Aim. Daptomycin plus fosfomycin combination therapy is a valuable strategy for treating staphylococcal osteoarticular infections. Considernig that each gram of fosfomycin contains 330 mg of sodium, electrolytic imbalance due to sodium overload could pose safety issues, especially in the cardiopatic patients and/or in the frail elderly. The aim of this study was to compare the efficacy of using reduced vs. standard daily dose fosfomycin in combination with daptomycin in a cohort of patients with osteoarticular infections. Method. This analysis included adult patients with osteoarticular infections admitted to the Infectious Diseases Unit of our University hospital in the period Nov 2022 – Feb 2024 and who were treated with daptomycin (8-10 mg/kg/daily) plus 24h-continuous infusion (CI) fosfomycin at the standard-dose of 16 g daily (standard-dose group) or at the reduced-dose of 8-12 g daily (reduced-dose group). All the patients underwent therapeutic drug monitoring (TDM) of fosfomycin for granting a pharmacodynamic target attainment of 24h-area under the concentration-time curve over minimum inhibitory concentration (AUC24h/MIC) >95 against Staphylococcus aureus with an MIC value up to 32 mg/L and of 70%t>MIC. Estimated glomerular filtration rate (eGFR) was assessed at each TDM session. Patient clinical outcome was assessed. Results. The standard- and the reduced-dose groups included 43 (29 males, 67.4%) and 21 (11 males, 52.4%) patients, respectively. No differences in median age (54 vs. 63 years, p=36), weight (80 vs. 76 kg, p=0.13) and type of diagnosis [prosthetic joint infections (16 vs. 29, p=0.38), osteomyelitis (2 vs. 9, p=0.72), septic arthritis (3 vs. 3, p=0.39) and spondilodiscitis (0 vs. 2, p=1.0)] were observed between the two groups. Median eGFR was similar in the standard vs. the reduced-dose group (109 vs. 98 mL/min/1.73m2, p=0.004). In the reduced-dose group, CI fosfomycin was administerd at 8 and 12 g/daily in 12 and 9 patients, respectively. There was no difference between the standard- and reduced-dose groups in attainment of the pharmacodynamic targets of AUC24h/MIC>95 (41/43 vs. 20/21, p=1.0), of 70%t>MIC (43/43 vs. 21/21 p=1.0) and of clinical cure (39/43 vs. 19/21, p=1.0). Conclusions. Combination therapy of 8-10 mg/kg/daily daptomycin plus 8-12 g/daily CI fosfomycin may be as effective as that of 8-10 mg/kg/daily daptomycin plus 16 g/daily CI fosfomycin. The fosfomycin reduced-dose strategy allows to decrease the daily sodium load by 25-50% compared to the standard dose, thus reducing the risk of cardiac adverse events. TDM may be a valuable strategy for individualizing fosfomycin dose in patients with osteoarticular infections

Aim. Ciprofloxacin is recommended as anti-biofilm therapy for gram-negative periprosthetic joint infection. With ciprofloxacin monotherapy, resistance in gram-negative bacteria was observed. Therefore, we evaluated in vitro synergistic activity of fosfomycin, ciprofloxacin and gentamicin combinations against biofilms formed by E. coli and P. aeruginosa strains. Method. E. coli ATCC 25922, P. aeruginosa ATCC 27853 and 15 clinical isolates were used for this study. MIC values were determined by Etest. Biofilms were formed on porous sintered glass beads for 24h and exposed to antibiotics for further 24h. Viability of bacteria on the glass beads after antibiotic treatment was detected by cfu counting of the sonicated beads. The minimum biofilm eradication concentration (MBEC) was defined as the lowest concentration of antibiotic required to kill biofilm cells. Synergistic activity against biofilm was evaluated by calculation of the fractional inhibitory concentration index (FICI). Results. Table 1 summarizes the antimicrobial susceptibility of planktonic (MIC), biofilm bacteria (MBEC) and synergism. Among 9 E. coli isolates, the synergism was observed in 78% of isolates treated with fosfomycin/gentamicin, 44% treated with gentamicin/ciprofloxacin and 22% treated with fosfomycin/ciprofloxacin. Among 8 P. aeruginosa isolates, the synergism was observed 75% of isolates treated with gentamicin/ciprofloxacin, 63% treated with fosfomycin/gentamicin and 50% treated with fosfomycin/ciprofloxacin. Conclusions. Based on our results, fosfomycin in combination with gentamicin seems to be a promising therapeutic approach against E. coli biofilm related infections. Combination of gentamicin with ciprofloxacin represent the most optimal treatment option for P. aeruginosa biofilm. For any figures or tables, please contact the authors directly

Aim. We evaluated the efficacy and safety of treatment regimens in a pathogen and surgery specific mode according to a standardized algorithm for the treatment of periprosthetic joint infection (PJI) based on combinations with 15g/d intravenous fosfomycin followed by oral antibiotics for totally 12 weeks. Method. Consecutive patients with PJI caused by at least one of the following isolates were prospectively included: staphylococci (MIC ≤32 mg/l), streptococci (MIC ≤128 mg/l), enterococci (MIC ≤128 mg/l), Enterobacteriaceae (MIC ≤32 mg/l) and Pseudomonas spp. (MIC ≤128 mg/l). PJI was defined by the proposed European Bone and Joint Infection Society (EBJIS) criteria. Follow up with clinical (joint function and quality of life scores), laboratory and radiological evaluation at 3, 12 and 24 months after last surgery is performed. Infection outcome was assessed as the proportion of infection-free patients. The probability of infection-free survival was estimated using the Kaplan-Meier survival method. Results. 50 patients were screened for eligibility, of which 2 were excluded due to intolerance or allergy to fosfomycin, 1 due to isolation of fosfomycin resistant pathogen and 2 patients died due to unrelated cause to infection. The remaining 45 patients were included. Due to persistence of infection, 3 patients underwent prosthesis explantation after initial debridement and retention, 1 patient underwent debridement of Girdlestone-situation; all 4 infections were caused by S. aureus. At 2 patients debridement of hematoma after Girdlestone approach was performed. 41 patients were infection-free (91%) after a median follow-up of 6 month (range, 1 – 14 months). Nausea (n=14) and hypokalemia (n=13) were the most frequent adverse events and resolved after fosfomycin discontinuation; 5 patients had diarrhea and vomiting was observed in 2 patients. Isolated pathogens were staphylococci (n=30), streptococci (n=3), enterococci (n=5) and gram-negative rods (n=2). Cultures were negative in 9 patients and polymicrobial in 2 patients. The infection occurred postoperatively in 31 patients (69%) and hematogenously in 14 (31%). Two-stage exchange was performed in 27 (60%), debridement with retention in 13 (29%) and one-stage exchange in 5 patients (11%). Conclusions. The applied PJI treatment algorithm including intravenous fosfomycin in the initial postoperative period was associated with infection-free outcome of 91% after a median follow-up of 6 month. The Kaplan-Meier survival method showed the probability of infection-free survival of 88.5% after 1 year. Adverse events occurred in 21 patients (46%) mostly nausea and hypokalemia were reported. Adverse events were mild and resolved completely

Background. Vancomycin and fosfomycin are antibiotic commonly used in Methicillin-resistant Staphylococcus aureus (MRSA) infection. This study compares the efficacy of articulating cement spacer implegnated with vancomycin and articulating cement spacer implegnated with fosfomycin to inhibit MRSA. Methods. Vancomycin implegnated articulating cement spacers and Fosfomycin implegnated articulating cement spacers were immersed in sterile phosphate buffered saline(PBS) and then incubated at 37 C. The samples were collected and change daily. Aliquots were tested for MRSA inhibition by disc diffusion method. The inhibition zones diameters were measured. Results. Vancomycin group showed an MRSA inhibition zone up to four weeks. However, Fosfomycin group showed inhibition zone in day 3 in some samples but after that no sample had the potential to inhibit MRSA. Conclusion. In this experiment. Vancomycin impregnated articulating cement spacers showed longer efficacy to inhibit MRSA when compared to Fosfomycin

Aim. Rifampicin plays an important role in the treatment of staphylococcal prosthetic joint infection, as rifampicin-containing combinations have shown a high efficacy against S. aureus biofilm infections. However, the emergence of rifampin-resistant strains is a feared complication and the use of rifampicin in those cases seems unwarranted. Therefore, we evaluated the activity of bacteriophage Sb1 in combination with different antibiotics against the biofilm of four rifampicin-resistant MRSA strains as alternative therapeutic approach. Method. Four rifampicin-resistant MRSA strains were used in this study. The MIC for all tested antibiotics was determined by Etest. Biofilms were formed on porous glass beads for 24h and exposed to Sb1 (10. 7. PFU/mL) for 24h followed by exposure to antibiotic for 24h. Viability of bacteria after antimicrobial treatment was detected by beads sonication and plating of the sonication fluids. The minimum biofilm eradication concentration (MBEC) was defined as the lowest concentration of antibiotic required to kill all cells resulting in the appearance of no colony after plating of the sonication fluid (detection limit <20 CFU/mL). The synergistic effects were observed when Sb1 combined with antibiotics used at least 2 log-reduction lower concentrations. Results. All strains were susceptible to the three antibiotics except for MRSA3, resistant to fosfomycin, according to the EUCAST breakpoints. All tested antibiotics presented high MBEC values (ranging from 64 to >1024 µg/mL) when tested alone against biofilm (Table 1). A sequential administration of Sb1 followed by vancomycin (VAN) showed no synergistic effect against any of the tested strains, whereas the combination with fosfomycin (FOF) showed synergism in 50% of the strains with improvement of the eradication activity. The combination of Sb1 with daptomycin (DAP) showed the highest synergistic effects in 100% of the strains, with a 2 or 3-log reduction in the MBEC. Conclusions. Sb1 bacteriophage in combination with daptomycin seems a promising alternative for the treatment of rifampicin-resistant MRSA biofilm infections. Table 1 (not included). Antimicrobial activities against rifampicin-resistant MRSA strains. For the table, please contact authors directly

Aim. The increase of antimicrobial resistance reduces treatment options for implant-associated infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Bacteriophages present a promising alternative to treat biofilm-related infections due to their rapid bactericidal activity and activity on multi-drug resistant bacteria. In this study, we investigated the synergistic activity of lytic bacteriophage Sb-1 with different antibiotics against MRSA biofilm, using a real-time highly sensitive assay measuring growth-related heat production (microcalorimetry). Methods. Rifampin, fosfomycin, vancomycin and daptomycin were tested alone and in combination with S. aureus specific phage, Sb-1, against MRSA (Staphylococcus aureus*). MRSA biofilm was formed on porous glass beads (Φ 4 mm, pore size 60 µm) and incubated for 24 h at 37° C in BHI. After 3 times washing biofilms were exposed first to different titers of bacteriophages, ranging from 102 to104 plaque-forming unite (pfu)/ml and after 24h treated again with subinhibitory concentration of antibiotics (corresponding to 1/4, 1/8, 1/16, 1/32 × MHICbiofilm). After 24h antibiotic treatment, the presence of biofilm on glass beads was evaluated by isothermal microcalorimetry for 48h. Heat flow (µW) and total heat (J) were measured. Results. MHICs of rifampin, fosfomycin, daptomycin and vancomycin when tested alone were 256 μg/ml, >4096 μg/ml, 128μg/ml and 2048μg/ml, respectively. Synergistic activity against biofilm MRSA was observed when vancomycin was tested at subinhibitory concentrations 512 μg/ml, 256 μg/ml, 128 μg/ml and 64 μg/ml in combination with subinhibitory titers of Sb-1 at 102, 103, 104 pfu/ml. Complete inhibition of heat production was observed only in combination with a higher titer of Sb-1 (104 pfu/ml). High synergistic activities were also observed in the presence of rifampin, fosfomycin and daptomycin. Conclusions. While MHICs of antibiotics against MRSA biofilm were above drug concentrations reachable in clinical practice, the co-administration with bacteriophage Sb-1 strongly reduced the antibiotic doses needed to eradicate MRSA biofilm. The use of bacteriophage and antibiotics in combination represent an effective strategy to treat implant-associated infections

Aim. To retrospectively investigate the clinical outcome after surgical, single-stage treatment of orthopaedic infections using antibiotics delivered locally by a calcium sulphate/hydroxyapatite biocomposite. Method. In order to identify the patients, we retrospectively searched several patient associated hospital-based databases using free text search with the term “Cerament” between November 2015 and November 2018. 58 cases with confirmed osteomyelitis and in which the bone substitute loaded with Gentamicin and/or Vancomycin had been used were identified and further evaluated. Results. Mean age was 58.9 years (range: 25–89). 46 (79.3 %) patients had at least 12 months follow up. The remaining 12 patients had a mean follow up time of 10.0 months (range 7–11). Infection was eradicated in 54 patients (93.1 %). In one the patients with recurrent infection repeated surgery with addition of bone substitute loaded with fosfomycin eventually eradicated the infection. One patient died of causes not related to the infection nor the treatment. Five patients presented transient white wound drainage but no signs of infection. No other side effects were identified. Conclusions. Local administration of antibiotics and dead space management using a calcium sulphate/hydroxyapatite biocomposite. 1. in combination with single-stage surgical debridement, stabilisation and postoperative culture-specific systemic antibiotics resulted in a high amount of eradicated infections and in line with other authors

Aim. Prosthetic joint infections (PJI) due to Enterobacter cloacae are rare and often severe. The aim of this study is to describe cases with E. cloacae PJI. Method. We conducted a retrospective and a monocentric study in an orthopedic unit where complex bone and joint infections are managed. From 2012 to 2016, we included patients with PJI which perioperative samples were positive with E. cloacae. We collected background, clinical, biological and microbiological data of the current infection, surgical and medical treatment, and the outcome of these patients. Results. A total of twenty patients were included which 8 were male. Location was hip in 14 cases, knee in 5 cases and ankle in one case. The median time between arthroplasty and revision for infection was 3 years. Fourteen patients had at least two surgeries for previous PJI. The median time between the last surgery and the revision for E. cloacae infection was 31 days. Eleven patients were infected by extended-spectrum beta-lactamases (ESBL) strains. Most frequently, the antibiotics used were carbapenem in 9 cases, cefepim in 7 cases, a quinolone in 7 cases and fosfomycin in 4 cases. Infection was cured in 10 cases (50%) with a median time of follow-up of 24 months. Five patients had a recurrent infection, three due to Staphylococcus epidermidis, one to Staphylococcus epidermidis and Propionibacterium acnes and one to Escherichia coli. Four patients had a relapse of E. cloacae infection. One patient died from non-infectious cause (stroke). Conclusions. PJI infections due to E.cloacae usually occur early after the last prosthetic surgery, typically in patients with complex surgical history. A poor outcome, observed in nearly half of the patients could be explained in part by an association of factors: multiple risks factors, complex infectious history, a high rate of multiple resistance to antibiotics, unfavorable skin conditions

Aim. Treatment of enterococcal periprosthetic joint infections (PJI) is challenging due to heterogeneous pathogenesis, non-standardized management strategies and lack of biofilm-active antibiotics. Previous studies report treatment success from 50–76%. We evaluated the characteristics and outcome of enterococcal PJI, in particular the influence of antimicrobial treatment regimens. Method. Consecutive patients with enterococcal PJI treated at two specialized orthopaedic institutions were retrospectively included from 2010 to 2017. PJI was defined by the proposed European Bone and Joint Infection Society (EBJIS) criteria. Adequate antimicrobial treatment was considered when the antibiotic was appropiate for the treatment of enterococcal bone infections (activity, dose, oral bioavailability, bone penetration). The treatment success (defined as no relapse of enteroccal infection) and clinical success(i.e. infection-free status) was evaluated and compared using Fishers exact test. Results. We included 75 episodes with enterococcal PJI, involving 41 hip, 30 knee, 2 elbow, 1 shoulder prosthesis. The median patient age was 76 years (range, 30–90 years), 48 (64%) were female. The infection occurred perioperatively in 61 episodes (81%), haematogenously in 13 (17%) and by contiguous spread in 1 case. Sinus tract was present in 16 patients (21%), predominantly in polymicrobial compared to monomicrobial infections (13 vs. 3 episodes, p= 0.01). Preoperative serum C-reactive protein level was elevated in 63/75 patients (84%) and synovial fluid leukocyte count was increased in 25/29 patients (86%). Enterococci grew in synovial fluid in 76%, in periprosthetic tissue in 78% and in sonication fluid in 73% of patients. Predominantly, E. faecalis was identified (n=64), followed by E. faecium (n=10) and E. casseliflavus (n=1); mixed infections were diagnosed in 38 patients (51%). Two-stage prosthesis exchange was performed in 44 (59%), debridement and retention in 13 (17%), resection arthroplasty in 11 (15%) and one-stage exchange in 10 patients (13%). Of 66 patients with available follow-up data (median, 31.8 months; range, 0.3–83.3 months), the treatment success was 85% (56/66), however, clinical success was only 68% (45/66). Treatment success was similar in monomicrobial and polymicrobial infections. Adequate antimicrobial treatment was associated with significant better outcome (91% vs. 38%, p=0.002). Treatment with fosfomycin (19/20, 95%) and combination therapy (45/50, 90%) was associated with better outcome, however, did not reach statistical significance (p >0.05). Conclusions. The treatment outcome of enterococcal PJI was high (85%), however, a second episode of PJI caused by a new pathogen was common in the later course. Adequate antimicrobial treatment was the only significant factor associated with better treatment success

PJI du to Enterobacter cloacae are rare and often severe. The aim of our study is to define the history of patients with such infections and their outcome. We conducted a retrospective monocentric study in an orthopedic unit where complex bone and joint infections are supported. From 2011 to 214 we selected patients with E. cloacae PJI based on data from the microbiology laboratory. In their files we collected information on their background, their medical and surgical history, antibiotics they received in the year before infection, the suspected portal of entry, the management and the outcome. Twelve patients were included, 7 male and 5 female. PJI was located to the hip in 8 cases, the knee in 3 cases and the ankle in one case. The average time between the placing of the first prosthesis and infection was 3 years. Eleven patients had one or more surgery for previous PJI. The average time elapsed since the last surgery was 30 days. Eleven patients had been treated with antibiotic combinations for at least 6 weeks, in the year before E cloacae infection. A portal of entry was identified only two times: urinary tract infection in one patient and catheter-related infection in one patient. Antibiotics the more often prescribed were carbapenems (n = 5) and cefepime (n = 4), each combined with quinolones (n =4) or fosfomycin (n = 3). Two patients required an additional debridement within an average of 18 days. Infectious outcome was favorable in 8 cases (67%) with a median duration of follow-up of 26 months. Two patients had a recurrent infection, one due to Streptococcus oralis and one to Candida albicans. One patient had a relapse of E cloacae infection. One patient died from unknown cause. PJI infections due to E.cloacae usually occur early after prosthetic surgery, typically in patients with complex surgical history. Despite a high rate of multi-resistance to antibiotics, outcome may be favorable in a large majority of patients

Aims

This study aimed to assess the performance of an automated multiplex polymerase chain reaction (mPCR) technique for rapid diagnosis of native joint septic arthritis