6.3%) |
| 2 | 41 (17.2%) |
| 3 | 47 (19.7%) |
| 4 | 48 (20.2%) |
| 5 | 36 (15.1%) |
| 6 | 24 (10.1%) |
| 7 | 8 (3.4%) |
| 8 | 3 (1.3%) |
| 9 | 2 (0.8%) |
| 10 | 1 (0.4%) |
| 11 | 1 (0.4%) |
| Rheumatic disease | |
| Yes | 11 (4.6%) |
| No | 227 (95.4%) |
| Diabetes | |
| Yes | 50 (21.0%) |
| No | 188 (79.0%) |
| Septic revision before | |
| yes, 1 or more septic revisions | 70 (29.4%) |
| No | 168 (70.6%) |
| Aseptic revision before | |
| yes, 1 or more septic revisions | 13 (5.5%) |
| No | 225 (94.5%) |
Table 6.
Characteristics of periprosthetic joint infections.
| Type of Infection | |
|---|---|
| Monobacterial | 201 (84.5%) |
| Polybacterial | 37 (15.5%) |
| Bacteria | |
| ETT | 191 (80.3%) |
| DTT | 21 (8.8%) |
| MRS | 26 (10.9%) |
Table 7.
Type of bone cement.
| Copal G+C 1 | 35 (14.7%) |
| Copal G+V 2 | 9 (3.8%) |
| Copal G+C, mixed 3 | 186 (78.2%) |
| Copal G+V, mixed 4 | 7 (2.9% |
| Palacos +G, mixed 5 | 1 (0.4%) |
1 rapid-curing, radiopaque bone cement containing gentamicin and clindamycin; 42.7 g of COPAL® G+C powder contains 1.0 g gentamicin (as gentamicin sulfate) and 1.0 g clindamycin (as clindamycin hydrochloride); produced by Heraeus Medical GmbH, Wehrheim, Germany. 2 rapid-curing, radiopaque bone cement containing Gentamicin and Vancomycin; 43.0 g of COPAL® G+V cement powder contains: 0.5 g gentamicin (as gentamicin sulfate) and 2.0 g vancomycin (as vancomycin hydrochloride); produced by Heraeus Medical GmbH, Wehrheim, Germany. 3 Copal G+C® mixed with (1) vancomycin/(2) meropenem/(3) streptomycin/(4) ofloxacin/(5) fosfomycin/(6) streptomycin/(7) vancomycin, ampicillin/(8) vancomycin, amphotericin B/(9) vancomycin, ofloxacin/(10) clindamycin, gentamicin. 4 Copal G+V® mixed with (1) vancomycin/(2) meropenem/(3) cefazolin. 5 Palacos +G® (fast-curing, radiopaque bone cement containing 2% gentamicin; produced by Heraeus Medical GmbH, Wehrheim, Germany) mixed with (1) vancomycin/(2) vancomycin, ofloxacin.
Table 8.
Intravenously administered antibiotics or antimycotics and number.
| Antibiotic One | Antibiotic Two | Antibiotic Three | Antibiotic Four | Number |
|---|---|---|---|---|
| Vancomycin | Rifampicin | 54 | ||
| Flucloxacillin | Rifampicin | 43 | ||
| Ampicillin/sulbactam | Rifampicin | 41 | ||
| Vancomycin | Imipenem | 20 | ||
| Imipenem | Rifampicin | 6 | ||
| Penicillin G | Rifampicin | 4 | ||
| Cefuroxim | Rifampicin | 8 | ||
| Vancomycin | Fosfomycin | 8 | ||
| Levofloxacin | Rifampicin | 7 | ||
| Imipenem/cilastatin | Rifampicin | 1 | ||
| Daptomycin | Rifampicin | 5 | ||
| Vancomycin | Meropenem | 4 | ||
| Ciprofloxacin | Meropenem | 3 | ||
| Vancomycin | Imipenem | Rifampicin | 1 | |
| Vancomycin | Meropenem | Rifampicin | 3 | |
| Amoxicillin/clavulansäure | Rifampicin | 2 | ||
| Cefuroxim | 1 | |||
| Flucloxacillin | Piperacillin/tazobactam | 2 | ||
| Meropenem | 2 | |||
| Amoxicillin/clavulansäure | Daptomycin | 1 | ||
| Ampicillin | Rifampicin | 1 | ||
| Ampicillin/sulbactam | Fosfomycin | 1 | ||
| Ampicillin/sulbactam | Imipenem | 1 | ||
| Vancomycin | Ampicillin/sulbactam | 1 | ||
| Ampicillin/sulbactam | Metronidazol | 1 | ||
| Ampicillin/sulbactam | Amikacin | Ethambutol | Pyrazinamid | 1 |
| Ampicillin/sulbactam | Clindamycin | 1 | ||
| Cephazolin | Clindamycin | 1 | ||
| Vancomycin | Ciprofloxacin | 1 | ||
| Cotrimoxazol | Rifampicin | 1 | ||
| Flucloxacillin | Fosfomycin | 1 | ||
| Flucloxacillin | Levofloxacin | Rifampicin | 1 | |
| Flucloxacillin | Meropenem | Rifampicin | 1 | |
| Flucloxacillin | Moxifloxacin | 1 | ||
| Vancomycin | Fosfomycin | Imipenem | 1 | |
| Fosfomycin | Meropenem | 1 | ||
| Gentamicin | Penicillin G | 1 | ||
| Levofloxacin | Meropenem | 1 | ||
| Vancomycin | Levofloxacin | 1 | ||
| Levofloxacin | Metronidazol | 1 | ||
| Penicillin G | 1 | |||
| Voriconazol | Rifampicin | 1 |
Table 9.
Administered oral antibiotics or antimycotics and number.
| Antibiotic One | Antibiotic Two | Antibiotic Three | Antibiotic Four | Number |
|---|---|---|---|---|
| Levofloxacin | Rifampicin | 141 | ||
| Amoxicillin/clavulansäure | Rifampicin | 31 | ||
| Cotrimoxazol | Rifampicin | 11 | ||
| Linezolid | Rifampicin | 6 | ||
| Amoxicillin/clavulansäure | Levofloxacin | 11 | ||
| Clindamycin | Rifampicin | 7 | ||
| Ciprofloxacin | 4 | |||
| Clindamycin | Levofloxacin | 4 | ||
| Moxifloxacin | Rifampicin | 3 | ||
| Amoxicillin/clavulansäure | Levofloxacin | Rifampicin | 1 | |
| Ampicillin/Sulbactam | Rifampicin | 2 | ||
| Ciprofloxacin | Linezolid | 2 | ||
| Clarythromycin | Levofloxacin | Rifampicin | 2 | |
| Cotrimoxazol | 2 | |||
| Levofloxacin | 2 | |||
| Amikacin | Ethambutol | Pyrazinamid | Rifabutin | 1 |
| Amoxicillin/clavulansäure | Metronidazol | 1 | ||
| Cefuroxim | Clindamycin | 1 | ||
| Ciprofloxacin | Levofloxacin | 1 | ||
| Cotrimoxazol | Fluconazol | 1 | ||
| Cotrimoxazol | Levofloxacin | 1 | ||
| Cotrimoxazol | Levofloxacin | Rifampicin | 1 | |
| Levofloxacin | Metronidazol | 1 | ||
| Rifampicin | Voriconazol | 1 |
Table 10.
Histological examination, microbiological examination, and clinical chemistry.
| Membrane Type (Krenn) | |
|---|---|
| type 1 | 27 (11.3%) |
| type 2 | 52 (21.8%) |
| type 3 | 14 (5.9%) |
| type 4 | 145 (60.9%) |
| Neutrophil granulocytes per high-power field | 6.0 ± 16.2 (0–100) |
| Membrane type 2 or 3 (Krenn) at time of re-implantation | |
| Yes | 66 (27.7%) |
| No | 172 (72.3%) |
| Two or more samples positive (of 5) at time of re-implantation | |
| Yes | 8 (3.4%) |
| No | 230 (96.6%) |
| WBC at time of re-implantation | 6.4 ± 1.9 (3.1–12.7) |
| CRP at time of re-implantation [mg/L] | 13.7 ± 15.7 (0–89) |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Blersch, B.P.; Sax, F.H.; Schuster, P.; Fink, B. Predictive Factors for Risk of Reinfection in Septic Two-Stage Revision of Total Hip and Knee Arthroplasties. Antibiotics 2025, 14, 167. https://doi.org/10.3390/antibiotics14020167
AMA Style
Blersch BP, Sax FH, Schuster P, Fink B. Predictive Factors for Risk of Reinfection in Septic Two-Stage Revision of Total Hip and Knee Arthroplasties. Antibiotics. 2025; 14(2):167. https://doi.org/10.3390/antibiotics14020167
Chicago/Turabian StyleBlersch, Benedikt Paul, Florian Hubert Sax, Philipp Schuster, and Bernd Fink. 2025. "Predictive Factors for Risk of Reinfection in Septic Two-Stage Revision of Total Hip and Knee Arthroplasties" Antibiotics 14, no. 2: 167. https://doi.org/10.3390/antibiotics14020167
APA StyleBlersch, B. P., Sax, F. H., Schuster, P., & Fink, B. (2025). Predictive Factors for Risk of Reinfection in Septic Two-Stage Revision of Total Hip and Knee Arthroplasties. Antibiotics, 14(2), 167. https://doi.org/10.3390/antibiotics14020167
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.
