Journal of Antimicrobial Chemotherapy

Long-acting cabotegravir and rilpivirine combination (LA-CAB/RPV) is approved for HIV treatment whilst long-acting cabotegravir alone (LA-CAB) is approved for HIV prevention, both in adults. However, individuals who become pregnant might prefer to discontinue it due to lack of definitive data on safety. The aim of this study was to characterise the tail-phase maternal and fetal pharmacokinetics of LA-CAB/RPV following discontinuation at steady-state early in pregnancy. A virtual population of non-pregnant women (n = 100 per scenario) initiated intramuscular injections of LA-CAB/RPV at the approved dosage and continued maintenance dose (400/600 mg once monthly or 600/900 mg once every two months) until steady state. We simulated discontinuation at steady state after only one injection during pregnancy. Tail-phase pharmacokinetics of CAB and RPV from LA injections were characterised during gestation and until 6 months postpartum. Pharmacokinetic tails of LA-CAB/RPV were driven by the residual drug in the muscle depot which stabilised at steady state and reduced steadily upon dosing discontinuation. Upon discontinuation of the monthly dosing, predicted median (IQR) maternal plasma concentrations for LA-CAB were 415 (386-448) ng/mL at delivery and 125 (115-139) ng/mL 6 months postpartum. For LA RPV, these were 11.6 (11.0-12.6) ng/mL and 7.84 (7.30-8.49) ng/mL at delivery and 6 months postpartum, respectively. Pharmacokinetic tails of LA-CAB/RPV extend to several months postpartum, with levels falling below established minimum effective concentration in most women after gestation week 33. Potential strategies to minimise potential risks associated with LA-CAB/RPV discontinuation in this population are needed.

BackgroundCefiderocol is a siderophore-conjugated cephalosporin antibiotic used to treat multi drug resistant Gram negative infections, including metallo-beta-lactamase producing Enterobacterales. Antimicrobial useage is guided by antimicrobial susceptibility testing (AST) which is hampered by differences between EUCAST and CLSI breakpoints, methodological challenges of AST, and lack of information on clinical outcome related to AST. ObjectivesThis study assessed the agreement between AST methods under EUCAST and CLSI breakpoints in a collection of 57 blaNDM producing Enterobacterales isolated from a UK hospital network. MethodsAll isolates, including Klebsiella pneumoniae, Enterobacter hormaechei, Escherichia coli and Citrobacter freundii, were whole-genome sequenced and tested with disk diffusion and MIC gradient test strip, and broth microdilution MICs were determined for a subset. Categorical agreement between methods was calculated using both EUCAST and CLSI breakpoints. Mutations and acquired resistance genes associated with cefiderocol resistance were identified and compared with AST results. ResultsThe disk diffusion method, based on EUCAST interpretation, classified 94.7% of isolates as cefiderocol resistant and 5.3% as susceptible, with 22.8% within the Area of Technical Uncertainty. The CLSI breakpoint classified one isolate as resistant (1.8%) and 5.26% intermediate. Category agreement of broth microdilution and disk diffusion for E. coli using EUCAST guidelines was 38.5%. Mutations associated with cefiderocol resistance were highly prevalent and varied between species. ConclusionsThe discordant EUCAST and CLSI breakpoint values provided have large impacts on the classification of isolates susceptibility to cefiderocol, which will impact global cefiderocol usage and surveillance of resistance, further complicated by poor agreement between AST methods.

Cefiderocol exhibits excellent in vitro activity against Pseudomonas aeruginosa; however, resistance can emerge. We investigated the molecular mechanisms underlying cefiderocol resistance (MIC >2 mg/L) in 103 clinical strains collected from 61 hospitals (2021-2024). MICs ranged from 4 to >128 mg/L, with 39.8% of strains showing MICs >8 mg/L. Although 37.8% were classified as difficult-to-treat resistant (DTR), acquired {beta}-lactamases were detected in 72.8% of strains, including carbapenemases (39.8%), mainly NDM-1 (29.1%), and Extended Spectrum {beta}-Lactamases (ESBLs) (38.8%). Cloning of 11 {beta}-lactamases into pUCP24, including the acquired cephalosporinase PAC-1 and ESBLs (VEB-1, and VEB-9), resulted in marked increases in cefiderocol MICs (up to 128-fold). Introduction of 6 mutations in the PDC enzyme into a PAO1{Delta}blaPDC-1 background increased MICs up to 4 mg/L and conferred cross-resistance to ceftolozane/tazobactam, notably F121L, G157D, T70I, and E219K. Alterations in siderophore transporters or regulators were identified in 38.8% of strains, most frequently a PirR frameshift (R132fs), consistent with PirR inactivation, which was confirmed in the PAO1 strain to contribute to cefiderocol resistance. Overall, cefiderocol resistance in clinical strains is multifactorial, mainly involving acquired {beta}-lactamases (ESBLs, carbapenemases) and impaired siderophore uptake (PiuA/PiuD, PirA, PiuC), leading to high-level resistance (>8 mg/L). The polyclonal distribution and diversity of mechanisms highlight the need for routine susceptibility testing and surveillance. Detection of NDM producers is critical, as cefiderocol should be used with caution in this context.

APC148 is a novel metallo-beta-lactamase inhibitor with broad activity against Ambler class B enzymes including NDM, VIM and IMP. It is being developed for patients with serious infections caused by multidrug-resistant Gram-negative bacteria. APC148 is combined with the broad-spectrum beta-lactam antibiotic meropenem and the serine-beta-lactamase inhibitor avibactam, which targets Ambler class A, C, and some class D (OXA-48-like) enzymes. In combination with meropenem and avibactam, APC148 demonstrated superior in vitro activity against a global, multidrug resistant collection of Enterobacterales, showing its promising activity against beta-lactamase producing pathogens. In this randomized, placebo-controlled, first-in-human study, the safety, tolerability and pharmacokinetics of APC148 were evaluated in healthy adults. Single doses ranging from 50 mg to 760 mg APC148 were administered intravenously over 3 h to 46 participants across six dose groups. APC148 was well tolerated at all dose levels. All adverse events were of mild intensity, and no serious adverse events or adverse events leading to study- or treatment discontinuation occurred. The pharmacokinetics of APC148 were dose-proportional with low plasma clearance, low to moderate volume of distribution and a mean plasma half-life of 2.6 h. APC148 is well tolerated in humans at therapeutically relevant doses and represents a promising candidate in the fight against antibiotic-resistant bacteria. (This study has been registered at ClinicalTrials.gov under registration number NCT06360640).

BackgroundHospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP), particularly those caused by multi-drug resistant organisms (MDROs), often require newer antibiotic treatment. The efficacy and safety of newer antibiotics compared to generic antibiotics in randomized controlled trials (RCTs) have not been evaluated before. MethodsIn this systematic review, we searched RCTs in the United States National Library of Medicine (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, Ovid MEDLINE, Clinical Trials.gov and Google Scholar databases published between 2013 and 2025. The primary efficacy endpoint was 28-day all-cause mortality. Secondary efficacy endpoints were clinical and microbiological response. Safety endpoint was nephrotoxicity. ResultsWe identified eight eligible RCTs involving 2,881 patients (1,450 patients treated with newer antibiotics and 1,431 patients treated with generic antibiotics) with HABP/VABP. The meta-analysis did not reveal any significant differences between newer and generic antibiotics for all-cause mortality at day 28 (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.72-1.30), clinical response (RR 1.04, 95%CI 0.93-1.17), and microbiological response (RR 1.05, 95%CI 0.89-1.24). However, newer antibiotics showed significant lower occurrences of nephrotoxicity compared to colistin component (RR 0.30, 95%CI 0.11-0.79). In subgroup analysis, newer antibiotic regimens demonstrated significant improvement in microbiological eradication of carbapenem-resistant Gram-negative bacilli (RR 1.50, 95%CI 1.18-1.90). ConclusionsNewer antibiotics showed similar efficacy and safety in treating HABP/VABP compared to generic drugs. The superiority in microbiological eradication of carbapenem-resistant Gram-negative bacilli of newer antibiotics could suggest that future trials should be targeted for those patients to improve understanding of their therapeutic use and pathophysiology of these conditions. Key pointsNewer antibiotics, despite broader antimicrobial coverage, have not significantly outperformed generic comparators in terms of 28-day all-cause mortality, clinical, or microbiological response in patients with Gram-negative HABP/VABP. This may reflect limitations in current trial designs focused primarily on regulatory approval.

ObjectivesMultidrug-resistant (MDR) Klebsiella pneumoniae is an increasingly important cause of recurrent urinary tract infections (UTIs), particularly in high-risk patients such as those with neurogenic bladder, where therapeutic options are limited. Bacteriophage therapy represents a promising alternative, but pre-clinical models and characterization of phages active against UTI-derived strains remain scarce. We therefore aimed to isolate and characterize bacteriophages targeting a clinical MDR K. pneumoniae strain causing recurrent UTI and evaluate their activity under urinary conditions. MethodsThree bacteriophages were isolated from environmental samples using an ESBL-producing K. pneumoniae clinical isolate obtained from a neurogenic bladder patient. Phages were characterized by genome sequencing, electron microscopy, stability assays, one-step growth curves, and host-range analysis across 79 clinical UTI isolates. Phage activity was quantified in LB medium and human urine using bacterial growth kinetics and a lytic activity score. ResultsThree lytic phages from the former siphoviridae family (EDIRA083, EDIRA088, and EDIRA092) belonging to distinct genera were identified. Genomic analysis confirmed the absence of lysogeny-associated, virulence, or antibiotic-resistance genes. Latent periods ranged from 8 to 40 minutes and burst sizes from 38 to 170 virions per infected bacterium. Host-range analysis revealed narrow activity for EDIRA083 and EDIRA088, whereas EDIRA092 infected 29% of the 79 clinical isolates tested. In liquid phage infection assays, overall lytic activity was consistently higher and more sustained in human urine than in LB, suggesting reduced fitness of resistant mutants under urinary conditions. ConclusionsThese results identify three genetically distinct lytic phages targeting MDR K. pneumoniae and highlight the importance of testing phage activity under infection-relevant conditions. Their activity in urine supports further evaluation of these phages as candidates for therapeutic development against MDR Klebsiella UTI.

In this study we explored phenotypic resistance using traditional Kirby-Bauer methods in human and animal derived Campylobacter isolates that were concurrently resistant to both azithromycin and ciprofloxacin to an expanded panel of antimicrobials, including clindamycin, fosfomycin, ampicillin sulbactam and tigecycline. Out of 236 Campylobacter isolates, over 85% of C. jejuni and C. coli were resistant to clindamycin, over 60% were resistant to ampicillin sulbactam and over 30% to fosfomycin. Less than 2% of isolates were resistant to tigecycline and there was no observed resistance to Imipenem.

Urinary tract infections (UTIs) are among the most common infectious diseases worldwide, with Escherichia coli being the predominant uropathogen. The increasing prevalence of extended-spectrum beta-lactamase (ESBL)-producing strains and their association with fluoroquinolone resistance pose a significant challenge to empirical therapy, particularly in community settings. The aim of this study was to determine the epidemiology and predictive factors associated with ESBL-producing E. coli and its concomitant fluoroquinolone resistance in community-acquired clinical isolates. A retrospective cross-sectional study was conducted analyzing 244 clinical E. coli isolates. Demographic and microbiological data were collected, including age, sex, sample type, and antibiotic susceptibility. Associations between variables and ESBL production were assessed using Pearsons chi-squared test, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Of the isolates, 165 (68%) were ESBL-producing. A significant association was observed between age group and ESBL production (p < 0.001), with the highest frequency in the 20-39 age group. Most ESBL-positive isolates were obtained from women (73%), although odds ratio (OR) analysis suggested a non-significant trend toward a higher probability in men (OR = 1.29; 95% CI: 0.72-2.31). High rates of fluoroquinolone resistance were identified among the ESBL-producing isolates, with 30% resistance to levofloxacin and 35% to ciprofloxacin (p < 0.001). Urine samples showed the highest concentration of ESBL-positive isolates, with a significant association between sample type and resistance (p < 0.001). The high prevalence of ESBL-producing E. coli and its concomitant resistance to fluoroquinolones highlight a critical challenge for the empirical treatment of urinary tract infections in Mexico, underscoring the need to strengthen antimicrobial use management and local surveillance strategies.

BackgroundCampylobacter is a major food-borne pathogen causing diarrhea. In severe cases, treatment typically involves fluoroquinolones (FQ) and macrolides. However, high proportions of FQ resistance (FQR) have made macrolides the remaining first-line treatment option. As part of the Campylobacter surveillance program in Germany, we investigated multidrug resistance (MDR) in clinical Campylobacter samples collected 2010 to 2022. MethodsA total of 6,980 samples was single-colony purified and analyzed for antimicrobial resistance phenotypes. Genome sequencing was performed for 2,912 samples, and antimicrobial resistance genes were mapped. Cultures showing MDR were further analyzed for contaminating DNA and studied using scanning electron microscopy (SEM). FindingsWe found that 453 (6%) Campylobacter samples were resistant to both FQ and macrolides. Two of the C. jejuni samples were resistant to antibiotics from ten different classes. Genome analysis revealed that these samples, despite being derived from single colonies, contained >10% Enterococcus DNA reads. SEM confirmed the presence of coccoid bacteria interspersed with spiral-shaped Campylobacter. Additional culture-based purification resulted in pure C. jejuni isolates that retained FQR but lost macrolide resistance. We further showed that presence of MDR Enterococcus spp. in the mixed samples protected C. jejuni from above-MIC (minimum inhibitory concentration) of several ribosome-targeting antimicrobials whereas pure Campylobacter were susceptible. These findings revealed that Campylobacter may gain antimicrobial resistance advantages through close interactions with Enterococcus spp. InterpretationMDR phenotypes in Campylobacter cultures may arise through close, dual-species interactions with other highly resistant intestinal bacteria, such as MDR Enterococcus spp. and may have practical implications for antibiotic treatment. FundingThis study was funded by the German Ministry of Health dedicated to the National Reference Centre for Salmonella and other Bacterial Enteric Pathogens.

Klebsiella pneumoniae ST383 has emerged as a high-risk clone, characterized by carbapenem resistance and increasing detection of hypervirulence determinants. We describe a novel ST383 lineage in Lebanon, defined by the acquisition of ICEKp5, which carries the yersiniabactin locus. Three ST383 K. pneumoniae clinical isolates (LBN_CAKp91, LBN_CTKp3, LBN_CTKp11) recovered from a Lebanese medical center were subjected to whole-genome sequencing. Comparative genomic analysis included regional ST383 strains and previously characterized Lebanese isolates. The study isolates formed a tight, monophyletic cluster (3-9 SNPs) that is phylogenetically distinct from the previously reported Lebanese ST383 clone (>164 SNPs) and grouped most closely to an Egyptian ST383 strain (59-65 SNPs). All three isolates carried ICEKp5 with yersiniabactin lineage ybt14, a feature absent in the earlier Lebanese ST383 clone. The isolates were the only ST383 strains to harbor the full spectrum of hypervirulence determinants to date, including capsule regulators (rmpA, rmpA2), aerobactin (iucABCD, iutA), yersiniabactin, and the hypervirulence biomarker peg-344. All isolates carried dual carbapenemases (blaOXA-48 and blaNDM-5) in addition to blaCTX-M-15 and blaCTX-M-14b. The genetic environments of blaOXA-48 and blaNDM-5 were highly conserved across geographically diverse ST383 isolates, indicating common plasmid origins. This study documents the emergence of a novel hypervirulent extensively drug-resistant (XDR) ST383 K. pneumoniae lineage in Lebanon. The acquisition of ICEKp5, combined with plasmid-borne hypervirulence and resistance determinants, reveals the concerning convergence of hypervirulence and XDR. Enhanced surveillance and infection control measures are urgently needed to monitor this emerging high-risk clone.

ObjectivesTo quantify how urine sample type and polymicrobial context impact antimicrobial resistance (AMR) in urinary tract infections (UTIs), using routine diagnostics at scale. MethodsIn this retrospective, single-centre study, we analysed 188,687 urine cultures from the Institute of Medical Microbiology, University of Zurich, Switzerland (January 2015 to May 2023). We compared midstream urine (MU), indwelling catheter (IDC), and intermittent catheter (IMC) samples. Samples were classified as negative, bacteriuria, or UTI, by meeting a microbiological UTI threshold ([&ge;]105 CFU/mL). We compared sample types using covariate-adjusted regression and constrained ordination for community composition. In bimicrobial cultures, we assessed co-occurrence using adjusted pairwise odds ratios and degree-preserving permutation null models, supported by partner-choice analyses. AMR was modelled as acquired resistance (AR) and total resistance (TR: acquired + intrinsic) probabilities, with predictor contributions quantified using mutual information. ResultsAmong 186,819 MU, IMC, IDC samples, 56,867 met the UTI threshold. Catheter-associated UTIs (IDC and IMC) were ~60% more likely to be polymicrobial than MU samples. Community composition differed by sample type (p<0{middle dot}001). In IDC, Escherichia coli was less prevalent than in MU, but device-associated pathogens like Pseudomonas aeruginosa and Candida albicans were enriched. Most species-pairs showed no increased co-occurrence after adjusting for covariates, but a subset showed reproducible enrichment across methods (e.g., C. albicans-C. glabrata). Organism identity was the dominant determinant of AMR, with the highest mutual information across AR and TR. AR was higher in IDC for common uropathogens (e.g., E. coli). Co-isolation with hospital-associated partners (e.g., Enterococcus faecium) was associated with further AR increase. From 2015 to 2023, AR increased from ~48% to ~60%, with rising {beta}-lactam (+{beta}-lactamase inhibitor) resistance and declining fluoroquinolone resistance in Enterobacterales. ConclusionsSample type and co-isolated partners provide clinically actionable information beyond pathogen identity and could support more context-aware reporting and empiric prescribing.

The global dissemination of Enterobacterales producing both metallo-{beta}-lactamases (MBLs) and serine {beta}-lactamases (SBLs) represents a critical threat to modern medicine, as no currently marketed antibiotics effectively target MBL-mediated resistance. APC148 is a novel, selective zinc-chelating MBL inhibitor designed to restore {beta}-lactam activity in MBL positive isolates, when used in combination with a broad-spectrum carbapenem. In this study, we evaluated the in vitro efficacy of APC148 in triple combinations with either meropenem-avibactam (APC301) or cefepime-avibactam (APC302) against a diverse global collection (JMI collection) of 176 MBL- and SBL-producing Enterobacterales isolates (including NDM, VIM, and IMP variants). Using broth microdilution, the triple combinations were compared against several newly approved and late-stage pipeline antibiotic products. Both APC301 and APC302 demonstrated superior potency, achieving a MIC90 of 0.12 {micro}g/mL. When applying CLSI breakpoint interpretive criteria for the parent {beta}-lactams, 99.4% of the MBL and SBL-containing isolates were susceptible to APC301, while 97.2% were susceptible to APC302. These results indicate that the addition of a selective MBL inhibitor to an SBL-inhibitor/{beta}-lactam antibiotic effectively bypasses complex co-existing {beta}-lactam resistance mechanisms in multidrug-resistant (MDR) pathogens. Given that MDR Enterobacterales frequently harbor multiple {beta}-lactamase classes simultaneously, these triple combinations constitute a highly promising clinical strategy to address the therapeutic void in MBL-mediated resistance

ObjectiveThe rapid availability of phenotypic antimicrobial susceptibility results is crucial for the timely detection of multidrug-resistant Gram-negative organisms and for guiding optimized treatment strategies. Recently, novel methods have been introduced that enable direct antimicrobial susceptibility testing (AST) from positive blood cultures. However, their performance has not yet been systematically compared in head-to-head evaluations. This study aimed to assess the analytical performance of two rapid AST approaches--the agar diffusion-based EUCAST rapid AST (RAST) method and the automated QuickMIC system--using a challenging collection of highly resistant Gram-negative organisms. MethodsA total of 101 Gram-negative bacteria (Escherichia coli, n = 24; Klebsiella pneumoniae, n = 22; Acinetobacter baumannii, n = 30; Pseudomonas aeruginosa, n = 25) were spiked into blood cultures and processed according to the respective AST workflows. Broth microdilution (BMD) was performed from pure cultures as the reference method. Time to result (TTR), categorical agreement (CA), and essential agreement (EA) with BMD were evaluated. Boruta analysis was applied to identify genetic determinants associated with AST errors. ResultsOverall TTR for QuickMIC was 3 h 44 min with a CA of 86.2%, an EA of 92.3 % for Enterobacteriaceae and 97.0 % for non-fermenters. Overall CA of RAST ranged from 90.7%-93.7% across reading time points. Overall, very major discrepancy rates were low (QuickMIC n=0.7%, RAST n=0.1%). Presence of NDM-5 and KPC was most frequently associated with errors for QuickMIC and EUCAST RAST, respectively. ConclusionsBoth rapid AST approaches yielded robust results in this diverse and highly resistant bacterial study population, directly from positive blood cultures, with a short turnaround time. These findings underscore the potential of rapid AST methods to facilitate timely optimization of antimicrobial therapy in bloodstream infections, even in the context of extensively drug-resistant pathogens. ImportanceAccurate antimicrobial susceptibility testing (AST) is essential for stewardship and effective therapy, especially as rising antimicrobial resistance increases the risk of empiric treatment failure. Traditional AST methods are limited by slow turnaround times, creating a need for rapid alternatives. This study evaluated the diagnostic accuracy of two rapid AST methods--EUCAST RAST and QuickMIC--using 101 genetically characterized, carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii tested directly from positive blood cultures. Broth microdilution served as the reference. Both rapid assays provided results within 3.5-6 hours and demonstrated high categorical and essential agreement with few very major discrepancies. Incorrect results were more common in isolates harboring NDM-5 and KPC carbapenemases. Overall, the findings support EUCAST RAST and QuickMIC as reliable tools for challenging resistant pathogens and highlight their potential to enable earlier detection of carbapenem-resistant phenotypes and more timely initiation of appropriate, last-resort antimicrobial therapy.

BackgroundPreoperative biliary stenting alters biliary colonization and may reduce the effectiveness of perioperative antibiotic prophylaxis in pancreatoduodenectomy. Although broader-spectrum regimens have been associated with improved infectious outcomes, their microbiological adequacy in routine clinical practice remains poorly defined. We therefore evaluated the real-world adequacy of a prolonged ampicillin-sulbactam protocol, its association with infectious outcomes and survival, and the potential impact of a universal piperacillin-tazobactam strategy. MethodsWe analyzed all consecutive patients who underwent elective pancreatoduodenectomy from 2002 to 2023 at our tertiary center. Demographic, operative, microbiological, and outcome data were retrieved from a prospectively maintained database. Patients were stratified by stent status. Adequacy of prophylaxis was defined as the full in vitro susceptibility of all bile isolates. The outcomes included 30-day infectious morbidity, clinically relevant POPF, PPH, DGE, reoperation, 30- and 90-day mortality and long-term survival. A coverage simulation was performed to compare ampicillin-sulbactam with a hypothetical universal piperacillin-tazobactam. Statistical methods included chi-square/Fishers exact tests, Mann-Whitney U tests, Cox models, McNemars test and Poisson regression. ResultsOf 956 patients, 424 (44%) had a biliary stent. Technical complications were comparable between groups, and rates of POPF and PPH were not increased. However, infectious morbidity was higher in stented patients, including sepsis (RR 1.62, 95% CI 1.05-2.51) and postoperative cholangitis (RR 2.20, 95% CI 1.36-3.56). Thirty- and 90-day mortality were increased (RR 2.88 and 2.73) but lost significance after adjustment. Bile cultures predominantly yielded Enterococcus and Enterobacterales with low ampicillin-sulbactam susceptibility. Overall adequacy was 21.7%. Among patients with bile cultures (n = 474), ampicillin-sulbactam covered 43.7% (207/474) versus 81.2% (385/474) with piperacillin-tazobactam; in stented patients with cultures (n = 397), coverage increased from 41.8% to 78.1%. Adequate ampicillin-sulbactam coverage was not associated with reduced infectious outcomes in Poisson models. ConclusionPreoperative stenting creates a polymicrobial, partially resistant biliary niche that ampicillin-sulbactam does not sufficiently cover. Our data shows that a piperacillin-tazobactam strategy substantially improves coverage and was therefore implemented at our center. Core message- Stented patients exhibit a distinct infectious risk profile characterized by Enterococcus-and Enterobacterales-dominated bile colonization rather than increased rates of technical complications. - In stented patients, real-world microbiological coverage of ampicillin-sulbactam was limited, and in vitro susceptibility did not independently translate into reduced postoperative infectious morbidity. - Broader prophylaxis, such as piperacillin/tazobactam, aligns with the actual flora and nearly doubles theoretical coverage, addressing the mismatch between stent-associated biofilms and narrow regimens.

Objectives: Optimising parenteral antimicrobial use is central to antimicrobial resistance (AMR) control, yet its appropriateness is difficult to assess. We aimed to develop a quantitative indicator to evaluate the appropriateness of parenteral antimicrobial therapy in hospitalised patients with bloodstream infections. Methods: We developed the Susceptibility-Spectrum Discrepancy Index (S2DI), reflecting the discrepancy between antimicrobial susceptibility of blood culture isolates and the spectrum width of prescribed agents. Using a database from 67 National Hospital Organization hospitals in Japan, we identified patients with Staphylococcus aureus or Escherichia coli bacteraemia from 2017 to 2023. An expert panel of 10 infectious disease physicians independently ranked antimicrobial susceptibility (A) and spectrum width of commonly used agents (B). S2DI was defined as B minus A on day 7 after treatment initiation, with values closer to zero indicating more appropriate therapy. S2DI was calculated for individual cases, aggregated at the hospital level, and analysed using linear mixed-effects models with hospital-level random effects. Results: A total of 4,505 S. aureus and 9,563 E. coli bacteraemia cases were included. Median S2DI was 1 (IQR 0-1) for S. aureus and 2 (IQR 0-3) for E. coli. For both pathogens, later calendar years were significantly associated with more favourable S2DI, suggesting gradual improvement in antimicrobial use. In E. coli bacteraemia, female sex and younger age were also associated with more appropriate therapy. Conclusions: Although variation across hospitals persists, appropriateness of parenteral antimicrobial use has improved over time. S2DI is a simple metric that may support optimisation of antimicrobial use.

BACKGROUNDAutomated antimicrobial susceptibility testing (AST) systems are crucial for accurate, timely detection of drug-resistant microbial isolates. This meta-analysis assessed the performance of the BD Phoenix ("Phoenix", BD Diagnostic Solutions), Vitek(R) 2 ("Vitek 2", bioMerieux), and DxM MicroScan WalkAway ("MicroScan", Beckman Coulter, Inc.) AST systems relative to common reference methodology. METHODSA systematic literature search in Ovid (MEDLINE and Embase) yielded 275 unique (not duplicated) records, with 44 additional records retrieved from handsearching; 39 studies met inclusion criteria. Categorical agreement (CA), essential agreement (EA), very major errors (VMEs), and major errors (MEs) for the three instruments were compared to a common reference method. Ratios of proportions were analyzed using random-effect meta-regression. RESULTSThe instruments did not differ significantly in CA, EA, or ME. Vitek 2 showed a higher overall VME rate than Phoenix ([~]44% higher; Vitek 2-to-Phoenix ratio = 1.44; p=0.062 [approaching significance]) and MicroScan (74% higher; ratio = 1.74; p=0.045). No appreciable difference was observed for VME between Phoenix and MicroScan. Subgroup analyses should be interpreted cautiously due to limited overall significance indicating varying performance across systems. Vitek 2 generally had higher relative VMEs for gram-negative organisms and lower relative VMEs for gram-positive organisms, whereas Phoenix showed the opposite pattern. MicroScan had relatively low VMEs when stratified by Clinical and Laboratory Standards Institute (CLSI) criteria; no differences in VMEs were observed using European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. CONCLUSIONAlthough some VME differences were noted, overall performance of the three systems was comparable. Organism- and drug-specific VME patterns--and updates to CLSI criteria over time--highlight the importance of continued monitoring of current breakpoints for all three instruments.

Many studies have identified antibiotic resistant (ABR) Escherichia coli on meat. Appropriate hand hygiene and cooking practices should minimise the risk of gastrointestinal colonisation with ABR E. coli found on meat, and the subsequent chance of causing resistant opportunistic extraintestinal infection. There are large gaps in our understanding of the prevalence, origins and zoonotic potential of ABR E. coli found on meat, however, and particularly for meat reared in extensive farming systems. Wales is a devolved nation within the United Kingdom having large populations of extensively-reared sheep and beef cattle. To help address knowledge gaps around ABR E. coli on extensively reared meat, therefore, beef mince and lamb loin/leg steaks/chops were purchased from 50 (beef) and 46 (lamb) independent butchers across Wales. Following enrichment culture, 200 g meat samples were found to be positive for E. coli resistant to amoxicillin (31% positivity), streptomycin (28%), spectinomycin (29%), amoxicillin-clavulanate (11%), 3rd generation cephalosporins (2%) and fluoroquinolones (5%). Phylogenetic analysis confirmed that Welsh lamb meat ABR E. coli isolates (n=79) are more closely related to those found in faecal samples collected around sheep (n=352) than around beef cattle (n=361) on Welsh farms. This suggests that faecal contamination at or around slaughter is their primary origin. We found no closely related meat/infection clones (<20 SNPs distant and the same antibiotic resistance genes) when comparing ABR E. coli from Welsh meat (n=92) and those causing extraintestinal infections in people (n=2387) in an English region bordering Wales. We conclude, therefore, that the wider zoonotic implications of finding ABR E coli on beef and lamb meat sold at independent butchers in Wales are small.

Objectives: To identifiy risk factors for antimicrobial resistance (AMR) in seven pathogen-antimicrobial combinations in patients with cancer and cancer survivors. Methods: Using data from patients with recent or past cancer diagnostic codes in Oxfordshire, UK, we examined associations between 22 potential risk-factors and AMR in blood culture isolates, collected between 1-April-2015 and 31-March-2025. Results: Among 5,975 bacteraemias in 4,365 adults, we analysed 3,141 (52.6%) due to Enterobacterales and 620 (10.4%) due to Enterococcus faecalis/faecium in 2,752 patients. Fourteen risk-factors for antimicrobial-resistant bacteraemia were identified, varying across pathogen-antimicrobial combinations. Compared with no previous antimicrobial susceptibility test result, prior resistance to the same antibiotic in any culture in the last year was strongly associated with AMR across all pathogen-antimicrobial combinations (all p<=0.001). Prior antibiotic exposure and younger age were also positively associated with AMR in four and five combinations, respectively. Cancer type showed modest effects; lymphoid/haematopoietic malignancies were associated with higher odds (vs colorectal cancer) of trimethoprim-sulfamethoxazole-resistant Enterobacterales (aOR=2.07 95%CI 1.40-3.06) and vancomycin-resistant Enterococcus bacteraemia (aOR=6.68, 1.21-36.91). Conclusions: Previous resistance was the greatest risk factor for bacteraemia with AMR in cancer patients and survivors, with prior antibiotic exposure and age also contributing. Lymphoid/haematopoietic malignancies increased risk of resistance to specific antimicrobials. Keywords: antimicrobial resistance, bacteraemia, cancer, risk factors

WHO recommends bedaquiline-pretomanid-linezolid- (BPaL) and BPaL-moxifloxacin (BPaLM) for treatment of rifampicin-resistant tuberculosis, informed by the TB-PRACTECAL results. However, clinical explanatory data of these drugs exposure and Mycobacterium tuberculosis clearance rates and toxicity relationships remain understudied. We therefore investigated the relationship between the patients exposure to anti-TB drugs in TB-PRACTECAL trial investigational regimens and their treatment outcomes. PRACTECAL-PKPD was a prospective pharmacokinetics and pharmacodynamics study nested in TB-PRACTECAL. Patients with rifampicin-resistant pulmonary tuberculosis were enrolled from Belarus and South Africa. The first objective was to develop drug exposure metrics for bedaquiline, pretomanid, linezolid, moxifloxacin and clofazimine. The efficacy objectives were to establish an exposure-response model for each drug and regimen to both bactericidal activity and long-term treatment outcomes. The safety objective was to investigate the exposure-toxicity relationship of each drug. Antimicrobial exposure did not correlate with the speed of sputum bacterial clearance, however there was a 20% increased bacillary killing rate with BPaLM compared to the standard of care arm whilst BPaL and BPaL-clofazimine (BPaLC) displayed a 15% decreased bacillary killing rate compared to the standard of care arm. Linezolid plasma exposure was higher amongst patients with anaemia or neutropenia compared to those without. No other exposure-toxicity relationships were identified for all other drugs. Absence of correlation between drug exposure and bacillary clearance suggest that the dosages used achieve saturation of bacillary killing, while remaining safe.

The rise of multidrug-resistant (MDR) bacteria, particularly carbapenem-resistant Enterobacterales (CRE), poses a significant threat to public health. Infections caused by CRE, such as Escherichia coli and Klebsiella pneumoniae, are associated with high rates of antibiotic treatment failure. {beta}-lactam antibiotics, like meropenem, remain crucial in treating these infections, but their efficacy is undermined by {beta}-lactamase production. This study investigates the potential of APC24-7, a novel broad-spectrum {beta}-lactamase inhibitor (BLi) with dual activity, to restore antimicrobial activity of meropenem against CRE clinical isolates. The in-vitro analysis of a diverse panel of clinically relevant E. coli and K. pneumoniae isolates expressing both serine- and metallo-{beta}-lactamases demonstrated that APC24-7 effectively restored meropenem activity by reducing the minimum inhibitory concentrations (MICs) to below breakpoint. Time-kill assays confirmed that the combination therapy showed dose-dependent bacterial killing, with significant potentiation of meropenem activity against isolates expressing both serine- and metallo-{beta}-lactamases. In-vivo efficacy evaluation in a murine thigh infection model further confirmed APC24-7s potential to restore meropenem efficacy against meropenem resistant strains. These findings suggest that APC24-7offers a promising strategy to combat infections caused by {beta}-lactamase-producing Enterobacterales.