Pierre Fillâtre

Purpose Acute bacterial meningitis (ABM) is a life-threatening infection requiring rapid diagnosis and prompt antibiotic treatment. Current guidelines tend to restrict neuroimaging studies before lumbar puncture (LP), to avoid delays in antibiotic initiation. We evaluated real-world management and factors associated with delayed antibiotic administration in adults presenting to the emergency department (ED) with suspected meningitis. Methods We conducted a retrospective multicenter observational study using routinely collected clinical data in four French hospitals between September 2019 and March 2025. Adult patients presenting with suspected ABM, cerebrospinal fluid pleocytosis (≥ 5 cells/mm³), and receiving antibiotic therapy were included. Factors associated with antibiotic delay were assessed using an exploratory 6-hour threshold (multivariable logistic regression) and continuous time-to-antibiotic analysis (log-normal Accelerated Failure Time [AFT] model). Results In total, 146 patients were included, among whom 33 had confirmed ABM. Median time from ED admission to appropriate antibiotics was 385.0 [223.2–631.5] minutes overall. Only 2/33 (6.1%) ABM received antibiotics within the first hour after ED admission. Brain imaging before LP was performed in 86 (58.9%) patients, although French guidelines criteria were met in only 51/145 (35.2%) of cases. In multivariable analyses, pre-LP imaging was independently associated with a higher risk of delay beyond 6 h (OR 2.75 [1.26–6.00]; p = 0.012) and a 61% increase in median time to antibiotics (Time Ratio = 1.61 [1.04–2.50]; p = 0.032). Conclusion Significant delays in antibiotic administration persist for suspected meningitis. Pre-LP neuroimaging is frequently performed outside guideline indications and is associated with longer times to antibiotic initiation. Standardized protocols and audit-feedback strategies may help reduce delays in antibiotic administration for suspected ABM.

Encéphalites infectieuses : facteurs pronostiques et séquelles à long terme: L’encéphalite infectieuse est une affection rare, avec une incidence estimée à 7/100000 habitants/an dans les pays occidentaux. L’étude nationale de cohorte des encéphalites infectieuses en France (ENCEIF) a inclus prospectivement 494 patients entre 2016 et 2019 au sein de 62 centres hospitaliers en France Métropolitaine (132 (27%) encéphalites à Herpes simplex virus 1 (HSV-1), 65 (16%) à Varicella zoster virus (VZV), 26 (5%) au virus de l’encéphalite à tiques). L’admission en réanimation a été nécessaire dans 42% des cas. HSV-1 était majoritaire chez les patients nécessitant une admission en réanimation (72 patients, soit 36% des encéphalites infectieuses). Les facteurs associés au mauvais pronostic (Glasgow outcome scale ≤ 3) à la sortie d’hospitalisation étaient : l’immunodépression, les signes focaux à l’admission, les anomalies à l’imagerie cérébrale, une faible cellularité du liquide cérébrospinal et le délai d’initiation de l’aciclovir. Ce délai influe fortement sur le pronostic des encéphalites à HSV-1, mais nous n’avons pas retrouvé d’impact significatif sur les encéphalites à VZV. Les fortes doses d’aciclovir n’étaient pas associées au pronostic dans les encéphalites à HSV-1 ou à VZV. Concernant le devenir à long terme, les variables associées indépendamment au pronostic étaient l’age, l’immunodépression, les anomalies à l’imagerie cérébrale, l’hospitalisation en réanimation et l’agent étiologique. L’amélioration du pronostic fonctionnel prend du temps au décours d’une encéphalite infectieuse et elle peut être incomplète. Le pronostic fonctionnel au décours d’une encéphalite infectieuse reste mauvais. La vie quotidienne des patients et des proches est durablement impactée.

Background: In early January 2021, an outbreak of nosocomial cases of COVID-19 emerged in Western France, with RT-PCR tests repeatedly negative on nasopharyngeal samples but positive on lower respiratory tract samples. Whole genome sequencing (WGS) revealed a new variant, currently defining a novel SARS-CoV-2 lineage: B.1.616. In March, WHO classified this variant as ‘under investigation’ (VUI). We analyzed the characteristics and outcomes of COVID-19 cases related to this new variant. Methods: Clinical, virological, and radiological data were retrospectively collected from medical charts in the two hospitals involved. We enrolled patients with at least one of the following: i) positive SARS-CoV-2 RT-PCR on a respiratory sample; ii) seroconversion with anti-SARS-CoV-2 IgG/IgM; iii) suggestive symptoms and typical features of COVID-19 on chest CT scan. Cases were categorized as either: i) B.1.616; ii) variant of concern (VOC); iii) unknown. Findings: From January 1 ^st to March 24 ^th , 2021, 114 patients fulfilled the inclusion criteria: B.1.616 (n=34), VOC (n=32), and unknown (n=48). B.1.616-related cases were older than VOC-related cases (81 years [73-88], vs 73 years [67-82], P P P =0.018), and increased lethality (logrank test P =0.01): 28-day mortality 15/34 (44%) with B.1.616, vs. 5/32 (16%) for VOC, P =0.036. Interpretation: We report a nosocomial outbreak of COVID-19 cases related to a new variant, B.1.616, poorly detected by RT-PCR on nasopharyngeal samples, with high lethality. Research in context: Evidence before this study: Among the numerous SARS-CoV-2 variants described worldwide, only 3 are currently classified as Variant of Concern (VOC) by the WHO, since they are associated with either an increased risk in transmissibility, severity, or significant reduction in neutralization by antibodies: B.1.1.7, B.1.351 and P.1 (Pango lineage nomenclature). With the ongoing circulation of SARS-CoV-2 in many places worldwide, the emergence of new variants may reduce the efficacy of vaccines and jeopardize our prospects to control the pandemic. In early January 2021, an outbreak of cases highly suggestive of COVID-19 despite negative RT-PCR tests on repeated nasopharyngeal (NP) samples was reported in Western France, leading to several nosocomial clusters. Whole-genome sequencing (WGS) from lower respiratory tract samples identified a new lineage of SARS-CoV-2 virus, classified as B1.616. Consequently, the French public health agency (Santé publique France) and the WHO classified B.1.616 as ‘variant under investigation’ (VUI). Added value of this study: Our observational study, conducted from January 1 ^st to March 24 ^th 2021 in the B.1.616 identified area, provides the first clinical and virological description of B.1.616-associated COVID-19. The 34 cases had clinical, biological and radiological findings in line with classical features of COVID-19, while RT-PCR tests on nasopharyngeal (NP) samples failed to detect SARS-CoV-2 in most patients. Indeed, this gold-standard test was positive in only 15% of the first tests in B.1.616-related COVID-19 patients. Of note, the diagnostic performance of RT-PCR tests was satisfactory on lower respiratory tract samples, suggesting that failure to detect B.1.616 on NP samples would be due to a viral load below the limit of detection in the upper respiratory tract, rather than to genomic mismatches between routine RT-PCR targets and this variant. In our cohort, B.1.616 was independently associated with worse clinical outcome, with high 28-day mortality (44%). Implications of all the available evidence: Diagnosis of B.1.616-related COVID-19 cases should not rely on RT-PCR tests on NP samples. In the epidemic area, strict infection control measures must be maintained as long as COVID-19 diagnosis is not ruled out, in order to limit nosocomial clusters and case fatality. Further studies are needed to confirm and investigate the association between genomic characteristics of B.1.616, and i) poor detection by RT-PCR tests on NP samples; ii) prognosis.

To describe the impact of extracorporeal membrane oxygenation (ECMO) devices on piperacillin exposure in ICU patients. This observational, prospective, multicentre, case–control study was performed in the ICUs of two tertiary care hospitals in France. ECMO patients with sepsis treated with piperacillin/tazobactam were enrolled. Control patients were matched according to SOFA score and creatinine clearance. The pharmacokinetics of piperacillin were described based on a population pharmacokinetic model, calculating the proportion of time the piperacillin plasma concentration was above 64 mg/L (i.e. 4× MIC breakpoint for Pseudomonas aeruginosa). Forty-two patients were included. Median (IQR) age was 60 years (49–66), SOFA score was 11 (9–14) and creatinine clearance was 47 mL/min (5–95). There was no significant difference in the proportion of time piperacillin concentrations were ≥64 mg/L in patients treated with ECMO and controls during the first administration (P = 0.184) or at steady state (P = 0.309). Following the first administration, 36/42 (86%) patients had trough piperacillin concentrations P = 0.535). Creatinine clearance ≥40 mL/min was independently associated with piperacillin trough concentration P = 0.043], while ECMO support was not [OR = 0.5 (95% CI 0.1–2.1), P = 0.378]. ECMO support has no impact on piperacillin exposure. ICU patients with sepsis are frequently underexposed to piperacillin, which suggests that therapeutic drug monitoring should be strongly recommended for severe infections.