BACKGROUND: Aerosolized colistin has been increasingly used to treat multidrug-resistant gram-negative infections, particularly in the intensive care unit (ICU), as an alternative to intravenous colistin, which is limite...BACKGROUND: Aerosolized colistin has been increasingly used to treat multidrug-resistant gram-negative infections, particularly in the intensive care unit (ICU), as an alternative to intravenous colistin, which is limited by nephrotoxicity and poor pulmonary penetration. Systemic colistin use has been linked to the emergence of resistance, but the impact of inhaled colistin on resistance development remains unclear. METHODS: We conducted a time-series analysis using monthly data from April 2014 to December 2023 in the ICUs of a 2700-bed tertiary-care hospital comprising 108 adult ICU beds. Monthly antibiotic use and the incidence of colistin-resistant Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii from respiratory specimens were analysed using vector autoregressive (VAR) or vector error correction models (VECMs), depending on the presence of stationarity and cointegration. RESULTS: In bivariate VAR analyses, aerosolized colistin use was positively associated with subsequent increases in colistin-resistant K. pneumoniae and A. baumannii, with significant effects observed across multiple lags. In multivariate VAR models including other antibiotic classes, the temporal association persisted for K. pneumoniae. Sensitivity analyses using VECM also showed significant associations for E. coli, K. pneumoniae, P. aeruginosa and A. baumannii. In an additional analysis of non-respiratory specimens, aerosolized colistin was also significantly associated with colistin-resistant A. baumannii. CONCLUSIONS: Aerosolized colistin use was temporally associated with increased resistance in major gram-negative pathogens, particularly K. pneumoniae and A. baumannii. These findings highlight the need for cautious use of inhaled colistin and support its inclusion in targeted antimicrobial stewardship efforts, given its potential contribution to the emergence of resistance.
BACKGROUND: Temocillin (TEM) is a seducing alternative to treat multidrug-resistant Enterobacterales thanks to a narrow spectrum, resistance to hydrolysis by ESBLs and some carbapenemases and limited impact on the gut mi...BACKGROUND: Temocillin (TEM) is a seducing alternative to treat multidrug-resistant Enterobacterales thanks to a narrow spectrum, resistance to hydrolysis by ESBLs and some carbapenemases and limited impact on the gut microbiota. However, its efficacy on Enterobacter cloacae complex (ECC) is unclear. We evaluated TEM efficacy against ECC, in vitro and in a high-inoculum murine peritonitis model. METHODS: Five TEM-susceptible E. xiangfangensis UTI strains and an isogenic pair of E. asburiae clinical isolates-E. asburiae TEM_S and E. asburiae TEM_R-were studied. MICs, bactericidal kinetics and emergence of resistance were assessed in vitro and in a murine peritonitis model using cefepime (FEP) as reference. Both in vitro and in vivo resistant mutants were sequenced. RESULTS: Among the six TEM-S isolates tested, resistant mutants emerged in vitro in all but one after 24 h exposure to 2× MIC TEM. In vivo, when infected with E. asburiae (both TEM-S and TEM-R), mice mortality was significantly higher when treated with TEM compared with FEP, and resistant mutants emerged in 5/12 mice infected with E. asburiae TEM_S (0/12 with FEP). When infected with TEM_S E. xiangfangensis isolates, no significant difference was evidenced between mice treated with TEM or with FEP. CONCLUSIONS: Rapid and frequent emergence of resistant mutants to TEM was evidenced in vitro for distinct TEM-susceptible ECC strains. This led to TEM inefficacy in a high-inoculum peritonitis model with TEM_S E. asburiae. TEM should be used with caution for the treatment of severe ECC infections, even against susceptible strains.
Monge-Olivares L, López-Hernández I, Fernández-Cuenca F
… +2 more, Pascual Hernández Á, López-Cerero L
J Antimicrob Chemother
· 2026 May · PMID 42141914
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OBJECTIVES: Carbapenemase-producing Gram-negative bacteria represent a major clinical challenge. Rapid detection and characterization of carbapenemase group is essential for guiding therapy and for infection control. We...OBJECTIVES: Carbapenemase-producing Gram-negative bacteria represent a major clinical challenge. Rapid detection and characterization of carbapenemase group is essential for guiding therapy and for infection control. We evaluated the performance of Certest ResisCheck® Carbapenemases, a novel lateral flow immunoassay (LFIA), for detecting the main carbapenemase groups from bacterial culture. MATERIALS AND METHODS: A multicentre collection of 351 well-characterized clinical Gram-negative isolates, studied by whole-genome sequencing, was tested using this assay. 57 KPC, 53 NDM, 63 VIM, 68 OXA-48-like, 64 IMP and 100 carbapenem resistant non-carbapenemase producers were included. RESULTS: The LFIA showed an overall sensitivity of 96.4% and specificity of 100%. The positive predictive value (PPV) was 100%, and the negative predictive value (NPV) was 91.7%. No false-positives or cross-reactions with extended-spectrum β-lactamases (ESBLs) or cephalosporinases were observed either with isolates harbouring multiple carbapenemases. Detection rates for IMP and NDM variants reached 100%. Sensitivity for KPC, OXA-like and VIM was slightly lower (93.0%, 95.6% and 96.8%, respectively). Nine false-negative results were observed: KPC-31 (n = 4), VIM-63 (n = 2) and OXA-1054-producing (n = 3) isolates. Increasing the bacterial inoculum managed to obtain a positive result for KPC-31 and VIM-63, but OXA-1054 remained undetected. CONCLUSIONS: Certest ResisCheck® Carbapenemases is a rapid, accurate, and reliable tool for detecting carbapenemases in clinical settings. While some rare variants may escape detection, its strong performance across diverse bacterial species supports its use as part of routine diagnostics to guide timely antimicrobial therapy and control the spread of resistance.
Veldman KT, van Essen-Zandbergen A, Geurts Y
… +5 more, Harders F, Wit B, Stegeman JA, Hendrickx APA, Brouwer MSM
J Antimicrob Chemother
· 2026 May · PMID 42136198
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BACKGROUND: To minimize the risk of livestock becoming a reservoir of carbapenemase-producing Enterobacterales (CPE), it is prohibited to use carbapenems in food-producing animals in Europe. Nonetheless, CPE have been de...BACKGROUND: To minimize the risk of livestock becoming a reservoir of carbapenemase-producing Enterobacterales (CPE), it is prohibited to use carbapenems in food-producing animals in Europe. Nonetheless, CPE have been detected in several EU countries in pigs, poultry and cattle. OBJECTIVES: To detect and characterize CPE from farm animals in the Netherlands obtained within the European monitoring programme for antimicrobial resistance in animals and food. METHODS: Caecal samples from livestock animals are screened for the presence of CPE according to the recommended EURL-AR protocol and supplementary molecular screening. WGS was used to further study the isolates and compare with human-derived CPE. RESULTS: In 2024, two CPE isolates were detected in caecal samples from a pig and a broiler. Both were Escherichia coli producing OXA-244 and showed reduced susceptibility to meropenem, imipenem and ertapenem. WGS confirmed the presence of blaOXA-244 gene on a chromosomally located IS-element. Although both isolates belonged to ST58 and were genetically similar, neither represented a clonal relationship with each other, nor with human-associated OXA-244-producing E. coli from national CPE surveillance. Follow-up investigations on both farms did not reveal additional CPE. CONCLUSIONS: The finding of two OXA-244-producing E. coli isolates in livestock caecal samples demonstrates the added value of implementing a more sensitive screening method for detection of CPE with low-level resistance to carbapenems in the European AMR monitoring programme for animals and food.
Ciccullo A, Baldin G, Cervo A
… +16 more, Oreni L, Mazzitelli M, Gasparro G, Menozzi M, Cesaretti M, Bassani F, Lagi F, Lombardi F, Giacomelli A, Borghetti A, Fabbiani M, Rusconi S, Cattelan A, Antinori S, Mussini C, Di Giambenedetto S
J Antimicrob Chemother
· 2026 May · PMID 42136197
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BACKGROUND: Dolutegravir plus lamivudine (DTG+3TC) is widely used as a two-drug switch regimen for virologically suppressed PWH. We report long-term real-world data on effectiveness, tolerability, immunological recovery...BACKGROUND: Dolutegravir plus lamivudine (DTG+3TC) is widely used as a two-drug switch regimen for virologically suppressed PWH. We report long-term real-world data on effectiveness, tolerability, immunological recovery and metabolic/cardiovascular outcomes in a large, multicentre Italian cohort. METHODS: We performed a retrospective observational analysis of participants in the ODOACRE cohort who switched to DTG+3TC between January 2015 and January 2025 across eight Italian centres. Inclusion criteria were age ≥18, HIV-RNA <50 copies/mL for ≥6 months at switch, HBsAg negative. Primary outcomes were time to virological failure (VF) and time to treatment discontinuation (TD) for any cause. Kaplan-Meier survival analysis and Cox regression models were used to evaluate predictors. Changes in metabolic and immunological markers were assessed using linear mixed models and linear regression. RESULTS: A total of 2535 participants were included. Estimated probabilities of maintaining virological suppression were 99.5% at 48 weeks, 96.1% at 240 weeks and 90.4% at 480 weeks. In multivariate analysis, longer time since HIV diagnosis (per year aHR 1.038) and zenith HIV-RNA >500 000 copies/mL (aHR 2.205) predicted VF, whereas longer prior virological suppression was protective (per year aHR 0.869). During 9721.6 PYFU we observed 362 TDs (3.72 per 100 PYFU), with probabilities of regimen maintenance of 94.4%, 83.5% and 78.7% at weeks 48, 240 and 480, respectively. CONCLUSIONS: In our real-world cohort with extended follow-up, DTG+3TC as a switch regimen was associated with durable virological suppression and favourable tolerability. Metabolic findings should be considered descriptive and exploratory, within the limits of an observational, uncontrolled study.
Zhygalova Zhygalova I, Blanco López I, Dopazo Sotillo S
… +6 more, Carreira Sampayo U, Rubiñán Iglesias P, Sousa A, Cabrera Alvargonzález JJ, Pérez-Landeiro A, Pérez-Rodríguez MT
BACKGROUND: We aim to assess the clinical efficacy of β-lactam plus azithromycin compared with β-lactam monotherapy in the empirical treatment of community-acquired pneumonia (CAP). METHODS: We conducted a retrospective...BACKGROUND: We aim to assess the clinical efficacy of β-lactam plus azithromycin compared with β-lactam monotherapy in the empirical treatment of community-acquired pneumonia (CAP). METHODS: We conducted a retrospective matched cohort study in the Vigo Health Area (Spain), including adults discharged in 2023 with a primary diagnosis of CAP. Participants were classified according to the empirical therapy received and matched by severity. Exclusion criteria were immunocompromised status, alternative empirical regimens or initial admission to intensive care unit. Clinical efficacy was defined as the absence of oxygen requirement, fever and ≥50% reduction in C-reactive protein and/or procalcitonin at 72-96 h after treatment initiation. RESULTS: A total of 246 patients were included (121 receiving monotherapy and 125 receiving combination therapy). Although the SOFA score did not differ between groups, overall severity scores were higher in the monotherapy group. Clinical efficacy was similar between treatment groups (65% versus 62%, P = 0.597). In the multivariable analysis of the overall cohort, SOFA ≥2 was the only variable independently associated with reduced clinical efficacy [odds ratio 0.5, 95% confidence interval (0.33-0.93), P = 0.026], whereas treatment strategy was not significantly associated with clinical efficacy. CONCLUSIONS: The addition of azithromycin to β-lactam was not associated with improved clinical efficacy, either overall or in the subgroup with SOFA ≥2.
BACKGROUND AND OBJECTIVES: The increasing prevalence of MRSA challenges current therapeutic options and underscores the need for strategies that restore the efficacy of existing antibiotics. To evaluate the ability of fl...BACKGROUND AND OBJECTIVES: The increasing prevalence of MRSA challenges current therapeutic options and underscores the need for strategies that restore the efficacy of existing antibiotics. To evaluate the ability of flufenamic acid to enhance gentamicin activity against MRSA and to elucidate its mechanism of action. METHODS: The antibacterial activity of flufenamic acid combined with gentamicin was assessed by broth microdilution, time-kill assays and biofilm inhibition tests. Mechanistic studies included ion flux assays, membrane potential and charge measurements, metabolic profiling, reactive oxygen species (ROS) detection, and molecular docking against the biofilm-associated protein Bap. Efficacy was further examined in a Galleria mellonella infection model. RESULTS: Flufenamic acid reduced the MIC of gentamicin against MRSA from 32 mg/L to 1 mg/L and accelerated bactericidal killing. It disrupted Ca2+ and Cl- influx, leading to membrane depolarization and increased anionic surface charge, thereby promoting gentamicin uptake. Flufenamic acid also induced metabolic perturbation, enhanced ROS generation, and bound to Bap (binding energy: -7.678 kcal/mol), reducing biofilm amyloid content and increasing membrane permeability. In Galleria mellonella, the flufenamic acid/gentamicin combination significantly improved survival compared with gentamicin alone. CONCLUSIONS: Flufenamic acid acts as a synergistic ion modulator that resensitizes MRSA to gentamicin via disruption of membrane integrity, ion homeostasis and biofilm structure, supporting its potential as an adjunctive therapy against difficult-to-treat MRSA infections.
Aslan AT, Ezure Y, Tanriverdi ES
… +51 more, Dağ O, Cimen C, Kalem AK, Kayaaslan B, Alkan S, Köylü B, Ata EB, Çağlar B, Saltoğlu N, Önal U, Deniz S, Ural O, Öz M, Bakir M, Yilmaz M, Çakmak R, Batirel A, Akdoğan Ö, Baykam N, Erol Ç, Yanik-Yalçin T, Eren-Kutsoylu OÖ, Türe-Yüce Z, Kalin-Ünüvar G, Özer-Şimşek Z, Güzeldağ S, Köse A, Cihangiroğlu M, Yağci-Caglayik D, Sevinç MB, Aktaş Z, Öncül O, Ersöz G, Kocagöz AS, Hazirolan G, Ünalan-Altintop T, Dinç B, Tüzemen NÜ, Akçali A, Maçin S, Çalişkan A, Hasbek M, Ergon C, Ay-Altintop Y, Şimşek M, Otlu B, Ramsay KA, Harris PNA, Akova M, Paterson DL, Study Group for Carbapenem Resistance (SCARE)
J Antimicrob Chemother
· 2026 May · PMID 42128247
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BACKGROUND: Delays in appropriate antimicrobial therapy can increase the risk of all-cause mortality (ACM) in hospital-acquired bloodstream infections (HA-BSIs) caused by Gram-negative bacteria (GNB). We aimed to evaluat...BACKGROUND: Delays in appropriate antimicrobial therapy can increase the risk of all-cause mortality (ACM) in hospital-acquired bloodstream infections (HA-BSIs) caused by Gram-negative bacteria (GNB). We aimed to evaluate the effectiveness of early appropriate antimicrobial therapy (EAAT) compared with late appropriate antimicrobial therapy (LAAT) in this population. METHODS: This study used data from a multi-centre, prospective cohort including adult patients with HA-BSI caused by GNB across 22 Turkish hospitals. A hypothetical target trial allocating participants with HA-BSI caused by monobacterial GNB to either EAAT or LAAT was emulated using the weighting approach. The primary outcome was 14 day ACM; 28 day ACM was a secondary outcome. Cox proportional hazards models with inverse probability weighting were applied to account for confounding, with antibiotic treatment incorporated as a time-dependent variable. RESULTS: Among 680 patients, 14 day ACM occurred in 14.7% (40/272) of the EAAT group and 42.9% (175/408) of the LAAT group. EAAT was associated with a lower risk of 14 day ACM [adjusted hazard ratio (aHR) = 0.41; 95% CI: 0.28-0.61). Similarly, 26.1% (71/272) of the patients treated with EAAT and 49.5% (202/408) of those receiving LAAT died during 28 day follow-up (aHR = 0.66; 95% CI: 0.50-0.86). In the carbapenem-resistant GNB subset, EAAT reduced the hazard of 14 day ACM (aHR = 0.36; 95% CI: 0.21-0.60) and 28 day ACM (aHR = 0.60; 95% CI: 0.44-0.84). All prespecified and post hoc analyses consistently supported these findings. CONCLUSIONS: EAAT was associated with a survival benefit in individuals with HA-BSI due to GNB. Although these findings support early initiation of appropriate therapy, residual confounding cannot be excluded.
BACKGROUND: Polymyxins are last-resort antibiotics for multidrug-resistant Gram-negative infections, but their nephrotoxicity limits clinical use. OBJECTIVES: To compare the nephrotoxicity of colistin versus polymyxin B...BACKGROUND: Polymyxins are last-resort antibiotics for multidrug-resistant Gram-negative infections, but their nephrotoxicity limits clinical use. OBJECTIVES: To compare the nephrotoxicity of colistin versus polymyxin B and identify risk factors for acute kidney injury (AKI). METHODS: We retrospectively analysed 258 patients (132 colistin, 126 polymyxin B) with normal to moderately impaired renal function. Machine learning (ML) algorithms predicted AKI risk, and propensity score matching was used to evaluate the risk of colistin preference over polymyxin B. RESULTS: Colistin nephrotoxicity (defined as at least stage II KDIGO AKI) was significantly more frequent with colistin than polymyxin B in both unmatched (for colistin 31% versus for polymyxin B 19%, P = 0.04) and matched cohorts (34.4% for colistin versus 14.1% for polymyxin B, P = 0.01). ML identified lower baseline eGFR, higher uric acid, hypalbuminaemia, higher age, concomitant nephrotoxic drug use, weight, vasopressor use and polymyxin type as top predictors. Colistin preference over polymyxin B resulted in significant nephrotoxicity risk in both unmatched (OR: 2.08, 95% CI [1.14-3.79]) and matched cohorts (OR: 3.42, 95% CI [1.38-8.5]). Complete renal recovery occurred in only 41% of AKI cases within 30 days. CONCLUSIONS: Colistin demonstrates significantly higher nephrotoxicity than polymyxin B. The complex relationship between baseline renal function and AKI risk suggests careful monitoring for patients with moderate renal impairment, regardless of polymyxin choice.
BACKGROUND: Klebsiella pneumoniae carbapenemase (KPC) mutations are a major mechanism of ceftazidime-avibactam resistance. We aimed to investigate the antimicrobial activity of aztreonam-avibactam against KPC variant-pro...BACKGROUND: Klebsiella pneumoniae carbapenemase (KPC) mutations are a major mechanism of ceftazidime-avibactam resistance. We aimed to investigate the antimicrobial activity of aztreonam-avibactam against KPC variant-producing K. pneumoniae. METHODS: Antimicrobial susceptibility of 36 KPC variant-producing K. pneumoniae strains was determined by broth microdilution method. The bactericidal kinetic characteristics were analysed by time-kill assays. The interaction between aztreonam and avibactam was analysed by the checkerboard assay and inhibitory Emax model with a baseline effect parameter. blaKPC cloning, molecular docking and enzymatic kinetic analysis was performed to analyse the interactions between KPC variants and substrates. In vivo antibacterial activity was investigated using the Galleria mellonella infection model and the neutropenic mouse intraperitoneal infection model. RESULTS: Aztreonam-avibactam exhibited an MIC50 of 1 mg/L and an MIC90 of 2 mg/L against KPC variant-producing strains, with a rapid bactericidal effect; however, one KPC-14-producing strain showed resistance (8 mg/L). The inhibitory Emax model effectively fitted the observed values from checkerboard assay: aztreonam MICs decreased rapidly as avibactam concentration increased, and gradually reached a plateau. Despite a reduced susceptibility to avibactam inhibition, these KPC variants exhibit impaired aztreonam hydrolysis, with aztreonam MICs decreasing by 2- to 1024-fold relative to KPC-2. In vivo, aztreonam-avibactam significantly increased the survival rate of G. mellonella and reduced the bacterial load in the organs of mice infected with KPC variant-producing K. pneumoniae strain. CONCLUSIONS: Aztreonam-avibactam represents an effective therapeutic option for KPC variant-producing K. pneumoniae.
BACKGROUND: Horizontal gene transfer in Haemophilus spp. is associated with antimicrobial resistance development. Recently, a relationship between quinolone resistance and this transfer has been reported. This study aime...BACKGROUND: Horizontal gene transfer in Haemophilus spp. is associated with antimicrobial resistance development. Recently, a relationship between quinolone resistance and this transfer has been reported. This study aimed to investigate the mechanisms underlying quinolone resistance spread by focusing on both homogeneous and heterogeneous transfer to H. influenzae. METHODS: Quinolone-resistant strains of three Haemophilus spp., H. influenzae, H. haemolyticus, and H. parainfluenzae, were used as resistant donors. The H. influenzae laboratory strain Rd and the highly transformable strains 2017-22B and 2018-Y41 were used as recipients. Horizontal transfer assays were performed using genomic DNA from resistant donors or resulting transformants. RESULTS: Horizontal transfer assays demonstrated that quinolone resistance was transferred from the genomic DNA of H. influenzae and H. haemolyticus to all recipient strains. In contrast, resistance from H. parainfluenzae genomic DNA was transferred only to the strains with higher transformability. In all cases, transfer efficiency was higher when DNA from the transformants was used than when DNA from the original strain was used. Notably, genomic DNA from transformants obtained by transferring resistance from H. parainfluenzae to highly transformable H. influenzae strains transformed Rd into a quinolone-resistant variant. Furthermore, no significant differences in growth were observed between the parent strains and transformants. CONCLUSIONS: Our findings suggest that highly transformable strains, owing to their enhanced transformation capacity and retained fitness, may facilitate or amplify the dissemination of quinolone resistance under experimental conditions.
Hendrickx S, Ilbeigi K, Thoré ESJ
… +17 more, Bertram MG, Calvo-Alvarez E, Cintesun S, Olías-Molero AI, Corral MJ, Mateo-Barrientos M, Estaquier J, Pomel S, Alunda JM, Gul S, Van Bocxlaer K, Frézard F, Tavares J, Cordeiro Da Silva A, Costi MP, Maes L, Caljon G
J Antimicrob Chemother
· 2026 May · PMID 42108536
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Neglected tropical diseases such as leishmaniasis, Chagas disease, sleeping sickness and animal trypanosomiasis remain a significant global health challenge. This part of the roadmap outlines a streamlined path for progr...Neglected tropical diseases such as leishmaniasis, Chagas disease, sleeping sickness and animal trypanosomiasis remain a significant global health challenge. This part of the roadmap outlines a streamlined path for progressing from lead identification to a drug development candidate, tailored to the specific needs of kinetoplastid infections. Besides the medicinal upscaling of synthesis, this review highlights key experiments in pharmacology in non-rodent species, toxicology, pharmacokinetics and pharmaceutics. These include but are not limited to early evaluation of safety using refined in vitro and in vivo methods to enhance predictive value, bioavailability and distribution to target tissues, and formulation strategies leveraging various delivery systems to optimize efficacy and safety. Environmental toxicity is also addressed proactively, for which in silico tools are presented. Collectively, this roadmap provides a practical, scalable approach to deliver high-quality drug candidates capable of addressing the urgent needs for kinetoplastid diseases (Figure 1).
van der Wekken-Pas L, Hidalgo-Tenorio C, Rockstroh JK
… +8 more, van Bremen K, Richel O, Molto J, Lambert JS, de Kanter C, Konopnicki D, Burger D, Colbers A
J Antimicrob Chemother
· 2026 May · PMID 42090286
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INTRODUCTION: Pregnancy is associated with physiological changes, resulting in altered pharmacokinetics, which may impact antiretroviral drug exposure. To assure health and prevent vertical transmission of HIV, it is imp...INTRODUCTION: Pregnancy is associated with physiological changes, resulting in altered pharmacokinetics, which may impact antiretroviral drug exposure. To assure health and prevent vertical transmission of HIV, it is imperative to reach adequate drug exposure. This study aims to determine the impact of pregnancy on bictegravir pharmacokinetics, examine mechanisms responsible for lower exposure, report on placental transfer, safety, and efficacy. MATERIALS AND METHODS: This open-label pharmacokinetic study, included women living with HIV who used bictegravir, emtricitabine with tenofovir alafenamide. Plasma samples were obtained in third trimester, as well as 4-6 weeks postpartum. If feasible, cord blood and maternal plasma at delivery were obtained. RESULTS: Sixteen participants were included. Geometric mean area under the curve for total bictegravir was 48.8 mg*h/L (coefficient of variation (CV) 25.9%) in third trimester and 99.2 mg*L/h (CV 32.9%) postpartum, with a geometric mean ratio (90% CI) of 0.49 (0.44-0.55); 24 h post-dosing, median (IQR) unbound fractions were 0.15 (0.13-0.18)% and 0.11 (0.10-0.13) during pregnancy and postpartum, respectively. Median (IQR) ratio between pregnancy and postpartum was 173.7% (127.8-305.7) for glucuronidation-metabolite (M15) and 200.7% (150.0-224.9) for sulfation-metabolite (M20). Low-level viraemia was noted in several participants, but no vertical transmission occurred. Cord blood maternal plasma ratio (IQR) was 1.3 (1.0-1.4). No congenital anomalies were reported. CONCLUSION: Although bictegravir exposure is decreased during pregnancy, mainly due to altered protein binding and increased glucuronidation and sulfation, trough levels remained above the PA-IC95. No vertical transmission occurred and no congenital anomalities were observed. Bictegravir was shown to have profound placental transfer.
BACKGROUND: Maribavir is currently administered at a dose of 400 mg twice daily (q12h) for the treatment of cytomegalovirus (CMV) infections in transplant recipients. However, virological failure rates of up to 40% have...BACKGROUND: Maribavir is currently administered at a dose of 400 mg twice daily (q12h) for the treatment of cytomegalovirus (CMV) infections in transplant recipients. However, virological failure rates of up to 40% have been reported in clinical practice, with potentially severe consequences and the selection of mutant strains. OBJECTIVES: This study aims to evaluate, in silico, the pharmacokinetic (PK) and pharmacodynamic (PD) interest of alternative maribavir dosing regimens using population pharmacokinetic (POPPK) modelling and Monte Carlo simulations. METHODS: A published two-compartment POPPK model with first-order absorption and an absorption lag time was implemented. Monte Carlo simulations (n = 10 000 virtual PK profiles) were performed for maribavir regimens of 400, 600, and 800 mg administered q12h and every 8 h (q8h). PK metrics, including trough concentration (C0) and area under the concentration-time curve (AUC), as well as probability of target attainment (PTA), were compared across regimens at steady state. RESULTS: The standard 400 mg q12h regimen resulted in the lowest PTA, falling below 90% for a pharmacologically active inhibitory concentration 50 of 2 mg/L. In contrast, q8h regimens substantially improved PTA across targets and were associated with reduced interindividual variability in C0. CONCLUSIONS: Increasing dosing frequency to a three-times-daily regimen improved PK/PD target attainment compared with the standard q12h regimen. These findings support the need for prospective clinical and pharmacoeconomic studies to assess the benefit-risk balance of alternative maribavir dosing strategies.
Fresán D, Sorlí L, Barceló-Vidal J
… +11 more, Rodrigo-Moreno A, Muñoz R, Gracia MP, Subirana I, Ramos I, Cerro Á, Lucas Á, Roberts J, Juanes AM, Benítez-Cano A, Luque S
BACKGROUND AND OBJECTIVES: Due to the unpredictable exposure of linezolid with a standard dosing regimen, therapeutic drug monitoring (TDM) has been recommended to guide it despite limited evidence on clinical endpoints....BACKGROUND AND OBJECTIVES: Due to the unpredictable exposure of linezolid with a standard dosing regimen, therapeutic drug monitoring (TDM) has been recommended to guide it despite limited evidence on clinical endpoints. The primary objective was to determine whether achieving therapeutic linezolid concentrations at the first TDM measurement is associated with clinical cure. Microbiological eradication and 7 day and 30 day mortality were also assessed. METHODS: We conducted a retrospective study in a cohort of patients with confirmed Gram-positive (Enterococcus/Staphylococcus spp.) infections and undergoing TDM. A steady-state linezolid trough concentration (Cmin,ss) of 2-8 mg/L was considered therapeutic. A multivariable logistic regression model assessed predictive factors associated with clinical cure. RESULTS: Four hundred patients (median age 68 years, 66.5% male) were included. Infections were mainly intra-abdominal (29.3%), skin/soft tissue or bone/joint (25.5%) and respiratory (21%). At first measurement only 34% of patients reached the therapeutic range, with 34.5% below range and 31.5% above range. Clinical cure rate was 76.3% and 30 day all-cause mortality was 20%. Multivariable logistic regression showed that achieving therapeutic Cmin,ss significantly increased the likelihood of clinical cure (OR 1.78, 95% CI 1.02-3.19). Conversely, a higher Charlson index, liver cirrhosis and sepsis/septic shock requiring ICU admission were risk factors for failure. Other clinical outcomes were not independently related to Cmin,ss. CONCLUSIONS: This study suggests that achieving early therapeutic linezolid concentrations is associated with a higher likelihood of clinical cure and highlights the limitations of an initial standard dosing. In this scenario, an early TDM may help to identify patients out-of-range who need guided dosing to ensure the achievement of pharmacokinetic/pharmacodynamic targets. Further prospective studies are needed to assess the impact of TDM on survival, microbiological outcomes and cost-effectiveness.
BACKGROUND: Monitoring antibiotic consumption and resistance is central to antimicrobial stewardship (AMS). However, this is particularly challenging in paediatrics due to weight-based dosing and heterogeneous patient po...BACKGROUND: Monitoring antibiotic consumption and resistance is central to antimicrobial stewardship (AMS). However, this is particularly challenging in paediatrics due to weight-based dosing and heterogeneous patient populations. OBJECTIVES: To explore the potential role of artificial intelligence (AI) in supporting the evaluation of antibiotic consumption and antimicrobial resistance within a paediatric tertiary-care paediatric hospital in Italy. METHODS: A retrospective analysis (2020-2024) was conducted at the IRCCS Istituto Giannina Gaslini, Genoa. Data included bloodstream infections (BSIs) caused by Staphylococcus aureus and Enterobacterales, intravenous formulations of antibiotic dispensing (expressed as defined daily doses [DDD], stratified according to the World Health Organization AWaRe classification), and both static and adaptive drug resistance indices (DRIs). Spearman's correlation was applied to assess associations. AI (Google Gemini v2.5 Flash) was used for data organization and preliminary analyses; and all outputs were verified by the authors. RESULTS: Use of Access antibiotics increased progressively, exceeding 60% of prescriptions in 2024, whereas Watch antibiotic use decreased to approximately 30%. Reserve antibiotic use fluctuated but showed an overall upward trend. Despite increasing hospital activity, normalized antibiotic consumption (DDD/1000 discharges or patient-days) remained stable or declined. For S. aureus BSIs, methicillin-resistant S.aureus (MRSA) rates and DRIs both declined. Enterobacterales displayed mixed trends, with some resistance indicators increasing, although overall resistance decreased. Most correlations were not statistically significant. CONCLUSIONS: AI-assisted analyses identified stewardship-relevant trends, but expert oversight remained essential. Broader multicentre paediatric studies incorporating patient-level outcomes are warranted to confirm the feasibility and validity of AI-assisted antimicrobial surveillance.
Findlay J, Shaw JM, Nordmann P
… +8 more, Hinchliffe P, Laffer EB, Born Y, Seth-Smith HMB, Egli A, Pfennigwerth N, Spencer J, Poirel L
J Antimicrob Chemother
· 2026 May · PMID 42089879
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OBJECTIVES: We describe the identification and characterization of the HMB-3 variant, produced by a P. asiatica isolate from a patient in Switzerland. MATERIALS AND METHODS: A carbapenem-resistant P. asiatica isolate was...OBJECTIVES: We describe the identification and characterization of the HMB-3 variant, produced by a P. asiatica isolate from a patient in Switzerland. MATERIALS AND METHODS: A carbapenem-resistant P. asiatica isolate was sent to the Swiss National Reference Center for Emerging Antibiotic Resistance for investigation. Antibiotic susceptibility testing was performed according to CLSI guidelines. WGS was performed on Illumina and Oxford Nanopore platforms. The blaHMB alleles were cloned into the pCR-Blunt II-TOPO plasmid. Site-directed mutagenesis was performed on blaHMB-1 and blaHMB-3 inserted into the pTOPO plasmids. Purified HMB-1, HMB-3, NDM-1 and IMP-1 were used for steady state kinetic measurements of hydrolysis of selected beta-lactams. RESULTS AND DISCUSSION: The isolate was obtained from a tracheostomy wound swab. Susceptibility testing showed that it was resistant to all beta-lactams, except aztreonam; however, no classical carbapenemase genes were identified by routine testing. WGS produced a complete chromosome of 6.1 Mb but no plasmids, and identified a gene encoding a novel MBL, namely HMB-3, differing from HMB-1 by 23 amino acid substitutions. HMB-3 was chromosomally encoded and located within a 25.6 kb genomic island. HMB-3 conferred resistance to most beta-lactam antibiotics, except piperacillin (MIC 4 mg/L), aztreonam (0.125 mg/L) and cefiderocol (2 mg/L). Site-directed mutagenesis of blaHMB-1 and blaHMB-3 revealed that a single amino acid change, E181H/H181E, in active site loop 10, could significantly alter the MIC of cefiderocol. HMB-3 demonstrated increased hydrolytic activity against cefiderocol compared with HMB-1 and NDM-1. CONCLUSIONS: Here we described a novel MBL enzyme responsible for acquired resistance to carbapenems and reduced susceptibility to cefiderocol in Pseudomonas spp.
BACKGROUND AND OBJECTIVES: Tigecycline is not usually recommended for patients under 18 years due to limited safety data and adverse events, and dosing guidelines for children under 8 remain undefined. However, it remain...BACKGROUND AND OBJECTIVES: Tigecycline is not usually recommended for patients under 18 years due to limited safety data and adverse events, and dosing guidelines for children under 8 remain undefined. However, it remains a critical treatment option for life-threatening multidrug-resistant infections in critically ill children. This study aimed to characterize the population pharmacokinetics (PopPK) of tigecycline in children, identify key covariates affecting PK variability and propose optimized dosing regimens tailored to specific infection types. MATERIALS AND METHODS: This study enrolled 20 children receiving intravenous tigecycline. One- and two-compartment models were explored. Monte Carlo simulations with age-stratified tigecycline dosing regimens were performed to evaluate the probability of target attainment (PTA) for various dosing regimens. RESULTS: A two-compartment model incorporating allometric scaling and a sigmoidal maturation function best described tigecycline PK. PTA analyses indicated that the standard dose was sufficient for children with infections caused by susceptible Streptococcus groups (breakpoint 0.125 mg/L) across community-acquired pneumonia (CAP), complicated intra-abdominal infections (cIAI) and complicated skin and skin structure infections (cSSSI). For susceptible Enterobacterales, Staphylococcus spp. or Enterococcus spp. (breakpoint 0.5 mg/L), the standard dose reached PK/pharmacodynamic (PD) targets for CAP, while cIAI required twice the standard dose. cSSSI necessitated higher dosing (150 mg) in adolescents; however, potential toxicity concerns necessitate extreme caution with such escalation. Infections caused by Enterobacteriaceae with intermediate resistance (breakpoint 4 mg/L) failed to achieve PK/PD targets even with increased doses exceeding 4.8 mg/kg. CONCLUSIONS: Overall, these results suggest that current dosing recommendations may be insufficient for less susceptible pathogens.