Case Report: Hip arthroplasty after fracture-related joint infection caused by extensively drug-resistant Klebsiella pneumoniae

This case-report focuses on a 23-year-old soldier suffering from a fracture-related hip joint infection (FRI) due to extensively drug-resistant Klebsiella pneumoniae and S. epidermidis. The patient underwent multiple septic revision surgeries including the removal of remaining shrapnel accompanied by last-resort antimicrobial therapy with cefiderocol and colistin. Additionally, the surgeries included repeated tissue sampling for microbiological and histopathological analysis. An antibiotic-loaded cemented filler containing cefiderocol was used to improve local antimicrobial therapy. The biopsies prior to and during hip replacement surgery confirmed successful microbe eradication. Hip arthroplasty restored hip joint function and significantly improved patient's quality of life. The utilization of a trabecular metal shell and a meta-diaphyseally anchored cementless hip stem ensured secure implant fixation and early patient mobilisation. An adjusted biofilm active oral antimicrobial therapy after arthroplasty intervention was continued to prevent early periprosthetic joint infection. This case emphasizes the difficulties of managing FRI and multidrug-resistant pathogens. It contributes valuable insight into navigating complex orthopedic cases while ensuring successful hip arthroplasty outcomes. In conclusion, early interdisciplinary collaboration, appropriate antimicrobial therapy along with tailored surgical interventions are crucial for managing such complex cases successfully.


Introduction
Fracture-related infections (FRI) representing major complications in musculoskeletal surgery resulting in devasting patient burden (1).FRI appear in overall 5% of fractures, assuming over 1.8 mio FRI worldwide per year.In the pathogenesis of FRI Staph.aureus and Staph.epidermidis are the most frequent pathogens, although gram-negative bacteria are frequently identified in FRI related to pelvic and open fractures (2).Polymicrobial infections are common, occurring in up to one third of cases (3,4).
Several risk factors for FRI has already been described, including patient individual factors, open fractures with severe soft tissue trauma and wound contamination with foreign material (5,6).
Recently, armed conflicts have led to a surge in complex musculoskeletal injuries, often involving fracture contamination by foreign material, resulting in high proportions of severe secondary multidrug-resistant tissue infections (7,8).Considering this situation, the combination with an extensive soft-tissue damage due to exploding bombs, grenades and mines creates an even higher therapeutic dilemma (9).In such situations, adequate treatment is crucial, including surgical debridement, foreign body removal as well as antimicrobial therapy to prevent mortality (10).
In case of extensive hip joint injuries caused by gunshots, shrapnel's or explosions at the battlefields, total hip arthroplasty (THA) is often required to restore patients joint function (11,12).
The rising prevalence of multidrug-resistant pathogens is one of the most pressing challenges in medicine of the 21st century (13).Even in orthopaedic surgery, the presence of multi-drug resistant septic arthritis poses a substantial therapeutic challenge (14).Consequently, the complication rates and the risk of periprosthetic joint infection are known to be significantly elevated in the light of previous septic arthritis.Besides intrinsic antibiotic resistance by certain bacteria, acquired resistance by mutation and horizontal gene transfer reducing the therapeutic options significantly (15).The Gram-negative enterobacterial species Klebsiella pneumoniae has gained infamy due to the rising number of severe infections and high mortality rates (16,17).Their mechanism of resistance commonly involves the presence of extended-spectrum β-lactamases (ESBL) and the expression of carbapenemases (18,19).
As a result, last-resort drug therapy is often needed in light of musculoskeletal and implant-associated infections, resulting in a high patient burden due to drug side effects and long-term hospitalization (20)(21)(22).
Consequently, this report seeks to elucidate the interplay between war-related injuries, pelvic FRI due to extensively drugresistant K. pneumoniae, with particular attention to the unique challenges posed by the restricted options for antimicrobial drug therapy as well as surgical arthroplasty interventions.Additionally, we will explore the success and outcomes of hip arthroplasty in this context.
This case analysis offers a distinctive perspective on the intricate challenges and advancements in addressing septic hip arthritis and multidrug-resistant pathogens in orthopedics, emphasizing the context of constrained arthroplasty possibilities.By navigating this complex terrain, we aim to enhance the understanding and advance the approach to managing these complex orthopedic cases, particularly within the realm of war-induced injuries and their ramifications on the success of hip arthroplasty.

Case description
A 23-years old male soldier (BMI 22.2 kg/m 2 , no history of comorbidities) with a complex acetabular and hip joint fracture caused by a shrapnel war injury was admitted to our institution in July 2022.The shrapnel shuttered the left hip joint and caused a bladder injury consecutively.Additionally, the shrapnel exit resulted in an incomplete injury of the right femoral nerve.
Further gunshot wounds resulting in a left tibial plateau fracture as well as a left shuttered elbow and metatarsus fracture.These injuries were initially treated in the patient's home country.
During the admission examination, the cardiopulmonary stable and responsive patient presented with non-irritating skin conditions observed over the left hip joint and the hip joint flexion was limited to 45°.Prior to the first surgical intervention, a comprehensive radiographic assessment, including x-ray and CT scans of the pelvis (Figure 1) and a hip joint aspiration (no bacterial growth) were performed.The CT scan revealed a multi-fragmentary acetabular and proximal femur fracture with pelvic dislocation of osseous fragments.No radiographic signs of bone consolidation were observed months after the initial trauma, raising suspicion of an infection.Therefore, the first surgical intervention consisted of septic debridement, removal of remaining foreign bodies followed by extensive lavage and a girdlestone procedure of the left hip with 5 intraoperative biopsies taken for subsequent microbiological analysis.The initial histopathological assessment from tissue samples taken during the first surgical procedure showed signs of an chronic septic infection.
Antimicrobial therapy with piperacillin-tazobactam and cotrimoxazole was initiated after K. pneumoniae was cultivated from the removed tissue samples by mid-July 2022 (Figure 2).The microbiological examination revealed two carbapenem-resistant K. pneumoniae strains that harbored OXA-48/NDM and OXA-48 carbapenemases (as determined by LAMP (loop-mediated isothermal amplification), respectively.Accordingly, the antimicrobial therapy was changed to cefiderocol, a newly available siderophore cephalosporin (Figure 2).The OXA-48 carrying strain was found to exert susceptibility to ceftolozan-tazobactam and ceftazidime-avibactam, whereas the OXA-48/NDM carrying strain was resistant to these antibiotics.Both strains were resistant to ciprofloxacin but susceptible to colistin and co-trimoxazole in the initial antimicrobial susceptibility testing, hence the strains were categorized as multidrug-resistant (MDR).
While the OXA-48/NMD carrying K. pneumoniae strain remained detectable in the tissue samples until the end of September 2022, the more susceptible OXA-48 carrying strain disappeared from the tissue samples soon after the start of the cefiderocol therapy.Interestingly, while the more resistant OXA-48/NMD carrying strain initially displayed co-trimoxazole sensitivity, it had acquired resistance to this drug by early September 2022.Given that the strain was, in addition, resistant to all beta lactam / beta lactamase inhibitor combinations as well as aminoglycosides, fluoroquinolones, fosfomycin and tigecycline, and retained only susceptibility to cefiderocol and colistin, the strain was re-classified as extensively drug-resistant (XDR).Thus, colistin was added to the ongoing antimicrobial therapy (Figure 2).Additionally, by mid-October 2023, a methicillin-resistant S. epidermidis was subsequently detected in all collected tissue samples, whereas the K. pneumoniae XDR strain could not be cultivated, anymore.Hence, daptomycin was added to the cefiderocol and colistin regimen (Figure 2).
In order to improve the local antimicrobial drug delivery, a drug-eluting customized cemented filler containing gentamicin, vancomycin and cefiderocol was implanted to the left acetabulum und proximal femur (Figures 3A,B).Consecutive blood chemistry analysis was performed three times a week to monitor the antimicrobial therapy as well as possible adverse side effects including potential hepatic and kidney toxicity.
A total of seven septic revision surgeries, including repeated tissue sampling for microbiological and histopathological analysis along with septic debridement, in combination with a local and systemic antimicrobial drug therapy using the last-resort drugs cefiderocol/ colistin and daptomycin were necessary to eradicate the XRD K. pneumoniae and to achieve sufficient wound healing.Additionally, wound conditioning was supported by superficial application of cold physical plasma (CPP).
In a multidisciplinary approach it was consented to allow soft tissue recovery over a period of three months and to continue an oral anti-infective therapy for this duration.However, the resistance profile of the confirmed XDR K. pneumoniae strain was not susceptible to oral antimicrobial suppression therapy, leaving a targeted oral therapy against S. epidermidis only.Therefore, it was decided to start an 3-month oral antimicrobial therapy with doxycycline (Figure 2).Three months later, the patient was readmitted to our institution for the explantation of the drug-eluting cemented filler and another series of biopsies in order to prepare the left hip for arthroplasty (Figures 3C,D).The microbiological examination of the intraoperative biopsies confirmed successful eradication of K. pneumoniae, while S. epidermidis was still Antimicrobial drug therapy over time.p.o. oral application, i.v.intravenous application.detected in extracted tissue samples of the left hip joint.Thus, the intravenous antimicrobial therapy with daptomycin was continued during the hospital stay and we decided to initiate an oral therapy with co-trimoxazole until hip arthroplasty (Figure 2).Another month later, the patient was readmitted to our institution.The patient presented with non-irritating skin conditions over the left hip joint, unremarkable laboratory results and a joint aspiration that showed no bacterial growth after 14 days of incubation.Thus, the primary hip arthroplasty, including intraoperative tissue sampling for microbiological analysis, was performed using a trabecular metal shell (TM modular multihole, Zimmer Biomet, Warsaw, Indiana) with an additional screw fixation in predetermined positions to ensure primary shell stability in combination with a meta-diaphyseally anchored hip stem (Smith + Nephew, Watford, UK) (Figure 4).After the surgical intervention the patient underwent regular clinical follow-up and an additional radiographic assessment 6 weeks and 3 month thereafter.The antimicrobial therapy was continued orally for 6 weeks with Rifampicin and Levofloxacin (Figure 2).Three month postoperatively, the patient presented pain free, walking without any assistive device.The 6 month clinical follow-up revealed implant survival without signs of periprosthetic joint infection.

Discussion
A shrapnel war injury shattering the hip joint and causing a secondary polymicrobial multidrug-resistant joint infection is a devasting condition in young patients.Furthermore, the management of FRI could be challenging due to bone defects as well as patient individual and environmental factors (23).
In this case report we reported a successful therapy of a polymicrobial FRI caused by extensively-drug resistant pathogens.Polymicrobial FRI occur in up to 30% of FRI cases overall, with Staph.epidermidis representing one of the most frequent pathogens and K. pneumoniae often associated with pelvic fracture, respectively (2).However, the extensive antimicrobial resistance of both pathogens in this case made the treatment even more challenging.
To achieve infection eradication, FRI therapy has to combine a sufficient surgical intervention with an appropriate antimicrobial therapy (1).Prompt surgical debridement in line with an intravenous antimicrobial therapy is crucial for infection control and the postoperative outcome (24,25).
The duration of antimicrobial therapy in FRI is still controversial with common regimes between 6 and 12 weeks (26).Even when a recent study highlighted comparable outcomes between short-term and prolonged intravenous therapy, the presence of extensively drug-resistant pathogens in this case-report hindered early oral therapy (27).Therefore, intravenous therapy was continued in accordance to current treatment recommendations until microbial tissue sample remained negative (26).
Due to changes in pathogen species or acquired resistance, therapy adjustments are often necessary in such complex cases.Besides intravenous antimicrobial treatment, the local application of antibiotic-loaded bone cement has been shown to be beneficial for infection control (28,29).In line with data by Morgenstern et al., who reported a significant reduction of infection rates due to local antibiotic application in open limb fractures, an antibioticloaded cemented filler was utilized to improve local antimicrobial therapy in our patient (30).Vancomycin, gentamicin and tobramycin are the most commonly added antibiotics in bone cement (31).Nevertheless, in some cases an individual composition is needed to address the infecting microbes.In this case report, an individualized antibiotic-loaded bone cement filler containing gentamicin, vancomycin and cefiderocol was used for local application and aided to successful infection control.
The successful cefiderocol application in bone cement has not been reported, yet.Even though this case illustrates the broad possibilities of cefiderocol application, its utilization as rescue drug in case of musculoskeletal infection is rarely studied.Only a small number of case series and case reports summarizes the cefiderocol mediated, successful treatment of infection due to multi-drug resistant gram-negative bacteria, and indicates its therapeutic potential to fight musculoskeletal infections (32-34).
Additionally, after repeated surgical interventions, CPP was used to support wound healing in this patient case.Recently, its feasibility in orthopaedic surgery has been reviewed and highlighted several promising applications (35).Particularly remarkable is CPPs effective action against biofilm and multidrug-resistent germs (36,37).
After the successful infection eradication, the implantation of a total hip arthroplasty restored patients joint function and mobility.Displaced proximal femoral fractures are known to be at high risk of avascular necrosis resulting in an early hip arthritis (38, 39).Thus, THA has been shown a valuable treatment option to restore the joint function even in young patients, especially in the presence of a concomitant displaced acetabular fracture (40,41).
In this case report a trabecular metal shell and a metadiaphyseally anchored cementless hip stem was used.Nevertheless, there is still controversy in arthroplasty regarding implant design and mode of fixation, with advantages as well as  disadvantages for cemented as well as cementless fixation (42,43).The potential risk of greater loss of femoral bone stock when stem revision of a cemented stem become necessary could be an argument for using a cementless stem in our young patient, but the even higher risk of periprosthetic fracture in cementless stems has to keep in mind (43,44).However, cementless femoral fixation has been shown to ensure a secure fixation and significantly improve the patient-reported outcome in young patients (45,46).It has to be mentioned that not only diaphyseally anchored femoral stems have to be used in revision total hip arthroplasty.Recently, a small cohort study found good clinical outcome after revision total hip arthroplasty using a short femoral stem design (47).
Taken together, the objective of this case report was to highlight the crucial interplay between hip surgical intervention and long-term local as well as systemic antimicrobial therapy for the successful treatment of open FRI.Furthermore, we highlight the need for further research related to the treatment of multidrug resistant musculoskeletal infections emphasizing the necessity to responsibly handle available rescue therapeutics.
However several limitations of this case description has to be noted.First of all, due to the uniqueness and restricted scope of a single case, there is limited generalizability.This case report focuses on a young patient without history of comorbidities.This could influence the patient-outcome significantly.Second, the infection-free implant survival is still a short-term observation and long-term data are needed to improve the strength of the described treatment strategy.Finally, the reported therapeutic approach is highly cost and recourse intensive and its implementation could only be feasible in specialized medical centers.

Summary
Overall, we report a successful total hip arthroplasty after a complex acetabular and femoral head war injury worsened by a difficult-to-treat polymicrobial joint infection.This case description highlight the importance of interdisciplinary collaboration in such complex cases as well as the excellent functional outcome properties of a staged hip arthroplasty intervention.

FIGURE 3
FIGURE 3 Pelvic x-rays (A,B) showing the customized cemented filler containing gentamicin, vancomycin and cefiderocol.Foreign body removal was performed before hip arthroplasty implantation (C,D).

FIGURE 4
FIGURE 4Pelvic x-rays (A,B) illustrating the postoperative result after hip arthroplasty implantation.