Clinical Microbiology and Infection最新文献

Background: Despite established antiviral therapy for herpes simplex virus, varicella zoster and cytomegalovirus encephalitis, the outcome remains poor.

Objectives: To assess pharmacokinetic (PK) and pharmacodynamic (PD) data of antiviral drugs in the central nervous system (CNS) to optimize the treatment of Herpesviridae encephalitis.

Sources: PUBMED search 1950 to September 2024, terms (1) "encephalitis" and ("HSV" or "VZV" or "CMV") or (2) cerebrospinal and ("(val)acyclovir" or "(val)ganciclovir" or "foscarnet" or "cidofovir").

Content: Antivirals against herpes viruses apparently act in a time-dependent manner. To suppress viral replication, drug concentration in the extracellular space at the site of the infection should be kept above the concentrations active in cell cultures for 24 h/d. Most data reflect delayed drug entry into lumbar cerebrospinal fluid (CSF). Ratios of the areas of the concentration/time curves (AUC) in CSF and serum (AUC_CSF/AUC_S) of acyclovir, ganciclovir and foscarnet are 0.15-0.3 in the absence of meningeal inflammation and increase in severe meningoencephalitis. Elimination half-lives (t_1/2β) are longer in CSF than in plasma. CSF concentrations are rough approximations of drug concentrations in the cerebral extracellular fluid. Lumbar CSF concentrations are usually higher than ventricular or cisternal CSF concentrations tending to overestimate cerebral extracellular fluid concentrations. Provided the availability of adequate measurements in individual CNS compartments, antiviral concentrations and efficacy may be predicted by future PK/PD modelling. Probenecid holds the potential to reduce the efflux of antiviral drugs from the CNS.

Implications: The long t_1/2β of antiviral drugs in CSF suggest relatively uniform steady state CSF levels at dosing intervals ≤12h and accumulation after repeated dosing. Probenecid is of unproven utility. To rapidly attain effective concentrations in the infected tissue, physiologically based pharmacokinetic and PK/PD modelling may be helpful. Until reliable PK/PD data are available, doubling the first dose should be considered.

Background: Biomarkers for paediatric bacterial meningitis are essential for an accurate diagnosis.

Objectives: To perform a systematic review of diagnostic accuracy on cerebrospinal fluid (CSF) and blood biomarkers for paediatric bacterial meningitis.

Data sources: Databases Medline, Excerpta Medica Database, Scopus, and Web of Science were used.

Study eligibility criteria: Eligible studies were those on novel diagnostic CSF and blood biomarkers from which data on biomarker concentration or diagnostic accuracy could be abstracted.

Participants: Paediatric patients (0-18 years) suspected of a central nervous system (CNS) infection.

Assessment of risk of bias: The Quality Assessment tool for Diagnostic Accuracy Studies (QUADAS)-2 tool was used to assess risk of bias.

Methods of data synthesis: The difference in biomarker concentrations were assessed by calculating standardized and weighted mean differences. A random-effects meta-analysis model was used. Hierarchical summary receiver-operating characteristic curves were constructed.

Results: We identified 3435 studies, of which 112 articles on 113 individual biomarkers (CSF n = 90 and blood n = 23) were included. In CSF, C-reactive protein (CRP), Interleukin (IL)-6, Tumor necrosis factor (TNF)-α, and Interleukin (IL)-8 showed the largest mean differences between bacterial meningitis and viral meningitis and IL-6, TNF-α, and IL-8 between bacterial meningitis and no CNS infection/inflammation. CSF CRP and ferritin showed excellent discrimination for bacterial versus viral meningitis (summary area under the curve [sAUC] 0.94; 95% CI, 0.92-0.97, sAUC 0.94; 95% CI, 0.90-1.0). CSF IL-6 and procalcitonin showed excellent discrimination for bacterial versus nonbacterial meningitis and versus no CNS infection/inflammation (sAUC IL-6: 0.98; 95% CI, 0.96-1.00, sAUC procalcitonin: 0.96; 95% CI, 0.94-0.99). Procalcitonin in blood showed good discrimination (AUC, 0.89; 95% CI, 0.68-1.00).

Discussion: We identified several CSF biomarkers with high diagnostic accuracy for the diagnosis of bacterial meningitis, including IL-6, procalcitonin, CRP, and ferritin. None of the blood biomarkers exhibited excellent discrimination for paediatric bacterial meningitis. Validation of these biomarkers in prospective, well-designed studies of diagnostic accuracy performed in children with suspected meningitis is needed.

Background: Rapid identification of bloodstream pathogens and associated antimicrobial resistance (AMR) profiles by molecular tests from positive blood cultures (PBCs) have the potential to improve patient management and clinical outcomes.

Objectives: A systematic review and meta-analysis were conducted to evaluate diagnostic test accuracy (DTA) of molecular tests from PBCs for detecting pathogens and AMR in the clinical setting.

Methods: .

Data sources: Medline, Embase, Cochrane, conference proceedings, and study bibliographies were searched.

Study eligibility criteria: Studies evaluating DTA of commercially available molecular tests vs. traditional phenotypic identification and susceptibility testing methods in patients with PBCs were eligible.

Participants: Patients with PBCs.

Tests: Commercially available molecular tests.

Reference standard: Traditional phenotypic identification and susceptibility testing methods (standard of care, SOC).

Assessment of risk of bias: Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2.

Methods of data synthesis: Summary DTA outcomes were estimated using bivariate random-effects models for gram-negative bacteria (GNB), gram-positive bacteria (GPB), yeast, GNB-AMR, GPB-AMR, and specific targets when reported by ≥ 2 studies (PROSPERO CRD42023488057).

Results: Seventy-four studies including 24 590 samples were analysed, most of which had a low risk of bias. When compared with SOC, molecular tests showed 92-99% sensitivity, 99-100% specificity, 99-100% positive predictive value, and 97-100% negative predictive value for identifying total GNB (43 studies), GPB (38 studies), yeast (24 studies), GNB-AMR (35 studies), and GPB-AMR (39 studies). For individual pathogen targets, 93-100% sensitivity, 98-100% specificity, 86-100% positive predictive value, and 99-100% negative predictive value were estimated. Five of seven AMR genes had 91-99% sensitivity and 99-100% specificity. Sensitivity was lower for IMP (four studies; 62%; 95% CI, 34-83%) and VIM (four studies; 70%; 95% CI, 38-90%) carbapenemases, where genes were not detected or were not harboured in Pseudomonas aeruginosa (i.e. low prevalence). Performance of molecular tests in detecting AMR was generally comparable when grouped by geographical region (Europe, North America, and East Asia).

Discussion: High DTA support the use of molecular tests in identifying a broad panel of pathogens and detecting AMR in GNB and GPB.