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

Aims. The management of periprosthetic joint infection (PJI) after total knee arthroplasty (TKA) is challenging. The correct antibiotic management remains elusive due to differences in epidemiology and resistance between countries, and reports in the literature. Before the efficacy of surgical treatment is investigated, it is crucial to analyze the bacterial strains causing PJI, especially for patients in whom no organisms are grown. Methods. A review of all revision TKAs which were undertaken between 2006 and 2018 in a tertiary referral centre was performed, including all those meeting the consensus criteria for PJI, in which organisms were identified. Using a cluster analysis, three chronological time periods were created. We then evaluated the antibiotic resistance of the identified bacteria between these three clusters and the effectiveness of our antibiotic regime. Results. We identified 129 PJIs with 161 culture identified bacteria in 97 patients. Coagulase-negative staphylococci (CNS) were identified in 46.6% cultures, followed by Staphylococcus aureus in 19.8%. The overall resistance to antibiotics did not increase significantly during the study period (p = 0.454). However, CNS resistance to teicoplanin (p < 0.001), fosfomycin (p = 0.016), and tetracycline (p = 0.014) increased significantly. Vancomycin had an 84.4% overall sensitivity and 100% CNS sensitivity and was the most effective agent. Conclusion. Although we were unable to show an overall increase in antibiotic resistance in organisms that cause PJI after TKA during the study period, this was not true for CNS. It is concerning that resistance of CNS to new antibiotics, but not vancomycin, has increased in a little more than a decade. Our findings suggest that referral centres should continuously monitor their bacteriological analyses, as these have significant implications for prophylactic treatment in both primary arthroplasty and revision arthroplasty for PJI. Cite this article: Bone Joint J 2021;103-B(6 Supple A):171–176

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

Aims

In orthopaedic and trauma surgery, implant-associated infections are increasingly treated with local application of antibiotics, which allows a high local drug concentration to be reached without eliciting systematic adverse effects. While ceftriaxone is a widely used antibiotic agent that has been shown to be effective against musculoskeletal infections, high local concentrations may harm the surrounding tissue. This study investigates the acute and subacute cytotoxicity of increasing ceftriaxone concentrations as well as their influence on the osteogenic differentiation of human bone progenitor cells.

Introduction. Management of periprosthetic joint infection (PJI) after total knee arthroplasty (TKA) is a challenging task. Antibiotic management remains elusive due to differences in epidemiology and resistance between countries and reports. Increasing resistance of bacteria is a concern. The aim of this study was to investigate the development of antibiotic resistance of main causative bacteria in a single center. Methods. A retrospective review of all revision TKA between 2006 and 2018 in a tertiary referral center was performed. Included were cases meeting the consensus criteria for PJI with at least two positive cultures. Three chronological groups were created using a two-step cluster analysis. Results. In 129 cases of PJI there were 161 different bacteria identified by growth in culture. Of all bacteria 76.4% were gram positive, 23.6% were gram negative. Coagulase-negative Staphylococci (CNS) were diagnosed in 46.6% cultures, followed by Staphylococcus aureus in 19.8% of cultures. Overall antibiotic resistance (p=0.454) and Staphylococcus aureus resistance (p=0.788) have not increased during the study period. CNS resistance to teicoplanin (4% to 44%; p<0.001), fosfomycin (16% to 44%, p=0.016) and tetracycline (0% to 28%, p=0.014) increased significantly. Vancomycin had an 84.4% overall sensitivity and 100% CNS sensitivity and remained the most effective agent. Conclusion. The increasing resistance to several antibiotics over a little more than a decade is concerning. This study suggests that referral centres should continuously monitor obtained cultures as this has significant implications for both prophylactic treatment in primary as well as empirical antibiotic treatment in PJI. Resistance profiles may differ between centres and are subject to dynamic changes

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

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. 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

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

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

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. 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

Objectives. Vancomycin and fosfomycin are antibiotics commonly used to treat methicillin-resistant Staphylococcus aureus (MRSA) infection. This study compares the in vitro inhibitory effects against MRSA of articulating cement spacers impregnated with either vancomycin or fosfomycin. Methods. Vancomycin-impregnated articulating cement spacers and fosfomycin-impregnated articulating cement spacers were immersed in sterile phosphate-buffered saline (PBS) solutions and then incubated. Samples were collected for bioactivity evaluation. The aliquots were tested for MRSA inhibition with the disc diffusion method, and the inhibition zone diameters were measured. The inhibition zone differences were evaluated using the Wilcoxon Rank Sum Test. Results. The vancomycin group had significantly larger inhibition zones than the fosfomycin group from day three through to completion of the fourth week of incubation (p < 0.001). The vancomycin group exhibited a MRSA inhibition zone up to four weeks but the fosfomycin group showed an inhibition zone for only three days and after that did not show the the potential to inhibit MRSA. Conclusion. This in vitro study found that the inhibitory effect of vancomycin-impregnated articulating cement spacers against MRSA outperformed fosfomycin-impregnated articulating cement spacers. Further comparing our results to other published reports suggests there might be a limitation of the disc diffusion bioassay to show a large inhibitory zone in a high concentration of a highly soluble antibiotic. Cite this article: V. Yuenyongviwat, N. Ingviya, P. Pathaburee, B. Tangtrakulwanich. Inhibitory effects of vancomycin and fosfomycin on methicillin-resistant Staphylococcus aureus from antibiotic-impregnated articulating cement spacers. Bone Joint Res 2017;6:132–136. DOI: 10.1302/2046-3758.63.2000639

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

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

Summary Statement. Combination of antibiotics with N-acetylcisteine and sub-MIC concentration of erythromycin was evaluated in two collection and 16 clinical strains of staphylococci isolated from PJI. The results were strain-dependent, so it evidences the necessity of perform individual studies of biofilm susceptibility. Objectives. Staphylococci are the most common cause of prosthetic joint infections (PJI) (1), making the treatment of this disease difficult due to the increased resistance to antibiotics of biofilms. Combination between antibiotics and other compounds could be a good alternative. The aim of this study was to evaluate the effect of the combination of two compounds with nine antibiotics in biofilms formed by staphylococcal strains isolated from PJI. Methods. 16 clinical strains (8 S. aureus and 8 S. epidermidis) isolated from patients with PJI as well as 2 collection strains (S. aureus 15981 and S. epidermidis ATCC 35984) were tested against 9 antibiotics (rifampin, vancomycin, tigecycline, clindamycin, cotrimoxazole, ciprofloxacin, cloxacillin, daptomycin and fosfomycin) in combination with NAC 1024 μg/mL and erythromycin at subinhibitory concentration (0.12 μg/mL), which was established after the determination of MIC according to EUCAST recommendations. The Calgary Biofilm Device (CBD) was used to determine the susceptibility of the biofilms to these combinations. The Minimal Biofilm Eradication Concentration (MBEC) for the all the antibiotics alone was determined in a previous study. All the experiments were performed by triplicate. Results. All the S. aureus strains showed homogeneous results, and the addition of NAC or erythromycin at the tested concentrations has not a clear effect in the antibiotic susceptibility of the biofilm, although combination of tigecycline with NAC seems even to increase the MBEC in most cases. Almost all clinical strains were MRSA. Regarding S. epidermidis strains, the results were strain-dependant. The combination with NAC seems to increase the MBEC for rifampin and tigecycline in some strains. However, there was a slight MBEC decrease with cotrimoxazole, ciprofloxacin, cloxacillin, daptomycin and fosfomycin. Erythromycin combinations resulted to be successful only in a few cases, and there is no an apparent relationship between erythromycin resistance and combination results. It is especially remarkable that one strain (P-23.2) showed a slight decrease of the MBEC combining both substances with most of the antibiotics tested. Conclusion. None of the combinations tested was clearly effective against biofilms for all strains of both species. This heterogeneity showed the necessity of making an individual study of each strain. The search of new strategies to fight against PJI is mandatory and further investigation is needed

Biofilm-associated infections in wounds or on implants are difficult to treat. Eradication of the bacteria is nearly always impossible, despite the use of specific antibiotics. The bactericidal effects of high-energy extracorporeal shock waves on Staphylococcus aureus have been reported, but the effect of low-energy shock waves on staphylococci and staphylococcal biofilms has not been investigated. In this study, biofilms grown on stainless steel washers were examined by electron microscopy. We tested ten experimental groups with Staph. aureus-coated washers and eight groups with Staph. epidermidis. The biofilm-cultured washers were exposed to low-energy shock waves at 0.16 mJ/mm. 2. for 500 impulses. The washers were then treated with cefuroxime, rifampicin and fosfomycin, both alone and in combination. All tests were carried out in triplicate. Viable cells were counted to determine the bactericidal effect. The control groups of Staph. aureus and Staph. epidermidis revealed a cell count of 6 × 10. 8. colony-forming units/ml. Complete eradication was achieved using the combination of antibiotic therapy (single antibiotic in Staph. aureus, a combination in Staph. epidermidis) and shock wave application (p < 0.01). We conclude that shock waves combined with antibiotics could be tested in an in vitro model of infection

Bacterial infection in orthopaedic surgery can be devastating, and is associated with significant morbidity and poor functional outcomes, which may be improved if high concentrations of antibiotics can be delivered locally over a prolonged period of time. The two most widely used methods of doing this involve antibiotic-loaded polymethylmethacrylate or collagen fleece. The former is not biodegradable and is a surface upon which secondary bacterial infection may occur. Consequently, it has to be removed once treatment has finished. The latter has been used successfully as an adjunct to systemic antibiotics, but cannot effect a sustained release that would allow it to be used on its own, thereby avoiding systemic toxicity.

This review explores the newer biodegradable carrier systems which are currently in the experimental phase of development and which may prove to be more effective in the treatment of osteomyelitis.

Introduction: The emergence of multidrug resistant Gram negative bacilli susceptible to hardly any beta lactam compound has led to infections close to a therapeutic dead end. In such circumstances, Imipenem-cilastatin (I-C) is often the only remaining therapeutic option. We report our experience with the prolonged administration of high-doses of I-C in the treatment of osteoarticular infections with bacteria resistant to other beta-lactam agents (or 4. l. generation cephalosporins in 14 cases). Materials and methods: Our retrospective study over 7 years included 29 patients with septic arthritis (n=3) continuous osteitis (n=6), septic non-union(n=12) and prosthetic joint infections (n=8). Treatment included an extensive surgical debridement and post-operative combination antibiotherapy with intravenous I-C and aminoside (54%) and/or fluoroquinolones (46%) and/or fosfomycin (29%). Associated microorganisms requiring yet additional antimicrobial agents were associated in 17 (59%) cases. I-C was maintained for an average of 46 days (extremes 21–90), at an average dose of 3,8g/day (extremes 2–6). The bacteria warranting I-C were cephalosporinase hyperproducing Enterobacter cloacae (38%), extended spectrum beta-lactamases producing enterobacteria (31%), Pseudomonas aeruginosa (21%) and/or Acinetobacter baumanii (21%). Results: Early outcome was favorable in 24 patients (82%). Two patients relapsed with the bacteria requiring I-C. Three failed to negate succion fluid cultures : one was discharged with no change in his condition, one agreed to a leg amputation and the third died of candidemic septic shock in SICU with drainage fluid still bactériologie ally positive. Repeated secondary colonization and systemic infection with yeasts led to a monitoring of yeast load. Per os amphotencin B and immediate treatment of urinary colonization prevented further systemic dissemination of candical infections. No other tolerance incidents were noted. Acquired resistance occurred only once in a P. aeruginosa isolate while Imipenem-cilastatin was chosen to cover an ESBL producing Escherichia coli. Secondary treatment with ceftazidime was then successful in eradicating P. aeruginosa. Conclusion: I-C has been widely used for the treatment of mixed flora infections as a wide spectrum antibiotic. We report good tolerance of high posology long term administration in documented osteoarticular indications if yeast colonization is properly monitored, and eradication rates are comparable to those reported in infections with susceptible bacteria