Biofilm-active antibiotic treatment improves the outcome of knee periprosthetic joint infection: Results from a 6-year prospective cohort study

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Biofilm-active antibiotic treatment improved the outcome of knee periprosthetic joint infection: Results from a 6-year prospective cohort ¨ Max Gellert , Sebastian Hardt , Karolin Koder , Nora Renz , Carsten Perka , Andrej Trampuz PII: DOI: Reference:

S0924-8579(20)30043-1 https://doi.org/10.1016/j.ijantimicag.2020.105904 ANTAGE 105904

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International Journal of Antimicrobial Agents

Received date: Accepted date:

16 April 2019 11 January 2020

¨ Please cite this article as: Max Gellert , Sebastian Hardt , Karolin Koder , Nora Renz , Carsten Perka , Andrej Trampuz , Biofilm-active antibiotic treatment improved the outcome of knee periprosthetic joint infection: Results from a 6-year prospective cohort, International Journal of Antimicrobial Agents (2020), doi: https://doi.org/10.1016/j.ijantimicag.2020.105904

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Highlights – International Journal of Antimicrobial Agents 

The infection-free survival after 1 and 2 years was significantly better for patients who received biofilm-active antibiotics than for those who did not.

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In addition, biofilm-active antibiotic treatment was associated with lower pain intensity and better joint function

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The role of biofilm-active antibiotics needs to be validated in larger cohort studies.

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Biofilm-active antibiotic treatment improved the outcome of knee periprosthetic joint infection: Results from a 6-year prospective cohort

Max Gellert1¶, Sebastian Hardt1¶, Karolin Köder1, Nora Renz1, Carsten Perka1, Andrej Trampuz1*

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Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin,

Humboldt-Universität zu Berlin, and Berlin Institute of Health, Center for Musculoskeletal Surgery (CMSC), Berlin, Germany,

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Both authors contributed equally to this work.

* Corresponding author E-mail: [email protected] (AT) Center for Musculoskeletal Surgery Charité - Universitätsmedizin Berlin Charitéplatz 1, D-10117 Berlin, Germany Phone: +49 30 450 615 073

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Abstract Biofilm-active antibiotics are suggested to improve the outcome in periprosthetic joint infection (PJI). However, the type, dose and duration of antibiotic treatment is rarely specified and their impact on the outcome is unknown. In this prospective cohort study, we compared the infection and functional outcome in patients with knee PJI treated with and without biofilm-active antibiotics. The infection and functional outcome were evaluated by the Kaplan-Meier survival method to estimate the probability of infection-free survival; comparison between subgroups was performed by log-rank test. The influence of variables on the survival probability was analyzed using univariate and multivariate Cox proportional-hazards regression models. The functional outcome was evaluated by pain intensity and the Knee Injury and Osteoarthritis Outcome Score (KOOS). Of 131 patients, 55 (42%) were treated with and 76 patients (58%) without biofilm-active antibiotics. At follow-up with a median of 3.7 years (range, 2.0-7.6 years), the infection-free survival probability was 74% (95% CI, 61%to 85%) after 1 year and 56% (95% CI, 47% to 66%) after 2 years. The infection-free survival after 1 year was better for patients who received biofilm-active antibiotics than for those who did not (83% vs. 70%, p = 0.040) and remained superior after 2 years (67% vs. 48%, p = 0.038). In addition, biofilm-active antibiotic treatment was associated with lower pain intensity (p = 0.006) and higher KOOS in all five subscales. In patients with knee PJI, biofilm-active antibiotic therapy was associated with better infection outcome, lower pain intensity and better joint function.

Keywords: Periprosthetic joint infection; biofilm; antibiotic treatment; knee prosthesis.

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1. Introduction Periprosthetic joint infection (PJI) occurs in 1% and 2% after total knee arthroplasty (TKA) [1] and is associated with considerable morbidity and healthcare costs [2-5]. The treatment goal is the eradication of the biofilm and thereby cure of infection, at the same time achieving a pain-free and functional prosthetic joint. While surgical treatment is well standardized, the role of antibiotics remains controversial, poorly evaluated in used very heterogeneously [6]. In most studies, used antibiotics were not specified, nor their impact on the treatment outcome analyzed. Since the formation of biofilms plays a crucial role in the pathogenesis of PJI, antibiotic treatment with biofilm-active antibiotics was suggested by many authors [2, 7]. Biofilm bacteria are up to 1000 times more resistant than their planktonic counterparts when antibiotics lacking biofilm activity are used [8-10]. While biofilmactive antibiotics were shown to eradicate “young” (immature) biofilms [10], the clinical evidence supporting their role in the treatment of PJI is scarce [11, 12]. Nevertheless, many authors recommend the use of biofilm-active antibiotics in treatment guidelines, which may be associated with higher rate of adverse effects, risk of resistance emergence and medical costs. In this study we compared the infection and functional outcome of knee PJI treated with and without biofilm-active antibiotics. Biofilm-active antibiotics were defined according to in vitro, experimental and limited number of clinical studies and are summarized in the “Pocket Guide to Diagnosis and Treatment of PJI” (Supplementary material). We hypothesized that patients treated with biofilm-active antibiotics had a better infection and functional outcome, as determined by the infection-free probability, pain intensity and joint function.

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2. Material and methods 2.1. Ethics statement The study protocol was approved by the institutional ethical committee (EA/040/14) and was performed in accordance with the Declaration of Helsinki. The study was registered with the public clinical trial identification NCT02530229 at https://www.clinicaltrials.gov.

2.2. Study design This prospective cohort study was conducted in a tertiary healthcare center, providing advanced specialty care to a population of about four million inhabitants. The definition criteria for PJI, diagnostic procedures and surgical treatment algorithm remained unchanged during the complete study period (2011-2016). Whereas in the first study period (2011-2013) no biofilm-active antibiotics were used, biofilm-active antibiotics were introduced in the second study period (2014-2016), following newly introduced institutional guidelines, summarized in the “Pocket Guide to Diagnosis and Treatment of PJI” (Supplementary material).

2.3. Study population Consecutive patients with knee PJI treated at our institution between January 2011 and December 2016 were included in the prospective cohort. Patients were identified by using the institutional electronic patient documentation system. The patient could be included more than once, if the interval between PJI episodes was at least 24 months and the isolated pathogen was different. Patients with difficult-to-treat pathogens, such as rifampin-resistant staphylococci, ciprofloxacin-resistant gramnegative and fungi, were excluded.

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2.4. Data collection Using a case report form the following data was extracted: age, gender, height, weight, date of primary implantation, previous surgical interventions, length of hospital stay, pathogenesis of infection (perioperative, haematogenous or contiguous), signs and symptoms (fever, joint pain, sinus tract, range of motion), type and date of surgical interventions, radiological findings, laboratory findings, microbiologic results, histopathology results, antimicrobial and surgical therapy, treatment outcome. The patients were evaluated in the outpatient clinic by an orthopedic surgeon (S.H., T.P.) and infectious diseases specialist (A.T., N.R.) at 3, 6, 12 and 24 months after surgery. Physical exam, laboratory studies and x-ray were performed, and information on subsequent surgeries, Visual Analog Scale (VAS) for pain and the Knee Injury and Osteoarthritis Outcome Score (KOOS) was collected [13]. If the patient did not appear for the scheduled appointment, he or she, the relatives or the general practitioner was contacted by phone or email.

2.5. Definition of infection PJI was defined when at least one of the following criteria was fulfilled [14]: (i) visible purulence of a preoperative aspirate or intraoperatively (as determined by the surgeon), (ii) presence of a sinus tract communicating with the prosthesis (iii) synovial fluid with >2000 leukocytes/µl or >70% granulocytes, (iv) inflammation in periprosthetic permanent tissue sections seen by histopathologic examination (corresponding to type II and type III according to the Krenn and Morawietz classification) [15], or (v) microbial growth in preoperative joint aspirate, intraoperative periprosthetic tissue or sonication fluid of the removed implant (>50 CFU/ml sonication fluid).

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Low-virulence microorganisms, such as coagulase-negative staphylococci or Cutibacterium spp. were considered pathogens, if the same organism grew in at least two samples. Depending on the time from primary implantation (or aseptic revision) to onset of infection, PJI was classified as early (<3 months after surgery), delayed (3 to 24 months after surgery) or late infection (>24 months after surgery). Each episode was evaluated by an infectious diseases specialist and an orthopedic surgeon.

2.6. Surgical treatment strategy The surgical treatment strategy was standardized [2, 16] and remained unchanged during both study periods, as described in the supporting information (“Pocket Guide to Diagnosis and Treatment of PJI”). In brief, in acute infections (<4 weeks of symptom duration), implant retention was performed, if the prosthesis was stable and soft tissues were not compromised. In these patients, extensive debridement and change of mobile prosthesis parts was performed as the routine procedure. In chronic infections (≥4 weeks of symptom duration), the prosthesis was exchanged in one-stage or two-stage procedure, depending on pathogen, bone stock and soft tissue conditions. A short interval (2-4 weeks) or long interval (6-8 weeks) was used until reimplantation, depending on the local and systemic disease course.

2.7. Antimicrobial treatment strategy In the first study period (2011-2013), biofilm-active antibiotics were not included in the institutional treatment guidelines. Mostly intravenous ampicillin/sulbactam or cefazolin for 2-3 weeks, followed by oral clindamycin, amoxicillin/clavulanic acid or cotrimoxazol were used to complete 3 to 6 months of antibiotic treatment. The choice of antibiotic was guided by the microbiology result and history of allergies.

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In the second study period (2014-2016), biofilm-active antibiotics were introduced following the treatment algorithm [2, 17, 18], summarized in the “Pocket Guide to Diagnosis and Treatment of PJI” (see Supporting information). Biofilm-active antibiotics against staphylococci and Cutibacterium spp. included oral rifampin in combination with another active antibiotic – intravenous in the first 2-3 weeks, followed by oral antibiotic for the subsequent 9-10 weeks. Against penicillinsusceptible streptococci and enterococci, intravenous penicillin or ampicillin in the first 2-3 weeks, followed by oral amoxicillin for the subsequent 9-10 weeks were used; oral ciprofloxacin was used against quinolone-susceptible gram-negative bacteria. The total antibiotic duration was 12 weeks, of which at least 2 weeks were intravenously administered.

2.8. Evaluation of infection and functional outcome Infection outcome was defined according to the modified Delphi-based consensus as follows [19]: (i) infection-free status, characterized by an unremarkable surgical incision site without drainage, fistula or significant pain, and no recurrence of infection caused by same organism as initially; (ii) no subsequent surgical intervention for infection; and (iii) no occurrence of PJI-related mortality. Patients without prosthesis reimplantation or who received a permanent arthrodesis were not considered as treatment failure, if no signs or symptoms of infection were present at follow up. Functional outcome was evaluated by the VAS for pain and the KOOS [13]. The VAS measured pain intensity with a numerical rating scale from 0 to 10 points, with 0 meaning no pain and 10 the worst pain imaginable. The KOOS, a patient-based questionnaire following total knee replacement, consists of five subscales including

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pain, symptoms, function in daily living, function in sport and recreation, and kneerelated life quality. Standardized answer options are given in five Likert boxes, each question assigned a score from 0 to 4 points. A normalized score was calculated for each subscale, where 100 indicates no symptoms and 0 extreme symptoms (The 2012 User's Guide to: Knee injury and Osteoarthritis Outcome Score KOOS, accessed 1 December 2019, available from: http://www.koos.nu/).

2.9. Statistical analysis For the sample size calculation, the following parameters were used: power 90%, α risk 5%, a significance level 5% (one-sided), drop-out rate is 20%. The proportion of relapse-free patients within first year after surgery was estimated to be 85% when with biofilm-active antibiotics and 70% for those treated with standard antibiotics (without biofilm activity), i.e. a non-inferiority margin of δ = -10%. For comparison of categorical variables Fisher’s exact test was applied, for comparison of continuous variables the Mann-Whitney U test was used. The probability of failure-free survival and 95% confidence interval (95% CI) was estimated using the Kaplan-Meier survival method. Survival curves of patients receiving biofilm-active and non-active antibiotic treatment was compared by log-rank test. The influence of different variables on the survival probability was analyzed using a univariate and multivariate Cox proportional-hazards regression model, determined by the Akaike information criterion using forward and backward selection. A p-value <0.05 was considered significant. For statistical analysis the program R (Version 3.1.3., available from: https://www.R-project.org/.) and for graphics the software Prism (Version 8; GraphPad, La Jolla, CA) was used. Sample size calculation was performed with the nQuery Advisor® (version 7.0).

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3. Results 3.1. Patient demographic data and infection characteristics Of 173 patients with knee PJI were identified during the study period, of whom 32 were excluded due to isolation of difficult-to-treat pathogens (Figure 1). Of the remaining 131 patients, 76 patients (58%) were treated without and 55 patients (42%) with biofilm-active antibiotics. In the first study period (2011-2013), biofilmactive antibiotics received 5 of 65 patients (8%), whereas in the second study period (2014-2016) 50 of 66 patients (76%). Table 1 shows the demographic data and infection characteristics of patients with knee PJI. Both groups were similar regarding age, gender, body mass index, duration of hospital stay, type of infection, clinical, radiological or laboratory findings (p values are not shown).

3.2. Microbiological findings Table 2 shows the pathogen distribution isolated in synovial fluid, periprosthetic tissue samples, blood cultures and sonication fluid. Coagulase-negative staphylococci were identified in 41 patients (31%), Staphylococcus aureus in 18 patients (14%), streptococci in 10 patients (8%) and enterococci in 3 patients (2%). Polymicrobial PJI was diagnosed in 25 patients (19%) and culture-negative in 15 patients (11%). No significant differences about the pathogen type between both groups were found (p values are not shown).

3.3. Surgical treatment Table 3 summarizes the surgical treatment of knee PJI. Two-stage exchange of the prosthesis was performed in 102 patients (78%), most common using a long interval of ≥6 weeks (in 84 patients), one-stage exchange was performed in 13 patients

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(19%) and prosthesis retention in 16 patients (12%). In two-stage exchange revision, antibiotic-loaded static spacer was inserted in the prosthesis-free interval, containing the combination of 0.5 g gentamicin and 1 g vancomycin per 40 g of polymethyl methacrylate (PMMA).

3.4. Outcome evaluation Of 131 included patients, follow-up data was available for 103 patients (79%). Among the remaining 28 patients without follow-up data, 11 died, five moved to unknown address and from 12 we have not received response despite repeated contact attempt through general physician and relatives. The median follow-up period was 3.7 years (range, 2.0-7.6 years), 55 of 69 patients (80%) were infection-free. Figure 2 shows the overall Kaplan-Meier infection-free survival probability, which was 74% (95% CI 61% to 85%) after one year and 56% (95% CI 47% to 66%) after two years. The median infection-free survival for the whole study population was 38.6 months. Figure 3 shows the infection-free survival in 103 patients with knee PJI, stratified into 43 patients treated with biofilm-active antibiotics and 60 patients treated without biofilm-active antibiotics. The infection-free survival after one year was better for patients who received biofilm-active antibiotics than for those who received biofilmnonactive antibiotics (83% vs. 70%, p = 0.040). After two years, the infection-free survival was also better for patients who received biofilm-active antibiotics than for those who did not (67% vs. 48%, p = 0.038). The median survival rate of patients with biofilm treatment was 21.6 months, for those with non-biofilm active antibiotics 17.4 months.

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Figure 4 shows the relative frequency of the pain VAS for patients at follow-up. The median pain intensity was lower in patients who received biofilm-active antibiotics than those who did not (3 versus 5 points; p = 0.006). No patient treated without biofilm-active antibiotics had a pain VAS score of >7 points. Table 4 summarizes the results of the univariate and multivariate analysis of factors associated with treatment failure. In the univariate analysis, the risk of treatment failure was 48% lower in patients who received biofilm-active antibiotics in reference to those who did not (p = 0.047). Late PJI reduced the risk of treatment failure by 58% in reference to early infections (p = 0.048) and a delayed infection by 53% in reference to early infections (p = 0.091). Being female reduced the risk of a treatment failure by 44% compared with being male (p = 0.049). For every additional surgery, the risk of treatment failure was 12% higher (p = 0.023). The multivariate analysis combined antimicrobial therapy, age and the number of surgeries for each patient. The biofilm-active antibiotic therapy reduced the risk of infection relapse by 49% (p = 0.043), every additional surgery had a 13 % higher risk of treatment failure (p = 0.017). However, the age did not have a statistically significant effect on the risk of infection relapse. Figure 5 shows the mean KOOS evaluation at follow-up for patients treated with and without biofilm-active antibiotics including five subscales: pain, symptoms, function in daily living, function in sport and recreation and knee related quality of life. Biofilmactive therapy achieved in every subscale better result than biofilm-nonactive therapy. Particularly noticeable was the better result for pain and knee related quality of life, which is the most responsive subscale of the KOOS [20].

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4. Discussion Treatment with biofilm-active antibiotics is suggested to be associated with better outcome in patients with PJI than conventional antibiotics possessing no biofilm activity. However, clinical evidence supporting this assumption is scarce and is mostly extrapolated from smaller observational studies or case series [21-25], extrapolated from other implant-associated infections (such as prosthetic valve endocarditis) [26] or derives from experimental models of foreign-body infection [2731]. We evaluated the outcome of patients with knee PJI treated with and without biofilmactive antibiotics in a prospective cohort. In this study, the definition criteria for infection, surgical treatment and outcome evaluation were standardized and did not change during the investigation, allowing the investigation of the influence of antibiotics alone [2, 32, 33]. This standardized study design, including the prospective character of the study and sufficient long follow-up period, is paramount for derivation of meaningful data since the type, combination and duration of antibiotic therapy is only one of several factors influencing the treatment outcome. In most previously published studies, antimicrobial therapy was not included in the outcome analysis and their impact was not possible to evaluate [34-37]. The relapse-free survival in our cohort, evaluated after 1 and 2 years, was significantly better for patients who were treated with biofilm-active antibiotics (83% and 67%, respectively) compared to patients who were treated with biofilm-nonactive antibiotics (70% and 48%, respectively). Biofilm-active antibiotic treatment was also associated with lower pain intensity and higher KOOS in all 5 subscales. While several authors showed

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To our knowledge, this is the first report demonstrating the association of biofilmactive antibiotics with better functional outcome in PJI. The overall infection-free survival probability in our cohort was 74% after 1 year and 56% after 2 years with a median infection-free survival of 38.6 months. Other authors reported a higher success rate (mean of 79%) after two-stage revision of total knee arthroplasty [38] and success rates ranging from 83% to 100% after one-stage exchange revision of hip and knee arthroplasty [39-41]. Possible reasons for worse outcome found in our cohort are longer follow-up period (median, 3.7 years), active follow-up evaluation by contacting patients, using infection definition criteria including also low-grade infections [33] and applying stringent criteria for defining treatment outcome using the Delphi consensus definitions [19]. An important limitation of the study is an unintended albeit reasonable bias caused by the enforced infectious diseases leadership approach in the second study period, despite there was no change in surgical technique between both study periods. A further weakness of the study is the missing information about potential adverse events and allergic reactions to administered antibiotics. Biofilm-active antibiotics may cause more drug-related side effects than conventional antibiotics without biofilm activity. It is assumed that the better outcome probably outweighs the frequency and severity of adverse events. However, this assumption needs to be confirmed in future studies. Furthermore, biofilm-active antibiotic therapy may cause rapid emergence of antimicrobial resistance. However, antibiotics used in sufficient dose and appropriate combination did not show in previous studies increased frequency of antimicrobial resistance [42-44]. Finally, the patient compliance regarding antibiotic intake was not measured in this study, which may influence the treatment outcome.

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5. Conclusion Biofilm-active antibiotic therapy was associated with significantly better treatment outcome of knee PJI regarding infection outcome, pain intensity and joint function. This is one of rare studies addressing the association of biofilm-active antibiotics and the treatment outcome in PJI. Future studies need to investigate the role of individual antibiotic substances, their dose, combinations and treatment duration on the infection and functional outcome of PJI in order to further optimize the treatment outcome.

Declarations Funding: This work was supported by the PRO-IMPLANT Foundation from Berlin, Germany (https://www.pro-implant-foundation.org), a non-profit organization supporting research, education and patient care in the field of implant-associated infections. Competing Interests: The authors have declared that no competing interests exist. Ethical Approval: The study protocol was approved by the institutional ethical committee (EA/040/14) and was performed in accordance with the Declaration of Helsinki.

Supplementary material “Pocket Guide to Diagnosis and Treatment of PJI”

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Legend to figures

Fig. 1. Flow chart of included study subjects.

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Fig. 2. Kaplan-Meier curve of infection-free survival in 103 patients with knee PJI. The dotted lines represent the 95% confidence interval.

Fig. 3. Kaplan-Meier curve of infection-free survival in 103 patients with knee PJI, stratified into patients treated with and without biofilm-active antibiotics.

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Fig. 4. Relative frequency in percentage of the Visual Analog Scale (VAS) at followup evaluation, stratified into patients treated with and without biofilm-active antibiotics.

Fig. 5. Mean Knee injury and Osteoarthritis Outcome Score (KOOS) evaluation at follow-up, evaluating pain, symptoms, function in daily living (F-DL), function in sport and recreation (F-S&R) and knee related quality of life (QoL), stratified into patients treated with and without biofilm-active antibiotics.

24

Table 1. Demographic data and infection characteristics of 131 patients with PJI treated with and without biofilm-active antibiotic therapy. Characteristic

All patients

Patients treated

Patients treated

(n = 131)

with biofilm-active

without biofilm-

antibiotics

active antibiotics

(n = 55)

(n = 76)

Age, median (range) – years

71 (39-90)

73 (44-90)

71 (39-85)

Male gender

54 (41%)

21 (38%)

33 (43%)

Body mass index, median (range) -

29.4 (17.9 – 50.6)

29.3 (17.9 – 50.6)

29.4 (18.3 – 46.7)

3 (1-3)

3 (1-3)

3 (2-3)

15 (7-54)

15 (9-54)

15 (7-42)

Perioperative

115 (88%)

51 (93%)

64 (84%)

Haematogenous

12 (9%)

3 (5%)

9 (12%)

Contiguous

4 (3%)

1 (2%)

3 (4%)

Early (<3 months)

14 (11%)

4 (7%)

10 (13%)

Delayed (3-24 months)

49 (37%)

20 (36%)

29 (38%)

Late (>24 months)

68 (52%)

31 (56%)

37 (49%)

Joint pain

125 (95%)

53 (96%)

72 (95%)

Sinus tract

21 (16%)

10 (18%)

11 (15%)

kg/cm

2

ASA risk classification, median (range) Duration of hospital stay, median (range) – days Pathogenesis of infection

Onset of infection after surgery

Clinical findings

Radiological signs of prosthesis

25

loosening

46 (35%)

18 (33%)

28 (37%)

<5

72 (55%)

28 (51%)

44 (58%)

5-50

41 (31%)

18 (33%)

23 (30%)

51-100

7 (5%)

5 (9%)

2 (3%)

>100

11 (8%)

4 (7%)

7 (9%)

Type I (particle type)

9 (7%)

2 (4%)

7 (9%)

Type II (infectious type)

91 (70%)

40 (73%)

51 (67%)

Type III (combined type)

22 (17%)

8 (15%)

14 (18%)

Type IV (indifferent type)

9 (7%)

5 (9%)

4 (5%)

Preoperative serum-CRP (mg/l)

Periprosthetic tissuehistology[40]

NOTE. Data are no. (%) of patients if not otherwise indicated. The numbers are rounded therefore the sum may not be 100%. CRP, C-reactive protein.

26

Table 2. Microbiological findings in 131 patients with knee PJI treated with and without biofilm-active antibiotics. Isolated pathogen

All patients

Patients treated

Patients treated without

(n = 131)

with biofilm-active

biofilm-active

antibiotics

antibiotics

(n = 55)

(n = 76)

41 (31%)

16 (29%)

25 (33%)

18 (14%)

6 (11%)

12 (16%)

10 (8%)

3 (5%)

7 (9%)

3 (2%)

2 (4 %)

1 (1%)

6 (5%)

3 (6%)

3 (4%)

Cutibacterium spp.

5 (4%)

3 (6%)

2 (3%)

Other microorganism

8 (6%)

5 (%)

3 (4%)

Polymicrobial infection

25 (19%)

14 (25%)

11 (14%)

Negative culture

15 (11%)

3 (5%)

12 (16%)

Coagulase-negative 1

staphylococci

Staphylococcus aureus Streptococcus spp.

2

3

Enterococcus spp. Gram-negative bacilli

4

NOTE. Data are no. (%) of patients. The numbers are rounded therefore the sum may not be100%. 1

Including S. epidermidis (n = 31), S. capitis (n = 1), S. warneri (n = 5), S. haemolyticus (n = 2), S.

lugdunensis (n = 2) and S. hominis (n = 2). 2

Among 18 S. aureus isolates, 3 (17%) were methicillin-resistant.

3

Including S. oralis/mitis (n = 4), S. agalactiae (n = 2). S. gallolyticus (n = 2), S. dysgalactiae (n = 1),

S. thermophilus (n = 1). 4

Including Escherichia coli (n = 2), Delftia acidovorans (n = 1), Pseudomonas aeruginosa (n = 1),

Citrobacter koseri (n = 1), Proteus mirabilis (n = 1).

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Table 3. Surgical treatment in 131 patients with knee PJI. Treatment

All patients

Patients treated

Patients treated

(n = 131)

with biofilm-active

without biofilm-

antibiotics

active antibiotics

(n = 55)

(n = 76)

One-stage exchange

13 (10)

5 (9)

8 (11)

Two-stage exchange

102 (78)

44 (80)

58 (76)

Short interval (<6 weeks)

18

6

13

Long interval (≥6 weeks)

84

36

47

Debridement and prosthesis

16 (12)

6 (11)

10 (13)

retention NOTE. Data are no. (%) of patients.

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Table 4. Univariate and multivariate analysis of factors associated with treatment failure in 131 patients with knee PJI. Factors

Univariate analysis

Multivariate analysis

HR (95% CI)

P-value

HR (95% CI)

P value

0.52

0.047

0.51 (0.27-0.98)

0.043

1.03 (0.99-1.06)

0.172

1.13 (1.02-1.25)

0.017

Infection-related Treatment with biofilmactive vs. biofilmnonactive antibiotics (reference)

(0.27-0.99)

Late vs. early PJI (reference)

0.42 (0.18-0.99)

0.048

0.47 (0.2-1.13)

0.091

Patient age

1.01 (0.98-1.05)

0.430

Female gender

0.56 (0.31-1.00)

0.049

Aseptic revision

0.62 (0.33-1.17)

0.139

No. of surgeries

1.12 (1.02-1.24)

0.023

Delayed vs. early PJI (reference) Patient-related

Surgery-related

HR, hazard ratio; 95% CI, 95% confidence interval.

29