Efficacy of single antibiotic therapy versus antibiotic combination in implant-free staphylococcal post-surgical spinal infections: a retrospective observational study.

BACKGROUND: Post-surgical spinal infections (pSSIs) are a serious complication of spinal surgeries, with Staphylococcus spp. being one of the most prominent bacteria identified. Optimal antimicrobial therapy for staphylococcal spinal infections without spinal implants is not well documented. METHODS: This single center retrospective 7-year observational study described and compared the outcome (treatment failure or mortality rate one year after diagnosis) of 20 patients with staphylococcal-implant-free pSSI treated with single or combination antibiotics. RESULTS: Median duration of treatment was 40 days (IQR 38-42), with 6 days (IQR 5-7) on intravenous antibiotics and 34 days (IQR 30-36) on oral therapy. Four patients (20%) underwent new surgical debridement, all due to surgical failure, and 1 patient died within the first year without significant differences between both treatment group. CONCLUSION: This study raises the possibility of single antibiotic therapy for patients with implant-free post-surgical spinal infections due to Staphylococcus spp.

Evaluating the heart valve tissue diffusion of amoxicillin in infective endocarditis: a pilot prospective observational non-comparative study.

OBJECTIVES: Treating patients with infective endocarditis (IE) due to streptococci and enterococci currently involves high-dosage antibiotics. Recent literature suggests a 30%-70% diffusion rate could be extrapolated to human heart valve tissue. The objective of this study was to evaluate the diffusion coefficient of amoxicillin in heart valve tissue of patients operated for IE. METHODS: Adult patients were prospectively included that underwent surgery at the European Hospital Georges Pompidou for IE due to streptococci and enterococci and had previous IV amoxicillin treatment. Plasma (taken 48 h preoperatively) and heart valve tissue amoxicillin concentrations were measured with a validated LC-MS/MS method. The MIC values of amoxicillin were measured for all available isolates. RESULTS: Seventeen patients were included. Eleven (64.7%) patients had native valve IE and six (35.3%) had prosthetic valve IE. Fourteen IE cases (82.4%) were due to streptococci, one (5.9%) was due to enterococci and two (11.8%) were Haemophilus spp, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae group infections. Median (IQR) amoxicillin dose administered was 10.5 (8.0-12.0) g/day corresponding to 138.2 (112.5-160.0) mg/kg/day. The median amoxicillin plasma concentrations pre-surgery and intra-tissular weighted concentrations were 31.9 (25.9-51.9) mg/L and 19.0 (7.9-31.4) µg/g, respectively. Median tissue/plasma concentration ratio was 0.47 (0.24-0.67), with a median amoxicillin plasma/MIC ratio of 487 (179-745), and median amoxicillin tissue/MIC ratio of 42 (14-116). CONCLUSIONS: With a significant diffusion coefficient, amoxicillin dosage in heart valve tissues showed a concentration/MIC ratio well above current recommendations for bactericidal activity. Our study suggests that lower doses can be considered for susceptible bacteria.

Diagnostic uncertainty in infectious diseases: Advocacy for a nosological framework.

Diagnostic uncertainty (DU) is frequent in infectious diseases (ID), being recorded in 10% to over 50% of patients. Herein, we show that in several fields of clinical practice, high rates of DU are constant over time. DUs are not taken into account in guidelines, as therapeutic propositions are based on an established diagnosis. Moreover, while other guidelines underline the need for rapid broad-spectrum antibiotic therapy for patients with sepsis, many clinical conditions mimic sepsis and lead to unnecessary antibiotic therapy. Considering DU, many studies have been carried out to look for relevant biomarkers of infections, which also attest to non-infectious diseases mimicking infections. Therefore, diagnosis is often primarily a hypothesis, and empirical antibiotic therapy should be reassessed when microbiological data are available. However, other than for urinary tract infections or unexpected primary bacteremia, the high frequency of sterile microbiological samples implies that DU remains central in follow-up, which does not facilitate clinical management or antibiotic optimization. The main way to resolve the therapeutic challenge of DU could be to precisely describe the latter through a consensual definition that would facilitate consideration of DU and its mandatory therapeutic implications. A consensual definition of DU would also clarify responsibility and accountability for physicians in the antimicrobial approval process and l provide an opportunity to instruct their students in this large field of medical practices and to productively conduct relevant research.

Characterization of Pseudomonas aeruginosa l,d-Transpeptidases and Evaluation of Their Role in Peptidoglycan Adaptation to Biofilm Growth.

Peptidoglycan is an essential component of the bacterial cell envelope that sustains the turgor pressure of the cytoplasm, determines cell shape, and acts as a scaffold for the anchoring of envelope polymers such as lipoproteins. The final cross-linking step of peptidoglycan polymerization is performed by classical d,d-transpeptidases belonging to the penicillin-binding protein (PBP) family and by l,d-transpeptidases (LDTs), which are dispensable for growth in most bacterial species and whose physiological functions remain elusive. In this study, we investigated the contribution of LDTs to cell envelope synthesis in Pseudomonas aeruginosa grown in planktonic and biofilm conditions. We first assigned a function to each of the three P. aeruginosa LDTs by gene inactivation in P. aeruginosa, heterospecific gene expression in Escherichia coli, and, for one of them, direct determination of its enzymatic activity. We found that the three P. aeruginosa LDTs catalyze peptidoglycan cross-linking (LdtPae1), the anchoring of lipoprotein OprI to the peptidoglycan (LdtPae2), and the hydrolysis of the resulting peptidoglycan-OprI amide bond (LdtPae3). Construction of a phylogram revealed that LDTs performing each of these three functions in various species cannot be assigned to distinct evolutionary lineages, in contrast to what has been observed with PBPs. We showed that biofilm, but not planktonic bacteria, displayed an increase proportion of peptidoglycan cross-links formed by LdtPae1 and a greater extent of OprI anchoring to peptidoglycan, which is controlled by LdtPae2 and LdtPae3. Consistently, deletion of each of the ldt genes impaired biofilm formation and potentiated the bactericidal activity of EDTA. These results indicate that LDTs contribute to the stabilization of the bacterial cell envelope and to the adaptation of peptidoglycan metabolism to growth in biofilm. IMPORTANCE Active-site cysteine LDTs form a functionally heterologous family of enzymes that contribute to the biogenesis of the bacterial cell envelope through formation of peptidoglycan cross-links and through the dynamic anchoring of lipoproteins to peptidoglycan. Here, we report the role of three P. aeruginosa LDTs that had not been previously characterized. We show that these enzymes contribute to resistance to the bactericidal activity of EDTA and to the adaptation of cell envelope polymers to conditions that prevail in biofilms. These results indicate that LDTs should be considered putative targets in the development of drug-EDTA associations for the control of biofilm-related infections.

Clinical and biological diagnosis and follow-up of patients treated for endovascular infections due to Coxiellaburnetii.

The objective of this study was to evaluate the effectiveness of the recommended treatment for endovascular infections due to Coxiella burnetii. This single-center retrospective study was conducted in 13 patients with endovascular infection due to C. burnetii between January 2001 and December 2020 for a definite or possible endovascular infection due to C. burnetii with a minimum follow-up of 18 months post-infection. Clinical and biological data, including serology, blood and tissue PCR results, doxycycline and hydroxychloroquine assays were collected. Among the 13 patients, 11 had endocarditis (8 definite and 3 possible) and 2 had a vascular infection. At the time of diagnosis, fever was present in only 46% of cases. In case of endocarditis, 73% of patients had a pathological echocardiography. Biologically, the CRP level was low (52 mg/l ± 44). Autoimmune antibodies (antinuclear factor, neutrophil anticytoplasm) were present in 23% of patients. At the time of diagnosis, tissue PCR was very sensitive (100%) unlike blood or serum (29%). Blood levels of doxycycline and hydroxychloroquine were within expected values. Only one patient experienced treatment failure at two years, requiring surgery. For the 7 patients whose phase I IgG titres fell below 1/800, a minimum of 18 months of treatment was necessary. In the long term, the clinical and biological cure was 100% and 92% respectively, underlining the importance of monitoring the serum dosages of doxycycline and hydroxychloroquine. Given its sensitivity, tissue PCR could be added to the major Duke criteria.

TIVAP-related infection due to Gram-negative aerobic bacilli: should TIVAP stay or should it go?

We aimed to describe the outcome of totally implantable venous-access port (TIVAP)-related infections due to Gram-negative aerobic bacilli (Pseudomonas aeruginosa and other Pseudomonas spp., Acinetobacter spp., and Stenotrophomonas maltophilia), or GNAB, and assess the safety of conservative treatment. We conducted a retrospective study in a French teaching hospital, from January 2016 to December 2020, including adult patients treated for TIVAP-related infection due to GNAB. Success of conservative treatment was defined as a functional TIVAP 3 months after infection with no recurrence. We performed a bivariate analysis and analyzed causes for treatment failure. We included 68 patients (53 TIVAP-related bloodstream infections, 11 TIVAP-related infections, and 4 probable TIVAP-related infections) due to GNAB, mostly P. aeruginosa (50/68, 74%). TIVAP removal was initially decided for 49/68 patients (72%). Among the 19/68 (28%) patients with conservative treatment (all for infections caused by P. aeruginosa), 5/19 (26%) had successful treatment, 7/19 (37%) experienced failure (without sepsis or septic shock), 6/19 (32%) died within 3 months without TIVAP removal and no signs of infection recurrence, and 1 patient had TIVAP removal as it was no longer required. TIVAP-related infections caused by GNAB frequently require TIVAP removal. Conservative treatment can be performed in selected patients with a non-complicated infection caused by P. aeruginosa, who can benefit from the continuation of antineoplastic chemotherapy or palliative care. Treatment failures were not associated with sepsis or septic shock.

Modulation of the Specificity of Carbapenems and Diazabicyclooctanes for Selective Activity against Mycobacterium tuberculosis.

Treatment of multidrug-resistant tuberculosis with combinations of carbapenems and ß-lactamase inhibitors carries risks for dysbiosis and for the development of resistances in the intestinal microbiota. Using Escherichia coli producing carbapenemase KPC-2 as a model, we show that carbapenems can be modified to obtain drugs that are inactive against E. coli but retain antitubercular activity. Furthermore, functionalization of the diazabicyclooctanes scaffold provided drugs that did not effectively inactivate KPC-2 but retained activity against Mycobacterium tuberculosis targets.

Assessment of version 2.5 of QMAC-dRAST for rapid antimicrobial susceptibility testing with reduced sample-to-answer turnaround time and an integrated expert system.

OBJECTIVE: To assess the performance of the new rapid antimicrobial susceptibility testing (AST) QMAC-dRAST V2.5 system. METHODS: ASTs were performed using QMAC-dRAST-V2.5 and a disk diffusion method, directly from positive blood bottles with Gram-negative bacteria. Discrepancies between the results obtained using the two methods were categorized into very major errors (VME, S with dRAST vs. R with disk diffusion), major errors (ME, R vs. S, respectively), minor errors (mE, S vs. I or I vs. R, respectively), and very minor errors (Vme, I vs. S or R vs. I, respectively). For each AST, results were recorded after 4, 5, and 6h of incubation. RESULTS: From 106 bacteremia, 1416 individual AST results were obtained. Overall agreement between results using the two methods was 91%, ranging from 76.9% to 99.1% depending upon the antibiotic, with 128 errors, i.e. 14/1416 (1%) VME, 59/1416 (4.2%) ME, 25/1416 (1.8%) mE and 30/1416 (2.1%) Vme. VMEs were encountered for Klebsiellasp and Serratia marcescens isolates with low-level piperacillin and amikacin resistance, respectively. Using the integrated QMAC-dRAST-V2.5 expert system, all 14 VMEs and 3 mEs were eliminated, leading to 92.2% categorical agreement. After 45min of pre-incubation in the QMAC-dRAST-V2.5 device, 22.2% of the 1416 AST results were obtained after 4h, an additional 31.4% after 5h and a further 46.3% after 6h. CONCLUSION: QMAC-dRAST-V2.5 is an optimized version of QMAC-dRAST V2.0, particularly with respect to utilization of an expert system and reduced TAT according to the antibiotic tested.

Introducing an Open-Source Course Management System (Moodle) for Blended learning on infectious diseases and microbiology: A pre-post observational study.

INTRODUCTION: Attendance at face-to-face courses is low in the 2nd and 3rd years of medical school in France, possibly because of a lack of interactivity. We used Moodle (an open-source course management system) to introduce blended learning on Infectious Diseases and Microbiology through interactive quizzes and sessions of online-based continuous assessment. This pre-post observational study assessed changes in students' attendance and student as well as teacher satisfaction. METHODS: During the 2017-2018 academic session of Infectious Diseases and Microbiology, we used Moodle to include interactive quizzes during courses and to organize five continuous assessment sessions. Pre-post comparisons (2017-2018 vs. 2016-2017) were performed for the following outcomes: attendance rate, satisfaction questionnaire and exam performance. In addition, the students' and teachers' perception of Moodle-based interactive quizzes and continuous assessment sessions in 2017-2018 was assessed with Likert-like scales, closed and open-ended questions. A thematic analysis of the free comments was performed through inductive coding by two coders. RESULTS: In 2017-2018 vs. 2016-2017, mean (±SD) attendance rate was higher [12.5 (±7.2) % vs. 7.9 (±3.5) % of students, P<0.001] and clinical case-based courses, which encompassed 93% of Moodle-based courses in 2017-18, were more frequently considered to improve teaching and learning (81.9% vs. 73.8%, P=0.01). Students more frequently judged the teaching organization and structure to be adequate (85.5% vs. 80.2%, p=0.03) and more frequently recommended to next-year students that they attend courses (96.1% vs. 42.1%, P<0.001). CONCLUSION: Using Moodle for blended learning on Infectious Diseases and Microbiology improved student satisfaction and attendance at face-to-face courses.

A Case of Phage Therapy against Pandrug-Resistant Achromobacter xylosoxidans in a 12-Year-Old Lung-Transplanted Cystic Fibrosis Patient.

Bacteriophages are a promising therapeutic strategy among cystic fibrosis and lung-transplanted patients, considering the high frequency of colonization/infection caused by pandrug-resistant bacteria. However, little clinical data are available regarding the use of phages for infections with Achromobacter xylosoxidans. A 12-year-old lung-transplanted cystic fibrosis patient received two rounds of phage therapy because of persistent lung infection with pandrug-resistant A. xylosoxidans. Clinical tolerance was perfect, but initial bronchoalveolar lavage (BAL) still grew A. xylosoxidans. The patient's respiratory condition slowly improved and oxygen therapy was stopped. Low-grade airway colonization by A. xylosoxidans persisted for months before samples turned negative. No re-colonisation occurred more than two years after phage therapy was performed and imipenem treatment was stopped. Whole genome sequencing indicated that the eight A. xylosoxidans isolates, collected during phage therapy, belonged to four delineated strains, whereby one had a stop mutation in a gene for a phage receptor. The dynamics of lung colonisation were documented by means of strain-specific qPCRs on different BALs. We report the first case of phage therapy for A. xylosoxidans lung infection in a lung-transplanted patient. The dynamics of airway colonization was more complex than deduced from bacterial culture, involving phage susceptible as well as phage resistant strains.

Oral switch versus standard intravenous antibiotic therapy in left-sided endocarditis due to susceptible staphylococci, streptococci or enterococci (RODEO): a protocol for two open-label randomised controlled trials.

INTRODUCTION: Left-sided infective endocarditis (IE) is a serious infection with a heavy burden for patients and healthcare system. Oral switch after initial intravenous antibiotic therapy may reduce costs and improve patients' discomfort without increasing unfavourable outcomes. We describe the methodology of two simultaneously conducted open-label randomised trials aiming to assess non-inferiority of oral switch as compared with entirely intravenous antibiotic therapy for the treatment of left-sided IE. METHODS AND ANALYSIS: Two simultaneous multicentre open-label prospective randomised trials assessing non-inferiority of oral switch during antibiotic treatment as compared with entirely intravenous therapy in patients with left-sided IE are ongoing. One trial is dedicated to left-sided IE caused by multisusceptible staphylococci (Relais Oral Dans le traitement des Endocardites à staphylocoques ou streptOcoques (RODEO)-1) and the other is dedicated to left-sided IE caused by susceptible streptococci or enterococci (RODEO-2). It is planned to randomise 324 patients in each trial after an initial course of at least 10 days of intravenous antibiotic therapy either to continue intravenous antibiotic therapy or to switch to oral antibiotic therapy. The primary outcome is treatment failure within 3 months after the end of antibiotic treatment, a composite outcome defined by all-cause death and/or symptomatic embolic events and/or unplanned valvular surgery and/or microbiological relapse (with the primary pathogen). Secondary outcomes include patient quality of life, echocardiographic outcome, costs and efficiency associated with IE care. Statistical analysis will be performed with a non-inferiority margin of 10% and a one-sided 2.5% type I error. ETHICS AND DISSEMINATION: Written informed consent will be obtained from all participants. This study was approved by Tours Research ethics committee (CPP TOURS-Region Centre-Ouest 1, 2015-R26, 23 February 2016). Study findings will be published in peer-reviewed journals and disseminated through presentation at relevant national and international conferences. TRIAL REGISTRATION NUMBER: EudraCT Number: 2015-002371-16 and NCT02701608; NCT02701595.

Influence of Renal Function and Age on the Pharmacokinetics of Levofloxacin in Patients with Bone and Joint Infections.

Despite its efficacy and toxicity being exposure-related, levofloxacin pharmacokinetics in patients with bone and joint infections has been poorly described to date, so the possible need for a dose adjustment is unknown in this population. A prospective population pharmacokinetic study was conducted in 59 patients to answer this question. The final model consisted of a one-compartment model with first-order absorption and elimination. Mean parameter estimates (% interindividual variability) were 0.895 h-1 for the absorption rate constant (Ka), 6.10 L/h (40%) for the apparent clearance (CL/F), 90.6 L (25%) for the apparent distribution volume (V/F). Age and glomerular filtration rate (GFR), estimated by the modification of diet in renal disease formula, were related to CL/F by power models, and CL/F was found to increase for increasing GFR and decreasing age. For a similar GFR, the simulated area under the curve (AUC) was 55% higher in 70 years-old patients compared to 30 year-old patients. Based on this model, a 750 mg dose should provide an optimal exposure (AUC/ minimum inhibitory concentration (MIC) ≥100), with the possible exception of patients older than 60 years and with GFR <70 mL/min/m² who may necessitate a dose reduction, and patients with infections caused by bacteria with MIC close to 1 mg/L who may need an increase in the dose.

Comparison Between ESC and Duke Criteria for the Diagnosis of Prosthetic Valve Infective Endocarditis.

OBJECTIVES: The primary objective was to assess the value of the European Society of Cardiology (ESC) criteria, including 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in prosthetic valve infective endocarditis (PVE). Secondary objectives were: 1) to assess the reproducibility of 18F-FDG-PET/CT; 2) to compare its diagnostic value with that of echocardiography; and 3) to assess the diagnostic value of the presence of a diffuse splenic uptake BACKGROUND: 18F-FDG PET/CT has been added as a major criterion in the ESC 2015 infective endocarditis (IE) guidelines, but the benefit of the ESC criteria has not been prospectively compared with the conventional Duke criteria. METHODS: Between 2014 and 2017, 175 patients with suspected PVE were prospectively included in 3 French centers. After exclusion of patients with uninterpretable 18F-FDG PET/CT, 115 patients were evaluated, including 91 definite and 24 rejected IE, as defined by an expert consensus. RESULTS: Cardiac uptake by 18F-FDG PET/CT was observed in 67 of 91 patients with definite PVE and 6 with rejected IE (sensitivity 73.6% [95% confidence interval (CI): 63.3% to 82.3%], specificity 75% [95% CI: 53.3% to 90.2%]). The ESC 2015 classification increased the sensitivity of Duke criteria from 57.1% (95% CI: 46.3% to 67.5%) to 83.5% (95% CI: 74.3% to 90.5%) (p < 0.001), but decreased its specificity from 95.8% (95% CI: 78.9% to 99.9%) to 70.8% (95% CI: 48.9% to 87.4%). Intraobserver reproducibility of 18F-FDG PET/CT was good (kappa = 0.84) but interobserver reproducibility was less satisfactory (kappa = 0.63). A diffuse splenic uptake was observed in 24 (20.3%) patients, including 23 (25.3%) of definite PVE, and only 1 (4.2%) rejected PVE (p = 0.024). CONCLUSIONS: 18F-FDG PET/CT is a useful diagnostic tool in suspected PVE, and explains the greater sensitivity of ESC criteria than Duke criteria. However, 18F-FDG PET/CT also presents with important limitations concerning its feasibility, specificity, and reproducibility. Our study describes for the first time a new endocarditis criterion, that is, the presence of a diffuse splenic uptake on 18F-FDG PET/CT.

Individual decontamination measures reduce by two the incidence of surgical site infections in spinal surgery.

BACKGROUND: In spinal surgery, incidence of surgical site infections (SSI) is estimated between 1 and 10%. It results in increased morbidity, mortality and cost of management. Individual Staphylococcus aureus (SA) decolonization has already proved efficiency to prevent those events in various surgical domains. The aim of this study was to evaluate a strategy of prevention of SSI and in particular the decolonization of the nasal carriage of SA by a protocol with Mupirocin application. METHODS: We conducted a bicentric observational study on 5314 spinal surgery patients over a seven-year period. In both center, we compared periods before and after implementation of two measures: modification of antibioprophylaxis and staphylococcus decolonization. Homogeneity of the different samples of patients was assessed through measure of individual and surgical variables. We measured monthly incidence of SSI and evaluated its evolution in order to assess efficiency of these interventions. RESULTS: The incidence of SSI decreased by half, from 7.3% to 3% at the Beaujon Hospital and from 8.3% to 3.9% at the Georges-Pompidou European Hospital (GPEH). We do not observe any significant decrease of SA rate in these SSI. CONCLUSION: We believe that Staphylococcus aureus decolonization should be recommended in spinal surgery, and should be combined with an overall improvement of the quality of care.

Comparative evaluation of the QMAC-dRAST V2.0 system for rapid antibiotic susceptibility testing of Gram-negative blood culture isolates.

To comparatively evaluate the performance of the rapid antimicrobial susceptibility testing (AST) system QMAC-dRAST V2.0 and of standard disk diffusion in agar, AST was performed directly from 100 positive blood culture bottles with Gram-negative bacilli. AST results provided by QMAC-dRAST showed 92.9% agreement with disk diffusion method results. Discrepancies observed between results obtained with QMAC-dRAST and disk diffusion method conducted to 10 very major errors (0.8%, S with QMAC-dRAST vs R with disk diffusion method), 40 major errors (3.2%, R vs S, respectively), 15 minor errors (1.2%, S vs I or I vs R, respectively) and 23 very minors errors (1.8%, I vs S or R vs I, respectively). For very major and major errors, in only 36% of the cases did the repeat QMAC-dRAST confirm the initial result, whereas a repeat AST using disk diffusion method confirmed the initial result in 92% of cases. AST results obtained using microdilution in liquid medium confirmed those obtained with QMAC-dRAST and disk diffusion method in 4% and 89%, respectively. Repeatability and reproducibility tests performed on QMAC-dRAST using reference strains showed 94% to 100% of R/S/I categorical agreement.

Predictive factors of death associated with infective endocarditis in adult patients with congenital heart disease.

AIMS: Infective endocarditis is a severe infection which can occur in adult patients with congenital heart disease. We aimed to determine outcomes and risk factors of death in adult congenital heart disease and to investigate differences with infective endocarditis in non-congenital heart disease. METHODS AND RESULTS: Between March 2000 and June 2018, 671 consecutive episodes of infective endocarditis in adult patients were retrospectively recorded. Cases were classified according to the modified Duke classification. All adult congenital heart disease cases were managed by infectious disease specialists and adult congenital heart disease cardiologists. During this period, 142 infective endocarditis episodes (21%) occurred in adult congenital heart disease patients with simple (46.5%), moderate (21.1%), or complex (32.4%) congenital heart disease. In-hospital mortality was 12.7%. The strongest predictive factors of in-hospital death in multivariate analysis were complexity of congenital heart disease (odds ratio (OR) 8.02, 95% confidence interval (CI) 1.53-42.07), age (OR 1.05, 95% CI 1.00-1.19) and white blood cell count 12 g/L or greater (OR 8.72, 95% CI 2.42-31.43). Patients with congenital heart disease were significantly younger (median age 36 vs. 67 years, P<0.001), had undergone more redo cardiac surgeries (35.7% vs. 11.3%, P<0.01) and presented with more right-sided infective endocarditis (39.4% vs. 7.9%, P<0.01) than patients without congenital heart disease. Congenital heart disease was associated with two-fold lower in-hospital mortality rates (OR 0.37, 95% CI 0.19-0.74), independently of age, gender, obesity, renal function and side of infective endocarditis. CONCLUSION: Although mortality associated with infective endocarditis is lower in adult patients with congenital heart disease than patients without congenital heart disease, infective endocarditis mortality is particularly high in patients with complex congenital heart disease. Education and prevention about the risk of infective endocarditis is essential, especially in this group.

Predictive factors of death associated with infective endocarditis in adult patients with congenital heart disease.

AIMS: Infective endocarditis is a severe infection which can occur in adult patients with congenital heart disease. We aimed to determine outcomes and risk factors of death in adult congenital heart disease and to investigate differences with infective endocarditis in non-congenital heart disease. METHODS AND RESULTS: Between March 2000 and June 2018, 671 consecutive episodes of infective endocarditis in adult patients were retrospectively recorded. Cases were classified according to the modified Duke classification. All adult congenital heart disease cases were managed by infectious disease specialists and adult congenital heart disease cardiologists. During this period, 142 infective endocarditis episodes (21%) occurred in adult congenital heart disease patients with simple (46.5%), moderate (21.1%), or complex (32.4%) congenital heart disease. In-hospital mortality was 12.7%. The strongest predictive factors of in-hospital death in multivariate analysis were complexity of congenital heart disease (odds ratio (OR) 8.02, 95% confidence interval (CI) 1.53-42.07), age (OR 1.05, 95% CI 1.00-1.19) and white blood cell count 12 g/L or greater (OR 8.72, 95% CI 2.42-31.43). Patients with congenital heart disease were significantly younger (median age 36 vs. 67 years, P<0.001), had undergone more redo cardiac surgeries (35.7% vs. 11.3%, P<0.01) and presented with more right-sided infective endocarditis (39.4% vs. 7.9%, P<0.01) than patients without congenital heart disease. Congenital heart disease was associated with two-fold lower in-hospital mortality rates (OR 0.37, 95% CI 0.19-0.74), independently of age, gender, obesity, renal function and side of infective endocarditis. CONCLUSION: Although mortality associated with infective endocarditis is lower in adult patients with congenital heart disease than patients without congenital heart disease, infective endocarditis mortality is particularly high in patients with complex congenital heart disease. Education and prevention about the risk of infective endocarditis is essential, especially in this group.

Impact of relebactam-mediated inhibition of Mycobacterium abscessus BlaMab ß-lactamase on the in vitro and intracellular efficacy of imipenem.

OBJECTIVES: Imipenem is one of the recommended ß-lactams for the treatment of Mycobacterium abscessus pulmonary infections in spite of the production of BlaMab ß-lactamase. Avibactam, a second-generation ß-lactamase inhibitor, was previously shown to inactivate BlaMab, but its partner drug, ceftazidime, is devoid of any antibacterial activity against M. abscessus. Here, we investigate whether relebactam, a novel second-generation inhibitor developed in combination with imipenem, improves the activity of this carbapenem against M. abscessus. METHODS: The impact of BlaMab inhibition by relebactam was evaluated by determining MICs, time-kill curves and M. abscessus intracellular proliferation in human macrophages. Kinetic parameters for the inhibition of BlaMab by relebactam were determined by spectrophotometry using nitrocefin as the substrate. The data were compared with those obtained with avibactam. RESULTS: Combination of relebactam (4 mg/L) with ß-lactams led to >128- and 2-fold decreases in the MICs of amoxicillin (from >4096 to 32 mg/L) and imipenem (from 8 to 4 mg/L). In vitro, M. abscessus was not killed by the imipenem/relebactam combination. In contrast, relebactam increased the intracellular activity of imipenem, leading to 88% killing. Relebactam and avibactam similarly potentiated the antibacterial activities of ß-lactams although BlaMab was inactivated 150-fold less effectively by relebactam than by avibactam. CONCLUSIONS: Inhibition of BlaMab by relebactam improves the efficacy of imipenem against M. abscessus in macrophages, indicating that the imipenem/relebactam combination should be clinically considered for the treatment of infections due to M. abscessus.

Multicentre randomised controlled trial to investigate usefulness of the rapid diagnostic ßLACTA test performed directly on bacterial cell pellets from respiratory, urinary or blood samples for the early de-escalation of carbapenems in septic intensive care unit patients: the BLUE-CarbA protocol.

INTRODUCTION: The dramatic increase of the incidence of infections caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) has led to an increase of 50% of carbapenem consumption all around Europe in only 5 years. This favours the spread of carbapenem-resistant Gram-negative bacilli (GNB), causing life-threatening infections. In order to limit use of carbapenems for infections actually due to ESBL-PE, health authorities promote the use of rapid diagnostic tests of bacterial resistance. The objective of this work conducted in the intensive care unit (ICU) is to determine whether an early de-escalation of empirical carbapenems guided by the result of the ßLACTA test is not inferior to the reference strategy of de-escalating carbapenems after the antibiogram result has been rendered. METHODS AND ANALYSIS: This multicentre randomised controlled open-label non-inferiority clinical trial will include patients suffering from respiratory and/or urinary and/or bloodstream infections documented with GNB on direct examination and empirically treated with carbapenems. Empirical carbapenems will be adapted before the second dose depending on the results of the ßLACTA test performed directly on the microbiological sample (intervention group) or after 48-72 hours depending on the definite antibiogram (control group). The primary outcome will combine 90-day mortality and percentage of infection recurrence during the ICU stay. The secondary outcomes will include the number of carbapenems defined daily doses and carbapenem-free days after inclusion, the proportion of new infections during ICU stay, new colonisation of patients' digestive tractus with multidrug-resistant GNB, ICU and hospital length of stay and cost-effectiveness ratio. ETHICS AND DISSEMINATION: This protocol has been approved by the ethics committee of Paris-Ile-de-France IV, and will be carried out according to the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines. The results of this study will be disseminated through presentation at scientific conferences and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03147807.

In Vitro and Intracellular Activity of Imipenem Combined with Tedizolid, Rifabutin, and Avibactam against Mycobacterium abscessus.

Mycobacterium abscessus infections are difficult to treat because of their resistance to many antibiotics. In vitro, tedizolid combined with imipenem displayed a moderate synergistic effect (fractional inhibitory concentration index, 0.41) but no bactericidal activity. Intracellularly, tedizolid 2 µg/ml (half of the MIC), corresponding to the peak serum concentration, increased the efficacy of imipenem at 8 and 32 µg/ml. Addition of avibactam and rifabutin, alone or in combination, improved the activity of the imipenem-tedizolid combination.