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High cure rate of periprosthetic hip joint infection with multidisciplinary team approach using standardized two-stage exchange

High cure rate of periprosthetic hip joint infection with multidisciplinary team approach using... Background: Two-stage exchange arthroplasty is still the preferred treatment choice for chronic PJI. However, the results remain unpredictable. We analyzed the treatment success of patients with an infected hip prosthesis, who were treated according to a standardized algorithm with a multidisciplinary team approach and evaluated with a strict definition of failure. Methods: In this single-center prospective cohort study, all hip PJI episodes from March 2013 to May 2015 were included. Treatment failure was assessed according to the Delphi-based consensus definition. The Kaplan-Meier survival method was used to estimate the probability of infection-free survival. Patients were dichotomized into two groups depending on the number of previous septic revisions, duration of prosthesis-free interval, positive culture with difficult-to-treat microorganisms, microbiology at explantation, and microbiology at reimplantation. Results: Eighty-four patients with hip PJI were the subject of this study. The most common isolated microorganisms were coagulase-negative staphylococci (CNS) followed by Staphylococcus aureus and Propionibacterium.Almost half of the study cohort (46%) had at least one previous septic revision before admission. The Kaplan-Meier estimated infection-free survival after 3 years was 89.3% (95% CI, 80% to 94%) with 30 patients at risk. The mean follow-up was 33.1 months (range, 24–48 months) with successful treatment of PJI. There were no statistical differences in infect eradication rate among the dichotomized groups. Conclusions: High infect eradication rates were achieved in a challenging cohort using a standardized two-stage exchange supported by a multidisciplinary approach. Keywords: Hip, Outcome, Periprosthetic joint infection, Two-stage exchange Introduction revisions for hip PJI in the USA performed between Periprosthetic joint infection (PJI) is a serious and challen- January 1, 2009, and December 31, 2013 [2]. Although the ging complication following total hip arthroplasty (THA). best treatment option of PJI is unclear, two-stage exchange Despite developments in preventative medicine and iden- arthroplasty is still the preferred treatment choice for tification of multiple risk factors, the incidence of PJI is chronic PJI [4] associated with high eradication rates still around 1% following primary THA [1]. With the around 90% [5–7]. However, results remain unpredictable growing numbers of THA each year [2, 3], the total num- and some recent studies are showing failure rates of > 20% ber of PJI is also rising, with nearly 52,000 registered with a strict definition of success [8–10]. Furthermore, there is still no consensus about the optimal treatment concept in a two-stage exchange arthroplasty. The most * Correspondence: doruk.akguen@charite.de controversial aspects are optimal duration of antibiotic Charité – Universitätsmedizin Berlin, corporate member of Freie Universität therapy, optimal length of prosthesis-free interval, timing Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Center for Musculoskeletal Surgery, Berlin, Germany of reimplantation, antibiotic-free period and aspiration Charite Universitätsmedizin, Augustenburger Platz 1, 13353 Berlin, Germany © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Akgün et al. Journal of Orthopaedic Surgery and Research (2019) 14:78 Page 2 of 8 prior reimplantation, and the role of reimplantation Diagnostic algorithm microbiology [8, 11]. The purpose of this study was to re- Each patient underwent a standardized comprehensive port the outcome of our two-stage revision protocol, in diagnostic algorithm. All patients were evaluated by a which a multi-disciplinary team guides the management thorough physical examination with respect to the clin- of all patients, and all diagnostic and treatment processes ical patient status and soft tissue conditions. Laboratory are based on a standardized algorithm. tests were performed including C-reactive protein (CRP), and plain anteroposterior and lateral radiographs were made. All patients with suspected PJI underwent a Methods diagnostic arthrocentesis. The synovial fluid analysis in- Study design and population cluded total cell count, differential leukocyte count, In this single-center prospectively followed cohort study, culture for aerobic and anaerobic organisms, and histo- all hip PJI episodes from 2013 to 2015 were included, logical analysis. A synovial fluid leukocyte count of more which were treated by a standardized comprehensive than 2000/mm or a finding with more than 70% neu- diagnostic and therapeutic algorithm with two-stage ex- trophils was our cutoff value for the diagnosis of PJI change. Native infected joints, joints with missing data, [18]. A positive histopathology was defined as a mean of joints with mega prostheses, and patients with a ≥ 23 granulocytes per ten high-power fields, correspond- follow-up period less than 24 months were excluded. ing to type 2 or type 3 periprosthetic membrane [19]. In The study protocol was reviewed and approved by the case of a dry tap, patients with chronic painful prosthesis institutional ethics committee (EA4/040/14). underwent a diagnostic surgery to gain at least five peri- prosthetic tissue samples for microbiological and histo- Data collection pathological analysis or a diagnostic explantation when On admission, age, gender, comorbidities, history of the the suspicion of infection was very high. The cultures infected joint, the score of the Charlson comorbidity were always incubated for 14 days. In case of fever or index (CCI) [12], laboratory values such as serum systemic infection signs, blood cultures for aerobic and C-reactive protein (CRP) and blood leukocytes, and anaerobic organisms were obtained and an intensive presumed route of infection (intraoperative versus search for potential primary focus of infection, such as hematogenous) were recorded. In addition, the following infectious endocarditis, dental (periodontitis, periapical data were extracted: number of revision surgeries be- dental abscess, or dental intervention), urogenital, and tween stages, length of hospital stay, total duration of gastrointestinal source, was done. The explanted pros- antimicrobial therapy, serum CRP value at the time of thesis was sent to sonication to increase the accuracy of reimplantation, and microbiological and pathological re- microbiologic diagnosis [20]. sults of revisions and reimplantation. Surgical and antimicrobial treatment Definitions The first stage consisted of removal of all implants, as In this cohort, PJI was diagnosed according to proposed well as infected and necrotic tissue, bone cement, and European Bone and Joint Infection Society (EBJIS) criteria all other foreign material with a following irrigation and [13], since these criteria were used in several outcome debridement of the surrounding tissues. In most epi- studies [14–16]. The definition for successfully treated PJI sodes, a cement spacer was not routinely used, unless was based on the Delphi-based international multidiscip- dead space management or the fixation of a proximal linary consensus [17] and was further modified; treatment femur fracture was necessary. was considered as successful, if all of the following criteria Antibiotic treatment was started intravenously (IV) were fulfilled at the latest follow-up: (i) infection eradica- after taking multiple tissue samples during the explant- tion, characterized by a healed wound without fistula, ation or in the case of patients presenting with sepsis drainage, or pain, and no recurrence of the infection preoperatively after synovial aspiration. Each patient caused by the same organism; (ii) no subsequent surgical underwent a standardized antimicrobial therapy, which intervention for persistent or perioperative infection after was based on a previously published concept [18] under reimplantation surgery; (iii) no occurrence of PJI related the surveillance of our infectious disease specialists [21]. mortality; and (iv) no long-term (> 6 months) antimicro- IV treatment was continued for the first 2 weeks after bial suppression therapy. surgery and followed by an oral regimen, if possible. In Microorganisms such as rifampin-resistant staphylo- case of a persistent infection (discharging wound and/or cocci, enterococci, ciprofloxacin-resistant gram-negative increasing CRP without any other focus and/or local bacteria, and fungi were defined as difficult-to-treat signs of infection), an irrigation and debridement (and (DTT) due to the absence of available antibiofilm-active spacer exchange, if applicable) of the explanted hip joint treatment [18]. was performed. All patients received antibiotics until Akgün et al. Journal of Orthopaedic Surgery and Research (2019) 14:78 Page 3 of 8 reimplantation surgery without an antibiotic-free period Statistical analysis and diagnostic aspiration. A reimplantation was per- Patients were dichotomized into two groups depend- formed, when the wound was healed, soft tissues were ing on the number of previous septic revisions (no ready for surgery, the general status of the patient was previous septic revision vs. ≥1previous septic revi- suitable, and there was no clinical sign of a persisting sion), duration of prosthesis-free interval (short < 6 infection. If DTT microorganisms were isolated, a lon- weeks vs. long > 6 weeks), positive culture with DTT ger prosthesis-free interval (> 6 weeks) was preferred microorganisms (DTT vs. non-DTT), microbiology at [22]. The reimplantation was used in every patient as explantation (polymicrobial vs. monomicrobial), and another opportunity to perform one more thorough de- microbiology at reimplantation (positive vs. negative). bridement of the surrounding soft tissues and bone A two-tailed Fisher’sexact test wasemployed to find prior to placement of the definitive components. Dur- significant differences between dichotomized groups. ing each explantation and reimplantation, at least five The probability of infection-free survival and the re- periprosthetic tissue samples were collected for micro- spective 95% confidence interval (95% CI) was esti- biological analysis. After reimplantation, antibiotics mated using the Kaplan-Meier survival method. were administered for 2 weeks via the intravenous route Statistical analysis was performed using SPSS version followed by an oral biofilm-active (in non-DTT PJI) or 20 software (SPSS Inc., Chicago, IL) and the software non-biofilm-active antimicrobial treatment (in DTT Prism (Version 7.01; GraphPad, La Jolla, CA, USA). PJI) for a total treatment duration of at least 12 weeks A p value < 0.05 was considered significant. with a minimum of 6 weeks’ antimicrobial course after reimplantation. Results A therapy with biofilm-active antibiotics, such as ri- A total of 93 two-stage septic revision hip arthroplasties fampin or fluoroquinolones, was started only after reim- were performed from 2013 to 2015 at our institution. plantation, when all drains were removed, the wound Three patients died due to non-PJI-related causes. One was dry, and the bacterial load was reduced by initial patient from the failure group died due to myocardial in- antimicrobial therapy not to cause the emergence of re- farction. Two further patients died after 8 and 14 sistance [23, 24]. If medically stable, patients received months of follow-up due to an intracerebral hemorrhage antimicrobial therapy at home through a peripherally and cardiorespiratory failure, respectively. The latter two inserted central catheter (PICC) line, when oral anti- patients were excluded from further analysis due to microbial therapy was not possible due to multiple drug short-term follow-up. After applying the exclusion cri- resistance. teria described above, 84 patients with hip PJI were the In case of a relevant positive culture during reim- subject of this study. The presumed route of infection plantation (≥ 2 samples were positive for the same was perioperative in 72 and hematogenous in 12 epi- microorganism), or a polymicrobial infection (or if sodes. Further demographic, clinical, and laboratory the isolated microorganism was the same as the initial characteristics of the cohort are summarized in Table 1. infecting organism even if only one culture was posi- The mean follow-up was 33.1 months (range, 24–48 tive), antimicrobial therapy was continued for 12 months) with successful treatment of PJI. weeks after reimplantation. Otherwise, the standard We identified microorganisms in 73 of 84 cases (88%). therapy was given for 6 weeks after reimplantation as The most common isolated microorganism was planned. A chronic antibiotic suppression was used coagulase-negative staphylococci (CNS) followed by for patients with increased risk of relapse, including a Staphylococcus aureus and Propionibacterium (Table 2). history of multiple joint infections, deficient immune Thirteen patients (16%) underwent at least one revi- system, and comorbidities predisposing to PJI [25], sion surgery during the prosthesis-free interval due to after individualized decision-making through a multi- persistent infection, which was performed once in eight disciplinary team, including infectious disease special- episodes, twice in one episode, three times in two ists, internal medicine specialists, and orthopedic episodes, four times in one episode, and six times in surgeons, who were involved in every stage of PJI another episode. management for each patient. The mean time interval between stages was 8.7 weeks (range, 1–25 weeks). 21.4% of the patients (18 of 84) underwent a reimplantation after a short interval (< 6 Outcome analysis weeks). 21.4% of patients (18 of 84) had a positive cul- Patients were seen in the outpatient clinic after 3, 6, and ture at the time of reimplantation, and six of these 18 12 months and after that period annually. Clinical, labora- patients (33.3%) with a positive culture at reimplantation tory, and radiological evaluation were performed by an underwent a two-stage exchange after a short interval of orthopedic surgeon and an infectious disease specialist. < 6 weeks. The same microorganism was isolated at Akgün et al. Journal of Orthopaedic Surgery and Research (2019) 14:78 Page 4 of 8 Table 1 Patient demographic, clinical, and outcome characteristics Table 2 Microbiology at explantation, reimplantation, and reinfection Variable Hip PJI, n =84 Microorganism No. (%) Age, years∗ 70 ± 9 Explantation, n = 84 CNS 52 (62) CCI (age-adjusted)∗ 4 ± 1.9 S. aureus 13 (15) Previous septic revision 39 (46) Propionibacterium 13 (15) 1 septic revision 17 Enterococcus spp. 11 (13) 2 septic revisions 8 Streptococcus spp. 5 (6) > 2 septic revisions 14 Gram-negative 3 (4) CRP at admission (mg/l)∗ 44.9 ± 76.9 Others 13 (15) Microbiology Reimplantation, n = 18 CNS 14 (78) Monomicrobial 35 (42) S. aureus 2 (11) Polymicrobial 38 (45) Propionibacterium 2 (11) Negative 11 (13) Others 2 (11) Difficult-to-treat 18 (21) Polymicrobial 3 (17) Time to reimplantation (day)∗ 61 ± 29.8 Reinfection, n = 9 Negative 3 (33) Short (< 6 weeks) 18 (21) Klebsiella pneumoniae 2 (22) Long (> 6 weeks) 66 (79) Escherichia coli 1 (11) Surgery in prosthesis-free interval 13 (16) Staphylococcus capitis 1 (11) Total duration of antibiotic therapy (days)∗ 116 ± 35.1 Candida spp. 1 (11) Total length of hospital stay (days)∗ 33.8 ± 17.5 Enterobacter cloacae 1 (11) Positive microbiology at reimplantation 18 (21) CRP at reimplantation (mg/l)∗ 13.6 ± 14.9 Discussion Treatment failure 9 (11.7) Although two-stage exchange arthroplasty is being prac- ∗The values are given as the mean and the standard deviation ticed for more than 20 years in treatment of PJI, results The values are given as the number with the percentage of the group in parentheses remain unpredictable due to the lack of established standardization, and success rates in the literature are reported to be between 76 and 100% [5–8, 26–29] with reimplantation as the initially isolated microorganism in 7 varied definition of failure (Table 4). The lack of consen- of these 18 patients (39%). The Kaplan-Meier-estimated sus regarding what constitutes a successful treatment for infection-free survival after 3 years was 89.3% (95% CI, PJI makes it difficult to compare the results of many 80% to 94%) with 30 patients at risk. The survivorship of studies. Furthermore, the retrospective design and in- these patients is illustrated in Fig. 1. cluding patients without standardized antimicrobial and Interestingly, the microorganisms causing reinfection were in none of the nine failures, the same as isolated initially or at the time of reimplantation. The microbiol- ogy results of explantation, reimplantation, and reinfec- tion are summarized in Table 2. Six of 9 failures were early failures within 4 weeks after reimplantation and underwent an irrigation and debride- ment followed by a 12-week course of antimicrobial treatment. One patient had a reinfection with Candida spp. and underwent a two-stage revision with long-term antimicrobial suppression. One patient had a resection arthroplasty and did not get reimplanted due to low-demand and critical health status. Another patient underwent a further two-stage revision, which failed again, so a reimplantation was not performed due to Fig. 1 Kaplan-Meier survivorship graph showing the infection-free high risk of reinfection. survival of 84 hip PJI patients. The dotted lines represent the 95% There were no statistical differences in infect eradica- confidence intervals tion rate among the dichotomized groups (Table 3). Akgün et al. Journal of Orthopaedic Surgery and Research (2019) 14:78 Page 5 of 8 Table 3 Dichotomized data for the 84 patients A potential disadvantage of two-stage exchange arthroplasty is the high reported mortality. Ibrahim et al. Dichotomized groups Numbers Failure p value [6] showed, despite a high rate of infect eradication, a Previous septic revision 0.29 mortality rate of 15% (19 patients), which was also con- ≥139 6 firmed by Berend et al. [30]. Gomez et al. [10] suggested 045 3 that the success of two-stage revision arthroplasty be DTT 18 3 0.4 considered from the point of explantation rather than Non-DTT 66 6 the following reimplantation to account for failures. Duration of prosthesis-free interval 0.2 Lange et al. [26] also showed in his study that only 63% of his study cohort (82 of 130 hips) was reimplanted. Pa- Short (< 6 weeks) 18 0 tients reimplanted were younger and had lower CCI and Long (> 6 weeks) 66 9 a 68% lower mortality risk in the follow-up period. Un- Microbiology 1.0 like the previous studies, we could perform reimplanta- Polymicrobial 38 4 tion in all of our patients, but one (not involved in the Monomicrobial 35 4 cohort of 93 patients), and only three out of 93 patients Microbiology at reimplantation 0.4 died of causes unrelated to PJI after reimplantation in our short-term follow-up. It is well known that higher Positive 18 3 CCI and patients with previous septic revisions with Negative 66 6 subsequent failure combined with insufficient antimicro- bial treatment are associated with a higher risk of re- surgical treatment algorithm causes inhomogeneous infection and mortality, so, we propose that medical study cohorts, which are difficult to compare [8, 10, optimization of these patients through a multidisciplin- 30–32]. Our study was specifically designed to evalu- ary team prior two-stage revision plays a crucial role in ate the infect eradication outcome in an antimicro- reducing the mortality and failure rate [34]. bially and surgically homogenously treated cohort Our results showed similar eradication rates in epi- with a strict definition of treatment failure. In sodes infected by DTT microorganisms compared to the addition, previous septic revision and multiresistant rest of the cohort. With a long interval as proposed by microorganisms were not set as exclusion criteria. Zimmerli et al. [22], we achieved good eradication rates, Some studies [6, 10, 28] set these characteristics as despite the unavailability of an antibiofilm-active agent. exclusion criteria, as prior revisions and multiresis- In our algorithm, we always treat these microorganisms tancy were reported to be associated with worse out- with a long interval. Furthermore, in individual cases, a comes [29, 33]. This was not confirmed using our long-term suppression therapy can also contribute in re- treatment algorithm. Despite this, our outcome results ducing the risk of a recurrent infection. in a patient cohort where almost every second a pa- Positive culture during reimplantation was evident in tient had a previous septic failure surgery were com- 18 cases without any significantly higher risk for subse- parable with the current literature. quent failure compared to the culture-negative group. Table 4 Reported rates of infection eradication in literature with two-stage exchange Study Number of patients Period of study Definition of failure Rate of infection eradication (%) Chen et al. [5] 155 hips 2001–2010 Repeated operation 91.7 Long-term antibiotics Oussedik et al. [7] 39 hips 1999–2002 Recurrent infection 96 Tan et al. [8] 186 knees 1999–2013 Delphi-based definition [17]76 81 hips Lange et al. [26] 82 hips 2003–2008 Kamme et al. [47] 85.4 Triantafyllopoulos 239 knees 1998–2014 Wound healing problems 91.2 et al. [27] 261 hips Elevated ESR/CRP Long-term suppression Fink et al. [28] 36 hips 2002–2006 Clinical signs of infection 100 CRP more than 10 mg/dl Osteolysis Berend et al. [30] 186 hips 1996–2009 Further surgery for infection 83 Ibrahim et al. [6] 125 hips 2000–2008 Recurrence of infection Leung et al. [48] 50 hips 1998–2006 Recurrence of infection 79 Akgün et al. Journal of Orthopaedic Surgery and Research (2019) 14:78 Page 6 of 8 We were recently able to show in a cohort of patients identified biofilm formation on the sonicated spacers and with hip and knee PJI (same hip patient cohort used also reported the association between an infection of the ce- in this study) that positive culture at reimplantation was ment spacer and poor clinical outcome and significantly independently associated with two times the risk of sub- higher failure and reinfection rate after two-stage ex- sequent failure [16]. Possible reasons for lacking signifi- change arthroplasty [44–46]. Furthermore, in a compari- cance in this study could be the lower number of son study from Marczak et al., the reinfection rate was patients, significantly higher rate of failure in PJI involv- similar in patients with and without spacer and five pa- ing the knee joint, short follow-up, and differences in tients from the spacer group underwent spacer exchange used statistical methods (multivariate regression analysis due to recurrence of infection [43]. Additionally, several vs. Fisher exact test). Tan et al. identified also recently mechanical complications may occur when cement that the risk of treatment failure was significantly higher spacers are used, such as spacer fractures, dislocations, and reinfection occurred earlier for the cases with a and femoral fractures. In our hands, resection arthroplasty positive culture at reimplantation [8]. Unlike these stud- has an important role in two-stage exchange arthroplasty ies, previous studies could not show any association be- with similar success rates in terms of infection control and tween positive culture and worse outcomes [11, 35, 36]. should be considered especially in cases treated with But this seems to be due to the small sample size of shorter intervals and when complications related to these studies. Differently, in our study than in other spacers are expected. studies, patients with a relevant culture at reimplanta- Our study has some limitations. It is not a controlled tion were administered a prolonged antimicrobial treat- but an observational study and all cases were from one ment, which could have prevented some failures. Also, single center. The mean follow-up time of 2 years is con- in a randomized controlled trial, it was shown that the sidered to be only a short time [17], and a longer addition of 3 months of oral antibiotics appeared to im- follow-up is needed not to miss a possible relapse after a prove infection-free survival at short-term follow-up few years. Another limitation includes the relatively [37]. We recommend, therefore, to always implement an small sample size of our study despite the sample being antimicrobial treatment after reimplantation, if possible large for a single center over 3 years, so the missing sig- with antibiofilm-active agents, and treating physicians nificance between dichotomized groups could be attrib- should be aware of possible worse outcomes associated uted to this limitation. with positive cultures at reimplantation. Despite suggestions from many authors, to apply a Conclusion prosthesis free interval of 2–8 weeks followed by an anti- In conclusion, with a standardized therapeutic algorithm biotic holiday of 2 weeks and preoperative aspiration be- using a two-stage exchange arthroplasty, high infect fore proceeding to second stage [4, 38, 39], we postulate eradication rates were achieved, irrespective of risk fac- that a short interval could be as effective in PJI eradica- tors predictive of failure. A multidisciplinary team tion as the long interval in selected patients. The key to should review each patient and compose an individual- success when using short intervals seems to be the avail- ized treatment plan based on a strict algorithm. ability of an antibiofilm-active agent. None of our 18 ep- Abbreviations isodes treated with a short interval had a recurrence of CCI: Charlson comorbidity index; CRP: C-reactive protein; DTT: Difficult-to- infection. We do not recommend waiting for CRP in treat; IV: Intravenously; PJI: Periprosthetic joint infection; THA: Total hip serum to be normalized and an antibiotic-free period arthroplasty with joint aspiration before reimplantation, as cultures Acknowledgements from synovial fluid and CRP seem to be uncertain pa- Not applicable rameters to exclude persistent infection [40–42]. Wait- ing for CRP to normalize and an antibiotic-free period Funding This research did not receive any funding. with joint aspiration prior reimplantation can delay re- implantation unnecessary. Availability of data and materials The implantation of a temporary antibiotic-impregnated The datasets used and/or analysed during the current study are available spacer in the interim period is used worldwide in from the corresponding author on reasonable request. two-stage exchange arthroplasty, since it enables preserva- Authors’ contributions tion of the joint space, ensures high local concentrations DA contributed to the conception and design, acquisition, analysis, and of antibiotics, and the reimplantation sometimes can be interpretation of data, drafting of the manuscript, and final approval of the easier due to the absence of scar tissue in the acetabulum version to be published. MM contributed to the critical revision and final approval of the version to be published. CP also contributed to the critical and medullary canal [43]. Nevertheless, spacers may act as revision and final approval of the version to be published. 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Two stage revision hip arthroplasty in periprosthetic joint infection. Comparison study: with or without the use of a spacer. Int Orthop. 2017;41(11):2253–8. 44. Sorli L, Puig L, Torres-Claramunt R, Gonzalez A, Alier A, Knobel H, et al. The relationship between microbiology results in the second of a two-stage exchange procedure using cement spacers and the outcome after revision total joint replacement for infection: the use of sonication to aid bacteriological analysis. J Bone Joint Surg Br. 2012;94(2):249–53. 45. Mariconda M, Ascione T, Balato G, Rotondo R, Smeraglia F, Costa GG, et al. Sonication of antibiotic-loaded cement spacers in a two-stage revision protocol for infected joint arthroplasty. BMC Musculoskelet Disord. 2013;14:193. 46. Nelson CL, Jones RB, Wingert NC, Foltzer M, Bowen TR. Sonication of antibiotic spacers predicts failure during two-stage revision for prosthetic knee and hip infections. Clin Orthop Relat Res. 2014;472(7):2208–14. 47. Kamme C, Lindberg L. Aerobic and anaerobic bacteria in deep infections after total hip arthroplasty: differential diagnosis between infectious and non-infectious loosening. Clin Orthop Relat Res. 1981;154:201–7. 48. Leung F, Richards CJ, Garbuz DS, Masri BA, Duncan CP. Two-stage total hip arthroplasty: how often does it control methicillin-resistant infection? Clin Orthop Relat Res. 2011;469(4):1009–15. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Orthopaedic Surgery and Research Springer Journals

High cure rate of periprosthetic hip joint infection with multidisciplinary team approach using standardized two-stage exchange

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Springer Journals
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Copyright © 2019 by The Author(s).
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Medicine & Public Health; Orthopedics; Surgical Orthopedics
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1749-799X
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10.1186/s13018-019-1122-0
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Abstract

Background: Two-stage exchange arthroplasty is still the preferred treatment choice for chronic PJI. However, the results remain unpredictable. We analyzed the treatment success of patients with an infected hip prosthesis, who were treated according to a standardized algorithm with a multidisciplinary team approach and evaluated with a strict definition of failure. Methods: In this single-center prospective cohort study, all hip PJI episodes from March 2013 to May 2015 were included. Treatment failure was assessed according to the Delphi-based consensus definition. The Kaplan-Meier survival method was used to estimate the probability of infection-free survival. Patients were dichotomized into two groups depending on the number of previous septic revisions, duration of prosthesis-free interval, positive culture with difficult-to-treat microorganisms, microbiology at explantation, and microbiology at reimplantation. Results: Eighty-four patients with hip PJI were the subject of this study. The most common isolated microorganisms were coagulase-negative staphylococci (CNS) followed by Staphylococcus aureus and Propionibacterium.Almost half of the study cohort (46%) had at least one previous septic revision before admission. The Kaplan-Meier estimated infection-free survival after 3 years was 89.3% (95% CI, 80% to 94%) with 30 patients at risk. The mean follow-up was 33.1 months (range, 24–48 months) with successful treatment of PJI. There were no statistical differences in infect eradication rate among the dichotomized groups. Conclusions: High infect eradication rates were achieved in a challenging cohort using a standardized two-stage exchange supported by a multidisciplinary approach. Keywords: Hip, Outcome, Periprosthetic joint infection, Two-stage exchange Introduction revisions for hip PJI in the USA performed between Periprosthetic joint infection (PJI) is a serious and challen- January 1, 2009, and December 31, 2013 [2]. Although the ging complication following total hip arthroplasty (THA). best treatment option of PJI is unclear, two-stage exchange Despite developments in preventative medicine and iden- arthroplasty is still the preferred treatment choice for tification of multiple risk factors, the incidence of PJI is chronic PJI [4] associated with high eradication rates still around 1% following primary THA [1]. With the around 90% [5–7]. However, results remain unpredictable growing numbers of THA each year [2, 3], the total num- and some recent studies are showing failure rates of > 20% ber of PJI is also rising, with nearly 52,000 registered with a strict definition of success [8–10]. Furthermore, there is still no consensus about the optimal treatment concept in a two-stage exchange arthroplasty. The most * Correspondence: doruk.akguen@charite.de controversial aspects are optimal duration of antibiotic Charité – Universitätsmedizin Berlin, corporate member of Freie Universität therapy, optimal length of prosthesis-free interval, timing Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Center for Musculoskeletal Surgery, Berlin, Germany of reimplantation, antibiotic-free period and aspiration Charite Universitätsmedizin, Augustenburger Platz 1, 13353 Berlin, Germany © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Akgün et al. Journal of Orthopaedic Surgery and Research (2019) 14:78 Page 2 of 8 prior reimplantation, and the role of reimplantation Diagnostic algorithm microbiology [8, 11]. The purpose of this study was to re- Each patient underwent a standardized comprehensive port the outcome of our two-stage revision protocol, in diagnostic algorithm. All patients were evaluated by a which a multi-disciplinary team guides the management thorough physical examination with respect to the clin- of all patients, and all diagnostic and treatment processes ical patient status and soft tissue conditions. Laboratory are based on a standardized algorithm. tests were performed including C-reactive protein (CRP), and plain anteroposterior and lateral radiographs were made. All patients with suspected PJI underwent a Methods diagnostic arthrocentesis. The synovial fluid analysis in- Study design and population cluded total cell count, differential leukocyte count, In this single-center prospectively followed cohort study, culture for aerobic and anaerobic organisms, and histo- all hip PJI episodes from 2013 to 2015 were included, logical analysis. A synovial fluid leukocyte count of more which were treated by a standardized comprehensive than 2000/mm or a finding with more than 70% neu- diagnostic and therapeutic algorithm with two-stage ex- trophils was our cutoff value for the diagnosis of PJI change. Native infected joints, joints with missing data, [18]. A positive histopathology was defined as a mean of joints with mega prostheses, and patients with a ≥ 23 granulocytes per ten high-power fields, correspond- follow-up period less than 24 months were excluded. ing to type 2 or type 3 periprosthetic membrane [19]. In The study protocol was reviewed and approved by the case of a dry tap, patients with chronic painful prosthesis institutional ethics committee (EA4/040/14). underwent a diagnostic surgery to gain at least five peri- prosthetic tissue samples for microbiological and histo- Data collection pathological analysis or a diagnostic explantation when On admission, age, gender, comorbidities, history of the the suspicion of infection was very high. The cultures infected joint, the score of the Charlson comorbidity were always incubated for 14 days. In case of fever or index (CCI) [12], laboratory values such as serum systemic infection signs, blood cultures for aerobic and C-reactive protein (CRP) and blood leukocytes, and anaerobic organisms were obtained and an intensive presumed route of infection (intraoperative versus search for potential primary focus of infection, such as hematogenous) were recorded. In addition, the following infectious endocarditis, dental (periodontitis, periapical data were extracted: number of revision surgeries be- dental abscess, or dental intervention), urogenital, and tween stages, length of hospital stay, total duration of gastrointestinal source, was done. The explanted pros- antimicrobial therapy, serum CRP value at the time of thesis was sent to sonication to increase the accuracy of reimplantation, and microbiological and pathological re- microbiologic diagnosis [20]. sults of revisions and reimplantation. Surgical and antimicrobial treatment Definitions The first stage consisted of removal of all implants, as In this cohort, PJI was diagnosed according to proposed well as infected and necrotic tissue, bone cement, and European Bone and Joint Infection Society (EBJIS) criteria all other foreign material with a following irrigation and [13], since these criteria were used in several outcome debridement of the surrounding tissues. In most epi- studies [14–16]. The definition for successfully treated PJI sodes, a cement spacer was not routinely used, unless was based on the Delphi-based international multidiscip- dead space management or the fixation of a proximal linary consensus [17] and was further modified; treatment femur fracture was necessary. was considered as successful, if all of the following criteria Antibiotic treatment was started intravenously (IV) were fulfilled at the latest follow-up: (i) infection eradica- after taking multiple tissue samples during the explant- tion, characterized by a healed wound without fistula, ation or in the case of patients presenting with sepsis drainage, or pain, and no recurrence of the infection preoperatively after synovial aspiration. Each patient caused by the same organism; (ii) no subsequent surgical underwent a standardized antimicrobial therapy, which intervention for persistent or perioperative infection after was based on a previously published concept [18] under reimplantation surgery; (iii) no occurrence of PJI related the surveillance of our infectious disease specialists [21]. mortality; and (iv) no long-term (> 6 months) antimicro- IV treatment was continued for the first 2 weeks after bial suppression therapy. surgery and followed by an oral regimen, if possible. In Microorganisms such as rifampin-resistant staphylo- case of a persistent infection (discharging wound and/or cocci, enterococci, ciprofloxacin-resistant gram-negative increasing CRP without any other focus and/or local bacteria, and fungi were defined as difficult-to-treat signs of infection), an irrigation and debridement (and (DTT) due to the absence of available antibiofilm-active spacer exchange, if applicable) of the explanted hip joint treatment [18]. was performed. All patients received antibiotics until Akgün et al. Journal of Orthopaedic Surgery and Research (2019) 14:78 Page 3 of 8 reimplantation surgery without an antibiotic-free period Statistical analysis and diagnostic aspiration. A reimplantation was per- Patients were dichotomized into two groups depend- formed, when the wound was healed, soft tissues were ing on the number of previous septic revisions (no ready for surgery, the general status of the patient was previous septic revision vs. ≥1previous septic revi- suitable, and there was no clinical sign of a persisting sion), duration of prosthesis-free interval (short < 6 infection. If DTT microorganisms were isolated, a lon- weeks vs. long > 6 weeks), positive culture with DTT ger prosthesis-free interval (> 6 weeks) was preferred microorganisms (DTT vs. non-DTT), microbiology at [22]. The reimplantation was used in every patient as explantation (polymicrobial vs. monomicrobial), and another opportunity to perform one more thorough de- microbiology at reimplantation (positive vs. negative). bridement of the surrounding soft tissues and bone A two-tailed Fisher’sexact test wasemployed to find prior to placement of the definitive components. Dur- significant differences between dichotomized groups. ing each explantation and reimplantation, at least five The probability of infection-free survival and the re- periprosthetic tissue samples were collected for micro- spective 95% confidence interval (95% CI) was esti- biological analysis. After reimplantation, antibiotics mated using the Kaplan-Meier survival method. were administered for 2 weeks via the intravenous route Statistical analysis was performed using SPSS version followed by an oral biofilm-active (in non-DTT PJI) or 20 software (SPSS Inc., Chicago, IL) and the software non-biofilm-active antimicrobial treatment (in DTT Prism (Version 7.01; GraphPad, La Jolla, CA, USA). PJI) for a total treatment duration of at least 12 weeks A p value < 0.05 was considered significant. with a minimum of 6 weeks’ antimicrobial course after reimplantation. Results A therapy with biofilm-active antibiotics, such as ri- A total of 93 two-stage septic revision hip arthroplasties fampin or fluoroquinolones, was started only after reim- were performed from 2013 to 2015 at our institution. plantation, when all drains were removed, the wound Three patients died due to non-PJI-related causes. One was dry, and the bacterial load was reduced by initial patient from the failure group died due to myocardial in- antimicrobial therapy not to cause the emergence of re- farction. Two further patients died after 8 and 14 sistance [23, 24]. If medically stable, patients received months of follow-up due to an intracerebral hemorrhage antimicrobial therapy at home through a peripherally and cardiorespiratory failure, respectively. The latter two inserted central catheter (PICC) line, when oral anti- patients were excluded from further analysis due to microbial therapy was not possible due to multiple drug short-term follow-up. After applying the exclusion cri- resistance. teria described above, 84 patients with hip PJI were the In case of a relevant positive culture during reim- subject of this study. The presumed route of infection plantation (≥ 2 samples were positive for the same was perioperative in 72 and hematogenous in 12 epi- microorganism), or a polymicrobial infection (or if sodes. Further demographic, clinical, and laboratory the isolated microorganism was the same as the initial characteristics of the cohort are summarized in Table 1. infecting organism even if only one culture was posi- The mean follow-up was 33.1 months (range, 24–48 tive), antimicrobial therapy was continued for 12 months) with successful treatment of PJI. weeks after reimplantation. Otherwise, the standard We identified microorganisms in 73 of 84 cases (88%). therapy was given for 6 weeks after reimplantation as The most common isolated microorganism was planned. A chronic antibiotic suppression was used coagulase-negative staphylococci (CNS) followed by for patients with increased risk of relapse, including a Staphylococcus aureus and Propionibacterium (Table 2). history of multiple joint infections, deficient immune Thirteen patients (16%) underwent at least one revi- system, and comorbidities predisposing to PJI [25], sion surgery during the prosthesis-free interval due to after individualized decision-making through a multi- persistent infection, which was performed once in eight disciplinary team, including infectious disease special- episodes, twice in one episode, three times in two ists, internal medicine specialists, and orthopedic episodes, four times in one episode, and six times in surgeons, who were involved in every stage of PJI another episode. management for each patient. The mean time interval between stages was 8.7 weeks (range, 1–25 weeks). 21.4% of the patients (18 of 84) underwent a reimplantation after a short interval (< 6 Outcome analysis weeks). 21.4% of patients (18 of 84) had a positive cul- Patients were seen in the outpatient clinic after 3, 6, and ture at the time of reimplantation, and six of these 18 12 months and after that period annually. Clinical, labora- patients (33.3%) with a positive culture at reimplantation tory, and radiological evaluation were performed by an underwent a two-stage exchange after a short interval of orthopedic surgeon and an infectious disease specialist. < 6 weeks. The same microorganism was isolated at Akgün et al. Journal of Orthopaedic Surgery and Research (2019) 14:78 Page 4 of 8 Table 1 Patient demographic, clinical, and outcome characteristics Table 2 Microbiology at explantation, reimplantation, and reinfection Variable Hip PJI, n =84 Microorganism No. (%) Age, years∗ 70 ± 9 Explantation, n = 84 CNS 52 (62) CCI (age-adjusted)∗ 4 ± 1.9 S. aureus 13 (15) Previous septic revision 39 (46) Propionibacterium 13 (15) 1 septic revision 17 Enterococcus spp. 11 (13) 2 septic revisions 8 Streptococcus spp. 5 (6) > 2 septic revisions 14 Gram-negative 3 (4) CRP at admission (mg/l)∗ 44.9 ± 76.9 Others 13 (15) Microbiology Reimplantation, n = 18 CNS 14 (78) Monomicrobial 35 (42) S. aureus 2 (11) Polymicrobial 38 (45) Propionibacterium 2 (11) Negative 11 (13) Others 2 (11) Difficult-to-treat 18 (21) Polymicrobial 3 (17) Time to reimplantation (day)∗ 61 ± 29.8 Reinfection, n = 9 Negative 3 (33) Short (< 6 weeks) 18 (21) Klebsiella pneumoniae 2 (22) Long (> 6 weeks) 66 (79) Escherichia coli 1 (11) Surgery in prosthesis-free interval 13 (16) Staphylococcus capitis 1 (11) Total duration of antibiotic therapy (days)∗ 116 ± 35.1 Candida spp. 1 (11) Total length of hospital stay (days)∗ 33.8 ± 17.5 Enterobacter cloacae 1 (11) Positive microbiology at reimplantation 18 (21) CRP at reimplantation (mg/l)∗ 13.6 ± 14.9 Discussion Treatment failure 9 (11.7) Although two-stage exchange arthroplasty is being prac- ∗The values are given as the mean and the standard deviation ticed for more than 20 years in treatment of PJI, results The values are given as the number with the percentage of the group in parentheses remain unpredictable due to the lack of established standardization, and success rates in the literature are reported to be between 76 and 100% [5–8, 26–29] with reimplantation as the initially isolated microorganism in 7 varied definition of failure (Table 4). The lack of consen- of these 18 patients (39%). The Kaplan-Meier-estimated sus regarding what constitutes a successful treatment for infection-free survival after 3 years was 89.3% (95% CI, PJI makes it difficult to compare the results of many 80% to 94%) with 30 patients at risk. The survivorship of studies. Furthermore, the retrospective design and in- these patients is illustrated in Fig. 1. cluding patients without standardized antimicrobial and Interestingly, the microorganisms causing reinfection were in none of the nine failures, the same as isolated initially or at the time of reimplantation. The microbiol- ogy results of explantation, reimplantation, and reinfec- tion are summarized in Table 2. Six of 9 failures were early failures within 4 weeks after reimplantation and underwent an irrigation and debride- ment followed by a 12-week course of antimicrobial treatment. One patient had a reinfection with Candida spp. and underwent a two-stage revision with long-term antimicrobial suppression. One patient had a resection arthroplasty and did not get reimplanted due to low-demand and critical health status. Another patient underwent a further two-stage revision, which failed again, so a reimplantation was not performed due to Fig. 1 Kaplan-Meier survivorship graph showing the infection-free high risk of reinfection. survival of 84 hip PJI patients. The dotted lines represent the 95% There were no statistical differences in infect eradica- confidence intervals tion rate among the dichotomized groups (Table 3). Akgün et al. Journal of Orthopaedic Surgery and Research (2019) 14:78 Page 5 of 8 Table 3 Dichotomized data for the 84 patients A potential disadvantage of two-stage exchange arthroplasty is the high reported mortality. Ibrahim et al. Dichotomized groups Numbers Failure p value [6] showed, despite a high rate of infect eradication, a Previous septic revision 0.29 mortality rate of 15% (19 patients), which was also con- ≥139 6 firmed by Berend et al. [30]. Gomez et al. [10] suggested 045 3 that the success of two-stage revision arthroplasty be DTT 18 3 0.4 considered from the point of explantation rather than Non-DTT 66 6 the following reimplantation to account for failures. Duration of prosthesis-free interval 0.2 Lange et al. [26] also showed in his study that only 63% of his study cohort (82 of 130 hips) was reimplanted. Pa- Short (< 6 weeks) 18 0 tients reimplanted were younger and had lower CCI and Long (> 6 weeks) 66 9 a 68% lower mortality risk in the follow-up period. Un- Microbiology 1.0 like the previous studies, we could perform reimplanta- Polymicrobial 38 4 tion in all of our patients, but one (not involved in the Monomicrobial 35 4 cohort of 93 patients), and only three out of 93 patients Microbiology at reimplantation 0.4 died of causes unrelated to PJI after reimplantation in our short-term follow-up. It is well known that higher Positive 18 3 CCI and patients with previous septic revisions with Negative 66 6 subsequent failure combined with insufficient antimicro- bial treatment are associated with a higher risk of re- surgical treatment algorithm causes inhomogeneous infection and mortality, so, we propose that medical study cohorts, which are difficult to compare [8, 10, optimization of these patients through a multidisciplin- 30–32]. Our study was specifically designed to evalu- ary team prior two-stage revision plays a crucial role in ate the infect eradication outcome in an antimicro- reducing the mortality and failure rate [34]. bially and surgically homogenously treated cohort Our results showed similar eradication rates in epi- with a strict definition of treatment failure. In sodes infected by DTT microorganisms compared to the addition, previous septic revision and multiresistant rest of the cohort. With a long interval as proposed by microorganisms were not set as exclusion criteria. Zimmerli et al. [22], we achieved good eradication rates, Some studies [6, 10, 28] set these characteristics as despite the unavailability of an antibiofilm-active agent. exclusion criteria, as prior revisions and multiresis- In our algorithm, we always treat these microorganisms tancy were reported to be associated with worse out- with a long interval. Furthermore, in individual cases, a comes [29, 33]. This was not confirmed using our long-term suppression therapy can also contribute in re- treatment algorithm. Despite this, our outcome results ducing the risk of a recurrent infection. in a patient cohort where almost every second a pa- Positive culture during reimplantation was evident in tient had a previous septic failure surgery were com- 18 cases without any significantly higher risk for subse- parable with the current literature. quent failure compared to the culture-negative group. Table 4 Reported rates of infection eradication in literature with two-stage exchange Study Number of patients Period of study Definition of failure Rate of infection eradication (%) Chen et al. [5] 155 hips 2001–2010 Repeated operation 91.7 Long-term antibiotics Oussedik et al. [7] 39 hips 1999–2002 Recurrent infection 96 Tan et al. [8] 186 knees 1999–2013 Delphi-based definition [17]76 81 hips Lange et al. [26] 82 hips 2003–2008 Kamme et al. [47] 85.4 Triantafyllopoulos 239 knees 1998–2014 Wound healing problems 91.2 et al. [27] 261 hips Elevated ESR/CRP Long-term suppression Fink et al. [28] 36 hips 2002–2006 Clinical signs of infection 100 CRP more than 10 mg/dl Osteolysis Berend et al. [30] 186 hips 1996–2009 Further surgery for infection 83 Ibrahim et al. [6] 125 hips 2000–2008 Recurrence of infection Leung et al. [48] 50 hips 1998–2006 Recurrence of infection 79 Akgün et al. Journal of Orthopaedic Surgery and Research (2019) 14:78 Page 6 of 8 We were recently able to show in a cohort of patients identified biofilm formation on the sonicated spacers and with hip and knee PJI (same hip patient cohort used also reported the association between an infection of the ce- in this study) that positive culture at reimplantation was ment spacer and poor clinical outcome and significantly independently associated with two times the risk of sub- higher failure and reinfection rate after two-stage ex- sequent failure [16]. Possible reasons for lacking signifi- change arthroplasty [44–46]. Furthermore, in a compari- cance in this study could be the lower number of son study from Marczak et al., the reinfection rate was patients, significantly higher rate of failure in PJI involv- similar in patients with and without spacer and five pa- ing the knee joint, short follow-up, and differences in tients from the spacer group underwent spacer exchange used statistical methods (multivariate regression analysis due to recurrence of infection [43]. Additionally, several vs. Fisher exact test). Tan et al. identified also recently mechanical complications may occur when cement that the risk of treatment failure was significantly higher spacers are used, such as spacer fractures, dislocations, and reinfection occurred earlier for the cases with a and femoral fractures. In our hands, resection arthroplasty positive culture at reimplantation [8]. Unlike these stud- has an important role in two-stage exchange arthroplasty ies, previous studies could not show any association be- with similar success rates in terms of infection control and tween positive culture and worse outcomes [11, 35, 36]. should be considered especially in cases treated with But this seems to be due to the small sample size of shorter intervals and when complications related to these studies. Differently, in our study than in other spacers are expected. studies, patients with a relevant culture at reimplanta- Our study has some limitations. It is not a controlled tion were administered a prolonged antimicrobial treat- but an observational study and all cases were from one ment, which could have prevented some failures. Also, single center. The mean follow-up time of 2 years is con- in a randomized controlled trial, it was shown that the sidered to be only a short time [17], and a longer addition of 3 months of oral antibiotics appeared to im- follow-up is needed not to miss a possible relapse after a prove infection-free survival at short-term follow-up few years. Another limitation includes the relatively [37]. We recommend, therefore, to always implement an small sample size of our study despite the sample being antimicrobial treatment after reimplantation, if possible large for a single center over 3 years, so the missing sig- with antibiofilm-active agents, and treating physicians nificance between dichotomized groups could be attrib- should be aware of possible worse outcomes associated uted to this limitation. with positive cultures at reimplantation. Despite suggestions from many authors, to apply a Conclusion prosthesis free interval of 2–8 weeks followed by an anti- In conclusion, with a standardized therapeutic algorithm biotic holiday of 2 weeks and preoperative aspiration be- using a two-stage exchange arthroplasty, high infect fore proceeding to second stage [4, 38, 39], we postulate eradication rates were achieved, irrespective of risk fac- that a short interval could be as effective in PJI eradica- tors predictive of failure. A multidisciplinary team tion as the long interval in selected patients. The key to should review each patient and compose an individual- success when using short intervals seems to be the avail- ized treatment plan based on a strict algorithm. ability of an antibiofilm-active agent. None of our 18 ep- Abbreviations isodes treated with a short interval had a recurrence of CCI: Charlson comorbidity index; CRP: C-reactive protein; DTT: Difficult-to- infection. We do not recommend waiting for CRP in treat; IV: Intravenously; PJI: Periprosthetic joint infection; THA: Total hip serum to be normalized and an antibiotic-free period arthroplasty with joint aspiration before reimplantation, as cultures Acknowledgements from synovial fluid and CRP seem to be uncertain pa- Not applicable rameters to exclude persistent infection [40–42]. Wait- ing for CRP to normalize and an antibiotic-free period Funding This research did not receive any funding. with joint aspiration prior reimplantation can delay re- implantation unnecessary. Availability of data and materials The implantation of a temporary antibiotic-impregnated The datasets used and/or analysed during the current study are available spacer in the interim period is used worldwide in from the corresponding author on reasonable request. two-stage exchange arthroplasty, since it enables preserva- Authors’ contributions tion of the joint space, ensures high local concentrations DA contributed to the conception and design, acquisition, analysis, and of antibiotics, and the reimplantation sometimes can be interpretation of data, drafting of the manuscript, and final approval of the easier due to the absence of scar tissue in the acetabulum version to be published. MM contributed to the critical revision and final approval of the version to be published. CP also contributed to the critical and medullary canal [43]. Nevertheless, spacers may act as revision and final approval of the version to be published. TW contributed to a foreign body to which microorganisms may adhere, the conception and design, critical revision, and final approval of the version grow, and maintain infection [44, 45]. Several studies to be published. All authors read and approved the final manuscript. Akgün et al. Journal of Orthopaedic Surgery and Research (2019) 14:78 Page 7 of 8 Ethics approval and consent to participate 18. Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J The study protocol was reviewed and approved by the ethics committee Med. 2004;351(16):1645–54. Charite Universitätsmedizin (EA4/040/14). No consent to participate was 19. Krenn V, Morawietz L, Perino G, Kienapfel H, Ascherl R, Hassenpflug GJ, et al. needed. Revised histopathological consensus classification of joint implant related pathology. Pathol Res Pract. 2014;210(12):779–86. 20. Trampuz A, Piper KE, Jacobson MJ, Hanssen AD, Unni KK, Osmon DR, et al. 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Published: Mar 13, 2019

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