OBJECTIVES:There are few data on the penetration of daptomycin into the cerebrospinal fluid (CSF) of patients with bacterial meningitis. This ancillary study of the AddaMap trial aimed to assess the CSF penetration of intravenous daptomycin in 13 patients with pneumococcal meningitis. PATIENTS AND METHODS:Daptomycin was administered at 10 mg/kg/day to 13 patients with pneumococcal meningitis admitted to the Dijon University Hospital. Blood and CSF samples were collected on days 3 and 8. The population pharmacokinetics of daptomycin in plasma and CSF were studied using a two-compartment model. RESULTS:A large inter-individual variability in plasma areas under the curve (median, 25-75-percentile), 7843 h.mg/L (6606-9264), plasma peak, 107.5 mg/L (81.4-126.3) and trough 14 mg/L (7.6-19.3) concentrations and elimination half-lives, 8.8 hours (7.9-10.8), was observed. In CSF, the maximum concentration was 0.88 mg/L (0.57-2.82), and the elimination half-life was 23.8 hours (18.7-39.3). The AUC CSF/plasma ratio was 2.20% (1.7-2.3). Daptomycin CSF penetration was significantly correlated with CSF levels of proteins and lactate. CSF concentrations, 0.67 mg/L (0.39-0.86), were above the MIC90 of pneumococci resistant to beta-lactam. Simulations showed that a loading dose could reduce the time required to reach a biologically active concentration in CSF. CONCLUSION:We conclude that daptomycin administered at a dose of 10 mg/kg/day achieves CSF concentrations that may exert non-lytic anti-pneumococcal effects and demonstrate significant activity against highly resistant pneumococcal strains. These findings suggest that daptomycin could be considered as a valuable adjunctive therapy in the treatment of pneumococcal meningitis.

Background: Pneumococcal meningitis is a severe infection associated with high mortality and neurofunctional sequelae in up to 50% of survivors, despite appropriate antibiotic therapy and dexamethasone. Cerebrospinal fluid inflammation is exacerbated by pneumococcal components released during antibiotic-induced bacterial lysis. Among bactericidal, non-lytic antibiotics, daptomycin has shown the most promising preclinical efficacy. We conducted a proof-of-concept trial to assess the safety and potential clinical impact of adjunctive daptomycin added to standard treatment for pneumococcal meningitis. Methods: The AddaMAP study (NCT03480191) was a single-arm trial. Daptomycin (10 mg/kg/d 8 days) was added to the standard treatment with third-generation cephalosporin and dexamethasone in adult patient with pneumococcal meningitis. The primary outcome was the 30-day disability-free survival (DFS), defined as a modified Rankin Scale (mRS) score ≤ 2. Findings: Between 2018 and 2024, 86 patients were included (mean age 60 ± 14 years). Daptomycin was discontinued in four patients. At day 30, 10 patients had died (12%). Fifty-six patients achieved an mRS ≤2, corresponding to a DFS of 65·1% [95% CI, 54·1-75·1]. Interpretation: Adjunctive daptomycin added to standard treatment for pneumococcal meningitis was clinically active and well tolerated. The observed results suggest a potential clinical benefit compared to historical data, warranting further evaluation in a controlled trial to confirm its impact on patient outcomes. Optimization strategies, such as initial administration of dexamethasone followed by daptomycin and then beta-lactam therapy, as well as the use of a loading dose, could further improve outcomes.

OBJECTIVE:Invasive listeriosis carries high mortality, and acute kidney injury (AKI) may complicate hospitalization and worsen outcomes. However, its incidence, risk factors, and prognostic impact in this setting remain poorly described. We aimed to evaluate AKI in patients hospitalized for invasive listeriosis. METHODS:We conducted a retrospective multicenter cohort study including adults with microbiologically confirmed invasive listeriosis across six French university hospitals (2010-2023). AKI within 14 days was defined according to modified KDIGO criteria as a ≥ 1.5-fold increase in serum creatinine from admission value to peak during the first 14 days. Data included comorbidities, exposures, treatment, renal recovery, and mortality. AKI predictors were assessed using multivariable Cox regression. RESULTS:Among 150 patients (median age 76 years), 31% developed AKI within 14 days. In multivariable analysis, hypertension (HR: 6.60; 95% CI: 2.00-21.77; P = 0.002) and qSOFA ≥1 (HR: 2.90; 95% CI: 1.41-5.94; P = 0.003) were independently associated with AKI. Gentamicin-based therapy was not associated with AKI. AKI was associated with higher 30-day and 90-day mortality (37% vs 18% and 56% vs 24%, respectively; P < 0.001). CONCLUSIONS:AKI is frequent in listeriosis and associated with increased mortality. These findings highlight the importance of early risk stratification and renal monitoring in this population.

Among 15 strains of Listeria monocytogenes tested, a synergy between amoxicillin and ceftriaxone was observed in 14 (93%) according to minimal inhibitory concentration strips and 12 (80%) per the checkerboard methods, as well as for 2 of the 3 strains tested by the time-killing curve. This association may be an alternative treatment for listeriosis in the future.

Objectives Limited pharmacokinetics data support dalbavancin long-term use in off-label indications and the optimal dosing regimen is debated. We aimed to describe dalbavancin concentrations in an observational retrospective multicentre study.Methods Patients from 13 French hospitals, treated with 1500 mg doses of dalbavancin and for whom therapeutic drug monitoring was performed from June 2018 to March 2021 were included. Dalbavancin plasma concentrations were described at peak and 1, 2, 3, 4, 6 and 8 weeks after the last 1500 mg dose. Concentrations in patients weighing more or less than 75 kg and with a GFR greater or less than 60 mL/min were compared. Microbiological data were collected and dalbavancin MIC was measured when possible.Results One hundred and thirty-three patients were included (69% treated for bone and joint infections, 16% for endocarditis). Thirty-five patients received a single dose of dalbavancin and 98 received several administrations. Two, 3 and 4 weeks after the last dose, median plasma concentrations were respectively 25.00, 14.80 and 9.24 mg/L for the first doses and 34.55, 22.60 and 19.20 mg/L for the second or subsequent doses. Weight and renal function had an impact on pharmacokinetics. Infection was documented in 105 patients (Staphylococcus spp. in 68% of cases). Staphylococcus aureus was isolated in 32.5% of cases (median MIC: 0.047 mg/L) and Staphylococcus epidermidis in 27% of cases (median MIC of 0.047 mg/L).Conclusions Plasma concentrations of dalbavancin were consistent with those described in clinical trials and those sought during the industrial development of the molecule.

BACKGROUND:The leading cause of acute bacterial meningitis in adults is Streptococcus pneumoniae. This infection is associated with high rates of mortality and morbidity related, among other factors, to the excessive host response to the pneumococcal lysis. Experimental in vitro and in vivo data show that the combination of corticosteroids/third-generation cephalosporins and the non-lytic antibiotic, daptomycin, has synergistic effects with (1) a rapid cerebrospinal fluid sterilisation, (2) less brain damages and (3) less loss of cognitive performances. Despite these encouraging results, daptomycin has never been evaluated in adult patients with pneumococcal meningitis. METHODS AND ANALYSIS:The AddaMAP trial is a phase II, open-label, Simon's two-stage, multicentre trial that has been designed to assess the efficacy and safety of adding daptomycin (10 mg/kg/d for 8 days) to the recommended treatment (corticosteroids+third generation cephalosporin) in adults with confirmed pneumococcal meningitis. The main endpoint is the disability-free survival (defined as modified Rankin Scale mRS≤2) at day 30. Secondary outcomes are overall mortality, disability at D30 and D90 (mRS, Glasgow Coma Scale and Glasgow Outcome Scales, mini-mental score), hearing loss (Hearing Handicap Inventory Test at D30 and D90, routine audiometric test and Hearing-it test at D30), and quality of life (12-item Short Form Survey and WHO QOL BREF). Seventy-two analysable patients are required. ETHICS AND DISSEMINATION:The study protocol was approved by the Institutional Review Board of the IDF 1 of the ethics committee on 16 January 2018, and authorisation was obtained from the Agence Nationale de Securité des Médicaments et des Produits de Santé on 22 September 2017. The results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER:NCT03480191.

Abstract Introduction: An inadequate antibiotics’ prescription was found to be associated with worse prognosis in some infections. Emergency departments (ED) are pivotal for the initial prescription of antibiotics. However, its appropriateness and consequences have been rarely assessed. Methods: A retrospective, monocentric study included patients who consulted to the ED of our center and who were hospitalized with an advocated diagnosis of infection. Initial antibiotic therapy was graded as optimal, adapted, or inadequate. If reevaluation of this therapy was performed at day 2 (D2), the appropriateness of antibiotic therapy was again graded. The primary endpoint was the onset of an unfavorable event (i.e., death, transfer to intensive care unit, or re-hospitalization). Prognosis factors associated with survival without unfavorable event were assessed by multivariate analysis. Results: We included 484 patients. Respiratory (153, 40.4%), urinary-tract (83, 21.9%), and abdominal (76, 20.1%) infections were mostly diagnosed after reevaluation. Optimal, adapted, and inadequate initial prescriptions concerned respectively 328 (67.8%), 110 (22.7%) and 46 (9.5%) patients. Compared to an optimal prescription, an initial adapted prescription was associated with a poorer prognosis (HR = 1.95, CI95% [1.18-3.22]; p = 0.01). The reevaluation was performed in 436 (90.1%) patients. After reevaluation, optimal, adapted, and inadequate prescriptions concerned 326 (74.8%), 64 (14.7%), and 46 (10.5%) patients. After reevaluation, compared with optimal prescriptions, an inadequate prescription was associated with unfavorable events (HR = 3.52, CI95% [1.42-8.72]; p = 0.003). Conclusion: The appropriateness of both initial and D2 antibiotic therapies are associated with a better prognosis.

Background Vascular graft infection (VGI) remains a severe disease with high mortality and relapse rates. We performed a retrospective single-center cohort study to highlight factors associated with long-term all-cause mortality in patients with vascular graft infection. Methods All patients hospitalized in our facility over 10 years for VGI were included. VGI was defined by the presence of a vascular graft or an aortic stent graft (stent or fabric), associated with 2 criteria among clinical, biological, imaging, or microbiological elements in favor of VGI. The primary outcome was all-cause mortality. Empirical antibiotic therapy was considered as appropriate when all involved pathogens were susceptible in vitro to the antibiotics used. The surgical strategy was defined as nonoptimal when the graft was not removed in a late-onset surgery (>3 months) or no surgery was performed. Results One hundred forty-six patients were included. Empirical antibiotic therapy was administered in 98 (67%) patients and considered appropriate in 55 (56%) patients. Surgery was performed in 136 patients (96%) and considered as optimal in 106 (73%) patients. In multivariable analysis, appropriate empirical antibiotic therapy was associated with a lower probability of mortality (hazard ratio, 0.47 [95% confidence interval, .30-.79]; P = .002). Long-term survival did not differ according to whether the surgical strategy was considered optimal or not (log-rank = 0.66). Conclusions Appropriate empirical antibiotic therapy is a cornerstone of the management of VGI. Whenever possible, antibiotics must be associated with optimal surgical management. However, surgery could potentially be avoided in comorbid patients who are treated with appropriate antibiotics. Appropriate empirical antibiotic therapy for vascular graft infection is associated with better survival. Long-term survival does not differ whether or not the surgical strategy is considered optimal. Efficient antibiotic treatment may help to avoid surgery for patients with comorbidities, without causing long-term excess mortality.

During an epidemic period, we compared patients hospitalized for initial suspicion of COVID-19 but for whom an alternative diagnosis was finally retained (n = 152) with those who had COVID-19 (n = 222). Most common diagnoses were another infectious disease and heart failure. COVID-19-negative patients were more often active smokers had less often cough, fever, and digestive symptoms, as compared to the 222 COVID-19-positive patients. They had higher median neutrophil and lymphocyte counts and lower CRP level. In multivariate analysis, no current smoking, neurocognitive disorder, myalgia, and fibrinogen ≥4g/L were independently associated with a final diagnosis of COVID-19.

OBJECTIVES:As daptomycin adjunction is currently under clinical evaluation in the multicentre phase II AddaMAP study to improve the prognosis of pneumococcal meningitis, the present work aimed at evaluating the in vitro antimicrobial activity of daptomycin-based combinations against some of the most frequent species responsible for bacterial meningitis. METHODS:Clinically relevant strains of Streptococcus pneumoniae, Listeria monocytogenes, Haemophilus influenzae and Neisseria meningitidis were obtained from National Reference Centers. The antimicrobial activity of amoxicillin, cefotaxime and rifampicin, either alone or in association with daptomycin, was explored through the determination of minimum inhibitory concentration (MIC) and fractional inhibitory concentration index (FICI) as well as time-kill assay (TKA) using the broth microdilution method. RESULTS:All species taken together, the adjunction of daptomycin had no deleterious impact on the antimicrobial activity of amoxicillin, cefotaxime or rifampicin in vitro. Regarding Gram-positive bacteria, FICI and TKA analysis confirmed a global improvement of growth inhibition and bactericidal activity due to the adjunction of daptomycin. The synergistic effect prevailed for L. monocytogenes as demonstrated by FICI mainly <0.5 and a dynamic TKA-based synergy rate >50%. In addition, daptomycin-based associations did not modify the activity of β-lactam antibiotics or rifampicin against Gram-negative bacteria, notably N. meningitidis. CONCLUSION:These results bring comforting evidence towards the clinical potential of daptomycin adjunction in the treatment of bacterial meningitis, which supports the ongoing AddaMAP clinical trial.

•There is a need for reliable tools to predict the evolution of hospitalized patients suffering from COVID-19.•The likelihood of unfavourable evolution for patients hospitalized for COVID-19 with a National Early Warning Score 2 (NEWS2) below 7 at Day 7 of hospitalization is nearly non-existent.•Such a score could thus be used to allow earlier discharge of the patients and as a judgement criterion in therapeutic trials.

Med 2017;5:946–955. 6. Molyneaux PL, Cox MJ, Willis-Owen SA, Mallia P, Russell KE, Russell AM, et al. The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2014;190: 906–913. 7. Troy LK, Grainge C, Corte TJ, Williamson JP, Vallely MP, Cooper WA, et al.; Cryobiopsy versus Open Lung biopsy in the Diagnosis of Interstitial lung disease alliance (COLDICE) Investigators. Diagnostic accuracy of transbronchial lung cryobiopsy for interstitial lung disease diagnosis (COLDICE): a prospective, comparative study. Lancet Respir Med 2020;8:171–181. 8. Raghu G, Flaherty KR, Lederer DJ, Lynch DA, Colby TV, Myers JL, et al. Use of a molecular classifier to identify usual interstitial pneumonia in conventional transbronchial lung biopsy samples: a prospective validation study. Lancet Respir Med 2019;7:487–496. 9. Lukey PT, Harrison SA, Yang S, Man Y, Holman BF, Rashidnasab A, et al. A randomised, placebo-controlled study of omipalisib (PI3K/mTOR) in idiopathic pulmonary fibrosis. Eur Respir J 2019;53: 1801992. 10. Allden SJ, Ogger PP, Ghai P, McErlean P, Hewitt R, Toshner R, et al. The transferrin receptor CD71 delineates functionally distinct airway macrophage subsets during idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2019;200:209–219. 11. Molyneaux PL, Willis-Owen SAG, Cox MJ, James P, Cowman S, Loebinger M, et al. Host-microbial interactions in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2017;195: 1640–1650.

Bartonella henselae is the bacterial agent responsible for cat scratch disease. This infection is frequently the cause of localized lymphadenitis in children. It is also sometimes responsible for endocarditis, encephalitis, hepatic peliosis and in rare cases osteomyelitis. We describe the second known case of unifocal thoracic osteomyelitis in a 10-year-old child.

Background: Mechanical ventilation for pneumonia may contribute to lung injury due to factors that include mitochondrial dysfunction, and mesenchymal stem cells may attenuate injury. This study hypothesized that mechanical ventilation induces immune and mitochondrial dysfunction, with or without pneumococcal pneumonia, that could be mitigated by mesenchymal stem cells alone or combined with antibiotics. Methods: Male rabbits underwent protective mechanical ventilation (8 ml/kg tidal volume, 5 cm H2O end-expiratory pressure) or adverse mechanical ventilation (20 ml/kg tidal-volume, zero end-expiratory pressure) or were allowed to breathe spontaneously. The same settings were then repeated during pneumococcal pneumonia. Finally, infected animals during adverse mechanical ventilation received human umbilical cord-derived mesenchymal stem cells (3 x 10(6)/kg, intravenous) and/or ceftaroline (20 mg/kg, intramuscular) or sodium chloride, 4 h after pneumococcal challenge. Twenty-four-hour survival (primary outcome), lung injury, bacterial burden, immune and mitochondrial dysfunction, and lung transcriptomes (secondary outcomes) were assessed. Results: High-pressure adverse mechanical ventilation reduced the survival of infected animals (0%; 0 of 7) compared with spontaneous breathing (100%; 7 of 7) and protective mechanical ventilation (86%; 6 of 7; both P < 0.001), with higher lung pathology scores (median [interquartile ranges], 5.5 [4.5 to 7.0] vs. 12.6 [12.0 to 14.0]; P = 0.046), interleukin-8 lung concentrations (106 [54 to 316] vs. 804 [753 to 868] pg/g of lung; P = 0.012), and alveolar mitochondrial DNA release (0.33 [0.28 to 0.36] vs. 0.98 [0.76 to 1.21] ng/mu l; P < 0.001) compared with infected spontaneously breathing animals. Survival (0%; 0 of 7; control group) was improved by mesenchymal stem cells (57%; 4 of 7; P = 0.001) or ceftaroline alone (57%; 4 of 7; P < 0.001) and improved even more with a combination treatment (86%; 6 of 7; P < 0.001). Mesenchymal stem cells reduced lung pathology score (8.5 [7.0 to 10.5] vs. 12.6 [12.0 to 14.0]; P = 0.043) and alveolar mitochondrial DNA release (0.39 (0.34 to 0.65) vs. 0.98 (0.76 to 1.21) ng/mu l; P = 0.025). Mesenchymal stem cells combined with ceftaroline reduced interleukin-8 lung concentrations (665 [595 to 795] vs. 804 [753 to 868] pg/g of lung; P = 0.007) compared to ceftaroline alone. Conclusions: In this preclinical study, mesenchymal stem cells improved the outcome of rabbits with pneumonia and high-pressure mechanical ventilation by correcting immune and mitochondrial dysfunction and when combined with the antibiotic ceftaroline was synergistic in mitigating lung inflammation.

Objectives: Dalbavancin is a long-lasting lipoglycopeptide active against Gram-positive bacteria, especially methicillin-resistant staphylococci. Few data are available on dalbavancin use for treatment of prosthetic joint infections (PJIs). We describe a cohort of patients treated for PJI with dalbavancin and review the literature regarding this condition. Methods: All adult patients with PJI from the French dalbavancin national cohort from 1 June 2017 to 1 January 2019 were included. We collected clinical and microbiological characteristics and outcome through a standardised questionnaire. Clinical cure was defined as absence of clinical signs of infection at last visit. Failure was a composite criterion defined by persistence or reappearance of signs of infection, and/or switch to suppressive antibiotic treatment and/or death from infection. The literature review was performed using PubMed. Results: Seventeen patients were included. Bacteria were identified in 16 cases: Staphylococcus aureus ( n = 10), including methicillin-resistant S. aureus ( n = 1); and coagulase-negative staphylococci ( n = 10), including methicillin-resistant Staphylococcus epidermidis ( n = 4). Sixteen patients (94.1%) had received antibiotic therapy prior to dalbavancin use (mean of 2.2 +/- 1.3 lines). Clinical cure was achieved in 8/17 patients after a median follow-up of 299.0 (IQR 97.0-476.0) days. We reviewed all cases of PJI treated with dalbavancin available in the literature and the overall clinical cure was estimated at 73.1%. Conclusion: Our study and literature data suggest that use of dalbavancin in PJI could be considered, even as salvage therapy. Dalbavancin appears to be a safe and easy treatment for patients with staphylococcal PJIs. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

Background: Literature on health events in HIV-infected travellers is scarce, particularly in sub-Saharan African (SSA) migrants. Methods: We investigated health events in HIV-infected SSA migrants living in France during and after travel to their native country. All had a pre-travel plasma viral load (pVL) below 200 copies/mL and were on stable combined antiretroviral therapy (cART). Logistic regression models were used to assess the risk factors for at least one adverse health event or febrile event. Results: Among 264 HIV migrants, pre-travel median CD4 count was 439/mm3 and 27 migrants (6%) experienced a low-level viremia between 50 and 200 copies/mL. One hundred (38%) experienced at least one event (13 experienced two events). The most common events were gastrointestinal, including diarrhoea (n = 29, 26%), respiratory events (n = 20, 18%), and malaria (n = 17, 15%; 1 death). In multivariable analysis, a pre-travel low-level viremia and a lack of pre-travel medical advice significantly increased the risk for any event (OR 4.31, 95% CI, 1.41-13.1; and OR 3.62, 95% CI, 1.38-9.47; respectively). A lack of pre-travel advice significantly increased the risk for febrile event. Conclusions: Early and tailored counselling on pre-travel medical advice regarding diarrhoea and vector-borne diseases prophylactic measures in HIV-infected SSA migrants should be emphasised before travel to Africa.

ObjectivesTo describe hospitalisations for kidney disease (KD) among people living with HIV (PLHIV) in France and to identify the factors associated with such hospitalisations since data on the epidemiology of KD leading to hospitalisation are globally scarce.DesignObservational nationwide study using the French Programme de Médicalisation des Systèmes d’Information database.SettingFrance 2008–2013.ParticipantsAround 10 862 PLHIV out of a mean of 5 210 856 patients hospitalised each year. All hospital admissions with a main diagnosis code indicating KD (International Classification of Diseases, 10th revision codes, N00 to –N39) were collected.Main outcome measuresThe prevalence and incidence of KD leading to hospital admission in PLHIV and the associated risk factors.ResultsThe prevalence of patients hospitalised for KD was 1.5 higher in PLHIV than in the general population, and increased significantly from 3.0% in 2008 to 3.7% in 2013 (p<0.01). The main cause of hospitalisation for KD was acute renal failure (ARF, 25.4%). Glomerular diseases remained stable (6.4%) throughout the study period, focal segmental glomerulosclerosis being the main diagnosis (37.6%). Only 41.3% of patients hospitalised for glomerular disease were biopsied. The other common motives for admission were nephrolithiasis (22.1%) and pyelonephritis (22.6%).The 5-year cumulative incidence of KD requiring hospitalisation was 5.9% in HIV patients newly diagnosed for HIV in 2009. Factors associated with a higher risk of incident KD requiring hospitalisation were cardiovascular disease (HR 3.30, 95% CI 1.46 to 7.49), and, for female patients, AIDS (HR 2.45, 95% CI 1.07 to 5.58). Two-thirds of hospitalisations for incident ARF occurred in the first 2 years of follow-up.ConclusionsHospital admission for KD is more frequent in PLHIV than in the general population and increases over time. ARF remains the leading cause. Glomerular diseases are infrequently documented by renal biopsies. Older patients and those with cardiovascular disease are particularly concerned.