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"Lebeaux, David"
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Management of infections related to totally implantable venous-access ports: challenges and perspectives
Use of totally implantable venous-access ports (TIVAPs) is standard practice for patients with diseases such as solid-tumour cancers, haematological malignancies, and chronic digestive diseases. Use of TIVAPs allows long-term administration of venotoxic compounds, improves patients' quality of life, and reduces the risk of infection. Microbial contamination, formation of pathogenic biofilms, and infection, however, are associated with morbidity, mortality, and increased health-care costs. Local and systemic complications or infections related to specific pathogens might lead to device removal. Alternatively, conservative treatment with combined systemic antibiotics and antibiotic lock therapy might be useful. We discuss in-vitro and in-vivo basic and clinical research findings on the epidemiology, diagnosis, and prevention of TIVAP-related infections, the current challenges to management, promising strategies, and some treatments in development that are likely to improve outcomes of TIVAP-related infections, with a particular focus on antibiotic lock therapy.
Journal Article
Starvation, Together with the SOS Response, Mediates High Biofilm-Specific Tolerance to the Fluoroquinolone Ofloxacin
High levels of antibiotic tolerance are a hallmark of bacterial biofilms. In contrast to well-characterized inherited antibiotic resistance, molecular mechanisms leading to reversible and transient antibiotic tolerance displayed by biofilm bacteria are still poorly understood. The physiological heterogeneity of biofilms influences the formation of transient specialized subpopulations that may be more tolerant to antibiotics. In this study, we used random transposon mutagenesis to identify biofilm-specific tolerant mutants normally exhibited by subpopulations located in specialized niches of heterogeneous biofilms. Using Escherichia coli as a model organism, we demonstrated, through identification of amino acid auxotroph mutants, that starved biofilms exhibited significantly greater tolerance towards fluoroquinolone ofloxacin than their planktonic counterparts. We demonstrated that the biofilm-associated tolerance to ofloxacin was fully dependent on a functional SOS response upon starvation to both amino acids and carbon source and partially dependent on the stringent response upon leucine starvation. However, the biofilm-specific ofloxacin increased tolerance did not involve any of the SOS-induced toxin-antitoxin systems previously associated with formation of highly tolerant persisters. We further demonstrated that ofloxacin tolerance was induced as a function of biofilm age, which was dependent on the SOS response. Our results therefore show that the SOS stress response induced in heterogeneous and nutrient-deprived biofilm microenvironments is a molecular mechanism leading to biofilm-specific high tolerance to the fluoroquinolone ofloxacin.
Journal Article
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.
Journal Article
Nocardia polymerase chain reaction (PCR)-based assay performed on bronchoalveolar lavage fluid after lung transplantation: A prospective pilot study
Transplant recipients are at risk of pulmonary nocardiosis, a life-threatening opportunistic infection caused by Nocardia species. Given the limitations of conventional diagnostic techniques (i.e., microscopy and culture), a polymerase chain reaction (PCR)-based assay was developed to detect Nocardia spp. on clinical samples. While this test is increasingly being used by transplant physicians, its performance characteristics are not well documented. We evaluated the performance characteristics of this test on bronchoalveolar lavage (BAL) fluid samples from lung transplant recipients (LTRs).
We prospectively included all BAL samples from LTRs undergoing bronchoscopy at our institution between December 2016 and June 2017 (either surveillance or clinically-indicated bronchoscopies). Presence of microbial pathogens was assessed using techniques available locally (including microscopy and 10-day culture for Nocardia). BAL samples were also sent to the French Nocardiosis Observatory (Lyon, France) for the Nocardia PCR-based assay. Transplant physicians and patients were blinded to the Nocardia PCR results.
We included 29 BAL samples from 21 patients (18 surveillance and 11 clinically-indicated bronchoscopies). Nocardiosis was not diagnosed in any of these patients by conventional techniques. However, Nocardia PCR was positive in five BAL samples from five of the patients (24%, 95% confidence interval: 11-45%); four were asymptomatic and undergoing surveillance bronchoscopy, and one was symptomatic and was later diagnosed with influenza virus infection. None of the five PCR-positive patients died or were diagnosed with nocardiosis during the median follow-up of 21 months after the index bronchoscopy (range: 20-23 months).
In this prospective study, Nocardia PCR was positive on BAL fluid from one fourth of the LTRs. Nocardia PCR-based assays should be used with caution on respiratory samples from LTRs because of the possible detection of airway colonization using this technique. Larger studies are required to determine the usefulness of the Nocardia PCR-based assay in transplant recipients.
Journal Article
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.
Journal Article
Updates on Donor-Derived Infection in Solid Organ Transplantation, Report from the 2024 GTI (Infection and Transplantation Group) Annual Meeting
The annual meeting of the French GTI (Transplantation and Infection Group) focused on donor-derived infections (DDIs) in solid organ transplant (SOT) recipients. Given the ongoing organ shortage, rigorous donor screening is essential to detect potential infectious risks. Donor evaluation should include medical history, travel, vaccination status, serologies, and exposures. Various pathogens are of concern, including viruses (HIV, hepatitis, BK polyomavirus), multidrug-resistant bacteria, fungi, and emerging arboviruses like West Nile virus and dengue. HIV-positive donor to HIV-positive recipient (D+/R+) transplantations are increasingly accepted, with promising outcomes. Hepatitis E (HEV) is now the most common viral hepatitis and may lead to chronic infection in SOT recipients, requiring ribavirin treatment. Non-Candida fungal infections, though rare, are associated with high mortality and demand early recognition. Climate change and globalization are expanding the range of vector-borne infections, necessitating seasonal and regional screening. BK polyomavirus remains a major complication in kidney transplant recipients, and monitoring viral load is critical. Bacterial infections from donors are uncommon but should be evaluated based on site, organism, resistance profile, and treatment history. Overall, maintaining safety in transplantation requires constant vigilance, updated knowledge, and personalized risk-benefit analysis to adapt to emerging infectious threats—especially amid ongoing organ scarcity.
Journal Article
Impact of integrating objective structured clinical examination into academic student assessment: Large-scale experience in a French medical school
Objective structured clinical examinations (OSCE) evaluate clinical reasoning, communication skills, and interpersonal behavior during medical education. In France, clinical training has long relied on bedside clinical practice in academic hospitals. The need for a simulated teaching environment has recently emerged, due to the increasing number of students admitted to medical schools, and the necessity of objectively evaluating practical skills. This study aimed at investigating the relationships between OSCE grades and current evaluation modalities.
Three-hundred seventy-nine 4th-year students of University-of-Paris Medical School participated to the first large-scale OSCE at this institution, consisting in three OSCE stations (OSCE#1-3). OSCE#1 and #2 focused on cardiovascular clinical skills and competence, whereas OSCE#3 focused on relational skills while providing explanations before planned cholecystectomy. We investigated correlations of OSCE grades with multiple choice (MCQ)-based written examinations and evaluations of clinical skills and behavior (during hospital traineeships); OSCE grade distribution; and the impact of integrating OSCE grades into the current evaluation in terms of student ranking.
The competence-oriented OSCE#1 and OSCE#2 grades correlated only with MCQ grades (r = 0.19, P<0.001) or traineeship skill grades (r = 0.17, P = 0.001), respectively, and not with traineeship behavior grades (P>0.75). Conversely, the behavior-oriented OSCE#3 grades correlated with traineeship skill and behavior grades (r = 0.19, P<0.001, and r = 0.12, P = 0.032), but not with MCQ grades (P = 0.09). The dispersion of OSCE grades was wider than for MCQ examinations (P<0.001). When OSCE grades were integrated to the final fourth-year grade with an incremental 10%, 20% or 40% coefficient, an increasing proportion of the 379 students had a ranking variation by ±50 ranks (P<0.001). This ranking change mainly affected students among the mid-50% of ranking.
This large-scale French experience showed that OSCE designed to assess a combination of clinical competence and behavioral skills, increases the discriminatory capacity of current evaluations modalities in French medical schools.
Journal Article
A Rat Model of Central Venous Catheter to Study Establishment of Long-Term Bacterial Biofilm and Related Acute and Chronic Infections
Formation of resilient biofilms on medical devices colonized by pathogenic microorganisms is a major cause of health-care associated infection. While in vitro biofilm analyses led to promising anti-biofilm approaches, little is known about their translation to in vivo situations and on host contribution to the in vivo dynamics of infections on medical devices. Here we have developed an in vivo model of long-term bacterial biofilm infections in a pediatric totally implantable venous access port (TIVAP) surgically placed in adult rats. Using non-invasive and quantitative bioluminescence, we studied TIVAP contamination by clinically relevant pathogens, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus epidermidis, and we demonstrated that TIVAP bacterial populations display typical biofilm phenotypes. In our study, we showed that immunocompetent rats were able to control the colonization and clear the bloodstream infection except for up to 30% that suffered systemic infection and death whereas none of the immunosuppressed rats survived the infection. Besides, we mimicked some clinically relevant TIVAP associated complications such as port-pocket infection and hematogenous route of colonization. Finally, by assessing an optimized antibiotic lock therapy, we established that our in vivo model enables to assess innovative therapeutic strategies against bacterial biofilm infections.
Journal Article
New Approaches to Manage Infections in Transplant Recipients: Report From the 2023 GTI (Infection and Transplantation Group) Annual Meeting
Management of Post-Transplant Bacterial Infections Multidrug Resistant Enterobacterales Infections in Solid Organ Transplantation: Current Situation and New Non-Antibiotic Approaches Solid-organ transplantation (SOT) is the treatment of choice for patients diagnosed with end-stage organ disease, and the median survival of both recipients and grafts has significantly increased in the last years [1]. [...]some cefiderocol-resistant strains have been described, combining several resistance mechanisms. [...]plazomicin, an aminoglycoside developed for the treatment of carbapenem-resistant Enterobacteriaceae infections, had shown interesting results in the United States, but was not developed in Europe due to its low commercial potential. [...]in the face of this type of infection, optimizing the use of available molecules is a crucial point, including rapid diagnosis of resistance, determination of MICs (minimal inhibitory concentration) for the different molecules and combinations available, and optimization of dosages with the use of high doses and prolonged infusions.
Journal Article