Antimicrobial resistance is recognized by the WHO as one of the leading global public health challenges. Antimicrobial Stewardship Programmes (ASPs) aim to promote the rational and efficient use of antimicrobials, although their implementation faces various limitations. Digital tools and artificial intelligence (AI) emerge as strategies to improve the efficiency and outcomes of these programmes. To analyse the role of digital tools and AI in hospital-based ASP interventions and their impact on clinical, microbiological and antimicrobial use indicators. A systematic review was conducted following PRISMA methodology. A bibliographic search was performed in PubMed, Scopus and Cochrane Library (2014-25), as well as grey literature. Articles on hospitalized patients requiring antimicrobial treatment were included according to PICOS criteria. Risk of bias and methodological quality were assessed according to the type of study. Two independent researchers conducted the selection, evaluation and data extraction. A third researcher resolved discrepancies. Thirty-one studies met the inclusion criteria. The most commonly used tools were Clinical Decision Support Systems (58%), followed by alerts in electronic health records, machine learning models, telemedicine and mobile applications. Most studies showed improvements in therapeutic appropriateness and reduction in antibiotic consumption. However, the impact on clinical and microbiological indicators was heterogeneous and of low quality. Digital tools applied in ASPs improve prescription quality indicators and reduce antimicrobial consumption. Nevertheless, their impact on clinical and microbiological outcomes remains limited. Standardized indicators and robust methodological studies are needed to confirm their real impact on ASP outcomes. This protocol has been registered in PROSPERO with the ID: CRD42024601221.
Antimicrobial peptides and peptidomimetics have emerged as promising alternatives to traditional antibiotics for MDR bacterial infections. Their advancement, however, is often limited by toxicity and poor pharmacokinetics. In this review, we apply a rigorous quantitative framework to evaluate the therapeutic balance of potency and safety for these agents, offering new perspectives that extend beyond previous descriptive analyses. We systematically searched key biomedical databases (January 2000 to May 2025) for studies reporting antimicrobial potency, cytotoxicity, selectivity index, stability and in vivo efficacy. Bias was assessed using an adapted laboratory animal experimentation quality tool. Data were synthesized using a pooled geometric mean approach to compare therapeutic windows across compound. Of 136 peptides from 47 studies, natural antimicrobial peptides were most potent in vitro against Gram-negative bacteria but frequently caused significant host toxicity. Limited cytotoxicity data prevented robust selectivity analysis for these natural compounds. Peptidomimetics generally provided a wider safety margin than synthetic peptides, though toxicity was context dependent. Major translational barriers, including protein binding and cation effects, diminished in vivo efficacy. Notably, some rationally designed compounds achieved therapeutic benefit in animal models without acute toxicity, unlike traditional agents such as polymyxin B. Advancing antimicrobial peptides and peptidomimetics into clinical use will require overcoming the fundamental trade-off between potency and safety. Natural compounds remain restricted by toxicity, while synthetic agents and peptidomimetics promise better safety but face pharmacokinetic challenges. Future research should prioritize innovative delivery approaches to enhance efficacy and reduce toxicity, enabling these novel therapies to address MDR infections.
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a global public health concern, particularly due to increasing resistance to the last remaining monotherapy, ceftriaxone, in several Asian countries. We examined the AMR of gonococcal isolates obtained at the Bangrak STIs Center, Bangkok, Thailand in 2018-23, and used WGS on isolates resistant to ceftriaxone, cefixime and/or azithromycin. Genital and extragenital swabs from males, females and transgender women were cultured. Etest (five antimicrobials) and EUCAST breakpoints (v16.0), or disc diffusion method (ciprofloxacin) were used to determine AMR. WGS was performed using Illumina NextSeq 550. In 2018-23, 765 gonococcal isolates from 739 patients were cultured. Resistance to ceftriaxone, cefixime, azithromycin, tetracycline and ciprofloxacin was 0.5%, 0.8%, 1.7%, 83.7% and 95.7%, respectively. Ceftriaxone-resistant isolates, all resistant also to cefixime, were first detected in 2023 (n = 3, 1.2%). Additional cefixime-resistant isolates were found in 2022 (n = 2, 1.4%). Azithromycin-resistant isolates first emerged in 2020 (n = 1, 0.9%) and increased to nine (3.7%) isolates in 2023. All ceftriaxone-resistant isolates contained penA-60.001, but cefixime resistance was additionally caused by penA-34.019 and penA-10.001. All azithromycin-resistant isolates had 23S rRNA mutations and/or mosaic/semi-mosaic MtrD (subunit of the MtrCDE efflux pump). Resistance to ceftriaxone, cefixime and azithromycin has emerged in gonococcal strains circulating in Bangkok, Thailand, and resistance appears to be increasing. Resistance to these last options for monotherapy or dual therapy emphasize the need for strengthened national culture-based and genomic surveillance to prevent the spread of MDR and XDR strains in Thailand and globally, and implementation of the novel oral treatments, i.e. zoliflodacin and gepotidacin.
New Delhi metallo-β-lactamase (NDM), a broad-spectrum carbapenemase, can disseminate via plasmids and is a major global healthcare challenge. The gut acts as a niche for the exchange of such genes. This study investigates the transmission dynamics of blaNDM-bearing plasmids among co-colonized bacterial species in pregnant mothers/neonates. Rectal isolates from mothers and neonates underwent antimicrobial susceptibility testing, detection of blaNDM variants, molecular typing and whole-genome/plasmid sequencing. Transmissibility of blaNDM was evaluated through conjugation. Among mothers (n = 86) and sick neonates (n = 93) analysed, 17 were colonized with multiple carbapenem-resistant species; with nine patients colonized with multiple carbapenem-resistant Enterobacterales (CREs), primarily blaNDM-harbouring Escherichia coli and Klebsiella pneumoniae. Isolates were distinct and belonged to diverse sequence types, including epidemic clones (ST11/15/101/147/167/648). blaNDM variants (blaNDM-1 > blaNDM-5 > blaNDM-7 > blaNDM-4) were found to reside on large conjugative plasmids (46-271 kb), primarily belonging to IncFIA-FIB-FII replicons in these isolates. Comparison of blaNDM-plasmid backbones in co-colonized bacteria revealed high diversity and different blaNDM variants, while the immediate genetic environment of blaNDM was very similar. The diverse blaNDM plasmids indicated an independent acquisition of blaNDM instead of its transmission among co-colonized bacteria in individuals. However, in one neonate, co-colonized species (E. coli and K. pneumoniae) possessing blaNDM-5 showed similarities in plasmid backbones indicating possible transmission of blaNDM among these co-colonized species. In addition, similar blaNDM plasmid backbones were observed between isolates from different neonates. The high co-colonization of blaNDM-harbouring bacteria, some epidemic clones, calls for targeted intestinal CRE screening. However, exchange of such genes was very low in the gut, indicating independent acquisition of blaNDM.
Livestock are recognized reservoirs of antimicrobial resistance (AMR). However, current surveillance often overlooks key ecological aspects such as spatial-temporal patterns and quantification of shedding levels of resistant bacteria. In particular, early detection of low-level shedding of resistance to critically important antimicrobials (CIAs), including extended-spectrum cephalosporins (ESCs) and fluoroquinolones (FQs), remains limited. Using commensal Escherichia coli as an indicator, we applied a high-throughput Robotic Antimicrobial Susceptibility Platform (RASP) to assess phenotypic resistance in isolates from 900 samples collected across 10 pig herds over 3 years. Quantitative assessments of antimicrobial resistance (cfu/g) were performed using selective agars containing antimicrobials, with plating and data capture (colony counting) automated on the RASP. Broth microdilution and whole-genome sequencing were performed on CIA-R E. coli using RASP. Persistent resistance to ampicillin and tetracycline (∼5.8 log10 cfu/g) showed minimal variation between herds and years. Gentamicin resistance declined significantly (-0.23 log10 cfu/g/year, P < 0.0001), while ESC resistance rose significantly (0.16 log10 cfu/g/year, P = 0.015), although some herds showed no ESC shedding. Ciprofloxacin resistance was detected in 58% of samples but generally at lower levels (∼2.1 log10 cfu/g) with herd-level variability. Genomic analysis identified FQ-resistant sequence types ST744 and ST167 with global phylogenetic links, and ESC resistance was associated with blaCTX-M-1 on IncI1 plasmids. These findings reveal the ecological complexity of AMR in livestock and highlight limitations of standard surveillance in detecting rare resistances. Our study demonstrates how high-throughput robotics integrated with robust field design can enhance AMR monitoring and inform One Health strategies for mitigation.
The comparative efficacy of ceftaroline and ceftobiprole against standard of care for Staphylococcus aureus infections, including methicillin-resistant S. aureus remains uncertain. Thus, we conducted a systematic review and Bayesian meta-analysis to assess the efficacy and safety of ceftaroline and ceftobiprole monotherapy for non-urinary S. aureus infections. We registered the protocol in PROSPERO. We searched PubMed, Embase, Scopus, and Web of Science. We included randomized controlled trials and comparative non-randomized studies reporting adjusted estimates, enrolling patients with non-urinary S. aureus infections. The primary analysis assessed clinical cure in randomized trials using a Bayesian random-effects model with a vague prior. For ceftaroline, we additionally conducted an exploratory analysis using an observationally informed prior derived from non-randomized studies with variance inflation. Risk of bias was assessed with RoB 2 and ROBINS-I and certainty of evidence with GRADE. Sixteen studies met inclusion criteria [11 ceftaroline (1030 subjects); 5 ceftobiprole (1265 subjects)]. In the primary analysis, the pooled odds ratio for clinical cure was 1.38 (95% CrI 0.81-2.44) for ceftaroline and 0.99 (95% CrI 0.59-1.62) for ceftobiprole. The exploratory ceftaroline analysis using an observationally informed prior yielded an odds ratio of 1.45 (95% CrI 0.91-2.38). Adverse events and serious adverse events were similar between groups. Certainty of evidence was low for ceftaroline and moderate for ceftobiprole. Current evidence does not demonstrate superiority of ceftaroline or ceftobiprole over standard-of-care therapy for clinical cure in non-urinary S. aureus infections. Estimates remain imprecise and are largely driven by registrational trials and subgroup data. These findings support cautious, indication-specific interpretation rather than routine preference of these agents over established therapies.
Because antimicrobial resistance is one of the most pressing global health challenges of our time, it is crucial to find and develop new antimicrobial compounds, especially molecules with new targets and mechanisms of action. Among those, trans-translation, the main quality control system responsible for rescuing bacterial ribosomes present in non-stop complexes, is an appealing target. The objective of this study was to use in vitro and in vivo screening assays to evaluate organic compounds from the French Essential Chemical Library (Chimiothèque Nationale Essentielle, CNE) as trans-translation inhibitors. In vitro cell-free assays and whole-cell in vivo trans-translation assays were performed to screen compounds from the chemical library. MIC and chequerboard assays were performed to assess the compounds' inhibition of bacterial cell growth in ESKAPE pathogens, alone or in combination with current antibiotics. Our initial results revealed a new family of γ-carboline compounds capable of inhibiting trans-translation in both in vitro and in vivo Escherichia coli-based assays, without affecting canonical translation. One molecule from the γ-carboline family, namely compound 404, presented high activity and specificity. These findings raise the prospect of further optimization of γ-carboline compounds' activity in order to use them in combination with currently available antibiotics to combat resistant pathogenic bacteria.
While microbiology tests can guide management of infectious diseases, little is known about the prevalence of testing around the time of antibiotic initiation in long-term care facilities (LTCFs). The objectives of this study were to investigate prevalence and factors associated with microbiology testing around the time of antibiotic initiation, and subsequent treatment pathways in LTCFs. This retrospective cohort study included individuals aged ≥65 years who entered a LTCF in three Australian states between 1 January 2017 and 30 June 2019, and received a systemic antibiotic (n = 36 977). Prevalence of microbiology testing in the 14 days pre- and 7 days post-antibiotic initiation, and treatment pathways 14 days post-initiation, were determined. Multivariable logistic regression determined adjusted odds ratios (aORs) and 95% confidence intervals (95%CIs) for factors associated with testing. In total 15 407 (41.7%) individuals were tested around the time of antibiotic initiation, ranging from 22.9% (n = 585/2551 residents) of macrolide initiators to 79.3% (n = 413/521) of nitrofurantoin initiators. Individuals with urinary tract infections on LTCF entry (aOR 1.24, 95%CI 1.10-1.40) or initiating trimethoprim (aOR 2.80, 95%CI 2.50-3.13) were more likely to be tested. Males (aOR 0.81, 95%CI 0.77-0.85), and residents who received cephalosporins (aOR 0.75, 95%CI 0.68-0.84), penicillins (aOR 0.49, 95%CI 0.45-0.55), or with airways disease (aOR 0.87, 95%CI 0.82-0.91) had lower odds of testing. Among those tested, 14.5% (n = 2238) had a second dispensing of the same antibiotic, 11.4% (n = 1 751) switched antibiotic therapy and 5.9% (n = 904) were hospitalized within 14 days. With four in ten residents tested, and lower prevalence within certain resident subgroups, this study suggests a high dependence on initiating empiric therapy in LTCFs.
Prosthetic joint infections (PJI) of the hip and knee are most often caused by Staphylococcus spp. and require long-term treatment with rifampicin and fluoroquinolone as first-line treatment. However, resistance, contraindications or intolerance highlight the need for effective oral alternatives. Tetracyclines, with favourable bioavailability and bone penetration, represent a potential option. CYCLIOS, a multicentre retrospective matched case-control study, included adult patients with staphylococcal hip or knee PJI treated with curative intent. Cases received doxycycline as part of their antibiotic regimen, and controls were matched 1:2 on infection site, age, pathogen and date of multidisciplinary meeting. The primary endpoint was a composite of death or treatment failure at 2 years. Sixty-seven patients were analysed (23 doxycycline group, 44 control). The two groups were comparable except for immunosuppression (17% (4/23) versus 2% (1/44); P = 0.04). The median duration of doxycycline was 75 days (interquartile range [IQR]: 47-83). The primary endpoint occurred in 43% (10/23 and 19/44) of both groups (odds ratio [OR] 1.01, 95% confidence interval [CI] [0.36-2.84]; P = 0.98). Treatment-related adverse events were reported in 35% (8/23) versus 20% (9/44); P = 0.24, but premature discontinuation remained rare (4% (1/23) versus 5% (2/44); P = 1.00). In the conditional logistic regression model, doxycycline exposure was not associated with an increased risk of unfavourable outcome (univariate OR 1.06, 95% CI [0.40-2.81]; P = 0.91 and multivariate OR 0.97, 95% CI [0.23-4.25]; P = 0.97). In this multicentre real-life study, doxycycline-based regimen, no significant difference was observed between doxycycline-based regimens and comparator strategies, with acceptable tolerability. Given the observational design and limited sample size, these findings should be considered exploratory. Tetracyclines may represent a pragmatic therapeutic alternative when first-line options are not feasible.
Pregnant women are at increased risk of severe coronavirus disease 2019 with potential adverse consequences for maternal and fetal health. Although remdesivir (RDV), molnupiravir and azvudine are RNA-dependent RNA polymerase (RdRp) inhibitors of SARS-CoV-2, their placental transport characteristics are unclear. This study aimed to compare the placental permeability and transport mechanisms of these antiviral drugs using placental cell models. A cost-effective LC-MS/MS method quantified these drugs and their metabolites. Drug accumulation in placental cell models was compared, and drug permeability was assessed using BeWo Transwell transport assay. Transporter inhibitors, siRNA knockdown and transporter-overexpression cell models were used to investigate the transmembrane transport mechanisms. RDV, GS-441524 and EIDD-1931 accumulated more in BeWo cells at 37°C than at 4°C, indicating carrier-mediated uptake. RDV and GS-441524 exhibited lower permeability, whereas EIDD-1931 and azvudine exhibited higher permeability in BeWo cells. RDV was a potential substrate of equilibrative nucleoside transporter (ENT) 1/2 and concentrative nucleoside transporter (CNT) 3; GS-441524 of ENT1/2, CNT2/3 and organic anion transporter (OAT) 4; and EIDD-1931 of ENT1/2 and OAT4. Breast cancer resistance protein (BCRP) was implicated in efflux of all four compounds in BeWo cells, whereas P-glycoprotein (P-gp) was involved in efflux of RDV and GS-441524. RDV and GS-441524 displayed low placental permeability in BeWo cells, whereas EIDD-1931 and azvudine displayed high permeability. Multiple ENTs, CNTs, OAT4, P-gp and BCRP might be involved in placental transport of RDV, GS-441524, EIDD-1931 and azvudine. These findings offer new insights into the placental transport of RdRp inhibitors during pregnancy.
Selective digestive decontamination (SDD) is routinely applied in Dutch ICUs to prevent colonization by potentially pathogenic microorganisms. In the R-GNOSIS ICU study, conducted outside of the Netherlands, SDD consisted of a mix of an oropharyngeal paste and a gastric suspension containing colistin, tobramycin and nystatin. Although SDD improves patient outcomes, its impact on the pangenome and resistome of colonizing Escherichia coli remains poorly understood. This study aimed to determine whether SDD influences the genomic composition and resistance repertoire of E. coli isolates from ICU patients. We compared 129 genomes of E. coli isolates from patients that received SDD and patients that did not receive SDD, but standard care only (baseline patients) in five ICUs located across three European countries (R-GNOSIS ICU study). Comparative analyses were performed to assess differences in the pangenome, plasmidome and antibiotic resistance gene content between groups. The overall pangenome compositions of E. coli isolates from SDD-treated and baseline patients were highly similar. Accessory genome variation was strongly associated with phylogeny, but not with SDD exposure. Plasmidome differences were explained by the interaction of ICU location and phylogroup. A tobramycin resistance gene, flanked by IS26 elements and frequently co-occurring with blaCTX-M-15, was more prevalent in isolates from SDD patients. No mcr genes associated with transferable colistin resistance were detected. SDD did not significantly alter the overall pangenome or plasmidome composition of colonizing E. coli in ICU patients. However, a potentially mobile tobramycin resistance gene was more prevalent in E. coli from SDD patients.
Dalbavancin, a lipoglycopeptide with a half-life of 150-200 h, is a promising treatment option for prosthetic joint infections (PJIs) and other orthopaedic implant-associated infections (IAIs) caused by multidrug-resistant staphylococci. However, in vitro studies have shown that when exposed to low concentrations of dalbavancin, staphylococcal strains resistant to dalbavancin can emerge, potentially affecting its effectiveness in cases of recurrent infection. To investigate whether dalbavancin-resistant staphylococci emerge in vivo following long-term dalbavancin treatment for PJIs or orthopaedic IAIs. Nineteen patients who had received long-term dalbavancin treatment (≥12 weeks) following PJI or orthopaedic IAI and 25 control patients scheduled for elective prosthetic joint surgery were sampled from the nares and perineum. Each sample was subcultured on Mueller-Hinton II agar plates containing various concentrations of dalbavancin (0.0, 0.125, 0.5, and 2.0 mg/L). The growth of staphylococcal colonies was analysed using MALDI-TOF, and the MIC values of dalbavancin were determined using the gradient test method. Among dalbavancin-treated patients, 4 out of 19 displayed staphylococcal species resistant to dalbavancin (MIC value >0.25 mg/L according to EUCAST breakpoint tables). These four were all Staphylococcus epidermidis isolates, three from the nares and one from the perineum, and displayed MIC values of 0.38, 0.38, 0.5, and 0.75 mg/L. No resistant staphylococci were detected in the samples from the control group (P = 0.029, Fisher's exact test). The present study demonstrated the emergence of dalbavancin-resistant staphylococci following long-term treatment.
Critically ill infants and children often experience subtherapeutic cefotaxime exposure when administered licenced doses. Dose individualization guided by model informed precision dosing (MIPD) software is emerging, however, external validation of MIPD performance before implementing into clinical practice is necessary. This in silico study assessed the accuracy of an MIPD software in predicting cefotaxime concentrations among critically ill infants and children using the a priori ('empiric') and the a posteriori (Bayesian forecasting) approaches. The study population was between 1 month and 12 years of age receiving cefotaxime in a paediatric intensive care unit. Essential data was inputted into the MIPD software ID-ODSTM to perform the a priori (4 h and 6 h post dose) and the a posteriori (one- and two-measured serum cefotaxime concentrations) predictions. The concentrations predicted by ID-ODS were compared against measured concentrations, using bias, precision and linear regression methods. Thirty infants and children with 115 concentration measurements produced 194 simulations for analysis. The median age, weight and serum creatinine concentration were 22.8 months, 10.6 kg and 23 µM/L, respectively. The a priori approach showed high biases, low precisions, and significant underprediction [weighted mean prediction error (WMPE) -48.48%, -85.63%, weighted root mean squared prediction error (WRMSE) 98.86, 87.60% at 4 h and 6 h, respectively]. The a posteriori approach exhibited improved accuracy (WMPE 0.28%, -21.54%, WRMSE 76.41%, 58.98% for one and two samples, respectively). MIPD-guided dose adjustments achieved pre-defined PK-PD targets in >90% of simulations using the a posteriori approach. MIPD incorporating measured blood samples of cefotaxime increases the likelihood of achieved target drug concentrations in treating severe infections among critically ill infants and children.
We assessed the impact of a modified microbiology report and cascade that selectively reported narrower-spectrum β-lactams for low-risk AmpC Enterobacterales (AmpC-E). We conducted a controlled interrupted time series analysis to assess the proportion of patients receiving ceftriaxone or piperacillin/tazobactam on the fourth day of antibiotic treatment for low-risk AmpC-E infection (Serratia marcescens, Morganella morganii, Providencia spp., Citrobacter koseri) compared with a high-risk AmpC-E (Enterobacter cloacae complex, Klebsiella aerogenes, Citrobacter freundii) control group. Secondary outcomes included a pre-post measurement of antibiotic use on the fourth day of therapy, death at 30 days, and recurrent infection at 90 days. Patients with low-risk AmpC-E infections were more likely to receive ceftriaxone or piperacillin/tazobactam compared with high-risk AmpC-E controls [incidence rate ratio (IRR) 39.8, 95% CI 1.8-871.7, P = 0.02]. There was an upward shift and trend in ceftriaxone and piperacillin/tazobactam use during the implementation period in the low-risk AmpC-E group compared with the control group (IRR 3.3, 95% CI 0.9-11.9, P = 0.07 and slope 1.3, 95% CI 1.0-1.8, P = 0.10), with an associated reduction in fluoroquinolone use. During the implementation period, 30 day mortality (13.8% versus 12.1%, P = 0.70) and recurrent infection at 90 days (6.4% versus 5.7%, P = 0.83) were similar between low-risk and high-risk AmpC-E groups. Modification of microbiology reporting for low-risk AmpC Enterobacterales infections to selectively report narrower-spectrum β-lactams resulted in a rapid and sustained increase in use of ceftriaxone and piperacillin/tazobactam across two hospitals. Aligning this microbiology reporting with guidelines would have scalable impact on hospital antimicrobial stewardship.
Recent studies have shown progress in understanding the evolution of HIV antiretroviral resistance-associated mutations (RAMs) in the reservoir, particularly M184V, but data on non-nucleoside reverse transcriptase (RT) inhibitors RAMs (NNRTI-RAMs) remain limited. This study aimed to describe the evolution of NNRTI-RAMs in the reservoir, with or without M184V. This single-centre retrospective study included people living with HIV-1 (PLWHIV) who had one or more NNRTI-RAMs detected in plasma genotype, and who had blood samples collected after at least 1 year of virological suppression on antiretroviral therapy. RT NGS was performed at two time points during virological suppression: DNA1 (2019) and DNA2 (2024). Of 49 PLWHIV with NNRTI-RAMs, 40 had an M184V mutation in their previous HIV-1 RNA genotypes. At DNA1, NNRTI-RAMs and M184V were present in 44.9% (n = 22/49) and 65.0% (n = 26/40) of PLWHIV, respectively. In univariate analysis, NNRTI-RAM clearance at DNA1 was associated with shorter duration of replication under an NNRTI regimen at virological failure (VF) (5 versus 37 months, P = 0.013), longer duration between RNA and DNA1 genotypes (14 versus 9 years, P = 0.010) and older age (60 versus 55 years, P = 0.037). Only replication duration remained associated with the persistence of NNRTI-RAMs (P = 0.041) in multivariate analysis. Past M184V in RNA genotypes was not associated with NNRTI-RAM persistence at DNA1 or DNA2 (P = 0.477 and P = 0.711, respectively). No significant evolution of NNRTI-RAMs was observed between DNA1 and DNA2 (P > 0.999). In virologically suppressed PLWHIV, NNRTI-RAMs and M184V in the HIV blood reservoir decreased without evidence of interaction between their evolution.
Ibrutinib is a recognized risk factor for invasive fungal disease (IFD) recognized in the 2019 revised criteria of the European Organisation for Research and Treatment of Cancer. Cerebral aspergillosis (CA) under ibrutinib has been relatively frequently reported, but its particular characteristics remain insufficiently described. The CEREALS study was a nationwide retrospective cohort of 119 patients diagnosed with CA between 2006 and 2018. We analysed 10 patients who developed CA following ibrutinib therapy and compared their clinical, radiological and outcome data with those of other patients with haematological malignancies from this cohort. Nine patients received ibrutinib for chronic lymphocytic leukaemia and one for diffuse large B-cell lymphoma after a median of two prior treatment lines. None received anti-mould prophylaxis, although 80% of them presented additional IFD risk factors. CA occurred a median of 2.9 months after ibrutinib initiation. All cases resulted from haematogenous dissemination, with extracerebral involvement in 70% of the patients, mostly the lungs. Brain imaging revealed supratentorial abscesses without meningeal involvement in all patients, typically manifesting with focal neurological deficits. Serum galactomannan was positive in 33% of tested patients, exclusively in neutropenic individuals. Six-week mortality was 40%. Compared with other haematological malignancy patients in the CEREALS cohort, ibrutinib-associated CA showed exclusive haematogenous spread, infrequent serum galactomannan positivity and lower mortality (40% versus 62%). Cerebral aspergillosis during ibrutinib therapy shows particular features. An invasive microbiological workup is often required, as serum galactomannan appears to have limited sensitivity in this context.
Quantification of prescription of antimicrobial agents and use of paediatric outpatient services before, during and after the COVID-19 pandemic. We conducted a population-based study using Norwegian linked health registries and Japanese claims (2018-2023). Paediatric antibiotic prescription rates, broad-spectrum use, and proportion of antibiotic prescriptions with prior presumed bacterial infection diagnoses were analysed monthly, overall and by age groups and sex. Interrupted time series analyses were performed to evaluate pandemic-related changes, expressed in rate ratio (RR) and its CI, using March 2020 as the interruption point and the pre-pandemic trend/level as reference. Data on 5.5 million children and 19.5 million antibiotic prescriptions were analysed. Before the pandemic, antibiotic prescribing was higher in Japan (120-200/1000 children/month) than in Norway (10-20/1000). At pandemic onset, rates fell by 45% in Norway (RR = 0.55; 95% CI, 0.45-0.67) and by 53% in Japan (RR = 0.47; 95% CI, 0.41-0.55), then by 2023 had returned to expected levels. Broad-spectrum antibiotic use was much higher in Japan (70%) compared with Norway (10%) before the pandemic. However, Norway experienced a sharp 20% increase whereas Japan remained largely unchanged post-pandemic. The proportion of prescriptions with a prior presumed bacterial diagnosis was between 50% and 65% before the pandemic then decreased modestly by 5%-10% at pandemic onset, followed by gradual rebound in both countries. The COVID-19 pandemic significantly altered paediatric antibiotic prescribing in both countries. Sustained antibiotic stewardship efforts are needed to ensure appropriate paediatric antibiotic use in the post-pandemic era.
Scedosporium and Lomentospora species are intrinsically resistant moulds increasingly implicated in invasive infections. Olorofim, a novel orotomide antifungal, has demonstrated potent activity against several moulds. This study evaluated the antifungal susceptibility of clinical and environmental isolates, focusing on olorofim, and examined these data in a phylogenetic context. A total of 216 isolates (Scedosporium spp., n = 205; L. prolificans, n = 11) were collected from clinical and environmental sources across Taiwan. Antifungal susceptibility was determined using the CLSI M38-A3 method. Correlation analyses assessed cross-resistance patterns, while phylogenetic signal, Mantel tests, and variance partitioning were used to evaluate evolutionary structuring of MICs. Scedosporium apiospermum (46.3%) and S. boydii (15.7%) were the predominant species, exhibiting comparable triazole susceptibility profiles (MIC90: voriconazole 1-2 mg/L, posaconazole 4 mg/L, and isavuconazole 8 mg/L). L. prolificans displayed pan-resistance to all agents except olorofim. Olorofim exhibited the lowest MICs across Scedosporium spp. and L. prolificans (all MIC90 ≤ 0.12 mg/L). The isolate source exerted limited biological impact on antifungal susceptibility campared with species-specific characteristics. The association between antifungal susceptibility and species relatedness varied by drug: moderate for posaconazole, amphotericin B, and voriconazole; intermediate for olorofim; weak for isavuconazole; and absent for itraconazole. The majority of MIC variability (72.5%-89.2%) was observed within rather than between species. Susceptibility in Scedosporium and Lomentospora exhibits high intraspecies variability. Triazoles showed only moderate phylogenetic conservation and cross-resistance, whereas olorofim demonstrated potent, independent activity across all taxa. Given the limited predictive value of species identity, individual susceptibility testing remains essential.
Critically ill patients exhibit altered pharmacokinetics, rendering antibiotic dosing challenging. Achieving therapeutic antibiotic exposures may be improved with the use of precision dosing software programs. To quantify and compare both a priori and a posteriori predictive performance of an antibiotic precision dosing software program in a heterogenous cohort of critically ill adults with infection. The precision dosing program, ID-ODSTM, was used to predict a priori and a posteriori concentrations for piperacillin, meropenem, cefepime, flucloxacillin and vancomycin using clinical and demographic data derived from a previous study in critically ill adults (GUIDE trial). Predicted concentrations were compared to observed concentrations using pre-specified acceptance criteria (median predictive error (MDPE) ≤20% and median absolute predictive error (MDAPE) ≤30%), along with F20 and F30 metrics. Furthermore, the impact of predictions on theoretical dosing recommendations to achieve pre-defined drug exposures was assessed. The a priori predictive performance in 81 patients administered beta-lactams did not meet any pre-specified acceptance criteria (pooled MDPE -35% and MDAPE 58%). However, all beta-lactams met accuracy acceptance criteria for the a posteriori approach (pooled MDPE -3.6%), although only cefepime demonstrated acceptable precision and F20 and F30 acceptance. In 25 patients administered vancomycin, a priori predictive performance met all acceptance criteria for accuracy and precision.When assessing a priori theoretical dosing recommendation concordance, approximately one in three predictions led to an unnecessary dosing action. Concordance was similar with an a posteriori approach, however, overprediction was observed in 20% of meropenem predictions. In a heterogenous adult ICU population, the a priori predictive performance of vancomycin was shown to be acceptable. Conversely, the a priori predictive performance for the beta-lactams was not acceptable. Although predictive performance improved with the a posteriori approach for beta-lactams, only cefepime met acceptance criteria.
To assess the epidemiological susceptibility distribution of five β-lactam antibiotics for contemporary clinical isolates of non-faecalis Enterococcus species categorized as susceptible to ampicillin and to evaluate the performance of gradient diffusion (GD) tests compared to broth microdilution (BMD), the reference method for antimicrobial susceptibility testing. A total of 455 non-duplicate non-Enterococcus faecalis clinical isolates reported as ampicillin susceptible were collected from 43 French hospital laboratories. Identification to the species level was performed using MALDI-TOF mass spectrometry. MICs of amoxicillin, piperacillin, imipenem, meropenem and ceftobiprole were determined by BMD and GD. Results were interpreted according to the 2025 EUCAST recommendations. Agreement between GD and BMD was assessed using ISO and FDA criteria. All isolates were susceptible to amoxicillin, 94% (428/455) to ceftobiprole, 88% (401/455) to imipenem at high dose and 88% (402/455) to piperacillin. Enterococcus casseliflavus displayed the lowest MIC values across all β-lactams, followed by Enterococcus avium. In contrast, Enterococcus faecium, Enterococcus lactis, Enterococcus gallinarum and Enterococcus hirae exhibited right-shifted MIC distributions. Most species showed high MICs for meropenem, indicating low intrinsic activity. GD methods did not achieve FDA or ISO criteria for most species-antibiotic combinations. Overall, ampicillin may predict amoxicillin categorization for frequent non-faecalis enterococci, and with the exception of meropenem, most β-lactams may still have clinical value against these species. The different species exhibit distinct MIC distribution patterns for the tested β-lactams. Furthermore, substantial discrepancies observed between GD and BMD methods highlight the limited reliability of GD as an alternative to BMD.