OBJECTIVE: To investigate the emergence of resistance to cefiderocol (FDC) in clinical Enterobacter hormaechei isolates and to elucidate the underlying genetic mechanisms, with particular focus on mutations in a putative...OBJECTIVE: To investigate the emergence of resistance to cefiderocol (FDC) in clinical Enterobacter hormaechei isolates and to elucidate the underlying genetic mechanisms, with particular focus on mutations in a putative TonB-dependent receptor (TBDR). METHODS: Five non-duplicate clinical FDC-susceptible E. hormaechei isolates were exposed to stepwise increasing concentrations of FDC using disk diffusion and broth microdilution to select for spontaneous FDC-resistant mutants. WGS was performed to identify resistance-associated mutations. Site-directed mutagenesis via CRISPR-Cas9 was employed to confirm causality. Bacterial fitness was evaluated by growth curve experiments under both standard and iron-depleted conditions. RESULTS: Six spontaneous mutants exhibited increased FDC MICs ranging from 2 to 16 mg/L. All mutants carried distinct mutations in the TBDR gene, including frameshift mutations and premature stop codons. CRISPR-engineered strains harbouring identical mutations displayed the same resistance phenotype, confirming that disruption of TBDR is sufficient to confer increased FDC resistance. Susceptibility to other β-lactams remained unaffected. Growth analyses did not reveal an obvious growth defect in TBDR mutants compared to the parental strain under the tested in vitro conditions, including iron-depleted media. CONCLUSION: This study identifies mutations in a putative TBDR as a key mechanism mediating FDC resistance in E. hormaechei. The absence of an obvious growth defect under the tested in vitro conditions suggests that loss of this receptor does not impose a major growth disadvantage. These findings underscore the role of TBDRs in FDC uptake and highlight the potential for resistance development under antibiotic selection pressure through disruption of siderophore-mediated uptake pathways.
BACKGROUND: Chronic sub-inhibitory antimicrobial exposures may shape antibiotic resistance (AMR) dissemination at the animal, food and environment interface. Polyether ionophore coccidiostats remain widely used in poultr...BACKGROUND: Chronic sub-inhibitory antimicrobial exposures may shape antibiotic resistance (AMR) dissemination at the animal, food and environment interface. Polyether ionophore coccidiostats remain widely used in poultry production, yet their influence on AMR dissemination at sub-inhibitory exposure is unclear. OBJECTIVES: To determine whether sub-minimum inhibitory concentration (MIC) polyether ionophores enhance resistance plasmid transfer in vitro and to characterize their effects on gut microbiota and resistome dynamics in vivo during and after administration. METHODS: We investigated the effects of representative polyether ionophores at sub-MICs on resistance spreading phenotypes in vitro and gut resistome dynamics in VREfm-challenged broilers. In vitro plasmid conjugation and related phenotypes were quantified, and in vivo caecal microbiota and resistome were profiled by 16S rRNA gene sequencing and shotgun metagenomics. RESULTS: Sub-MIC polyether ionophores increased plasmid conjugation, copy number and biofilm formation in Enterococcus spp., whereas no comparable effects were observed in Escherichia coli. In vivo, salinomycin temporarily disrupted caecal microbiota development and, at Day 20, suppression of indigenous taxa (e.g. Faecalibacterium) was accompanied by a transient surge in VREfm colonization and vanA abundance; resistome expansion was non-persistent. After salinomycin cessation, recovery of beneficial genera like Akkermansia was associated with reduction of the total resistance gene burden towards pre-treatment baseline by Day 42. CONCLUSIONS: Polyether ionophores can promote resistance dissemination phenotypes in vitro, but gut ecological resilience may limit long-term impacts after cessation of exposure under recommended dosing conditions. The transient resistome surge during the treatment suggests increased shedding and potential environmental dissemination via manure, warranting surveillance and risk assessment.
Lasry D, Harrison LB, Bamba R
… +5 more, Corsini R, Yansouni CP, Cheng MP, Lee TC, Lawandi A
J Antimicrob Chemother
· 2026 May · PMID 42219900
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BACKGROUND: Pseudomonas aeruginosa readily evolves antimicrobial resistance through regulatory plasticity and stress-adaptive pathways. Clinically, antibiotics lacking intrinsic antipseudomonal activity are often favoure...BACKGROUND: Pseudomonas aeruginosa readily evolves antimicrobial resistance through regulatory plasticity and stress-adaptive pathways. Clinically, antibiotics lacking intrinsic antipseudomonal activity are often favoured with the assumption that they avoid selective pressure on P. aeruginosa. Whether subinhibitory exposure to such 'non-antipseudomonal antibiotics' (NAPA) can nevertheless select for canonical resistance pathways remains incompletely defined. METHODS: Three P. aeruginosa strains (ATCC 27853 and two bloodstream isolates) were serially passaged over 14 days in the presence of ertapenem, ceftriaxone or moxifloxacin at one-third the baseline MIC. MICs for antipseudomonal antibiotics (meropenem, ceftazidime, ciprofloxacin) were measured at serial time points and after a 3-day antibiotic-free recovery (Day 14). Whole-genome sequencing was performed longitudinally to identify mutations. RESULTS: NAPA exposure led to reproducible elevations in antipseudomonal MICs: ertapenem triggered up to a 29-fold increase in meropenem MIC, ceftriaxone up to a 31-fold rise in ceftazidime MIC and moxifloxacin up to a 12-fold increase in ciprofloxacin MIC. Elevated MICs persisted on Day 14 despite absence of further antibiotic pressure. Genomic analysis revealed convergent evolution of mutations in efflux regulator genes (nfxB, nalC, nalD, amrR) and the β-lactamase-regulating gene dacB, emerging during periods of MIC escalation and mapping to regulatory pathways governing efflux and AmpC expression. CONCLUSIONS: Subinhibitory exposure to antibiotics without intrinsic antipseudomonal activity reproducibly selected for heritable multidrug-resistant phenotypes in P. aeruginosa. Convergent mutations arose in regulatory genes classically associated with direct antipseudomonal antibiotic pressure, demonstrating that resistance architectures can be selected independent of target engagement and underscoring the potential for collateral resistance under antibiotic stress.
Haldorsen BC, Augustinussen MH, Matuschek E
… +10 more, Småbrekke L, Skjold F, Hegstad J, Holzknecht BJ, Helgason KO, Ilmavirta H, Kahlmeter G, Sundsfjord A, Hegstad K, NordicAST 2023 LRE-TRE Study Group
J Antimicrob Chemother
· 2026 May · PMID 42207601
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OBJECTIVES: This multicentre study aimed to assess performance of the EUCAST disc diffusion (DD) and MIC methods for linezolid susceptibility testing in a genetically diverse strain collection. METHODS: Nordic clinical m...OBJECTIVES: This multicentre study aimed to assess performance of the EUCAST disc diffusion (DD) and MIC methods for linezolid susceptibility testing in a genetically diverse strain collection. METHODS: Nordic clinical microbiology laboratories (n = 83) were invited to test a blinded collection of well-characterized Enterococcus faecalis (n = 10) and Enterococcus faecium (n = 10) strains using the EUCAST DD and gradient tests [Etest and MIC Test strips (MTS)] from two manufacturers (bioMerieux and Liofilchem). Results were compared to reference broth microdilution (BMD) MICs and genotype (presence/absence of linezolid resistance determinants). RESULTS: Forty-five laboratories provided DD, and 41 gradient test results. Comparing DD with reference MICs and genotype yielded overall categorical agreements (CA) of 87.0% and 97.8%, respectively. Essential agreement (EA) was 99.7% for Etest (bias +10.0%) and 84.5% for MTS (bias +71.0%). Susceptibility categorization with Etest and MTS showed CA of 90.5% and 84.1% with reference MICs, and 82.9% and 98.6% with genotype, respectively. Most discrepancies involved strains with borderline linezolid MICs (4-8 mg/L) and known linezolid resistance mechanisms. Linezolid exposure of strains with MIC 4 mg/L carrying transferable resistance genes (optrA or poxtA), led to MIC increasing above the clinical breakpoint. CONCLUSIONS: Etest and EUCAST DD had the highest CAs with linezolid reference MIC. EUCAST DD method and MTS gradient test consistently detected strains with confirmed resistance mechanisms. Our findings highlight the potential clinical implications of resistance determinants in MIC borderline strains and support the need for an area of technical uncertainty or a warning in breakpoint tables for linezolid in enterococci.
OBJECTIVES: Aminoglycosides are historically considered nephrotoxic, though contemporary once-daily dosing and preferential amikacin use may reduce this risk. We evaluated the incidence and risk factors for acute kidney...OBJECTIVES: Aminoglycosides are historically considered nephrotoxic, though contemporary once-daily dosing and preferential amikacin use may reduce this risk. We evaluated the incidence and risk factors for acute kidney injury (AKI) among patients receiving amikacin. METHODS: A retrospective cohort study of adult inpatients treated with amikacin between July 2018 and June 2022. Exclusion criteria were treatment <3 or >10 days, baseline eGFR <30 mL/min/1.73 m2, or insufficient renal follow-up. AKI was defined by KDIGO criteria. Charts of patients meeting AKI criteria were reviewed to assess likely aetiology. Multivariate logistic regression identified independent predictors. RESULTS: Of 974 courses, 608 met the inclusion criteria. Patients had a median age of 81.0 years, 52.5% were female and the median baseline eGFR was 67.1 mL/min/1.73 m2. AKI occurred in 48 patients (7.9%), with KDIGO stage 2-3 in 14 (2.3%). Aetiologies included prerenal azotaemia (21%), shock/sepsis (35%), urinary obstruction (17%), contrast exposure (2.1%) and other nephrotoxic medications (2.1%); in 11 patients (22.9% of patients with AKI and 1.8% of the entire cohort), no alternative cause was identified. Multivariate analysis showed independent predictors of AKI were older age, longer interval from admission to treatment and discontinuation due to an infectious indication. Baseline eGFR, daily dose and treatment duration were not associated with AKI. CONCLUSIONS: In this contemporary cohort, we observed a relatively low incidence of AKI, often secondary to, or exacerbated by, other underlying causes. These findings suggest that once-daily amikacin may potentially carry a lower nephrotoxic risk than historically reported. Further studies are warranted to confirm safety in broader patient populations.
BACKGROUND AND OBJECTIVES: Canonical hypervirulent Klebsiella pneumoniae sequence type 23 (ST23) causes severe infections while it generally maintains susceptibility to a broad spectrum of antimicrobials, yet the molecul...BACKGROUND AND OBJECTIVES: Canonical hypervirulent Klebsiella pneumoniae sequence type 23 (ST23) causes severe infections while it generally maintains susceptibility to a broad spectrum of antimicrobials, yet the molecular basis of this phenotypic characteristic remains poorly understood. The purpose of this study was to investigate whether the presence of the DISARM system prevents antimicrobial-resistant plasmid invasion in K. pneumoniae. METHODS: Comparative genomic analysis was performed to detect the distribution of DISARM among K. pneumoniae lineages. PacBio single-molecule real-time sequencing was employed to identify DISARM-associated DNA methylation motifs. Transformation and conjugation assays were conducted to evaluate the impact of DISARM on plasmid defence. RESULTS: Class 1 DISARM system was selectively enriched in ST23 K. pneumoniae strains. The DISARM methylase modified host 5'-GRACRAC-3' motifs, which were distributed in all conjugative plasmids in K. pneumoniae. The transformation efficiency of plasmid pCOLADuet-MTmotif containing the methylation cognate site was reduced 2.9-fold compared with that of the plasmid pCOLADuet-1 in a ST23 DISARM-positive strain KP2613. Conjugation of carbapenemase-encoding plasmids (carrying blaKPC-2, blaNDM-1 and blaNDM-5) decreased 12- to 117-fold in KP2613 and 4.5- to 15.7-fold in Escherichia coli BL21-DISARM(+) compared with DISARM-negative strains KP2613ΔDISARM and BL21-DISARM(-), respectively, indicating that Class 1 DISARM could effectively hinder the antimicrobial resistance plasmid invasion. Systematic deletion of individual DISARM genes revealed that disruption of any single gene did not fully abolish the DISARM-mediated defence or cause substantial growth defects. CONCLUSIONS: Class 1 DISARM provides robust protection against antimicrobial-resistant plasmids, potentially contributing to the high antimicrobial susceptibility observed in ST23 hypervirulent K. pneumoniae.
Cantón R, García-Castillo M, Hernández-García M
… +6 more, Sastre-Femenía MÀ, López-Causapé C, Ruiz-Garbajosa P, García Labrador L, Longshaw C, Oliver A
J Antimicrob Chemother
· 2026 May · PMID 42186121
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OBJECTIVE: The PERSEUS study was a retrospective analysis of cefiderocol use under the compassionate use and early access programmes in Spain for the treatment of MDR Gram-negative infections. We present the microbiologi...OBJECTIVE: The PERSEUS study was a retrospective analysis of cefiderocol use under the compassionate use and early access programmes in Spain for the treatment of MDR Gram-negative infections. We present the microbiological evaluation of 57 isolates collected from this study, along with their correlation to clinical outcomes. METHODS: Cefiderocol susceptibility testing was performed using standard broth microdilution (BMD) in iron-depleted media, commercial BMD panels (UMIC®, ComASP®), gradient MIC strips, and disk diffusion. Results were interpreted according to EUCAST 2024 criteria. WGS was used to characterize β-lactamase genes and mutations in genes implicated in cefiderocol resistance. Patients' clinical charts were reviewed. RESULTS: Most isolates were identified as Pseudomonas aeruginosa (72%). Cefiderocol demonstrated an overall susceptibility rate of 86%, outperforming most comparators except colistin. Commercial BMD devices demonstrated high concordance with the reference method, supporting their potential value for routine use. Molecular analysis revealed a high prevalence of class B metallo-β-lactamases, as well as mutations in iron transport genes, among resistant isolates. Notably, clinical cure was achieved even in patients infected with cefiderocol-resistant isolates treated with cefiderocol monotherapy, suggesting that some putative resistance mechanisms affect the MIC, without necessarily leading to clinical failure. CONCLUSIONS: Positive clinical outcomes in patients infected by cefiderocol-resistant isolates by EUCAST breakpoints highlight the need for standardized susceptibility testing, as well as deeper genotype-phenotype correlation studies. Cefiderocol remains a promising option for treating MDR Gram-negative infections, especially those caused by P. aeruginosa. Its adoption in clinical practice should be supported by validated testing methods and ongoing surveillance.
OBJECTIVES: Artemisinin-resistant Plasmodium falciparum has emerged in several East African countries neighbouring Madagascar. Despite the island's substantial malaria burden, recent data on artemisinin partial resistanc...OBJECTIVES: Artemisinin-resistant Plasmodium falciparum has emerged in several East African countries neighbouring Madagascar. Despite the island's substantial malaria burden, recent data on artemisinin partial resistance are limited, raising concerns about the potential emergence of resistant parasites. This study provides an updated overview of the prevalence and diversity of P. falciparum Kelch13 (pfkelch13) polymorphisms in Madagascar. METHODS: During a nationally representative, cross-sectional survey conducted between January and May 2024, dried blood samples were collected from 4850 febrile patients at 65 health facilities. Pfkelch13 genotyping was performed using a targeted amplicon deep sequencing approach. RESULTS: Of the 1944 P. falciparum-positive samples, 963 (49.5%) pfkelch13 sequences were successfully obtained, and 885 (91.9%) corresponded to the 3D7 wild-type. Non-synonymous and synonymous mutations were detected in 1.8% (17/963) and 6.2% (60/963) of isolates, respectively, whereas one isolate (0.1%) carried double mutations. Of the 18 mutations identified, 5 had not been previously reported. The two most frequent polymorphisms in Madagascar were the synonymous mutations C469C (3.0%, 29/963) and P417P (2.8%, 27/963). None of the WHO-validated artemisinin partial resistance markers were detected. CONCLUSION: This study provides an updated baseline of pfkelch13 polymorphisms in Madagascar, with no evidence of artemisinin partial resistance emergence. Importantly, no parasites harbouring a validated artemisinin resistance marker were detected across the regions sampled, suggesting that resistant parasites have not yet become established. These findings provide a valuable baseline for future genomic surveillance efforts aimed at the early detection of mutations associated with artemisinin partial resistance.
BACKGROUND: Peritoneal dialysis (PD) enables intraperitoneal antibiotic delivery, but the efficacy of ceftazidime/avibactam (CAZ/AVI) in PD fluid (PDF) is not well-characterized. OBJECTIVES: To assess the in vitro activi...BACKGROUND: Peritoneal dialysis (PD) enables intraperitoneal antibiotic delivery, but the efficacy of ceftazidime/avibactam (CAZ/AVI) in PD fluid (PDF) is not well-characterized. OBJECTIVES: To assess the in vitro activity of ceftazidime/avibactam against Pseudomonas aeruginosa in fresh PDF and patient-derived dialysate at isolate-specific MIC levels and at a clinically measured intraperitoneal peak concentration (Cmax). METHODS: MICs were determined for P. aeruginosa ATCC 27583 and nine clinical isolates using broth microdilution in CAMHB. Two isolates (123/19, 174/19) underwent time-kill experiments at MIC (8-16 µg/mL) and maximum peritoneal concentration (Cmax 64 µg/mL), with avibactam fixed at 4 µg/mL. Bacterial counts were evaluated over 24 h in CAMHB, icodextrin-containing PDF, and patient-derived dialysate (n = 4). RESULTS: Isolates showed variable growth. Ceftazidime/avibactam was bactericidal in CAMHB but only bacteriostatic in PDF and patient-derived dialysate (±1 log10 cfu/mL reduction at 8 h). No further reduction occurred at 24 h, even at Cmax. CONCLUSIONS: Reduced bacterial growth in PDF is associated with diminished ceftazidime/avibactam activity, yielding primarily bacteriostatic effects. Single-dose intraperitoneal administration may be insufficient to eradicate P. aeruginosa, as Cmax concentrations failed to achieve ≥3 log10 cfu/mL reduction in vitro. These findings highlight potential limitations of ceftazidime/avibactam in PD-related infections and might guide future dosing strategies research.
BACKGROUND: Stenotrophomonas maltophilia complex infections are difficult to treat because of intrinsic resistance mediated by the L1 metallo-β-lactamase and L2 serine β-lactamase. Although aztreonam/avibactam is clinica...BACKGROUND: Stenotrophomonas maltophilia complex infections are difficult to treat because of intrinsic resistance mediated by the L1 metallo-β-lactamase and L2 serine β-lactamase. Although aztreonam/avibactam is clinically available, aztreonam combined with ceftazidime/avibactam remains an alternative, but comparative pharmacodynamic data under clinically relevant exposures are limited. We compared aztreonam/avibactam and aztreonam + ceftazidime/avibactam under prolonged human-simulated dosing. METHODS: Three clinical S. maltophilia complex isolates (17061, 17639 and 16852) were studied in 96-h hollow fibre infection models. Human-simulated aztreonam/avibactam and aztreonam + ceftazidime/avibactam regimens were administered as 3-h extended or continuous infusions at total daily aztreonam doses of 6 g or 8 g. blaL1 and blaL2 expression was quantified by RT-qPCR, and population pharmacokinetic modelling with Monte Carlo simulation (n = 1000) verified target exposures. RESULTS: At 6 g/day of aztreonam, neither aztreonam/avibactam nor aztreonam + ceftazidime/avibactam achieved sustained bactericidal activity; extended infusions failed to produce killing, and continuous infusion produced only transient bactericidal effects followed by regrowth. In contrast, continuous-infusion aztreonam/avibactam at 8 g/day produced rapid and durable bactericidal activity across all isolates through 96 h with stable minimum inhibitory concentrations (MICs), whereas aztreonam + ceftazidime/avibactam at the same dose achieved early killing followed by regrowth. Transcriptionally, aztreonam/avibactam limited or uncoupled blaL1 and blaL2 induction even at intensified dosing, while aztreonam + ceftazidime/avibactam more consistently promoted blaL1 up-regulation and greater β-lactamase variability. CONCLUSIONS: Under human-simulated conditions, only continuous-infusion aztreonam/avibactam with intensified aztreonam exposure (8 g/day) achieved durable bactericidal activity against S. maltophilia complex, whereas adding ceftazidime did not improve pharmacodynamic outcomes and was associated with greater β-lactamase induction.
BACKGROUND: Enterococcus faecalis isolates with a daptomycin minimum inhibitory concentration (MIC) of 4 mg/L are classified as intermediate by the Clinical and Laboratory Standards Institute (CLSI). There is limited evi...BACKGROUND: Enterococcus faecalis isolates with a daptomycin minimum inhibitory concentration (MIC) of 4 mg/L are classified as intermediate by the Clinical and Laboratory Standards Institute (CLSI). There is limited evidence to guide the use of high-dose daptomycin for these infections when alternative therapy options cannot be used. OBJECTIVES: To determine the rate of clinical failure of E. faecalis invasive infections with a daptomycin MIC of 4 mg/L treated with high-dose daptomycin or best alternative therapy (BAT). METHODS: This was a single-centre, retrospective, observational, cross-sectional study that compared high-dose daptomycin to BAT for invasive E. faecalis infections. High-dose daptomycin was defined as ≥8 mg/kg/dose. The primary outcome was clinical failure, a composite endpoint including switch from definitive to alternative therapy secondary to clinical decline, infection-related hospital readmission while on definitive treatment for the index infection, or infection-related mortality within 30 days of definitive therapy completion. High-dose daptomycin versus BAT groups were matched and compared in a 1:3 ratio based on initial source of the positive E. faecalis isolate. RESULTS: Of 112 patients included, 28 patients received daptomycin and 84 received BAT. There was no difference in the primary outcome of clinical failure between the daptomycin and BAT groups (7% versus 5%, P = 0.64). All-cause mortality was similar between the daptomycin and BAT groups (11% versus 10%, P = 1.00). CONCLUSIONS: There was no difference observed in clinical failure rates between patients treated with high-dose daptomycin versus BAT. All-cause mortality was also similar between the groups. Further studies are needed to confirm these findings in high-burden E. faecalis infections with intermediate daptomycin susceptibility.
OBJECTIVES: To develop a population pharmacokinetic (PopPK) model of eravacycline in critically ill patients with carbapenem-resistant Acinetobacter baumannii (CRAB) pneumonia, characterize its pharmacokinetic profile, a...OBJECTIVES: To develop a population pharmacokinetic (PopPK) model of eravacycline in critically ill patients with carbapenem-resistant Acinetobacter baumannii (CRAB) pneumonia, characterize its pharmacokinetic profile, and optimize dosing regimens to ensure adequate drug exposure in this vulnerable population. METHODS: The plasma concentration of eravacycline was determined using liquid chromatography-tandem mass spectrometry. PopPK analysis was performed using nonlinear mixed-effects modelling, and the optimal dosing regimen was optimized via Monte Carlo simulation. RESULTS: A total of 104 plasma samples were collected from 18 patients for eravacycline concentration determination. The final PopPK model was a two-compartment model with body weight as a significant covariate on peripheral volume of distribution (V2). The population typical values for CL, central volume of distribution (V1) and V2 in the final model were 14.4 L/h, 177.6 L and 383.2 L, respectively. Monte Carlo simulations demonstrated that the PK/PD target for eravacycline was achievable with a standard dose (1 mg/kg, Q12 h) at an MIC of 0.125 mg/L in patients weighing 41-80 kg. However, this fixed-dosing strategy was suboptimal at higher MICs. CONCLUSIONS: This study successfully developed the first PopPK model for eravacycline in critically ill patients with CRAB pneumonia. The findings highlight substantial pharmacokinetic variability and demonstrate that weight-based dosing is crucial to ensure effective exposure, underscoring the necessity of PK/PD-guided personalized therapy.
OBJECTIVES: Armed conflicts exacerbate the burden of antimicrobial resistance (AMR) by disrupting healthcare systems, driving the emergence and spread of multidrug-resistant organisms. Antimicrobial stewardship (AMS) is...OBJECTIVES: Armed conflicts exacerbate the burden of antimicrobial resistance (AMR) by disrupting healthcare systems, driving the emergence and spread of multidrug-resistant organisms. Antimicrobial stewardship (AMS) is a key strategy to optimize antimicrobial use and preserve treatment options, yet its feasibility during conflict remains underexplored. This study assessed the feasibility and impact of an AMS programme introduced in a civilian hospital within the trauma evacuation pathway in Ukraine during an active conflict. METHODS: Using a retrospective, quasi-experimental before-and-after cohort design, outcomes were assessed across antibiotic consumption, prescribing patterns by WHO AWaRe category, mean antibiotic cost per course and hospital length of stay. RESULTS: Total antibiotic consumption decreased significantly, driven by reductions in third- and fourth-generation cephalosporins and fluoroquinolones, but this occurred alongside an increase in carbapenem use, indicating redistribution of prescribing rather than uniform reduction across classes. AWaRe analysis showed increased Access prescribing and reduced Reserve use overall. Monthly antibiotic costs decreased by 40.5%, and the median length of stay fell by 20.7%. CONCLUSIONS: This study provides evidence that AMS can be implemented and sustained within a civilian hospital during active conflict, despite the operational challenges of war. Stewardship may optimize antimicrobial selection and costs, although reductions in total use occurred alongside increased reliance on carbapenems in response to local resistance pressures. These findings underscore the need to embed AMS as a core component of humanitarian health responses, while maintaining continuous surveillance to detect and mitigate emerging selective pressure for multidrug-resistant organisms associated with intensified antimicrobial use.
Wehbe E, Sreeharan T, Sutrave G
… +15 more, Bui J, Lau C, Park JY, Sandaradura I, Darley D, Macdonald P, Milliken S, Fung JN, Jones G, Kizny Gordon A, Kliman D, Lu CY, Marriott D, Alffenaar JC, Stocker SL
J Antimicrob Chemother
· 2026 May · PMID 42153394
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BACKGROUND AND OBJECTIVES: CYP2C19 phenotype is a known contributor to the interpatient variability in voriconazole response. Alternative therapy is recommended for ultrarapid/rapid and poor metabolizers due to increased...BACKGROUND AND OBJECTIVES: CYP2C19 phenotype is a known contributor to the interpatient variability in voriconazole response. Alternative therapy is recommended for ultrarapid/rapid and poor metabolizers due to increased probability of subtherapeutic exposure and side effects, respectively. We aimed to evaluate whether CYP2C19 phenotype is associated with switching from voriconazole to alternative antifungal therapy, in settings where genetic results were not available at the time prescribing decisions were made. METHODS: A multicentre, retrospective observational study was conducted in three Australian hospitals. Patients who had previously taken voriconazole (from 1 May 2019 to 31 May 2024) were invited to undergo pharmacogenomic testing. Medical records were audited to compare switching decisions across patients with different CYP2C19 phenotypes. Differences in voriconazole exposure and voriconazole-related adverse effects were also explored. RESULTS: Among 194 patients, most were normal or intermediate metabolizers (69%); 21% were rapid, 7% ultrarapid, and 3% poor metabolizers (underpowered). Switching to alternative antifungal therapy (32%; 62/194) mainly occurred due to adverse effect incidence and was not associated with CYP2C19 phenotype (P = 0.9041). C-reactive protein levels were significantly higher in patients who switched therapy (P < 0.001). All ultrarapid metabolizers on standard voriconazole 400 mg/day had subtherapeutic concentrations and only those on higher doses (500-1200 mg/day) achieved therapeutic concentrations. CONCLUSIONS: CYP2C19 phenotype was not predictive of switching, which is a multifactorial prescribing decision likely influenced by therapeutic drug monitoring, inflammation and clinical status. Our observations on voriconazole dosing and exposure support a complementary prescribing approach: pharmacogenomic testing to identify patients who require atypical voriconazole dosing regimens and subsequent therapeutic drug monitoring to guide dose adjustments.
OBJECTIVE: Cardiopulmonary bypass (CPB) alters the pharmacokinetics (PK) of antibiotics administered as surgical prophylaxis (SAP) due to haemodilution, circuit interactions, protein binding and inflammation. This study...OBJECTIVE: Cardiopulmonary bypass (CPB) alters the pharmacokinetics (PK) of antibiotics administered as surgical prophylaxis (SAP) due to haemodilution, circuit interactions, protein binding and inflammation. This study investigated plasma and interstitial fluid (ISF) concentrations of cefuroxime in patients undergoing on- versus off-pump coronary artery bypass graft (CABG) surgery. METHODS: Patients undergoing on- or off-pump CABG received SAP with cefuroxime, consisting of a bolus of 3 g before skin incision and a second dose of 1.5 g at CPB weaning or at sternal closure, respectively. ISF concentrations were measured by two microdialysis catheters in the subcutaneous tissue of both upper arms. Plasma and ISF concentrations were determined up to 8 hours after the first dose. Pharmacokinetic analysis was performed by non-compartmental analysis. RESULTS: Fifteen patients were enrolled per group. Baseline characteristics and cardiovascular risk profile were comparable between groups. Median [minimum; maximum] surgical duration was 4.3 h [3.1 h; 6.1 h] in the on-pump and 3.4 h [1.8 h; 4.0 h] in the off-pump group, with a median bypass time of 1.7 h [0.8 h; 2.5 h]. The ƒAUC0-8h in plasma (on-pump versus off-pump group; mean ± SD: 417 ± 124 versus 542 ± 238 h·mg/L, P = 0.081) and in ISF (488 ± 212 versus 508 ± 209 h·mg/L, P = 0.835) did not differ significantly. Based on an extrapolation of the first dose, plasma concentrations remained above a minimum inhibitory concentration of 8 mg/L for up to 4.5 h in the on-pump and 4.8 h in the off-pump group. CONCLUSION: For a median bypass time of 1.7 h and considering all factors cumulatively, no significant impact of CPB on cefuroxime plasma and ISF concentrations was observed. A dose of 3 g cefuroxime administered intravenously 30-60 min before skin incision with a second repetitive dose of 1.5 g administered after CPB weaning in the on-pump group or after sternal closure in the off-pump group, resulted in adequate plasma and ISF concentrations in patients undergoing cardiac bypass surgery.