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Research Medical Journal of Antimicrobial Chemotherapy - current issue
<span class="paragraphSection"><div class="boxTitle">Abstract</div>Gonorrhoea constitutes a global public health threat. Although a range of antibiotics have been available to treat gonococcal infections for more than 80 years, <span style="font-style:italic;">Neisseria gonorrhoeae</span> has shown remarkable versatility in its ability to develop resistance to successive classes of drugs. As a result, national and international treatment guidelines have had to be regularly updated to take account of increases in the prevalence of gonococcal strains resistant to recommended antibiotics. Even when particular antibiotics are no longer empirically used to treat gonorrhoea, <span style="font-style:italic;">N. gonorrhoeae</span> often retains resistance, with strains becoming MDR over time. Future efforts to ensure gonorrhoea remains a treatable infection will require a multidisciplinary global approach including efforts to provide widely available and affordable diagnostic testing, robust international surveillance of resistance, and the development of new antibiotics coupled with enhanced antimicrobial stewardship to ensure optimal use of both new and older antimicrobial agents.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Objectives</div>This study aimed to gain a better understanding of how resistance determinants in <span style="font-style:italic;">Salmonella</span> and <span style="font-style:italic;">Campylobacter</span> contribute to 14-, 15- and 16-membered ring macrolide resistance phenotypes.<div class="boxTitle">Methods</div>A total of 126 azithromycin-resistant (Azi<sup>R</sup>) and -susceptible (Azi<sup>S</sup>) [<span style="font-style:italic;">Salmonella</span> (<span style="font-style:italic;">n</span> = 45) and <span style="font-style:italic;">Campylobacter</span> (<span style="font-style:italic;">n</span> = 81)] isolates were selected for antimicrobial susceptibility testing (AST) and WGS.<div class="boxTitle">Results</div>Seven functional macrolide resistance determinants, including <span style="font-style:italic;">erm</span>(42), <span style="font-style:italic;">mef</span>(C), <span style="font-style:italic;">mph</span>(A), <span style="font-style:italic;">mph</span>(E), <span style="font-style:italic;">mph</span>(G), <span style="font-style:italic;">msr</span>(E) and one point mutation (<span style="font-style:italic;">acrB</span>_R717L) were previously identified in Azi<sup>R</sup><span style="font-style:italic;">Salmonella</span>. These determinants resulted in an 8- and 16-fold 15-membered ring gamithromycin and azithromycin MIC<sub>50</sub> increase, respectively, compared with Azi<sup>S</sup> isolates, with a maximum MIC increase of up to 256. The same isolates also exhibited up to a 32-fold 14-membered ring erythromycin MIC<sub>50</sub> increase. <span style="font-style:italic;">Salmonella</span> with <span style="font-style:italic;">erm</span>(42) or <span style="font-style:italic;">acrB</span>_R717L showed up to 128-fold 16-membered ring macrolide tildipirosin MIC increase, compared with isolates that were susceptible or carrying other macrolide resistance genes. In <span style="font-style:italic;">Campylobacter</span>, all Azi<sup>R</sup> isolates had an MIC<sub>50</sub> ranging from 32 to 4096 mg/L of the various membered ring macrolides, whereases all susceptible <span style="font-style:italic;">Campylobacter</span> isolates had significantly lower MIC<sub>50</sub> values, ranging from 0.25 to 4 mg/L. The MIC<sub>50</sub> of the various ring macrolides for Azi<sup>R</sup><span style="font-style:italic;">Campylobacter</span> isolates was 16- to 4096-fold higher when compared with Azi<sup>S</sup><span style="font-style:italic;">Campylobacter</span>.<div class="boxTitle">Conclusions</div>Our study has revealed that the function of macrolide resistance genes in <span style="font-style:italic;">Salmonella</span> can be associated with specific macrolide ring structures, whereas the single 23S rRNA mutation in <span style="font-style:italic;">Campylobacter</span> results in significantly elevated MICs of all macrolides. for the various ring macrolides.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>Determining the optimal antibiotic (ATB) dosage in septic critically ill patients on continuous renal replacement therapy (CRRT) is still challenging. CRRT further disrupts antibiotic P<sub>K</sub>, already altered by sepsis-induced fluid shifts, volume of distribution (V<sub>D</sub>) changes and half-life modifications.<div class="boxTitle">Materials and methods</div>Our multi-disciplinary team—comprising an intensivist, nephrologist and clinical pharmacologist—conducted a prospective observational cohort study to evaluate the extent of ATB removal by CRRT and to assess the pharmacokinetic/pharmacodynamic (P<sub>K</sub>/P<sub>D</sub>) parameters of the most commonly used antibiotics for treating severe infections.<div class="boxTitle">Results</div>A total of 135 ATB therapeutic drug monitoring (TDM) assessments were conducted, measuring total drug concentrations (C) in both plasma (P) and ultrafiltrate in 85 septic patients undergoing CRRT. A high sieving coefficient (∼75%) was recorded for all antibiotics, with CRRT-related drug loss described by the following equations: (i) [C<sub>UF-ATB</sub>]<sub>(trough level)</sub> = 0.77 × [C<sub>P-ATB</sub>]<sub>(trough level)</sub> + 0.93 ng/mL; (ii) [C<sub>UF-ATB</sub>]<sub>(peak)</sub> = 0.77 × [C<sub>P-ATB</sub>]<sub>(peak)</sub> + 3.1 ng/mL. The V<sub>D</sub> exhibited wide variability, with values exceeding those reported in the literature. Lower ATB molecular weight and steric hindrance were associated with a higher elimination rate constant (K<sub>e</sub><sup>min⁻¹</sup>). ATB TDM consistently correlated with AUC and AUC/MIC, ensuring effective bactericidal activity.<div class="boxTitle">Conclusions</div>Despite its limitations, our study suggests to carry out a loading dose for the main antibiotics and consider the daily drug loss, as identified by the linear regression equation, along with daily TDM to guide further dosing adjustments.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Introduction</div>BTZ-043 is a first-in-class benzothiazinone for the treatment of TB with demonstrated early bactericidal activity. BTZ-043 is metabolized into two major metabolites: M1 and M2. The aim of this study was to characterize the pharmacokinetics (PK) and early exposure–response (pharmacokinetic/pharmacodynamic, PK/PD) relationship for BTZ-043.<div class="boxTitle">Methods</div>A population PK/PD model for BTZ-043 and its metabolites was developed using data from a sequential Phase 1b/2a, randomized, controlled clinical trial in participants with pulmonary TB. BTZ-043 was administered in daily doses ranging from 250 to 1750 mg over 14 days. The decrease in bacterial load was determined by culture of sputum samples to quantify cfu on solid medium, and time to positivity in liquid medium.<div class="boxTitle">Results</div>In total, 77 participants received the experimental treatment. PK were best described by two-compartment disposition models for BTZ-043 and M2, and a one-compartment disposition model for M1. When given without food, the bioavailability was 54% (95% CI: 43%–65%) lower than with food. The decrease in bacterial load was described by a bilinear model with estimated node at 48 h. Participants in the highest dose group in Stage 2 (1000 mg) had a 2-fold faster decrease in mycobacterial load during the initial 2 days compared with participants in the lowest dose group (250 mg), driven by an E<sub>max</sub> relationship to the BTZ-043<sub>total</sub> exposure (BTZ-043 + M2).<div class="boxTitle">Conclusions</div>We characterized the population PK/PD of BTZ-043 in trial participants with pulmonary TB. An exposure–response relationship was only apparent for the first 2 days on treatment, indicating the need for further dose-finding studies.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>Valaciclovir is frequently prescribed for cytomegalovirus infection prophylaxis. Its major metabolite 9-carboxymethoxymethylguanine (9-CMMG), when accumulated in renally impaired patients, is neurotoxic. Its synthesis involves enzymes that could be impacted in liver transplant recipients. This retrospective study aimed to describe the pharmacokinetic (PK) and safety profile of aciclovir and 9-CMMG early after liver transplantation in patients receiving valaciclovir prophylaxis.<div class="boxTitle">Methods</div>Consecutive (ideally five) blood samples were drawn. Plasma concentrations of aciclovir/9-CMMG were quantified by UPLC-MS/MS. Medical data were collected from digital records. A joint population PK model for aciclovir/9-CMMG was developed (Monolix 2023R1). Monte Carlo simulations were used to estimate <span style="font-style:italic;">C</span><sub>min</sub> and AUC<sub>0–24</sub>.<div class="boxTitle">Results</div>Fifty patients (21 women) in the postoperative phase of liver transplantation were enrolled, with median age of 56.0 years and median weight of 69.5 kg; 255 samples were collected 19.0 days after transplantation. No drug–drug interaction was reported. A one-compartment model with first-order absorption best described the pharmacokinetics (PK). Covariate analysis showed that aciclovir and 9-CMMG clearances correlated with estimated glomerular filtration rate (eGFR). In normorenal patients, receiving valaciclovir 2000 mg q8h, estimated AUC<sub>0–24</sub> values were 44.8 and 13.3 mg·h/L for aciclovir and 9-CMMG, respectively. The median estimated metabolic ratio of AUC<sub>0–24</sub> (9-CMMG/aciclovir) was 30.4% and 129.9% for patients with >90 and <30 mL/min/1.73 m<sup>2</sup> eGFR, respectively. There were no valaciclovir-related adverse events during hospitalization.<div class="boxTitle">Conclusions</div>This model allowed the PK and basal metabolic ratio of aciclovir and 9-CMMG in early liver transplantation to be defined. The correlation with renal function suggests important implications for therapeutic drug monitoring of these compounds, which will need confirmation in different cohorts.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Objectives</div>Multidrug-resistant <span style="font-style:italic;">Acinetobacter baumannii</span> (MDR-<span style="font-style:italic;">A. baumannii</span>) has become an emerging pathogen, causing ventilator-associated pneumonia (VAP), with limited treatment options available. MIN has re-emerged as a potential treatment option for MDR pathogens. However, evidence regarding MIN pharmacokinetic properties in critically ill patients is scarce and primarily limited to IV administration. To address the knowledge gap in regions where IV MIN is unavailable, a prospective, open-label study was conducted to describe the pharmacokinetic properties of orally administered MIN.<div class="boxTitle">Methods</div>The study included 24 critically ill patients with MDR-<span style="font-style:italic;">A. baumannii</span> VAP. A population PK (popPK) model was developed and the PTA for different MICs was assessed by Monte Carlo simulations. A one-compartment model with first-order absorption and linear elimination best described the data.<div class="boxTitle">Results</div>The values of the estimated population parameters were found equal to 183.3 L, 6.55 L/h and 1.66 h⁻¹, for the apparent volume of distribution (V/F), the apparent clearance (CL/F) and the absorption rate constant (ka), respectively (F representing oral bioavailability). PTA analysis showed that for a daily dose of 400 mg, adequate exposure [free AUC/MIC (fAUC/MIC > 25)] was achieved only for MICs ≤ 0.25 mg/L, while for the ratio of fAUC/MIC = 13.75, high PTA values are calculated up to MIC = 0.5 mg/L.<div class="boxTitle">Conclusions</div>This study provides a popPK model for oral MIN in critically ill adults. The developed popPK model contributes to a better understanding of MIN’s PK and can inform dosing strategies and future studies on MIN use in critical care settings.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>V116 is a novel 21-valent pneumococcal conjugate vaccine (PCV) intended for use in adults.<div class="boxTitle">Objectives</div>To estimate current V116 serotype coverage in adult patients in Canada compared with PCV15, PCV20 and PPSV23 vaccines, and to describe isolate demographics for the eight unique serotypes (15A, 15C, 16F, 23A, 23B, 24F, 31 and 35B) covered by V116.<div class="boxTitle">Methods</div>From 2018 to 2021 inclusive, the SAVE study collected 5854 invasive pneumococcal disease (IPD) isolates as part of a collaboration between the Canadian Antimicrobial Resistance Alliance and the Public Health Agency of Canada–National Microbiology Laboratory. Serotypes were determined by Quellung reaction and antimicrobial susceptibility testing performed using the CLSI broth microdilution method.<div class="boxTitle">Results</div>For adult patients (≥18 years), adults 50–64 years and adults ≥65 years, respectively, IPD isolate coverage was PCV15 (42.7%; 41.0%, 39.8%), PCV20 (59.0%; 60.2%, 52.2%), PPSV23 (70.4%; 75.1%, 60.0%), V116 (78.9%; 76.3%, 81.5%) and V116 plus PCV20 (92.2%; 91.0%, 89.3%). The eight unique V116 serotypes accounted for 19.7% and 26.8% of IPD isolates from adults and adults ≥65 years, respectively. Among the eight unique V116 serotypes, 15A and 23A demonstrated the highest rates of MDR (17.0% and 10.2%, respectively); 6.7% of 15A isolates were XDR.<div class="boxTitle">Conclusions</div>V116 provided significantly (<span style="font-style:italic;">P </span>< 0.05) greater coverage than PCV15, PCV20 and PPSV23 for adults, including older adults, across all Canadian geographic regions, and against IPD isolates with common antimicrobial resistance phenotypes, including MDR. The eight unique V116 serotypes accounted for a higher proportion of IPD isolate serotypes in patients aged ≥65 years than younger adults.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>Biannual mass drug administration of azithromycin (MDA-azithromycin) has been proposed as a strategy to reduce childhood mortality in high-mortality regions, particularly sub-Saharan Africa. However, its effectiveness across different age groups and potential risks, including antibiotic resistance, require further evaluation.<div class="boxTitle">Methods</div>We systematically searched PubMed, Cochrane CENTRAL, Web of Science and <a href="https://ClinicalTrials.gov">ClinicalTrials.gov</a> through September 2024 for randomized controlled trials (RCTs) comparing biannual MDA-azithromycin to placebo in children aged 1–59 months. The primary outcomes were mortality in children <1 year and 12–59 months. Secondary outcomes included adverse events and antibiotic resistance. Data were analysed using a random-effects model in Review Manager 5.4, with heterogeneity assessed via I<sup>2</sup>. Trial sequential analysis (TSA) evaluated cumulative evidence reliability, and the Cochrane RoB2 tool assessed risk of bias. PROSPERO registration: CRD42024589170.<div class="boxTitle">Results</div>Five RCTs (691 235 children) were included. Among children <1 year, azithromycin showed a non-significant mortality reduction (RR: 0.90 [0.78, 1.04]; <span style="font-style:italic;">P</span> = 0.14; I<sup>2</sup> = 55%), with TSA indicating inconclusive evidence. Among children 12–59 months, MDA-azithromycin significantly reduced mortality (RR: 0.85 [0.79, 0.91]; <span style="font-style:italic;">P</span> < 0.00001; I<sup>2</sup> = 26%), with TSA confirming sufficient evidence. Adverse events were rare, but antibiotic resistance data were limited, warranting further monitoring. Evidence quality ranged from moderate to very low, with one trial at high risk of bias.<div class="boxTitle">Conclusion</div>Biannual MDA-azithromycin significantly reduces mortality in children 12–59 months, supporting its use in high-mortality settings per WHO recommendations. Its impact on infants remains uncertain. Adverse events were minimal, but continued resistance surveillance is essential.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>The cefazolin inoculum effect (CzIE), defined here as a cefazolin MIC at high inoculum (10<sup>7</sup> colony-forming units/mL) ≥16 mg/L in MSSA, has been associated with less favourable clinical outcomes. However, detection of this phenotype is challenging in the clinical microbiology laboratory. We previously described modification of a rapid nitrocefin test using ampicillin disks rather than ampicillin powder for induction of the <span style="font-style:italic;">Staphylococcus aureus</span> β-lactamase (BlaZ).<div class="boxTitle">Objective</div>Evaluate the performance of the modified rapid nitrocefin test in a blinded fashion using MSSA isolates recovered from patients with bacteraemia.<div class="boxTitle">Methods</div>We evaluated 200 MSSA isolates recovered from Latin American (LA) and North American (NA) hospitals (67 and 133 from NA and LA, respectively). The CzIE was determined using the modified rapid nitrocefin test with ampicillin disks and compared with MIC determination at high inoculum (gold standard). All isolates were subjected to whole-genome sequencing on an Illumina Hi-Seq platform. Performance metrics were calculated for the complete dataset and according to specific BlaZ types.<div class="boxTitle">Results</div>The prevalence of the CzIE was 53% (105/200). Compared with the gold standard, the modified nitrocefin rapid test had a sensitivity of 96% and a specificity of 91.6%, with an overall accuracy of 94%. There were no false-positive results among <span style="font-style:italic;">blaZ</span>-negative MSSA strains.<div class="boxTitle">Conclusions</div>The modified nitrocefin rapid test exhibited a robust performance to detect the CzIE in isolates from the Americas. This methodology is inexpensive and can be implemented in clinical microbiology laboratories around the world, including those with limited resources.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Objectives</div>Biofilm formation is a mechanism exhibited by bacteria, making them 10–1000 times more resistant than planktonic cells. The aim was to collect the most suitable characteristics from already available antibiofilm peptides and design novel antibiofilm peptide sequences along with these characteristics altogether in one sequence.<div class="boxTitle">Methods</div>Antibiofilm peptides were collected from AMP database (APD3), and sequence analysis was performed to derive the most suitable features. An artificial design approach, modified database filtering technology, was chosen to design novel peptide sequences, and their activity was predicted by machine-learning prediction models. Antibacterial and antibiofilm potential of the selected peptide sequence (arginine-based peptide 12; RbP12) was assessed against <span style="font-style:italic;">Staphylococcus aureus</span> P10 and <span style="font-style:italic;">Pseudomonas aeruginosa</span> PA64.<div class="boxTitle">Results</div>A total of 34 peptides were designed, of which 22 were arginine based and 12 were serine based. All the designed peptides were predicted to have antibiofilm properties. RbP12 was found to inhibit the growth of <span style="font-style:italic;">S. aureus</span> P10 completely at an MIC of 85 mg/L, while the percentage inhibition of <span style="font-style:italic;">P. aeruginosa</span> PA64 was calculated to be 32.1%. Significant inhibition of biofilms by RbP12 was observed in the case of both <span style="font-style:italic;">S. aureus</span> P10 and <span style="font-style:italic;">P. aeruginosa</span> PA64. An MTT assay showed no significant cytotoxicity by RbP12 with 96% cell viability.<div class="boxTitle">Conclusions</div>RbP12 was found to have higher antibacterial and antibiofilm activity against <span style="font-style:italic;">S. aureus</span> P10 compared with <span style="font-style:italic;">P. aeruginosa</span> PA64. With 96% cell viability, usage of RbP12 on human skin is totally safe. Based on these results, the aim is to develop self-assembled peptide hydrogels for wound healing in future work.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>Legionnaires’ disease (LD) is typically treated with macrolides, including the azalide azithromycin, or quinolones. In 2013, guidelines for empirical treatment of community-acquired pneumonia at Christchurch Hospital, New Zealand were changed to prioritize oral azithromycin over IV clarithromycin.<div class="boxTitle">Objectives</div>To determine whether the change in antimicrobial guidelines led to altered outcomes for patients subsequently confirmed to have LD.<div class="boxTitle">Methods</div>Patients with confirmed LD between 2010 and 2020 were identified from clinical and laboratory data. Hospital records were used to identify mortality, ICU admission, length of hospital stay, time to clinical stability, and time to first anti-<span style="font-style:italic;">Legionella</span> treatment. Mean differences, risk ratios (RRs) and an interrupted time series with propensity adjustment were used to compare patient outcomes before and after the guideline change.<div class="boxTitle">Results</div>There were 323 patients included: 128 before and 195 after the change. Patient outcomes generally improved after the change including: mortality within 30 days (RR 0.4, 95% CI 0.2–0.8); ICU admission (RR 0.6, 95% CI 0.5–0.9); length of stay (difference −2.3 days, 95% CI −4.3 to −0.4); and time to clinical stability (difference −2.4 days, 95% CI −4.3 to −0.5). The interrupted time series analysis suggested improvements in patient outcomes may have occurred regardless of the guideline change.<div class="boxTitle">Conclusions</div>Outcomes for patients with LD were not worsened by the change in antimicrobial guidelines and may have improved. Overall rates of mortality were low. This result was reassuring given the harm that may result from unnecessary use of IV compared with oral antimicrobial agents.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Objectives</div>Ampicillin, a β-lactam antibiotic frequently prescribed for bacterial infections, is used off-label in neonates. Blood sampling limitations in neonatal pharmacokinetic (PK) studies make dried blood spots (DBS) a promising matrix for micro-sampling. This study aims to develop a population PK (PopPK) model using a DBS-based approach to optimize ampicillin dosing in Chinese neonatal patients.<div class="boxTitle">Methods</div>DBS samples were collected at predefined intervals from neonatal patients after ampicillin dosing. A PopPK model was developed using NONMEM 7.5, followed by model-based simulations to provide dosing recommendations in virtual population. During the simulations, the predicted blood concentrations were converted to unbound plasma concentrations using a blood-to-plasma ratio of 0.56 and an unbound fraction of 0.8. The PK/pharmacodynamic (PD) target was 100% of the time with the unbound drug plasma concentration above the MIC (%<span style="font-style:italic;">f</span>T > MIC), and the risk of toxicity threshold was defined as a steady-state peak plasma concentration exceeding 140 mg/L.<div class="boxTitle">Results</div>Data from 53 patients with 102 DBS samples were collected, and the ranges of body weight and postmenstrual age (PMA) were 1.91–4.25 kg and 34.3–41.4 weeks, respectively. Ampicillin PK were characterized using a one-compartment model with first-order elimination. An allometric scaling and renal maturation model were integrated into the model to describe the developmental PK in hospitalized neonates. Simulations suggest that the optimal dosing regimen is 25 mg/kg administered intravenously every 6 h across PMA of 32–42 weeks.<div class="boxTitle">Conclusions</div>We successfully developed a PopPK model of ampicillin using DBS sampling for Chinese neonates and proposed evidence-based dosing recommendations.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>Carbapenemase-producing Enterobacterales (CPE) are of international concern. Screening for CPE can encompass single- or two-step approaches, using culture, PCR or a combination. Each approach has benefits, but none are without disadvantage.<div class="boxTitle">Objectives</div>To reflect on the challenges and implications of PCR-positive/culture-negative CPE screening results and assess if PCR cycle threshold (Ct) value can be helpful in predicting positive culture results.<div class="boxTitle">Patients and methods</div>Risk factor-based CPE screening swabs were tested using a two-step algorithm: PCR followed by culture of PCR-positive specimens. Data on all PCR-positive specimens between 1 August 2022 and 31 May 2024 were extracted. ORs were estimated using receiver operating characteristic (ROC) curves to compare Ct values and culture. Youden’s index was calculated to establish the optimal Ct cut-off value. Compliance with the CPE screening pathway for newly identified CPE PCR-positive patients was assessed.<div class="boxTitle">Results</div>Of 61 268 CPE screens, 292 were PCR positive (0.5%), with 298 genes identified. Of these, 81.5% were culture confirmed. ROC analysis showed an AUC of 0.82 and Youden’s index yielding a Ct cut-off value of 33.7. Repeat CPE screens were obtained from 33 new PCR-positive, culture-negative inpatients. Further investigation was not possible for 17 new PCR-positive, culture-negative patients (11%).<div class="boxTitle">Conclusions</div>Molecular platforms alone cannot detect species or antimicrobial resistance. A molecular-followed-by-culture algorithm can reduce workloads associated with culture, resulting in comprehensive data, including antimicrobial susceptibility results, to support informed clinical, policy and epidemiological decision-making.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Objectives</div>Practice concerning post-transplant <span style="font-style:italic;">Pneumocystis</span> prophylaxis remains heterogeneous. SXT benefits must be balanced with frequent toxicity. We aimed to assess whether a low-dose SXT strategy might limit toxicities while maintaining an undisrupted prophylaxis compared with a standard dose in a retrospective cohort of heart transplant population.<div class="boxTitle">Methods</div>Patients undergoing heart transplant from two distinct centres, receiving daily SXT 20/100 mg versus daily SXT 80/400 mg between 2018 and 2020, were retrospectively included in the study. Demographic, immunosuppression and survival characteristics were collected to ensure group comparability. The occurrence of adverse effects and the rate of SXT discontinuation were compared between the two groups.<div class="boxTitle">Results</div>Overall, 359 patients were recruited in the study, 108 patients for the standard-dose group and 251 patients for the low-dose group. The leading cause of prophylaxis discontinuation was cytopenia. We observed significantly more discontinuation in the standard-dose compared with the low-dose group (24.1% and 6.4%, respectively, <span style="font-style:italic;">P</span> < 0.001). No patient with ongoing prophylaxis presented <span style="font-style:italic;">Pneumocystis</span> pneumonia or toxoplasmosis during the 2-year follow-up. Two <span style="font-style:italic;">Pneumocystis</span> infections in the low-dose group occurred during prophylaxis breaks. The rate of toxoplasmosis seroconversion was similar in both groups.<div class="boxTitle">Conclusions</div>This retrospective study suggests that a low-dose SXT <span style="font-style:italic;">Pneumocystis</span> prophylaxis strategy might offer a more favourable safety/efficacy profile than standard-dose prophylaxis after heart transplantation. These results should be confirmed in an interventional trial. Caution remains for toxoplasmosis serology D+/R− profiles.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>Few active antibiotic options are available to treat MBL-producing <span style="font-style:italic;">Pseudomonas aeruginosa</span> infections, and some of these options are either poorly tolerated or have pharmacokinetic limitations. The use of aztreonam monotherapy for treating MBL-producing <span style="font-style:italic;">P. aeruginosa</span> remains controversial due to the risk of selecting resistant mutants during treatment.<div class="boxTitle">Objectives</div>To describe the clinical outcomes of patients treated with ceftazidime-avibactam plus aztreonam for VIM-producing <span style="font-style:italic;">P. aeruginosa</span> infections. The assessed outcomes include clinical success, clinical cure, all-cause mortality at day 28, combination therapy-associated adverse events, infection relapse and microbiological recurrence.<div class="boxTitle">Methods</div>This retrospective observational single-centre study was conducted at Clínica Universidad de Navarra, Pamplona, Spain. Eight patients with VIM-producing <span style="font-style:italic;">P. aeruginosa</span> infections were included. Whole-genome sequencing of isolates was performed at Hospital Universitario Son Espases, Palma, Spain.<div class="boxTitle">Results</div>All isolates were susceptible to aztreonam and aztreonam-avibactam. No resistance mechanisms against these antibiotics were identified through whole-genome sequencing, except in one isolate that overexpressed the MexAB-OprM efflux pump. Clinical success and clinical cure were achieved in seven of eight patients, while all-cause mortality at day 28 was two of eight. Clinical cure was documented for five different infections and three distinct <span style="font-style:italic;">P. aeruginosa</span> clones. No adverse events related to antibiotic therapy were reported, and no infection relapses occurred after treatment. Microbiological recurrence was observed in two cases.<div class="boxTitle">Conclusions</div>In our experience, patients with VIM-producing <span style="font-style:italic;">P. aeruginosa</span> infections treated with ceftazidime-avibactam plus aztreonam mostly achieved clinical success. However, given the limited sample size, further research is required to validate these findings.</span>
<span class="paragraphSection">Antibiotic resistance, exacerbated by the spread of carbapenemase-producing Enterobacterales (CPEs), constitutes a public health priority. Carbapenemase enzymes are categorized according to the Ambler classification. Group A carbapenemases primarily include KPC, but also rarer enzymes such as SME (<span style="font-style:italic;">Serratia marcescens</span> enzyme), a chromosomally encoded carbapenemase first described in England in 1982. Since then, five SME variants have been described worldwide, all exclusively found in <span style="font-style:italic;">S. marcescens</span>, according to the Beta-Lactamase DataBase (<a href="http://www.bldb.eu/Enzymes.php">http://www.bldb.eu/Enzymes.php</a>).</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>Although less virulent than <span style="font-style:italic;">Pseudomonas aeruginosa,</span> non-<span style="font-style:italic;">aeruginosa Pseudomonas</span> (NAP) are opportunistic pathogens that cause invasive infections, mainly in immunosuppressed or intensive care patients. MDR strains of NAP are increasingly isolated, especially MBL-producing isolates.<div class="boxTitle">Objectives</div>We evaluated the activity of cefiderocol, ceftazidime/avibactam and ceftolozane/tazobactam against a collection of clinical isolates of NAP, which was voluntarily enriched with resistant strains.<div class="boxTitle">Methods</div>We retrospectively determined the MICs of cefiderocol, ceftazidime/avibactam and ceftolozane/tazobactam in 71 NAP clinical isolates. Most isolates of our collection were not susceptible to meropenem (75%) or ceftazidime (45%).<div class="boxTitle">Results</div>Among the first-line β-lactam–resistant isolates, the strains for which no carbapenemase was detected were susceptible to ceftolozane/tazobactam or ceftazidime/avibactam, except for one isolate. These latter associations were more active against <span style="font-style:italic;">P. fluorescens</span> isolates than against other NAP. Most isolates (94%) of our collection were susceptible to cefiderocol, with a median MIC of 0.25 mg/L. In particular, the 19 carbapenemase-producing strains, including 15 VIM-producing strains, were susceptible to cefiderocol. Cefiderocol MICs were higher for <span style="font-style:italic;">P. fluorescens</span> complex isolates (MIC<sub>50</sub> = 2 mg/L) than for <span style="font-style:italic;">P. putida</span> complex isolates (MIC<sub>50</sub> = 0.25 mg/L). Resistance to cefiderocol was detected in only four isolates, of which three <span style="font-style:italic;">P. fluorescens</span> complex isolates remained susceptible to ceftolozane/tazobactam and ceftazidime/avibactam.<div class="boxTitle">Conclusions</div>Ceftolozane/tazobactam and ceftazidime/avibactam may be of interest as second-line β-lactams against non–carbapenemase-producing strains. Cefiderocol was highly active against NAP of our collection, especially MBL-producing isolates. Further studies are needed to correlate <span style="font-style:italic;">in vitro</span> susceptibility of NAP to cefiderocol and clinical responses.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Objectives</div>Doxycycline post-exposure prophylaxis (doxycycline-PEP) can reduce incident cases of syphilis, chlamydia and possibly gonorrhoea especially among men who have sex with men with recent bacterial sexually transmitted infections (STIs). Owing to potential implementation of doxycycline-PEP internationally, global tetracycline/doxycycline resistance data for contemporary <span style="font-style:italic;">Neisseria gonorrhoeae</span> isolates has become imperative. We report tetracycline resistance data for gonococcal isolates (<span style="font-style:italic;">n</span> = 2993) from eight WHO Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP) countries in three WHO regions in 2021–2024, i.e. to estimate potential impact of doxycycline-PEP on the incident gonorrhoea cases in these WHO EGASP countries.<div class="boxTitle">Methods</div>WHO EGASP isolates cultured from men with urethral discharge in Cambodia (<span style="font-style:italic;">n</span> = 482), Indonesia (<span style="font-style:italic;">n</span> = 101), Malawi (<span style="font-style:italic;">n</span> = 121), The Philippines (<span style="font-style:italic;">n</span> = 843), South Africa (<span style="font-style:italic;">n</span> = 597), Thailand (<span style="font-style:italic;">n</span> = 250), Uganda (<span style="font-style:italic;">n</span> = 350) and Vietnam (<span style="font-style:italic;">n</span> = 249) in 2021–2024 were examined. MICs (mg/L) of tetracycline were determined using Etest.<div class="boxTitle">Results</div>The tetracycline resistance (range) using the current EUCAST (MIC > 0.5 mg/L) and CLSI (MIC > 1 mg/L) clinical resistance breakpoints in the eight WHO EGASP countries was 92.2% (83.5%–99.6%) and 80.6% (66.3%–98.6%), respectively. Using a previous minocycline-PEP resistance breakpoint (MIC > 2 mg/L) and breakpoint for high-level plasmid (<span style="font-style:italic;">tetM</span>)-mediated tetracycline resistance (MIC > 8 mg/L), the tetracycline resistance (range) was 77.3% (47.4%–98.6%) and 74.3% (31.3%–98.6%), respectively.<div class="boxTitle">Conclusions</div>The exceedingly high levels of gonococcal tetracycline resistance (independent of resistance breakpoint used) in the eight WHO EGASP countries elucidate that doxycycline-PEP will unlikely significantly reduce the gonorrhoea cases in these countries. Furthermore, doxycycline-PEP might rapidly select for additional gonococcal strains with tetracycline resistance (low- and high-level) and MDR/XDR strains, i.e. because these strains are mostly resistant to tetracycline.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Objectives</div>The 2020 vancomycin consensus guidelines recommend AUC-guided dosing over trough-based dosing to decrease nephrotoxicity. This study was performed to add data comparing these dosing methods in the outpatient setting.<div class="boxTitle">Methods</div>This retrospective cohort study compared trough-guided versus AUC-guided dosing in patients receiving vancomycin through two home infusion pharmacies (HIPs). Multivariate analysis was performed to report adjusted relative risks, adjusting for patient demographics and clinical characteristics. Eligible patients were ≥18 years old, had an absolute neutrophil count of ≥1000 cells/mm<sup>3</sup>, a baseline serum creatinine of <2.0 mg/dL at HIP intake, and ≥7 days of IV vancomycin at home. Primary outcome was rate of acute kidney injury (AKI) events, defined as the number of AKI events per treatment days. Secondary outcomes were rate of 30 day hospital readmission and number of HIP interventions (vancomycin dose changes).<div class="boxTitle">Results</div>Six hundred and sixty patients were included (303 trough, 357 AUC). The mean number of AKI events was 0.84 per treatment day for trough-guided versus 0.63 for AUC-guided dosing (<span style="font-style:italic;">P</span> = 0.11). In adjusted models, there were no significant associations between the exposure and AKI events [relative risk (RR) = 0.8, 95% CI 0.5–1.2, <span style="font-style:italic;">P </span>= 0.26], 30 day hospital readmissions (RR 1.0, 95% CI 0.8–1.3, <span style="font-style:italic;">P </span>= 0.71) or number of pharmacy interventions (RR = 1.0, 95% CI 0.9–1.2, <span style="font-style:italic;">P </span>= 0.67).<div class="boxTitle">Conclusions</div>There was no significant difference in AKI rates among patients receiving vancomycin via trough- or AUC-guided monitoring and dosing through a HIP. Further evaluation is needed to determine how to improve AKI rates using AUC-guided monitoring and dosing among patients receiving vancomycin therapy at home.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Objectives</div>To characterize the <span style="font-style:italic;">optrA</span>-, <span style="font-style:italic;">cfr</span>(D)- and <span style="font-style:italic;">vanA</span>-carrying linear plasmids detected in three MDR enterococcal clinical isolates.<div class="boxTitle">Methods</div><span style="font-style:italic;">Enterococcus faecium</span> (868), <span style="font-style:italic;">E. faecium</span> (1001) and <span style="font-style:italic;">Enterococcus faecalis</span> (2048), which were linezolid- and vancomycin-resistant due to the presence of <span style="font-style:italic;">optrA</span>, <span style="font-style:italic;">cfr</span>(D) and <span style="font-style:italic;">vanA</span> genes, were tested for their susceptibility to several antibiotics. Characterization of the genetic elements carrying antibiotic resistance genes and ST determination were achieved using WGS data. The plasmid topology was evaluated by S1-PFGE. Resistance gene transferability was assessed by filter-mating experiments.<div class="boxTitle">Results</div>The linezolid- and vancomycin-resistant enterococci also showed resistance to tedizolid, chloramphenicol, tetracycline, erythromycin, ampicillin and levofloxacin. Both <span style="font-style:italic;">E. faecium</span> 868 and <span style="font-style:italic;">E. faecium</span> 1001 belonged to ST80 (included in clade A1), whereas <span style="font-style:italic;">E. faecalis</span> 2048 was associated with ST6. WGS analysis revealed a plasmid co-localization of the <span style="font-style:italic;">optrA</span>, <span style="font-style:italic;">cfr</span>(D) and <span style="font-style:italic;">vanA</span> genes. <span style="font-style:italic;">optrA</span> was carried by Tn<span style="font-style:italic;">6674</span>-like or Tn<span style="font-style:italic;">7695</span>-like transposons; <span style="font-style:italic;">cfr</span>(D) was associated with a truncated <span style="font-style:italic;">guaA</span> gene, both flanked by IS<span style="font-style:italic;">1216</span> with opposite polarity; <span style="font-style:italic;">vanA</span> was found on a Tn<span style="font-style:italic;">1546</span>-like transposon containing IS<span style="font-style:italic;">1542</span> and IS<span style="font-style:italic;">1251</span> transposases. PFGE of S1 nuclease-treated and untreated DNAs displayed the linear topology of <span style="font-style:italic;">optrA-</span>, <span style="font-style:italic;">cfr</span>(D)- and <span style="font-style:italic;">vanA-</span>harbouring plasmids. Only <span style="font-style:italic;">E. faecium</span> 868 was able to transfer linezolid and vancomycin genes to an enterococcal recipient.<div class="boxTitle">Conclusions</div>To the best of our knowledge this is the first report on the occurrence of a linear plasmid in <span style="font-style:italic;">E. faecalis</span>. Linear plasmids can play a key role in the spread of oxazolidinone and glycopeptide resistance with serious consequences for public health.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div><span style="font-style:italic;">Pseudomonas aeruginosa</span> bloodstream infections (Pa-BSIs) are still a major cause of mortality in ICUs, posing many treatment uncertainties.<div class="boxTitle">Methods</div>This multicentre, retrospective study analysed data from 14 Italian hospitals, including all consecutive adults developing Pa-BSI in ICU during 2021–22 and treated with antibiotics for at least 48 h. The primary aim was to identify predictors of 30 day mortality using Cox regression. Results were adjusted with inverse probability of treatment weighting (IPTW) and for immortal time bias.<div class="boxTitle">Results</div>Overall, 170 patients were included. High-risk BSI (source: lung, intra-abdominal, CNS) occurred in 118 (69%) patients, and 54 (32%) had septic shock. In 37 (22%), 73 (43%), 12 (7%) and 48 (28%) the definitive backbone therapy was piperacillin/tazobactam, carbapenems, colistin or new antipseudomonal cephalosporins (ceftolozane/tazobactam, <span style="font-style:italic;">n</span> = 20; ceftazidime/avibactam, <span style="font-style:italic;">n</span> = 22; cefiderocol, <span style="font-style:italic;">n</span> = 6), respectively. Moreover, 58 (34%) received a second drug as combination therapy. The incidence of 30 day all-cause mortality was 27.6% (47 patients). By Cox regression, Charlson comorbidity index, neutropenia, septic shock and high-risk BSI were independent predictors of 30 day mortality, while previous colonization by <span style="font-style:italic;">P. aeruginosa</span>, use of antipseudomonal cephalosporins as definitive treatment, and combination therapy were shown to be protective. However, after IPTW adjustment, only the protective effect of antipseudomonal cephalosporins was confirmed (adjusted HR = 0.27, 95% CI = 0.10–0.69), but not for combination therapy. Hence, the treatment effect was calculated: antipseudomonal cephalosporins significantly reduced mortality risk [−17% (95% CI = −4% to −30%)], while combination therapy was beneficial only in the case of septic shock [−66% (95% CI = −44% to −88%].<div class="boxTitle">Conclusions</div>In ICU, antipseudomonal cephalosporins may be the preferred target therapy for the treatment of Pa-BSI; in addition, initial combination therapy may be protective in the case of septic shock.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>This study aims to explore effective interventions and observation indicators for reducing antibiotic use in neonates through quality improvement (QI) methods, while quantitatively analysing whether these methods increase the risk of neonatal mortality and serious adverse outcomes.<div class="boxTitle">Methods</div>By 27 August 2024, we reviewed all pertinent literature. A descriptive statistical analysis was conducted on all intervention measures, outcome indicators, process indicators, and balance indicators. The group utilizing QI interventions was designated as the intervention group, with the baseline period serving as the control group. The mortality rates and incidence of serious adverse outcomes were treated as dichotomous variables. The risk ratio (RR) and 95% CIs were effect indicators.<div class="boxTitle">Results</div>In total, 57 studies published between 2016 and 2024 were included. All studies were uncontrolled before-and-after studies. The most studied country was the United States of America. From these 57 studies, 27 effective intervention measures were identified, and all observation indicators and main results were presented in tabular form. According to the meta-analysis, the mortality rate in the intervention group decreased by 30% compared with the control group (RR = 0.7; 95% CI: 0.604–0.81; <span style="font-style:italic;">P</span> < 0.001), while there was no statistically significant difference in the risk of serious adverse outcomes between the two groups.<div class="boxTitle">Conclusions</div>QI methods can safely and effectively reduce the use of antibiotics in neonates, highlighting their potential for clinical applications.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Objectives</div>To evaluate the <span style="font-style:italic;">in vitro</span> and <span style="font-style:italic;">in vivo</span> antimicrobial activity of pleuromutilin derivatives modified with C14 side-chain against <span style="font-style:italic;">Streptococcus suis</span>.<div class="boxTitle">Methods</div>To determine the minimum inhibitory concentrations (MICs) of 268 pleuromutilin derivatives with C14 side-chain modifications against <span style="font-style:italic;">S. suis</span> ATCC 43 765 using the broth dilution method. Derivative B43, B49, B52, B53 and B54, which exhibited better antimicrobial activity, were selected for further investigation of their <span style="font-style:italic;">in vitro</span> antibacterial effect, cytotoxicity, and <span style="font-style:italic;">in vivo</span> antibacterial effect.<div class="boxTitle">Results</div>Determination activity of five derivatives against clinical strains (<span style="font-style:italic;">n</span> = 37), as well as growth and time-killing curves. Those experiments showed that all the five derivatives had good activity against <span style="font-style:italic;">S. suis in vitro</span>. Resistance-inducing assays demonstrated that, except for B43, the derivatives had similar abilities to induce resistance to tiamulin. In addition, the five derivatives did not have erythrocyte haemolytic toxicity (0.25–16 mg/L) and cytotoxicity (1.25–80 mg/L). In the mouse thigh infection model, the derivative of B49 exhibited superior antibacterial efficacy. About 40 mg/kg B49 had good activity and improved the survival rate of mice by 33.3% in the <span style="font-style:italic;">S. suis</span> mouse peritonitis model. Molecular docking study and scanning electron microscopy revealed that B49 can effectively bind to the active site of the 50S ribosome and disrupt cell membranes.<div class="boxTitle">Conclusions</div>A total of 68.66% of the 268 C14 side-chain modified pleuromutilin derivatives showed potent activity against <span style="font-style:italic;">S. suis</span>. Among them, B49 showed good <span style="font-style:italic;">in vitro</span> and <span style="font-style:italic;">in vivo</span> antimicrobial effects against <span style="font-style:italic;">S. suis</span>, indicating that B49 can be intensively studied as an antimicrobial candidate compound.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Introduction</div>Large language models (LLMs) are becoming ubiquitous and widely implemented. LLMs could also be used for diagnosis and treatment. National antibiotic prescribing guidelines are customized and informed by local laboratory data on antimicrobial resistance.<div class="boxTitle">Methods</div>Based on 24 vignettes with information on type of infection, gender, age group and comorbidities, GPs and LLMs were prompted to provide a treatment. Four countries (Ireland, UK, USA and Norway) were included and a GP from each country and six LLMs (ChatGPT, Gemini, Copilot, Mistral AI, Claude and Llama 3.1) were provided with the vignettes, including their location (country). Responses were compared with the country’s national prescribing guidelines. In addition, limitations of LLMs such as hallucination, toxicity and data leakage were assessed.<div class="boxTitle">Results</div>GPs’ answers to the vignettes showed high accuracy in relation to diagnosis (96%–100%) and yes/no antibiotic prescribing (83%–92%). GPs referenced (100%) and prescribed (58%–92%) according to national guidelines, but dose/duration of treatment was less accurate (50%–75%). Overall, the GPs’ accuracy had a mean of 74%. LLMs scored high in relation to diagnosis (92%–100%), antibiotic prescribing (88%–100%) and the choice of antibiotic (59%–100%) but correct referencing often failed (38%–96%), in particular for the Norwegian guidelines (0%–13%). Data leakage was shown to be an issue as personal information was repeated in the models’ responses to the vignettes.<div class="boxTitle">Conclusions</div>LLMs may be safe to guide antibiotic prescribing in general practice. However, to interpret vignettes, apply national guidelines and prescribe the right dose and duration, GPs remain best placed.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div><span style="font-style:italic;">Mycobacterium abscessus</span> is an important cause of pulmonary infections, particularly among people with cystic fibrosis. Current treatment options for <span style="font-style:italic;">M. abscessus</span> are suboptimal. Apramycin is a promising alternative aminoglycoside for <span style="font-style:italic;">M. abscessus,</span> in part due to its ability to avoid intrinsic aminoglycoside-modifying enzymes in this pathogen.<div class="boxTitle">Objectives</div>Define the pharmacodynamic activity of apramycin doses against <span style="font-style:italic;">M. abscessus</span>.<div class="boxTitle">Methods</div>Apramycin and amikacin pharmacodynamics were assessed against two amikacin-susceptible <span style="font-style:italic;">M. abscessus</span> subsp. <span style="font-style:italic;">abscessus</span> isolates (ATCC 19977 and NR-44261) using a 14-day hollow fibre infection model (HFIM). Viable bacterial counts were determined during exposure to amikacin (15–20 mg/kg q24h) and 3 fractionated doses of apramycin (15 mg/kg q12h, 30 mg/kg q24h, 60 mg/kg q48h) using pharmacokinetic profiles predicted in epithelial lining fluid.<div class="boxTitle">Results</div>Against ATCC 19977, apramycin activity exceeded that of amikacin, with maximum bacterial reductions between 1.51 and 2.18 log<sub>10</sub> cfu/mL for the different doses. Apramycin 15 mg/kg q12h displayed slightly better killing compared with the other apramycin dosing regimens between 96 and 144h before regrowth occurred. NR-44261 was not inhibited by amikacin and the activity of apramycin against this isolate was similar between the three doses (∼0.5 log<sub>10</sub> cfu/mL reductions). After 14 days of exposure to apramycin monotherapy, ATCC 19977 and NR-44261 became apramycin resistant with MICs of >32 mg/L.<div class="boxTitle">Conclusions</div>Apramycin exhibited greater pharmacodynamic activity than amikacin against amikacin-susceptible <span style="font-style:italic;">M. abscessus</span> isolates and may be a promising therapy for this pathogen. However, antibiotic combination strategies to minimize apramycin resistance from emerging may be necessary.</span>
<span class="paragraphSection">A recent study in <span style="font-style:italic;">Journal of Antimicrobial Chemotherapy</span><sup><a href="#dkaf060-B1" class="reflinks">1</a></sup> reported high levels of cefiderocol resistance in carbapenemase-producing Enterobacterales (CPE) using EUCAST disc diffusion breakpoints at a university teaching hospital in London, UK.</span>
<span class="paragraphSection">We carefully read the letter from Longshaw and colleagues, and we are very grateful to the authors for their interest in our article. The authors query whether we may have overestimated cefiderocol resistance in NDM-producing <span style="font-style:italic;">Enterobacterales</span> due to the use of the disc diffusion method only, without the use of broth microdilution.</span>
<span class="paragraphSection">We were concerned to read the recent research paper by Baltas <span style="font-style:italic;">et al</span>.<sup><a href="#dkaf074-B1" class="reflinks">1</a></sup> ‘<span style="font-style:italic;">Resistance profiles of carbapenemase-producing Enterobacterales in a large centre in England: are we already losing cefiderocol?</span>’ describing apparently high levels of resistance to cefiderocol in isolates of NDM-producing Enterobacterales from their institution.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>Acute sore throat is managed in community pharmacies in England and Wales under different clinical pathways: Acute Sore Throat Pharmacy First (ASTPF) and Sore Throat Test and Treat (STTT), respectively. ASTPF launched in 2024 and allows antibiotic supply with FeverPAIN scores 4 and 5. STTT launched in 2018 and allows antibiotic supply with FeverPAIN ≥2 or Centor ≥3, if point-of-care testing confirms presence of group A <span style="font-style:italic;">Streptococcus</span> (GAS).<div class="boxTitle">Objectives</div>To compare antibiotic supply rates of ASTPF and STTT, between 1 February 2024 and 30 July 2024, covering the first 6 months of ASTPF.<div class="boxTitle">Methods</div>A descriptive study using anonymized individual-level data from electronic pharmacy records of STTT and anonymized population-level aggregate data from electronic records of ASTPF consultations meeting the gateway criteria for reimbursement.<div class="boxTitle">Results</div>During the study period, 317 864 ASTPF and 27 684 STTT consultations were recorded across participating pharmacies, representing 551.0 and 874.9 consultations per 100 000 population in England (57 690 300) and Wales (3 164 400), respectively. The antibiotic supply rate was 72.7% (95% CI: 72.5% to 72.8%) for ASTPF and 29.9% (95% CI: 29.4% to 30.5%) for STTT.<div class="boxTitle">Conclusions</div>In this natural experiment in two similar healthcare systems with pharmacy-led sore throat services, we found different rates of antibiotic supply. Differences could be attributable to service implementation, pharmacists’ initial training, engagement with GPs, pathway differences (e.g. gateway criteria and use of point-of-care tests), symptom severity, or most likely a combination of multiple factors. This early analysis suggests adapting the ASTPF pathway, to include point-of-care testing, could lead to reductions in unnecessary antibiotic supply.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div>Bacteria adapt to changes in their natural environment through a network of stress responses that enable them to alter their gene expression to survive in the presence of stressors, including antibiotics. These stress responses can be specific to the type of stress and the general stress response can be induced in parallel as a backup mechanism. In Gram-negative bacteria, various envelope stress responses are induced upon exposure to antibiotics that cause damage to the cell envelope or result in accumulation of toxic metabolic by-products, while the heat shock response is induced by antibiotics that cause misfolding or accumulation of protein aggregates. Antibiotics that result in the production of reactive oxygen species (ROS) induce the oxidative stress response and those that cause DNA damage, directly and through ROS production, induce the SOS response. These responses regulate the expression of various proteins that work to repair the damage that has been caused by antibiotic exposure. They can contribute to antibiotic resistance by refolding, degrading or removing misfolded proteins and other toxic metabolic by-products, including removal of the antibiotics themselves, or by mutagenic DNA repair. This review summarizes the stress responses induced by exposure to various antibiotics, highlighting their interconnected nature, as well the roles they play in antibiotic resistance, most commonly through the upregulation of efflux pumps. This can be useful for future investigations targeting these responses to combat antibiotic-resistant Gram-negative bacterial infections.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Objectives</div>This study compared the efficacy of cefazolin in a mouse pneumonia model caused by a methicillin-susceptible <span style="font-style:italic;">Staphylococcus aureus</span> (MSSA) strain with cefazolin inoculum effect (CIE) and its <span style="font-style:italic;">blaZ-</span>eliminated derivative.<div class="boxTitle">Methods</div>An isogenic <span style="font-style:italic;">blaZ</span> gene-eliminated strain was derived from type A <span style="font-style:italic;">blaZ</span>-positive MSSA blood isolates exhibiting CIE: PNIDSA230 (parental strain, CIE+) and PNIDSA230c (<span style="font-style:italic;">blaZ</span>-eliminated strain, CIE−). Mice were inoculated with 2 × 10⁶ to 2 × 10⁷ cfu of MSSA via endotracheal tubes and treated with intraperitoneal cefazolin or oxacillin 5 h post-inoculation. Bacterial loads in the lungs (primary sites), liver, and kidneys (metastatic foci) were measured 24 h later.<div class="boxTitle">Results</div>Cefazolin reduced bacterial densities in the lungs of CIE-positive MSSA-infected mice (<span style="font-style:italic;">n</span> = 11) compared with untreated controls (<span style="font-style:italic;">n</span> = 11) (mean log10 cfu/g ± SD, 6.0 ± 1.6 versus 9.4 ± 2.7; <span style="font-style:italic;">P</span> = 0.006). However, the efficacy of cefazolin was significantly lower in CIE+ infections than in CIE− infections (mean log10 cfu/g ± SD, 6.0 ± 1.6 versus 4.4 ± 0.8, <span style="font-style:italic;">P</span> = 0.0258). Cefazolin-treated CIE− MSSA-infected mice showed no metastatic infections, while 7 of the 11 CIE+ MSSA-infected mice developed liver or kidney infections despite cefazolin treatment. Oxacillin treatment significantly reduced bacterial densities of the lungs, liver, and kidney in CIE-positive (<span style="font-style:italic;">n</span> = 4) and CIE-negative (<span style="font-style:italic;">n</span> = 4) MSSA-infected mice, with no significant differences between CIE-positive and CIE-negative MSSA infections.<div class="boxTitle">Conclusions</div>CIE may diminish cefazolin’s efficacy in severe MSSA infections and contribute to the development of metastatic infection foci. Oxacillin remains effective regardless of CIE status.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>Previous studies have primarily focused on nucleos(t)ide reverse transcriptase inhibitor pharmacology in peripheral blood mononuclear cells (PBMCs) and erythrocytes via dried blood spots (DBS), but not other major blood cells.<div class="boxTitle">Objectives</div>Our objectives were to describe and compare the concentrations of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in DBS, PBMCs, neutrophils, and platelets in people with HIV (PWH) and people without HIV (PWOH).<div class="boxTitle">Methods</div>DBS, PBMCs, neutrophils, and platelets were isolated from whole blood drawn from PWH and PWOH receiving tenofovir alafenamide and emtricitabine. TFV-DP and FTC-TP concentrations were quantified using LC-MS/MS in each cell type. Linear regression models controlled for time on drug, adherence, and time since last dose, where applicable, to determine geometric mean percent differences (95% confidence interval) by HIV status and estimated half-lives.<div class="boxTitle">Results</div>Data were available in 13 PWH (96% male) and 30 PWOH (53% male). Compared with PWOH, TFV-DP in DBS was 48.9% (15.6%, 91.9%) higher and FTC-TP in platelets was 36.3% (4.5%, 77.7%) higher; TFV-DP in platelets also trended higher [43.5% (−3.24%, 113%)]. No other cell types significantly differed by HIV status. TFV-DP and FTC-TP demonstrated the longest half-lives in neutrophils, followed by PBMCs and then platelets. After normalizing to cell volume, both drugs accumulated from greatest to least in PBMCs, neutrophils, platelets, and erythrocytes across both PWH and PWOH.<div class="boxTitle">Conclusions</div>Our findings highlight differential drug disposition across cell types that also vary by serostatus in DBS and platelets. The mechanisms and implications of these findings require additional research.</span>
<span class="paragraphSection">We carefully read the letter from Rawson and colleagues, and we are very grateful to the authors for their interest in our article. Their results show that, using a commercially available broth microdilution method (ComASP<sup>®</sup>, Liofilchem) to confirm resistant isolates as identified by disc diffusion (30 μg cefiderocol discs, Liofilchem) among a collection of 54 multi-drug resistant Gram-negative isolates, the majority tested susceptible using the commercial broth microdilution method.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Objectives</div>Letermovir, a cytomegalovirus prophylactic agent, is widely used in allogeneic HSCT recipients. As an inhibitor of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), it may interact with ciclosporin A (CsA), potentially impacting its pharmacokinetics. Inflammation can impair CYP3A-mediated drug metabolism, with severe inflammation reducing CsA metabolism. However, current data on the drug–drug interaction (DDI) between CsA and letermovir as a perpetrator are limited to healthy volunteers and lack evaluation in HSCT patients, particularly under minimal inflammation conditions, where such DDIs may occur.<div class="boxTitle">Methods</div>This retrospective, observational, single-centre study included seven adult HSCT recipients who received CsA and letermovir concurrently with no-to-mild inflammation (C-reactive protein ≤40 mg/L). CsA concentration/dose (C/D) ratios were calculated before and after letermovir initiation. Changes in CsA pharmacokinetics were analysed using Wilcoxon signed-rank tests.<div class="boxTitle">Results</div>A 240 mg dose of letermovir once daily significantly increased the median CsA C/D ratio from 0.39 to 0.90 (<span style="font-style:italic;">P</span> = 0.0156) and the median CsA trough concentration from 136 µg/L to 240 µg/L (<span style="font-style:italic;">P</span> = 0.0156). These changes were attributed to CYP3A4 inhibition by letermovir, given the stable no-to-mild inflammatory status and the lack of additional DDI.<div class="boxTitle">Conclusion</div>Letermovir significantly decreased CsA metabolism in HSCT patients through CYP3A4 inhibition, with clinical implications for dosing precision. Close therapeutic drug monitoring (generally twice weekly) is therefore recommended during letermovir initiation and discontinuation to mitigate risks of subtherapeutic levels or toxicity. This study highlights the significance of assessing DDIs in HSCT, where inflammation modulates metabolic interactions resulting in a complex interplay such as a disease–drug–drug interaction (D–DDI).</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>Antistaphylococcal penicillin (ASP) is the first-line therapy for MSSA bloodstream infection (BSI), with cefazolin as an alternative. However, ASPs are associated with a high risk of acute kidney injury (AKI) and overexposure. We implemented a kidney-sparing protocol based on: (i) systematic use of cefazolin in patients with creatinine clearance of <60 mL/min or any risk factor for AKI; and (ii) reduced ASP dose (75–100 mg/kg/day) with therapeutic drug monitoring.<div class="boxTitle">Methods</div>We compared all episodes of MSSA BSI in adults admitted during the 15 months before (control period) and the 12 months after (optimization period) protocol implementation. Primary outcome was sterile blood cultures by Day 3. Secondary outcomes included AKI, dialysis, MSSA BSI relapses, and mortality.<div class="boxTitle">Results</div>We included 100 patients in the control group and 104 in the optimization group. Baseline characteristics were similar in both groups, with a mean ± SD age of 73 ± 20 years, male predominance (73%), and high prevalence of chronic kidney disease (80%) and diabetes (31%). Initial treatment was ASP (cloxacillin) in 80/100 (80%) patients in the control group, versus 24/104 (23%) in the optimization group (<span style="font-style:italic;">P </span>< 0.001). Day 3 sterile blood cultures, and Day 30 mortality remained similar (respectively 95% versus 93%, and 21% versus 24%; not significant). AKI and dialysis requirements were less frequent during the optimization period, respectively 37% versus 56% (<span style="font-style:italic;">P </span>= 0.045), and 1% versus 8% (<span style="font-style:italic;">P </span>= 0.017).<div class="boxTitle">Conclusions</div>A kidney-sparing protocol for MSSA BSI based on systematic use of cefazolin in patients with AKI risk factor, and lower ASP doses, was associated with similar efficacy and lower risk of AKI and dialysis requirements.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>Antibiotic combination therapy is increasingly used to treat MDR pathogens. <span style="font-style:italic;">In vitro</span> studies suggest that the polymyxin B/rifampicin combination might be synergistic. Therefore, the pharmacodynamics of rifampicin as monotherapy and combined with polymyxin B were studied in <span style="font-style:italic;">Escherichia coli</span>- and <span style="font-style:italic;">Klebsiella pneumoniae</span>-infected mice.<div class="boxTitle">Methods</div>The rifampicin pharmacokinetics (oral doses 0.5–64 mg/kg) in murine plasma were studied to estimate the exposures to rifampicin. These exposures were subsequently correlated with the antibacterial effect in a sigmoid maximum-effect model. The minimum exposures needed for a static, 1 log<sub>10</sub> and 2 log<sub>10</sub> kill effect in two <span style="font-style:italic;">E. coli</span> and two <span style="font-style:italic;">K. pneumoniae</span> strains were determined for monotherapy and the combination. The pharmacodynamic interactions between polymyxin B and rifampicin were assessed using Loewe additivity and Bliss independence in both an <span style="font-style:italic;">E. coli</span> and a <span style="font-style:italic;">K. pneumoniae</span> strain.<div class="boxTitle">Results</div>Rifampicin monotherapy resulted in a static effect in <span style="font-style:italic;">E. coli</span> but not against <span style="font-style:italic;">K. pneumoniae</span>. When combined with polymyxin B, rifampicin <span style="font-style:italic;">f</span>AUC/MIC needed for stasis, 1 log<sub>10</sub> and 2 log<sub>10</sub> kill effect decreased with increasing polymyxin B exposures for all strains. Synergy was confirmed in Loewe additivity (interaction indices 0.11–0.51 for <span style="font-style:italic;">E. coli</span> and 0.04–0.19 for <span style="font-style:italic;">K. pneumoniae</span>) and Bliss independence (267% and 863%). Maximal killing (>2 log<sub>10</sub> kill) in combination therapy was found at rifampicin/polymyxin B <span style="font-style:italic;">f</span>AUC/MIC of 0.68/32.56 for <span style="font-style:italic;">E. coli</span> and 0.169/16.28 for <span style="font-style:italic;">K. pneumoniae.</span><div class="boxTitle">Conclusions</div>These <span style="font-style:italic;">in vivo</span> studies confirmed that there is a clear synergistic effect between polymyxin B and rifampicin, which was stronger for the <span style="font-style:italic;">K. pneumoniae</span> strain than for the <span style="font-style:italic;">E. coli</span> strain.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Objectives</div>Bloodstream infections (BSIs) due to vancomycin-resistant <span style="font-style:italic;">Enterococcus</span> spp. (VRE) are considered a predictor of mortality among frail patients. The aim of this study was to evaluate the risk factors associated with 30 day mortality and relapse of infection in enterococcal BSI caused by VRE and to evaluate the impact of antibiotic regimens in targeted therapy.<div class="boxTitle">Methods</div>We conducted a retrospective study of consecutive hospitalized patients in six teaching hospitals from August 2016 to August 2022 in Italy. All adult patients with a documented VRE BSI were included.<div class="boxTitle">Results</div>We enrolled 517 consecutive hospitalized patients with VRE BSI; of these BSIs 496 (96.5%) were caused by <span style="font-style:italic;">Enterococcus faecium</span> and 26 (5.1%) by <span style="font-style:italic;">Enterococcus faecalis</span>. The most frequently used antibiotics as backbone were linezolid (48.1%) and daptomycin (43.7%). Overall, the 30 day mortality was 32.1%. Upon Cox regression analysis, the risk factor independently associated with 30 day mortality was Charlson comorbidity index >3 points (<span style="font-style:italic;">P</span> < 0.001), whereas a Pitt score <4 points (<span style="font-style:italic;">P</span> = 0.031), surgery for source control of infection (<span style="font-style:italic;">P</span> = 0.016) and time to targeted therapy <24 h (<span style="font-style:italic;">P</span> = 0.006) were associated with survival. After propensity score adjustment, a daptomycin-based regimen (<span style="font-style:italic;">P</span> = 0.003) was associated with 30 day survival.<div class="boxTitle">Conclusions</div>VRE BSI is an important cause of mortality in frail/critically ill patients. Our data highlighted the role of daptomycin as backbone agent for the treatment of enterococcal BSI caused by vancomycin-resistant strains.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>Cefepime/enmetazobactam is a newly approved β-lactam/β-lactamase inhibitor combination with promising activity against MDR Gram-negative Enterobacterales, particularly ESBL- and OXA-48-producing isolates. Reliable susceptibility testing methods are essential to guide its clinical use.<div class="boxTitle">Objectives</div>To evaluate the performance of two commercial cefepime/enmetazobactam susceptibility testing methods, disc diffusion and Liofilchem<sup>™</sup> MTS gradient strips, using broth microdilution (BMD) as the gold standard.<div class="boxTitle">Methods</div>A total of 291 carbapenem-resistant Enterobacterales isolates, including 194 carbapenemase producers, were included. Susceptibility testing was performed using BMD, disc diffusion and Liofilchem<sup>™</sup> MTS strips. Results were interpreted following EUCAST and FDA 2025 breakpoints. Essential agreement (EA) and bias were calculated for gradient strip methods according to the ISO 20776-2021 guideline, whereas categorical agreement (CA), very major errors (VMEs) and major errors (MEs) were determined for disc diffusion according to the ISO 20776-2:2007 guideline.<div class="boxTitle">Results</div>The disc diffusion method demonstrated high CA (93.8% EUCAST, 95.9% FDA). VME rates exceeded acceptable thresholds using EUCAST breakpoints (20.8%) but were within limits for FDA (1.9%). Liofilchem<sup>™</sup> MTS strips achieved 88.3% (95% CI: 84.1%–91.5%) EA and a bias of −8.9%. Both methods accurately detected susceptibility in OXA-48-producing isolates but showed limitations for isolates close to the MIC breakpoints.<div class="boxTitle">Conclusions</div>Disc diffusion and Liofilchem<sup>™</sup> MTS strips represent reliable alternatives to BMD for routine cefepime/enmetazobactam testing.</span>
<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background</div>The rise in fungal infections caused by multidrug-resistant pathogens like <span style="font-style:italic;">Candida haemulonii sensu stricto</span> presents a significant global health challenge. The common resistance to current treatments underscores the urgency to explore alternative therapeutic strategies, including drug repurposing.<div class="boxTitle">Objectives</div>To assess the potential of repurposing tafenoquine, an antimalarial agent, for antifungal use against <span style="font-style:italic;">C. haemulonii sensu stricto</span>.<div class="boxTitle">Methods</div>The efficacy of tafenoquine was tested using <span style="font-style:italic;">in vitro</span> assays for minimum inhibitory concentration (MIC), minimum fungicidal concentration, biofilm inhibition, cell damage, cell membrane integrity, nucleotide leakage, sorbitol protection assay, and efflux pump inhibition. The compound’s cytotoxicity was assessed through a haemolysis assay, and <span style="font-style:italic;">in vivo</span> safety and efficacy were tested using <span style="font-style:italic;">Tenebrio molitor</span> larvae.<div class="boxTitle">Results</div>Tafenoquine exhibited potent fungicidal activity against <span style="font-style:italic;">C. haemulonii sensu stricto</span> with an MIC of 4 mg/L and significantly inhibited biofilm formation by 60.63%. Tafenoquine also impaired mitochondrial functionality, leading to compromised cellular respiration. Despite these effects, tafenoquine did not cause significant protein leakage, indicating a distinct mechanism from membrane-targeting agents. <span style="font-style:italic;">In vivo</span> study confirmed tafenoquine's non-toxic profile with no observed haemolysis or acute toxicity in the <span style="font-style:italic;">T. molitor</span> model. During antifungal treatment with tafenoquine, a survival rate of approximately 60% was observed after 3 days.<div class="boxTitle">Conclusions</div>The findings of this study highlight tafenoquine's potential as a promising candidate for antifungal drug repurposing, especially against <span style="font-style:italic;">C. haemulonii sensu stricto</span>. Its effectiveness in inhibiting fungal growth and biofilm formation underscores its viability for further clinical development as a novel antifungal therapy.</span>
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