JBJI Original full-length article J. Bone Joint Infect., 7, 279–288, 2022 Open Access https://doi.org/10.5194/jbji-7-279-2022 © Author(s) 2022. This work is distributed under Journal of Bone and Joint Infection the Creative Commons Attribution 4.0 License. Osteosynthesis-associated infection of the lower limbs by multidrug-resistant and extensively drug-resistant Gram-negative bacteria: a multicentre cohort study Efthymia Giannitsioti1 , Mauro José Salles2 , Andreas Mavrogenis3 , Dolors Rodriguez-Pardo4 , Ibai Los-Arcos4 , Alba Ribera5 , Javier Ariza5 , María Dolores del Toro6 , Sophie Nguyen7 , Eric Senneville7 , Eric Bonnet8 , Monica Chan9 , Maria Bruna Pasticci10 , Sabine Petersdorf11 , Natividad Benito12 , Nuala O’ Connell13 , Antonio Blanco García14 , Gábor Skaliczki15 , Pierre Tattevin16 , Zeliha Kocak Tufan17 , Nikolaos Pantazis18 , Panayiotis D. Megaloikonomos3 , Panayiotis Papagelopoulos3 , Alejandro Soriano19 , Antonios Papadopoulos1 , and the ESGIAI collaborators study group+ 1 Fourth Department of Internal Medicine, University General Hospital Attikon, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece 2 Division of Infectious Diseases, Department of Internal Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil 3 First Department of Orthopaedics, University General Hospital Attikon, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece 4 Department of Infectious Diseases, Hospital Universitari Vall d’Hebron, Barcelona, Spain 5 Department of Infectious Diseases, Hospital Universitari Bellvitge, Barcelona, Spain 6 Infectious Diseases Unit, Hospital Universitario Virgen Macarena, Instituto de Biomedicina de Sevilla (IBIS), Universidad de Sevilla, Seville, Spain 7 Infectious Diseases Department, Gustave Dron Hospital, Tourcoing, France 8 Department of Infectious Diseases, Clinique Pasteur, Toulouse, France 9 Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore, Singapore 10 Infectious Diseases Unit, University of Perugia, Perugia, Italy 11 Institute for Medical Laboratory Diagnostics, Helios University Clinic Wuppertal, Wuppertal, Germany 12 Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Institut d’Investigació Biomèdica Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain 13 Department of Clinical Microbiology, University Hospital Limerick, Limerick, Ireland 14 Bone and Joint Infection Unit, Department of Emergency Medicine, IIS-Fundación Jiménez Díaz Hospital, Madrid, Spain 15 Department of Orthopaedics, Semmelweis University, Budapest, Hungary 16 Infectious Diseases and Intensive Care Unit, Pontchaillou University Hospital, Rennes, France 17 Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Yildirim Beyazit University, Ankara Atatürk Education and Research Hospital, Ankara, Turkey 18 Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece 19 Department of Infectious Diseases, Hospital Clínic, Barcelona, University of Barcelona, IDIBAPS, Barcelona, Spain + A full list of authors appears at the end of the paper. Correspondence: Efthymia Giannitsioti (gianiemi@hotmail.com) Received: 17 May 2022 – Revised: 26 August 2022 – Accepted: 19 November 2022 – Published: 21 December 2022 Abstract. Purpose: The purpose of this study was the clinical and therapeutic assessment of lower-limb osteosynthesis-associated infection (OAI) by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Published by Copernicus Publications on behalf of EBJIS and MSIS. 280 E. Giannitsioti et al.: OAI of the lower limbs by MDR and XDR GNB Gram-negative bacteria (GNB), which have been poorly studied to date. Methods: A prospective multicentre observational study was conducted on behalf of ESGIAI (the European Society of Clinical Microbiology and In- fectious Diseases (ESCMID) Study Group on Implant-Associated Infections). Factors associated with remission of the infection were evaluated by multivariate and Cox regression analysis for a 24-month follow-up period. Results: Patients (n = 57) had a history of trauma (87.7 %), tumour resection (7 %) and other bone lesions (5.3 %). Pathogens included Escherichia coli (n = 16), Pseudomonas aeruginosa (n = 14; XDR 50 %), Kleb- siella spp. (n = 7), Enterobacter spp. (n = 9), Acinetobacter spp. (n = 5), Proteus mirabilis (n = 3), Serratia marcescens (n = 2) and Stenotrophomonas maltophilia (n = 1). The prevalence of ESBL (extended-spectrum β-lactamase), fluoroquinolone and carbapenem resistance were 71.9 %, 59.6 % and 17.5 % respectively. Most patients (n = 37; 64.9 %) were treated with a combination including carbapenems (n = 32) and colistin (n = 11) for a mean of 63.3 d. Implant retention with debridement occurred in early OAI (66.7 %), whereas the infected device was removed in late OAI (70.4 %) (p = 0.008). OAI remission was achieved in 29 cases (50.9 %). The type of surgery, antimicrobial resistance and duration of treatment did not significantly influence the outcome. Independent predictors of the failure to eradicate OAI were age > 60 years (hazard ratio, HR, of 3.875; 95 % confidence interval, CI95 %, of 1.540–9.752; p = 0.004) and multiple surgeries for OAI (HR of 2.822; CI95 % of 1.144–6.963; p = 0.024). Conclusions: Only half of the MDR/XDR GNB OAI cases treated by antimicro- bials and surgery had a successful outcome. Advanced age and multiple surgeries hampered the eradication of OAI. Optimal therapeutic options remain a challenge. 1 Introduction GNB, especially among Enterobacterales, bears novel diag- nostic and therapeutic challenges worldwide. In a case series Orthopaedic implantable devices have geometrically in- of chronic osteomyelitis during last decade, the incidence creased during the last decades due to technological and of MDR GNB was shown to increase over the years (Kout- medical advancements that have allowed orthopaedic in- serimpas et al., 2018), but data on orthopaedic implants are terventions which were not feasible in the past (Trampuz limited. In the era of antimicrobial resistance, treatment op- and Zimmerli, 2006). Osteosynthesis is mandatory to en- tions for orthopaedic implant infections are sparse, as erad- sure the anatomical reconstruction of damaged bone, pro- ication of these biofilm-related infections is very difficult moting fusion within time. However, osteosynthesis could (Trampuz and Zimmerli, 2006; Tschudin-Sutter et al., 2016; be complicated by infection (1 %–30 %) (Trampuz and Zim- Benito et al., 2016). For this purpose, a multinational co- merli, 2006), especially in elderly or frail populations with hort study on MDR/XDR GNB orthopaedic device infec- open fractures. In turn, osteosynthesis-associated infections tions was launched on behalf of the European Study Group (OAIs) may impair bone healing due to long-standing in- of Implant-Associated Infections (ESGIAI). Analysis of the flammatory process with increased risk of functional loss clinical characteristics, treatment options and outcomes of or even amputation of the infected limb (Trampuz and Zim- MDR/XDR GNB PJI have recently been published by our merli, 2006; Lew and Waldvogel, 2004; Metsemakers et al., group (Papadopoulos et al., 2019). However, pathogenicity, 2018). Moreover, remission of OAI can usually be achieved clinical features and therapeutic strategies are different in PJI via removal of the infected device (Trampuz and Zimmerli, and in fracture-related infections (Metsemakers et al., 2018; 2006; Metsemakers et al., 2018; Steinmetz et al., 2019). Steinmetz et al., 2019). There are very few case reports and However, explantation of the infected implant could be com- case series – often mixed with PJI – describing multiresis- plex, especially in frail patients; therefore, surgical debride- tant GNB orthopaedic device infection (Jorge et al., 2017; ment with implant retention can be a reliable therapeutic op- Pfang et al., 2019; Krajewski et al., 2014; Odio et al., 2015; tion (Tschudin-Sutter et al., 2016). Ribera et al., 2015; Siebenbürger et al., 2019). Therefore, we Although Gram-positive cocci are the most implicated aimed to analyse treatment options and predictors of outcome pathogens in osteomyelitis (Uçkay et al., 2012), Gram- in a larger series of patients with non-PJI osteosynthesis- negative bacteria (GNB) emerge as causative agents in 10 %– associated infection (OAI) of the lower limbs by MDR/XDR 20 % of cases in the form of mono- or polymicrobial os- GNB. teoarticular infections (Benito et al., 2016). Case series (with or without implantable devices) have been reported (Kanel- lakopoulou et al., 2009; Legout et al., 2006; Titécat et al., 2013), but most cases refer to prosthetic joint infection (PJI) (Benito et al., 2016), Nowadays, the emergence of multidrug- resistant (MDR) or even extensively drug-resistant (XDR) J. Bone Joint Infect., 7, 279–288, 2022 https://doi.org/10.5194/jbji-7-279-2022 E. Giannitsioti et al.: OAI of the lower limbs by MDR and XDR GNB 281 2 Materials and methods – MDR was defined as non-susceptibility to at least one agent in three or more antimicrobial categories 2.1 Study design (aminoglycosides; tetracyclines; cephalosporins; carbapenems; fluoroquinolones; penicillins and β- We conducted a multicentre retrospective evaluation of lactamase inhibitors; monobactams; phosphonic prospectively collected data from 2005 to 2015 on OAI of acids; and polymyxins). XDR was defined as non- the lower limbs caused by MDR and XDR GNB. The aim of susceptibility to at least one agent in all but two or the study was to identify factors associated with remission of fewer antimicrobial categories (i.e. bacterial isolates OAI. A total of 18 European and overseas medical institu- remain susceptible to only one or two categories) tions participated in the study, which was approved by each (Magiorakos et al., 2012). local ethics committee. – With respect to the evaluation of treatment, surgery for 2.2 Data collection infection performed upon diagnosis of OAI of the lower limbs was defined as (i) removal of the infected im- Data on patients’ age and comorbidities, history of trauma, plant (with or without exchange) or (ii) retention of prior history of bone infection treated by orthopaedic surgery, the implant with debridement. An early surgical pro- prior use of antibiotics and clinical presentation of the cur- cedure was defined as operation within 4 weeks of OAI, rent OAI episode were recorded. GNB isolates from tis- whereas a late surgical procedure was a procedure car- sue/bone/device or blood cultures and their resistance pat- ried out after 4 weeks. Antimicrobial treatment given tern (multidrug or extensively drug resistant) were identified. post-surgically was analysed as either monotherapy by The surgical treatment applied to each patient for the current a sole agent or as combined antibiotic treatment (more OAI event and the antimicrobial therapy (regimen, monother- than one concomitant agents). The duration of antimi- apy vs. combination, length of intravenous (IV) administra- crobial treatment was defined by a 6-week course of tion and total duration of treatment) were assessed. Factors antibiotics. related to remission of the infection were evaluated at the 24-month follow-up. Data were recorded using a case report – Outcome was defined as remission of OAI if no clini- form (CRF), which was completed by investigators at each cal, laboratory or microbiological sign of infection was participating centre. The evaluation of collected data was per- assessed during the 24-month post-treatment follow-up formed by Antonios Papadopoulos and Efthymia Giannitsi- period. Any other condition was considered to be non- oti. remission and treatment failure. 2.3 Definitions 2.4 Statistical analysis The definitions used in this work are as follows: Descriptive statistics were given by type of pathogen and re- – Osteomyelitis was identified upon location of the infec- sistance (MDR or XDR) and type of surgical treatment (im- tion (long and square bones) according to standard def- plant removal vs. implant retention with debridement). Mean initions and international consensus (Lew and Waldvo- values were expressed with standard deviations (SDs). Com- gel, 2004; Uçkay et al., 2012). Diagnosis of osteomyeli- parative analyses of the characteristics of the study popula- tis in the case of the fracture of peripheral bones and tion were carried out using two-sample t tests for continuous subsequent reconstitution surgery relied on positive in- variables and chi-square tests (or Fisher’s exact tests where traoperative tissue/bone cultures and/or histology along necessary) for categorical variables. Probabilities of remis- with compatible imaging diagnosis (Glaudemans et al., sion of the infection after surgical and medical therapy were 2019). Moreover, early infection was defined as the modelled using univariate and multivariate logistic regres- presence of OAI in the 4 weeks following the index sion. The risk of non-remission during the follow-up period surgery. Any OAI event that occurred later than 4 weeks was analysed using Cox regression survival analysis for com- post-surgery was defined as late infection. peting risks data. Taking the time to failure into considera- tion, Kaplan–Meier survival analysis was performed, and the – GNB isolates were identified by routine conven- log-rank (Mantel–Cox) statistic and related hazard ratio (HR) tional biochemical and metabolic tests or MALDI- with a 95 % confidence interval (CI) were reported. p val- ToF (matrix-assisted laser desorption ionization time- ues less than 0.05 were considered to be statistically signifi- of-flight) mass spectrometry. Antimicrobial susceptibil- cant. All analyses were performed using SPSS (version 22.0, ity was assessed at each participating centre accord- SPSS Inc., IBM). ing to the European Committee on Antimicrobial Sus- ceptibility Testing (EUCAST) recommendations (http:// www.eucast.org/clinical_breakpoint/, last access: 1 Jan- uary 2022). https://doi.org/10.5194/jbji-7-279-2022 J. Bone Joint Infect., 7, 279–288, 2022 282 E. Giannitsioti et al.: OAI of the lower limbs by MDR and XDR GNB 3 Results did not significantly differ between the implant removal and implant retention groups (Table S1 in the Supplement). How- A total of 57 patients with OAI were included in the ever, early OAI was initially mostly managed by implant re- study. Osteosynthesis was performed due to trauma (n = tention with debridement (66.7 %), whereas late OAI was 50; 87.7 %), tumour resection (n = 4; 7 %) and other, non- primary managed by implant removal (with or without ex- specified bone lesions (n = 3; 5.3 %). Early and late OAI change) (70.4 %; p = 0.008; Table S1). Among the 27 cases were detected in 28 and 29 patients respectively. In late of implant removal, reimplantation was assessed in 6 cases, cases, the median (interquartile range, IQR) time from the and debridement without insertion of a new orthopaedic de- index surgery to the surgery for OAI was 13 (8–40) months. vice was assessed in 21 cases (including 1 case of amputa- The demographics, clinical characteristics and treatment of tion). Remission of infection was achieved in 2 of 6 cases in patients subdivided by the type of surgical treatment are the reimplantation group vs. 14 of 21 cases in the no-device presented in Table S1. Patients’ mean age (SD) was 56.30 group (p = 0.187). (21.65) years with a female predominance (n = 34, 59.6 %). Overall, criteria for remission of the infection were A total of 29.8 % of patients presented with comorbidities. achieved only in 29 patients (50.9 %). Figure 1a illustrates A total of 19 patients (33.3 %) had undergone a previous the outcome of OAI split by early vs. late infection and type surgery for orthopaedic infection. Osteosynthesis was in- of surgery. Remission was achieved in 46.4 % of early in- strumented at the area of the hip (n = 15), femur (n = 13), fections (45 % with implant retention and 50 % with implant knee (n = 3), tibia (n = 19), ankle (n = 2) and metatarsal removal) and in 55.1 % of late infections (40 % with im- bones (n = 5). Soft tissue infection (59.6 %) and sinus tract plant retention and 63.1 % with implant removal). The type (42.1 %) were common clinical signs, whereas fever was of surgical intervention did not significantly affect the out- only present in 19.3 % of cases. Bone damage compatible come within the early vs. late OAI groups (p = 0.292; odds with osteomyelitis was documented in all patients. Prior use ratio (OR) of 1.902; CI95 % of 0.663–5.457; Fig. 1a). Remis- of antibiotics was present in 65 % of patients. sion was achieved in 54.5 % of MDR OAI cases (n = 24) vs. The distribution of pathogens as either MDR (n = 44, 38.5 % of XDR OAI cases (n = 5, p = 0.105) (Table 1). Re- 77.2 %) or XDR (n = 13, 22.8 %) is depicted in Ta- mission reached 50 % (MDR) vs. 25 % (XDR) in early OAI ble 1. All Escherichia coli strains (n = 16) were MDR, and 60 % (MDR) vs. 44.4 % (XDR) in late OAI cases. Fig- producing ESBL (extended-spectrum β-lactamases). XDR ure 1b illustrates the outcome of OAI split by early and late accounted for 50 % and 40 % of Pseudomonas aerugi- infection in MDR and XDR cases: no statistical difference nosa and Acinetobacter spp. strains respectively. Over- was assessed within groups (OR of 0.521; CI95 % of 0.147– all, pathogens were identified as follows: ESBL-producing 1.846; p = 0.358). pathogens, which, by definition, are resistant to aztre- Univariate and adjusted multivariate logistic regression onam (n = 41; 71.9 %); fluoroquinolone-resistant pathogens analysis demonstrated that the presence of comorbidities and (n = 34; 59.6 %); aminoglycoside-resistant pathogens (n = multiple previous surgeries correlated with treatment out- 24; 42.1 %); and carbapenem-resistant pathogens (n = 10; come in patients aged > 60 years. Although not statisti- 17.5 %). For GNB other than P. aeruginosa, resistance to co- cally significant, failure of remission of OAI was more fre- trimoxazole and tigecycline reached 35 % and 7 % respec- quent for XDR than for MDR pathogens (61.5 % vs. 45.5 %; tively. One XDR strain of P. aeruginosa was also resistant to p = 0.105) and in cases of extended antimicrobial treat- fosfomycin. All GNB strains were sensitive to colistin except ment (more than 42 d (n = 33) vs. less than 42 d (n = 24); for Proteus mirabilis and Stenotrophomonas maltophilia due p = 0.161) (Table 2). Figure 2 depicts the remission of OAI to intrinsic resistance. in patients split by age – more or less than 60 years old (log Various antimicrobial combinations were post-surgically rank x 2 = 7.919; 1 degree of freedom (DF); p = 0.005). Fac- administered in 64.9 % of the patients. Monotherapy was tors associated with infection eradication at the 24-month given to 35.1 % of patients. Overall, fluoroquinolones were follow-up were further analysed using the Cox regression administered in 8 cases (14 %), carbapenems in 32 cases model including age, MDR vs. XDR resistance, number of (56.1 %) and colistin in 11 cases (19.3 %). The mean (SD) revision procedures for OAI and total duration of antimicro- overall duration of antimicrobial therapy was 63.3 (38) d, bial treatment. Only an age > 60 years (HR of 3.875; CI95 % whereas the mean (SD) duration of intravenous administra- of 1.540–9.752; p = 0.004) and multiple surgeries for OAI tion was 59.4 (44.5) d. The long duration of intravenous an- (HR of 2.822; CI95 % of 1.144–6.963; p = 0.024) were in- tibiotics in some cases reflects the lack of oral alternatives for dependent predictors of failure (Table 3). the continuation of treatment after hospital discharge. The length of treatment as well as the number of administered antibiotics (monotherapy vs. combined therapy) did not sig- 4 Discussion nificantly affect remission of OAI. (Table 2). The clinical fea- tures of OAI, antimicrobial resistance patterns, the type and To our knowledge, this is the largest cohort study on lower- duration of antimicrobial administration, and the outcome limb OAI by MDR/XDR GNB. Only a few case reports J. Bone Joint Infect., 7, 279–288, 2022 https://doi.org/10.5194/jbji-7-279-2022 E. Giannitsioti et al.: OAI of the lower limbs by MDR and XDR GNB 283 Table 1. Identification of Gram-negative bacteria (GNB) multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria in osteosynthesis-associated infection of the lower limbs. Pathogens (n) MDR XDR Total GNB n = 44 (%) n = 13 (%) n = 57 (%) Escherichia coli 16 (36.36) 16 (28.07) Pseudomonas aeruginosa 7 (15.90) 7 (53.86) 14 (24.56) Enterobacter cloacae 8 (18.19) 1 (7.69) 9 (15.79) Klebsiella pneumoniae 6 (13.64) 1 (7.69) 7 (12.28) Acinetobacter spp. 3 (6.82) 2 (15.38) 5 (8.78) Proteus mirabilis 2 (4.55) 1 (7.69) 3 (5.26) Serratia marcescens 1 (2.27) 1 (7.69) 2 (3.51) Stenotrophomonas maltophilia 1 (2.27) – 1 (1.75) Table 2. Univariate and multivariate logistic regression analysis of factors related to the remission of osteosynthesis-associated infections (OAIs) of the lower limbs by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria (GNB). Variables Remission, No remission Univariate OR p Multivariate adjusted OR p n = 29 (50.9 %) n = 28 (49.1 %) (CI95 %) (CI95 %) Age > 60 (years)∗ 9 (31) 16 (57.1) 2.963 (1.000–8.776) 0.064 4.009 (1.147–14.011) 0.030 Male 12 (41.4) 11 (39.3) 0.917 (0.318–2.643) > 0.999 Female 17 (58.6) 17 (60.7) Comorbidities∗ 5 (17.2) 12 (42.9) 3.600 (1.063–12.195) 0.045 Clinical features of OAI History of trauma 24 (82.8) 26 (92.9) 2.708 (0.480–15.294) 0.423 Previous surgery for implant infection 10 (34.5) 9 (32.1) 0.900 (0.299–2.710) > 0.999 Early OAI 13 (44.8) 15 (53.6) 0.704 (0.248–1.998) 0.600 Late OAI 16 (55.2) 13 (46.4) Location below the knee 15 (51.7) 14 (50) 0.933 (0.330–2.638) > 0.999 Fever 6 (20.7) 5 (17.9) 0.833 (0.223–3.120) > 0.999 Soft tissue infection 19 (65.5) 15 (53.6) 0.607 (0.201–1.765) 0.424 Sinus tract 12 (41.4) 12 (42.9) 1.063 (0.371–3.042) > 0.999 MDR 24 (82.8) 20 (71.4) 0.521 (0.147–1.846) 0.358 0.301 (0.070–1.286) 0.105 XDR 5 (17.2) 8 (28.6) Acinetobacter spp. 1 (3.4) 4 (14.3) 4.667 (0.488–44.637) 0.194 Escherichia coli 7 (24.1) 9 (32.1) 1.489 (0.465–4.763) 0.565 Pseudomonas aeruginosa 8 (27.6) 6 (21.4) 0.716 (0.212-2.415) 0.760 Enterobacter cloacae 7 (24.1) 2 (7.1) 0.242 (0.045–1.285) 0.144 Klebsiella pneumoniae 4 (13.8) 3 (10.7) 0.750 (0.152–3.701) > 0.999 Use of fluoroquinolones 5 (17.2) 3 (10.7) 0.576 (0.124–2.679) 0.706 Use of carbapenems 17 (58.6) 15 (53.6) 0.814 (0.286–2.322) 0.792 Use of colistin 5 (17.2) 6 (21.4) 1.309 (0.350–4.902) 0.747 Combined antibiotics 19 (65.5) 18 (64.3) 0.947 (0.319–2.812) > 0.999 Antimicrobial treatment > 42 d∗ 14 (48.3) 19 (67.9) 2.262 (0.771–6.639) 0.182 2.407 (0.705–8.208) 0.161 Implant removal 16 (55.2) 11 (39.3) 1.902 (0.663–5.457) 0.292 Implant retention 13 (44.8) 17 (60.7) More than one surgical procedure for OAI∗ 4 (13.8) 10 (35.7) 3.472 (0.938–12.846) 0.070 7.092 (1.459–34.482) 0.015 ∗ Variables included in the multivariate model. and very small case series on carbapenem-resistant Enter- by the high prevalence of frailty of the host and by limited obacterales, P. aeruginosa and Acinetobacter spp. includ- therapeutic options (Legout et al., 2006; Martinez-Pastor et ing both PJI and other OAI have been described (Jorge et al., 2010; Grossi et al., 2016; Rodriguez-Pardo et al., 2014). al., 2017; Pfang et al., 2019; Krajewski et al., 2014; Odio In the above-mentioned reports, most patients had received et al., 2015; Ribera et al., 2015; Siebenbürger et al., 2019; antibiotics prior to the current OAI event, as in our cohort Pasticci et al., 2014; Papagelopoulos et al., 2007). Glob- (Benito et al., 2016; Pfang et al., 2019). The type of sur- ally, remission of OAI by GNB ranges from 27 % to 80 % gical intervention (removal vs. retention of the infected de- (Martínez-Pastor et al., 2010; Grossi et al., 2016), reflect- vice) was not associated with remission. However, a recent ing a high variability among studies. OAI is characterized study of 25 patients with osteoarticular infections (both PJI https://doi.org/10.5194/jbji-7-279-2022 J. Bone Joint Infect., 7, 279–288, 2022 284 E. Giannitsioti et al.: OAI of the lower limbs by MDR and XDR GNB Table 3. Multivariate Cox regression analysis of factors related to lack of eradication of osteosynthesis-associated infection (OAI) during a 24-month follow-up. Variables p HR 95,0 % CI for HR Lower Upper Age > 60 years 0.004 3.875 1.540 9.752 MDR vs. XDR GNB∗ 0.118 0.434 0.152 1.237 Antimicrobial treatment > 42 d 0.079 2.254 0.910 5.582 Multiple surgeries for OAI 0.024 2.822 1.144 6.963 ∗ The abbreviations used in the table are as follows: MDR – multidrug resistant, XDR – extensively drug resistant, and GNB – Gram-negative bacteria. Figure 2. Kaplan–Meier survival plot of remission of OAI the lower limbs by MDR/XDR GNB (log rank x 2 = 7.919, DF = 1, p = 0.005). did not significantly affect the outcome, which is a finding that could be potentially be explained by the small number of patients. However, the fact that early XDR OAI – mostly treated by implant retention – presented a very low remission rate (25 %) highlights the need for radical surgery in cases of extended antimicrobial resistance. Moreover, in our pre- viously published cohort of PJI by MDR/XDR GNB, higher remission rates of the infection (up to 80 %) were achieved with removal than with retention of the prosthesis (50 %) (Pa- padopoulos et al., 2019). Different patterns of treatment suc- cess between PJI and OAI may be due to the different nature and objectives of the orthopaedic devices (Metsemakers et al., 2018; Steinmetz et al., 2019). Removal of the infected im- Figure 1. Remission of OAI split by (a) type of surgical treatment or (b) type of antimicrobial resistance. plant is often postponed in OAI awaiting osseous healing and biomedical stability of the fractured bone. Therefore, the use of suppressive antibiotics can be applied until healing of the fracture is obtained, allowing the implant’s removal. (Stein- and non-PJI) by MDR/XDR GNB reported a cure rate of metz et al., 2019; Tschudin-Sutter et al., 2016). Thus, remis- 100 % in patients treated by implant removal vs. only 33 % sion of the infection can be hampered by slow osseous heal- in patients treated with implant retention (Pfang et al., 2019). ing and the need for complex and repetitive operations, the In our study, the overall infection eradication rate was lower initiation of embedded grafts, and revascularization (Tram- even after removal of the infected implant. The type of an- puz and Zimmerli, 2006; Steinmetz et al., 2019). Under these timicrobial resistance and the type of surgical intervention circumstances, the optimal surgical and antimicrobial treat- J. Bone Joint Infect., 7, 279–288, 2022 https://doi.org/10.5194/jbji-7-279-2022 E. Giannitsioti et al.: OAI of the lower limbs by MDR and XDR GNB 285 ment is difficult to define, and the strategy of multiple oper- ative tissue structures. The lack of healthy tissue and tissue ations in order to achieve healing and remission of the infec- reconstitution capacity promotes persistent and relapsing in- tion often fails. Our findings are in line with the study per- fection (Steinmetz et al., 2019; Jamei et al., 2017). formed by Jorge et al. (2017) for fracture-related infections, This work has important limitations. It is an observational which demonstrated that multiple surgeries, advanced age and retrospective cohort study. Therefore, the rates of antimi- and MDR P. aeruginosa were predictors of treatment fail- crobial resistance per institution are not available, as data for ure (Jorge et al., 2017). In our study, a trend towards a worse the study were collected through an invitation to the members outcome for XDR compared with MDR infections was ob- of the ESGIAI study group, and a population-based study served, but we failed to identify a significant difference due was not performed. The surgical management of cases of to the small sample size. Most patients were treated using a OAI is heterogenous, as a variety of surgical modalities and combination of antibiotics, as previously reported (Ribera et different techniques can be applied at different centres and al., 2015; Brouqui et al., 1995; Rodriguez-Baño et al., 2018). in different countries. Moreover, the impact of local-delivery For MDR and especially XDR cases with restricted antimi- antibiotic carriage systems in OAI was not explored. Analy- crobial treatment options, more experts recommend com- sis of the genetic mechanisms of antimicrobial resistance in bined therapy tailored to drug susceptibility tests (Ribera et MDR or XDR GNB isolates was not available. However, this al., 2015; Rodriguez-Baño et al., 2018). Colistin is often the is the largest cohort of patients with OAI of the lower limbs sole potent agent against the XDR GNB strains, including by MDR/XDR GNB to date, with international recruitment P. aeruginosa, K. pneumoniae and A. baumanii. The activity from expert centres, providing a valuable insight on the char- of colistin on biofilm formation has been proven in exper- acteristics and the outcomes of those particularly difficult to imental studies; however, high doses of the drug concomi- treat infections. tantly with other antibiotics are required (Lora-Tamayo et al., 2019). An in vivo experimental study demonstrated the clear- ance of a biofilm-related XDR GNB infection using a combi- 5 Conclusions nation of colistin with fosfomycin or tigecycline, which are often the last treatment resort in XDR isolates (Corvec et al., In conclusion, OAI of the lower limbs by MDR or XDR GNB 2013). Clinical data suggest the need for high-dose colistin was associated with low rates of remission at the 24-month for treatment effectiveness in osteoarticular infections by follow-up. Only an age > 60 years and multiple surgeries for XDR P. aeruginosa (Valour et al., 2013). The combined sys- OAI were linked to treatment failure. A continuous surveil- temic administration of colistin with its release by impreg- lance of emerging antimicrobial resistance and the efficacy of nated material has been proven to be successful (Krajewski novel antimicrobial treatments along with the optimization of et al., 2014; Papagelopoulos et al., 2007). However, the effi- surgical interventions in fracture-related infections should be cacy of IV colistin is significantly enhanced when combined further explored via large prospective studies. with a β-lactam (Ribera et al., 2015). The low rates of re- mission of OAI in our study might be partly explained by the Data availability. Patient data were collected using case report lack of fluoroquinolone administration due to high resistance forms, which were completed by the author from each participating rates. Ciprofloxacin has a proven penetration into the bone centre. The data are not publicly accessible, as they are provided and promotes a successful outcome in GNB osteoarticular by 19 European and overseas university and research institutions infections (Legout et al., 2006; Rodriguez-Pardo et al., 2014; which are subject to different laws regarding the deposition of clin- Brouqui et al., 1995). Fluoroquinolones’ resistance is one of ical data. the major drivers of the increased use of carbapenems (Pa- padopoulos et al., 2019; Martinez-Pastor et al., 2010). Novel therapeutic options for MDR/XDR GNB (like ceftazidime– Supplement. The supplement related to this article is available avibactam and ceftolozane–tazobactam) were not available online at: https://doi.org/10.5194/jbji-7-279-2022-supplement. at the time of our study. As oral treatment was not available, most patients were treated using IV antibiotics for approx- imately 60 d, much longer than suggested (Lew and Wald- Team list. Jaime Esteban-Moreno (Department of Clinical Micro- vogel, 2004; Metsemakers et al., 2018; Uçkay et al., 2012). biology, IIS-Fundación Jiménez Díaz, Madrid, Spain); Joaquín Gar- However, neither the combination of antibiotics nor a treat- cía Cañete (Bone and Joint Infection Unit, IIS-Fundación Jiménez Díaz, Madrid, Spain); Raúl Parrón (Bone and Joint Infection Unit, ment duration of more than 42 d had a significant impact on Department of Emergency Medicine, IIS-Fundación Jiménez Díaz the outcome, perhaps due to the sample size in our study. Hospital, Madrid, Spain); David Lye (Department of Infectious Dis- The eradication of infection was hampered by advanced age eases, Tan Tock Seng Hospital, Singapore); Rahmet Guner (Depart- and the need for multiple surgical operations. Obviously, the ment of Infectious Diseases and Clinical Microbiology, Faculty of immunological condition of the host, which is impaired with Medicine, Yildirim Beyazit University, Ankara Atatürk Education advanced age, may delay the ability of wound healing and and Research Hospital, Ankara, Turkey); Laura Morata (Depart- bone reconstruction, as could poor vascularity and degener- ment of Infectious Diseases, Hospital Clínic, Barcelona, Spain); https://doi.org/10.5194/jbji-7-279-2022 J. Bone Joint Infect., 7, 279–288, 2022 286 E. Giannitsioti et al.: OAI of the lower limbs by MDR and XDR GNB Ernesto Muñoz-Mahamud and Luis Lozano (Department of Ortho- Ethical statement. This study was approved by each of the par- pedics, Hospital Clínic, Barcelona, Spain); Carles Pigrau (Depart- ticipating centres according to the rules of the local ethics commit- ment of Infectious Diseases, Hospital Universitari Vall d’Hebron, tees regarding non-interventional, epidemiological, anonymously Barcelona, Spain); Pablo S. Corona (Department of Orthopedic collected data. Surgery, Reconstructive Surgery and Septic Division, Hospital Uni- versitari Vall d’Hebron, Barcelona, Spain); Maily Lung (Microbi- ology Department, Hospital Universitari Vall d’Hebron, Barcelona, Disclaimer. Publisher’s note: Copernicus Publications remains Spain); Taiana Cunha Ribeiro and Giselle B. Klautau (Division of neutral with regard to jurisdictional claims in published maps and Infectious Diseases, Department of Internal Medicine, Santa Casa institutional affiliations. de São Paulo School of Medical Sciences, São Paulo, Brazil); Sal- vatore Cardaci (Infectious Diseases Unit, University of Perugia, Pe- rugia, Italy); Yolanda Borrego Izquierdo (Infectious Diseases Unit, Review statement. This paper was edited by Irene Karharina Sig- Hospital Universitario Virgen Macarena, Seville, Spain); Isabel Mur mund and reviewed by two anonymous referees. (Unit of Infectious Diseases, Department of Internal Medicine, Hos- pital de la Santa Creu i Sant Pau, Institut d’Investigació Biomèdica Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain); Xavier Crusi, Marcos Jordán and José Carlos González (Depart- ment of Orthopedics, Hospital de la Santa Creu i Sant Pau, Insti- References tut d’Investigació Biomèdica Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain); Alba Rivera (Department of Clin- Benito, N., Franco, M., Ribera, A., Soriano, A., Rodriguez- ical Microbiology, Hospital de la Santa Creu i Sant Pau, In- Pardo, D., Sorlí, L., Fresco, G., Fernández-Sampedro, M., Do- stitut d’Investigació Biomèdica Sant Pau, Universitat Autònoma lores Del Toro, M., Guío, L., Sánchez-Rivas, E., Bahamonde, de Barcelona, Barcelona, Spain); Marie Ghéno, Enora Ouamara- A., Riera, M., Esteban, J., Baraia-Etxaburu, J. 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C., Stein, A., Drancourt, M., and ment of Internal Medicine, University General Hospital Attikon, Raoult, D.: Treatment of Pseudomonas aeruginosa-infected or- School of Medicine, National and Kapodistrian University of thopedic prostheses with ceftazidime ciprofloxacin antibiotic Athens, Athens, Greece); Vasilios G. Igoumenou (First Department combination, Antimicrob. Agents Chemother., 39, 2423–2425, of Orthopaedics, University General Hospital Attikon, School of https://doi.org/10.1128/AAC.39.11.2423, 1995. Medicine, National and Kapodistrian University of Athens, Athens, Corvec, S., Furustrand Tafin, U., Betrisey, B., Borens, O., and Greece; Oscar Murillo and Joan Gómez-Junyent (Infectious Dis- Trampuz, A.: Activities of fosfomycin, tigecycline, colistin, eases Department, Hospital Universitari de Bellvitge, Barcelona); and gentamicin against extended-spectrum-β-lactamase- Jacier Cabo (Orthopaedic Surgery Department, Hospital Universi- producing Escherichia coli in a foreign-body infection tari de Bellvitge, Barcelona); Fe Tubau (Microbiology Department, model, Antimicrob. Agents Chemother., 57, 1421–1427, Hospital Universitari de Bellvitge, Barcelona). https://doi.org/10.1128/AAC.01718-12, 2013. European Committee on Antimicrobial Susceptibility Testing (EUCAST): recommendations, http://www.eucast.org/clinical_ Author contributions. EG and AP conceived the idea and wrote breakpoint/, last access: 1 January 2022. the protocol. EG created the case report form. EG, MJS, AM, DRP, Glaudemans, A. W. J. M., Jutte, P. C., Cataldo, M. A., Cassar- ILA, AR, JA, MDdT, SN, ES, EB, MC, MBP, SP, NB, NO’C, ABG, Pullicino, V., Gheysens, O., Borens, O., Trampuz, A., Wörtler, GS, PT, ZKT, NP, PDM, PP, AS and AP collected important data K., Petrosillo, N., Winkler, H., Signore, A., and Sconfienza, L. and completed the case report form. EG and AP analysed data. EG M.: Consensus document for the diagnosis of peripheral bone in- wrote the manuscript. NP provided statistical assistance. MJS, PT, fection in adults: a joint paper by the EANM, EBJIS, and ESR AS, DRP, MDdT, AR, JA, NB, SP and ES provided significant com- (with ESCMID endorsement), Eur. J. Nucl. Med. Molec. Imag- ments on the first draft of the paper, and PT, AS and AP provided ing, 46, 957–970, https://doi.org/10.1007/s00259-019-4262-x, significant comments on the revised manuscript. The final version 2019. of the paper was approved by all authors. Grossi, O., Asseray, N., Bourigault, C., Corvec, S., Valette, M., Navas, D., Happi-Djeukou, L., Touchais, S., Bémer, P., Boutoille, D., and Nantes Bone and Joint Infections Study Group: Gram-negative prosthetic joint infections man- Competing interests. At least one of the (co-)authors is a mem- aged according to a multidisciplinary standardized approach: ber of the editorial board of Journal of Bone and Joint Infection. risk factors for failure and outcome with and without flu- The peer-review process was guided by an independent editor, and oroquinolones, J. Antimicrob. Chemother., 71, 2593–2597, the authors also have no other competing interests to declare. https://doi.org/10.1093/jac/dkw202, 2016. J. Bone Joint Infect., 7, 279–288, 2022 https://doi.org/10.5194/jbji-7-279-2022 E. 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