The Different Microbial Etiology of Prosthetic Joint Infections According to Route of Acquisition and Time After Prosthesis Implantation, Including the Role of Multidrug-Resistant Organisms

The aim of our study was to characterize the etiology of prosthetic joint infections (PJIs)-including multidrug-resistant organisms (MDRO)-by category of infection. A multicenter study of 2544 patients with PJIs was performed. We analyzed the causative microorganisms according to the Tsukayama's scheme (early postoperative, late chronic, and acute hematogenous infections (EPI, LCI, AHI) and "positive intraoperative cultures" (PIC)). Non-hematogenous PJIs were also evaluated according to time since surgery: 12 months. AHIs were mostly caused by Staphylococcus aureus (39.2%) and streptococci (30.2%). EPIs were characterized by a preponderance of virulent microorganisms (S. aureus, Gram-negative bacilli (GNB), enterococci), MDROs (24%) and polymicrobial infections (27.4%). Conversely, coagulase-negative staphylococci (CoNS) and Cutibacterium species were predominant in LCIs (54.5% and 6.1%, respectively) and PICs (57.1% and 15.1%). The percentage of MDROs isolated in EPIs was more than three times the percentage isolated in LCIs (7.8%) and more than twice the proportion found in AHI (10.9%). There was a significant decreasing linear trend over the four time intervals post-surgery for virulent microorganisms, MDROs, and polymicrobial infections, and a rising trend for CoNS, streptococci and Cutibacterium spp. The observed differences have important implications for the empirical antimicrobial treatment of PJIs.Acknowledgments: This work was supported by the Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness (grant number PI15/1026) (Co-funded by European Regional Development Fund/European Social Fund "Investing in your future"). REIPI (Spanish Network for Research in Infectious Disease) is supported by the Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness, and by the European Development Regional Fund “A way to achieve Europe”

Methicillin-resistant Staphylococcus aureus (MRSA) catheter-related bacteraemia in haemodialysis patients

Background: the aim of the study was to determine clinical and microbiological differences between patients with methicillin-resistant Staphylococcus aureus (MRSA) catheter-related bacteraemia (CRB) undergoing or not undergoing haemodialysis, and to compare outcomes. Methods: prospective multicentre study conducted at 21 Spanish hospitals of patients with MRSA bacteraemia diagnosed between June 2008 and December 2009. Patients with MRSA-CRB were selected. Data of patients on haemodialysis (HD-CRB) and those not on haemodialysis (non-HD-CRB) were compared. Results: among 579 episodes of MRSA bacteraemia, 218 (37.7 %) were CRB. Thirty-four (15.6 %) were HD-CRB and 184 (84.4 %) non-HD-CRB. All HD-CRB patients acquired the infection at dialysis centres, while in 85.3 % of the non-HD-CRB group the infection was nosocomial (p < .001). There were no differences in age, gender or severity of bacteraemia (Pitt score); comorbidities (Charlson score ≥ 4) were higher in the HD-CRB group than in the non-HD-CRB group (73.5 % vs. 46.2 %, p = .003). Although there were no differences in VAN-MIC ≥1.5 mg/L according to microdilution, using the E-test a higher rate of VAN-MIC ≥1.5 mg/L was observed in HD-CRB than in non-HD-CRB patients (63.3 % vs. 44.1 %, p = .051). Vancomycin was more frequently administered in the HD-CRB group than in the non-HD-CRB group (82.3 % vs. 42.4 %, p = <.001) and therefore the appropriate empirical therapy was significantly higher in HD-CRB group (91.2 % vs. 73.9 %, p = .029). There were no differences with regard to catheter removal (79.4 % vs. 84.2 %, p = .555, respectively). No significant differences in mortality rate were observed between both groups (Overall mortality: 11.8 % vs. 27.2 %, p = .081, respectively), but there was a trend towards a higher recurrence rate in HD-CRB group (8.8 % vs. 2.2 %, p = .076). Conclusions: in our multicentre study, ambulatory patients in chronic haemodialysis represented a significant proportion of cases of MRSA catheter-related bacteraemia. Although haemodialysis patients with MRSA catheter-related bacteraemia had significantly more comorbidities and higher proportion of strains with reduced vancomycin susceptibility than non-haemodialysis patients, overall mortality between both groups was similar

Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial.

INTRODUCTION: Despite the availability of new antibiotics such as daptomycin, methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia continues to be associated with high clinical failure rates. Combination therapy has been proposed as an alternative to improve outcomes but there is a lack of clinical studies. The study aims to demonstrate that combination of daptomycin plus fosfomycin achieves higher clinical success rates in the treatment of MRSA bacteraemia than daptomycin alone. METHODS AND ANALYSIS: A multicentre open-label, randomised phase III study. Adult patients hospitalised with MRSA bacteraemia will be randomly assigned (1:1) to group 1: daptomycin 10 mg/kg/24 h intravenous; or group 2: daptomycin 10 mg/kg/24 h intravenous plus fosfomycin 2 gr/6 g intravenous. The main outcome will be treatment response at week 6 after stopping therapy (test-of-cure (TOC) visit). This is a composite variable with two values: Treatment success: resolution of clinical signs and symptoms (clinical success) and negative blood cultures (microbiological success) at the TOC visit. Treatment failure: if any of the following conditions apply: (1) lack of clinical improvement at 72 h or more after starting therapy; (2) persistent bacteraemia (positive blood cultures on day 7); (3) therapy is discontinued early due to adverse effects or for some other reason based on clinical judgement; (4) relapse of MRSA bacteraemia before the TOC visit; (5) death for any reason before the TOC visit. Assuming a 60% cure rate with daptomycin and a 20% difference in cure rates between the two groups, 103 patients will be needed for each group (α:0.05, ß: 0.2). Statistical analysis will be based on intention to treat, as well as per protocol and safety analysis. ETHICS AND DISSEMINATION: The protocol was approved by the Spanish Medicines and Healthcare Products Regulatory Agency (AEMPS). The sponsor commits itself to publishing the data in first quartile peer-review journals within 12 months of the completion of the study

Multicentre, randomised, open-label, phase IV-III study to evaluate the efficacy of cloxacillin plus fosfomycin versus cloxacillin alone in adult patients with methicillin-susceptible Staphylococcus aureus bacteraemia: study protocol for the SAFO trial

Introduction: Methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is a frequent condition, with high mortality rates. There is a growing interest in identifying new therapeutic regimens able to reduce therapeutic failure and mortality observed with the standard of care of beta-lactam monotherapy. In vitro and small-scale studies have found synergy between cloxacillin and fosfomycin against S. aureus. Our aim is to test the hypothesis that cloxacillin plus fosfomycin achieves higher treatment success than cloxacillin alone in patients with MSSA bacteraemia. Methods: We will perform a superiority, randomised, open-label, phase IV-III, two-armed parallel group (1:1) clinical trial at 20 Spanish tertiary hospitals. Adults (≥18 years) with isolation of MSSA from at least one blood culture ≤72 hours before inclusion with evidence of infection, will be randomly allocated to receive either cloxacillin 2 g/4-hour intravenous plus fosfomycin 3 g/6-hour intravenous or cloxacillin 2 g/4-hour intravenous alone for 7 days. After the first week, sequential treatment and total duration of antibiotic therapy will be determined according to clinical criteria by the attending physician. Primary endpoints: (1) Treatment success at day 7, a composite endpoint comprising all the following criteria: patient alive, stable or with improved quick-Sequential Organ Failure Assessment score, afebrile and with negative blood cultures for MSSA at day 7. (2) Treatment success at test of cure (TOC) visit: patient alive and no isolation of MSSA in blood culture or at another sterile site from day 8 until TOC (12 weeks after randomisation). We assume a rate of treatment success of 74% in the cloxacillin group. Accepting alpha risk of 0.05 and beta risk of 0.2 in a two-sided test, 183 subjects will be required in each of the control and experimental groups to obtain statistically significant difference of 12% (considered clinically significant). Ethics and dissemination: Ethical approval has been obtained from the Ethics Committee of Bellvitge University Hospital (AC069/18) and from the Spanish Medicines and Healthcare Product Regulatory Agency (AEMPS, AC069/18), and is valid for all participating centres under existing Spanish legislation. The results will be presented at international meetings and will be made available to patients and funders

Multicentre, randomised, open-label, phase IV-III study to evaluate the efficacy of cloxacillin plus fosfomycin versus cloxacillin alone in adult patients with methicillin-susceptible staphylococcus aureus bacteraemia: study protocol for the SAFO trial

Introduction: Methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is a frequent condition, with high mortality rates. There is a growing interest in identifying new therapeutic regimens able to reduce therapeutic failure and mortality observed with the standard of care of beta-lactam monotherapy. In vitro and small-scale studies have found synergy between cloxacillin and fosfomycin against S. aureus. Our aim is to test the hypothesis that cloxacillin plus fosfomycin achieves higher treatment success than cloxacillin alone in patients with MSSA bacteraemia. Methods: We will perform a superiority, randomised, open-label, phase IV-III, two-armed parallel group (1:1) clinical trial at 20 Spanish tertiary hospitals. Adults (≥18 years) with isolation of MSSA from at least one blood culture ≤72 hours before inclusion with evidence of infection, will be randomly allocated to receive either cloxacillin 2 g/4-hour intravenous plus fosfomycin 3 g/6-hour intravenous or cloxacillin 2 g/4-hour intravenous alone for 7 days. After the first week, sequential treatment and total duration of antibiotic therapy will be determined according to clinical criteria by the attending physician.Primary endpoints: (1) Treatment success at day 7, a composite endpoint comprising all the following criteria: patient alive, stable or with improved quick-Sequential Organ Failure Assessment score, afebrile and with negative blood cultures for MSSA at day 7. (2) Treatment success at test of cure (TOC) visit: patient alive and no isolation of MSSA in blood culture or at another sterile site from day 8 until TOC (12 weeks after randomisation).We assume a rate of treatment success of 74% in the cloxacillin group. Accepting alpha risk of 0.05 and beta risk of 0.2 in a two-sided test, 183 subjects will be required in each of the control and experimental groups to obtain statistically significant difference of 12% (considered clinically significant)

Candida periprosthetic joint infection: A rare and difficult-to-treat infection

BACKGROUND: Candida periprosthetic joint infection (CPJI) is a rare, difficult-to-treat disease. The purpose of this study was to evaluate the clinical characteristics and outcomes of CPJI treated with various surgical and antifungal strategies. METHODS: We conducted a multicenter retrospective study of all CPJI diagnosed between 2003 and 2015 in 16 Spanish hospitals. RESULTS: Forty-three patients included: median age, 75 years, and median Charlson Comorbidity Index score, 4. Thirty-four (79.1%) patients had ≥1 risk factor for Candida infection. Most common causative species were C. albicans and C. parapsilosis. Thirty-five patients were evaluable for outcome: overall, treatment succeeded in 17 (48.6%) and failed in 18 (51.4%). Success was 13/20 (67%) in patients with prosthesis removal and 4/15 (27%) with debridement and prosthesis retention (p = 0.041). All 3 patients who received an amphotericin B-impregnated cement spacer cured. In the prosthesis removal group, success was 5/6 (83%) with an antibiofilm regimen and 8/13 (62%) with azoles (p = 0.605). In the debridement and prosthesis retention group, success was 3/10 (30%) with azoles and 1/5 (20%) with antibiofilm agents. Therapeutic failure was due to relapse in 9 patients, need for suppressive treatment in 5, persistent infection in 2, and CPJI-related death in 2; overall attributable mortality was 6%. CONCLUSIONS: CPJI is usually a chronic disease in patients with comorbidities and risk factors for Candida infection. Treatment success is low, and prosthesis removal improves outcome. Although there is insufficient evidence that use of antifungals with antibiofilm activity has additional benefits, our experience indicates it may be recommendable