International Journal of Antimicrobial Agents最新文献

{"title":"In reply to the Letter to the Editor regarding ‘Development and Validation of a Time-Varying Correction Factor for QT Interval Assessment in Drug-Resistant Tuberculosis Patients’","authors":"Thanakorn Vongjarudech , Elin Svensson","doi":"10.1016/j.ijantimicag.2025.107539","DOIUrl":"10.1016/j.ijantimicag.2025.107539","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 3","pages":"Article 107539"},"PeriodicalIF":4.9,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The importance of drug exposure in the development of cytomegalovirus resistance","authors":"Katie Lynch,&nbsp;Anne-Grete Märtson","doi":"10.1016/j.ijantimicag.2025.107537","DOIUrl":"10.1016/j.ijantimicag.2025.107537","url":null,"abstract":"<div><h3>Objective</h3><div>Human cytomegalovirus (CMV) is a widespread pathogen which remains asymptomatic in healthy individuals. However, CMV disease can be life-threatening in immunocompromised individuals, particularly in transplant patients. This disease is routinely managed by antiviral agents, including (val)ganciclovir, foscarnet, cidofovir, letermovir, and maribavir. Subtherapeutic antiviral drug exposure is a common occurrence and can lead to drug-resistant CMV development, a key contributor to disease progression. Breakthrough CMV often results in graft loss, end-organ failure, or death. By optimizing intracellular exposure levels of antiviral therapies, it may be possible to improve patient outcomes. Therefore, this review aims to explore the relationship between antiviral exposure and the development of drug-resistant CMV.</div></div><div><h3>Methods</h3><div>A literature search was conducted in Pubmed database including keywords “cytomegalovirus”, “resistance”, “pharmacokinetics”, “pharmacodynamics”, “drug exposure”, “ganciclovir”, “foscarnet”, “maribavir”, “letermovir”, “cidofovir”.</div></div><div><h3>Results</h3><div>There are several challenges to achieving optimal concentrations of current and novel CMV therapies. Narrow therapeutic indices and toxicity profiles of current CMV therapeutics contribute to their subtherapeutic exposure and, hence, suboptimal clinical outcomes. Alternately, novel antivirals such as letermovir and maribavir offer improved pharmacokinetic profiles. However, these agents are associated with rapid resistance development. Overall, a distinct gap exists in understanding the relationship between antiviral exposure and resistance development. As a result, current clinical markers used to predict clinical efficacy lack reliability. In future, resistance development in relation to drug exposure should be included as a clinical trial endpoint to gain understanding of exposure-resistance relationships.</div></div><div><h3>Conclusions</h3><div>With solid knowledge of exposure-resistance relationships, more predictive <em>in vitro</em> and <em>in vivo</em> markers of clinical efficacy can be identified. PK/PD targets that account for free EC50/EC90 and viral load should be defined to improve clinical outcomes and reduce the risk for emergence of R/R CMV.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 3","pages":"Article 107537"},"PeriodicalIF":4.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144077767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antimicrobial resistance trends, predictors, and burden in England: a retrospective study using the Clinical Practice Research Datalink from 2015 to 2021","authors":"Amer Taie ,&nbsp;Maria Gheorghe ,&nbsp;James Amos ,&nbsp;Alec Morton ,&nbsp;Jason Gordon ,&nbsp;Nia C. Jenkins ,&nbsp;Thomas E. Padgett ,&nbsp;Joe Hollinghurst ,&nbsp;Gemma Taylor","doi":"10.1016/j.ijantimicag.2025.107535","DOIUrl":"10.1016/j.ijantimicag.2025.107535","url":null,"abstract":"<div><h3>Objectives</h3><div>Evidence describing the burden of antimicrobial resistance (AMR) to health care systems is essential to inform health care policy to tackle AMR. This study aims to investigate trends, predictors, and clinical and economic burden of AMR within the English National Health Service.</div></div><div><h3>Methods</h3><div>We conducted a retrospective cohort study assessing 1,036,850 patients diagnosed with an infection as a hospital inpatient linked to the Clinical Practice Research Datalink within England between 2015 and 2021. Resistance was identified with specific <em>International Classification of Diseases</em>, 10th revision, codes. Predictors of AMR were determined using logistic regression and extreme gradient boosting trees. A 1:1 propensity score matched cohort of 78,153 patients with an AMR infection compared with those without was created. Incidence rate ratios were estimated between those 2 groups for hospital length of stay (from admission to discharge), rehospitalisations within 1 year of diagnosis of infection, and total hospital costs. Acceleration factors were estimated for time to all-cause mortality and first rehospitalisation.</div></div><div><h3>Results</h3><div>Between 2015 and 2020, AMR had a proportional increase of 10%. Resistant infections are associated with an additional 9.2 days length of stay and an additional hospitalisation cost of £3441 per patient compared with infections not reported as resistant. Within 1, 3, and 5 years 3.2%, 6.3%, and 7.3% more patients with AMR infections died and 7.8%, 5.3%, and 3.6% more patients were rehospitalised, respectively. Acceleration factors indicated patients with AMR infections die 27% earlier and rehospitalised 26% earlier than those with non-AMR infections.</div></div><div><h3>Conclusion</h3><div>AMR is a significant and growing threat to health care; this analysis suggests that AMR is associated with significant excess of health care use and increased mortality and readmission.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 3","pages":"Article 107535"},"PeriodicalIF":4.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144077742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of OXA-1224, a novel OXA-213-like β-lactamase encoded by the chromosome of Acinetobacter pittii","authors":"Zeshi Liu ,&nbsp;Siquan Shen ,&nbsp;Jing Lei ,&nbsp;Shuai Zhao ,&nbsp;Xue Zhang ,&nbsp;Chengkang Tang ,&nbsp;Shi Wu ,&nbsp;Ke Lei ,&nbsp;Jian Yin ,&nbsp;Yanping Zhang ,&nbsp;Yan Guo ,&nbsp;Yan Geng ,&nbsp;Fupin Hu","doi":"10.1016/j.ijantimicag.2025.107536","DOIUrl":"10.1016/j.ijantimicag.2025.107536","url":null,"abstract":"<div><h3>Objectives</h3><div>This study investigates the transfer mechanism and functional properties of OXA-1224, the novel <span>d</span>-class β-lactase in the clinical isolate <em>Acinetobacter pittii</em> (<em>A. pittii</em>) PT-01.</div></div><div><h3>Methods</h3><div>Bacterial identification was performed using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), and resistance genes were identified via polymerase chain reaction (PCR) and DNA sequencing. Antimicrobial susceptibility of <em>A. pittii</em> PT-01 and its recombinant transformants carrying <em>bla</em>_OXA-1224 was determined by broth microdilution method. Purified OXA-213 and OXA-1224 proteins were evaluated by the enzymatic reaction kinetics test.</div></div><div><h3>Results</h3><div><em>A. pittii</em> PT-01 was susceptible to amikacin, tigecycline, polymyxin B, ceftazidime, cefepime, cefoperazone-sulbactam, and piperacillin-tazobactam, but resistant to imipenem and meropenem. The strain harboured <em>bla</em>_OXA-72 and a novel <em>bla</em>_OXA-213 variant: <em>bla</em>_OXA-1224. Recombinant strains expressing <em>bla</em>_OXA-1224 showed an 8-fold and 16-fold increase in minimum inhibitory concentrations (MICs) for imipenem and meropenem, respectively, compared to the control strain <em>Acinetobacter baumannii</em> (<em>A. baumannii</em>) ATCC 17978. Enzymatic assays indicated that OXA-1224 had a higher <em>Km</em> value for nitrocefin and stronger affinity for imipenem (<em>Km</em> = 496.7) and meropenem (<em>Km</em> = 126.1) compared to OXA-213. Catalytic efficiency for imipenem and meropenem was also increased with OXA-1224 compared to OXA-213. OXA-1224 has a higher affinity for imipenem (<em>Km/Kcat</em> = 3.362) and meropenem (<em>Km/Kcat</em> = 4.837) compared to OXA-213 (<em>Km/Kcat</em> = 2.469, <em>Km /Kcat</em> = 2.547, respectively). However, OXA-1224 showed minimal activity against the third-generation cephalosporin ceftazidime (<em>Km</em> &gt; 1000).</div></div><div><h3>Conclusions</h3><div>The novel β<em>-</em>lactamase <em>bla</em>_OXA-1224 from a clinical <em>A. pittii</em> isolate confers resistance to carbapenems only in vitro, demonstrating increased MICs and greater catalytic efficiency for carbapenems compared to <em>bla</em>_OXA-213. However, its activity against cephalosporins remains limited.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 3","pages":"Article 107536"},"PeriodicalIF":4.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144077760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microfluidic evolution-on-a-chip reveals distinct evolution of polymyxin resistance associated with fitness optimum in Acinetobacter baumannii","authors":"Jinxin Zhao ,&nbsp;Yaqi Zhang ,&nbsp;Yu-Wei Lin ,&nbsp;Xingjian Wang ,&nbsp;Phillip J. Bergen ,&nbsp;Yan Zhu ,&nbsp;Jing Lu ,&nbsp;Meiling Han ,&nbsp;Jian Li","doi":"10.1016/j.ijantimicag.2025.107538","DOIUrl":"10.1016/j.ijantimicag.2025.107538","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 3","pages":"Article 107538"},"PeriodicalIF":4.9,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144077763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activity of imipenem-relebactam, ceftolozane-tazobactam and comparators against clinical isolates of Enterobacterales and Pseudomonas aeruginosa causing severe infections in hematological and oncological patients: A prospective multicenter study","authors":"Emilia Cercenado ,&nbsp;Luis Alcalá ,&nbsp;Álvaro Irigoyen-von-Sierakowski ,&nbsp;Belén Rodríguez-Sánchez ,&nbsp;Mercedes Marín","doi":"10.1016/j.ijantimicag.2025.107534","DOIUrl":"10.1016/j.ijantimicag.2025.107534","url":null,"abstract":"<div><h3>Objectives</h3><div>Studies regarding the activity of antimicrobials against isolates causing severe infections in oncological and hematological patients are scarce. Ceftolozane-tazobactam (TOL/TAZ) and imipenem-relebactam (IMP/REL) are among the new antimicrobials active against multiresistant gramnegative microorganisms. We evaluate the <em>in vitro</em> activity of these antimicrobials and comparators against recent clinical isolates from hematology and oncology patients in Spain.</div></div><div><h3>Methods</h3><div>A total of 55 centers participated in a nationwide study. The isolates were prospectively recovered from patients with bacteremia, lower respiratory tract infections (LRTIs), complicated urinary infections (cUTI), and complicated intra-abdominal infections (cIAIs). The activities of TOL/TAZ, IMP/REL, imipenem (IMP), meropenem (MER), ceftazidime (CAZ), cefepime (FEP), piperacillin-tazobactam (PIP/TAZ), levofloxacin (LEV), and amikacin (AK) were studied following the EUCAST guidelines. Resistance mechanisms were detected by standard methods.</div></div><div><h3>Results</h3><div>A total of 997 isolates (563 Enterobacterales (EB) and 434 <em>Pseudomonas aeruginosa</em> (PA)) were collected. The source of EB/PA were: bacteremia (n = 347/182), LRT (n = 51/139), urine (n = 95/64), and intraabdominal samples (n = 70/49). Among EB, 93.6%, 98.9%, 98.6%, 87.4%, 82.2%, 93.6%, 98.6%, 73.7%, and 97.3% were susceptible to TOL/TAZ, IMP/REL, MER, FEP, CAZ, PIP/TAZ, IMP, LEV, and AK, respectively. The corresponding values for PA were 92.2%, 90.1%, 87.8%, 81.9%, 81.7%, 75.7%, 75.2%, 63.3%, and 96.1%, respectively. A total of 14/17 isolates (EB/PA) were carbapenenase-producers, and 82 EB isolates were ESBL-producers. IMP/REL restored the activity of IMP in 14,7% of IMP-resistant PA.</div></div><div><h3>Conclusions</h3><div>TOL/TAZ and IMP/REL were the most active of the beta-lactams against PA. IMP/REL was the most active agent against EB; 30% of the isolates were resistant to levofloxacin.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 3","pages":"Article 107534"},"PeriodicalIF":4.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the clonal dynamics and transmission mechanism of carbapenem-resistant klebsiella pneumoniae in the ICU environment","authors":"Xinhong Han ,&nbsp;Meijun Song ,&nbsp;Qing Yu ,&nbsp;Junxin Zhou ,&nbsp;Huangdu Hu ,&nbsp;Yan Jiang ,&nbsp;Qiucheng Shi ,&nbsp;Yongyi Chen ,&nbsp;Qing Yang ,&nbsp;Xiaoxing Du ,&nbsp;Caiping Mao ,&nbsp;Yunsong Yu","doi":"10.1016/j.ijantimicag.2025.107532","DOIUrl":"10.1016/j.ijantimicag.2025.107532","url":null,"abstract":"<div><div>CRKP infections are a significant public health threat due to their high mortality and limited treatment options. This study aimed to investigate CRKP colonization and clonal dissemination mechanism in an ICU. From August 2019 to December 2019, 8668 samples were collected from patients and the ICU environment for CRKP screening. Positive samples underwent antimicrobial susceptibility testing, whole-genome sequencing, and molecular epidemiological analysis. Disinfectant sensitivity and ultraviolet (UV) resistance experiments were conducted to evaluate clonal persistence. The overall CRKP positive rate was 4.85% (420/8668), with higher rates in patients (14.77%, 247/1672) compared to environmental surfaces (2.47%, 173/6996). Intestinal and ventilator-related surfaces were identified as high-risk colonization sites. Molecular analysis revealed six sequence types, with ST11-KL64 (44.05%, 185/420) and ST15-KL112 (24.05%, 101/420) as dominant clones, both exhibiting elevated virulence. Notably, the emerging ST15-KL112 clone demonstrated enhanced resistance to disinfectants including chlorhexidine (MIC 8 mg/L) and benzalkonium chloride (32 mg/L). While most isolates produced KPC-2 (72.86%), OXA-232 prevalence (25.23%) exceeded prior reports. Crucially, ST11 strains survived standard UV disinfection (60-second exposure) at rates 1.3- to 5-fold higher than other clones (p &lt; 0.01). Our findings highlight the critical role of disinfectant resistance in sustaining CRKP transmission. To mitigate outbreaks, we advocate for disinfectant rotation protocols targeting disinfectant-resistant clones and prolonged UV exposure times in ICUs. The persistence of resistant CRKP clones in the ICU environment, particularly their high tolerance to disinfectants, highlights the urgent need for enhanced infection control strategies, including tailored disinfection protocols and surveillance programs.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 3","pages":"Article 107532"},"PeriodicalIF":4.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic framework and evolutionary dynamics of mcr-positive Klebsiella pneumoniae from 2000 to 2023","authors":"Xi-Wei Zhang ,&nbsp;Xi-Yi Huang ,&nbsp;Zhuo-Yang Zhou ,&nbsp;Bo-Lin Li ,&nbsp;Jie-Hong Lu ,&nbsp;Jing-Jie Song ,&nbsp;Xiao-Yan Li","doi":"10.1016/j.ijantimicag.2025.107533","DOIUrl":"10.1016/j.ijantimicag.2025.107533","url":null,"abstract":"<div><h3>Objective</h3><div>The international transmission of the colistin resistance gene <em>mcr</em> in Enterobacteriaceae poses significant public health burdens, while the understanding of the population structure and evolutionary history of <em>mcr</em>-positive <em>Klebsiella pneumoniae</em> worldwide remains unclear.</div></div><div><h3>Methods</h3><div>Here, we conducted a genomic analysis on 463 sequences of <em>K. pneumoniae</em> harbouring <em>mcr</em> genes from public database between 2000 and 2023.</div></div><div><h3>Results</h3><div>A total of 6 <em>mcr</em> variants (<em>mcr-1</em>, -<em>2</em>, -<em>3</em> and -<em>8</em> to -<em>10</em>) were detected, with <em>mcr</em>-<em>9</em> (36.1%), <em>mcr</em>-<em>1</em> (33.7%) and <em>mcr</em>-<em>8</em> (29.2%) genes being the most common. Of total isolates, 43.4% (201/463) carried carbapenemase genes (<em>bla</em>_NDM, <em>bla</em>_KPC, <em>bla</em>_IMP, <em>bla</em>_{OXA-48/181/232}, <em>bla</em>_VIM and <em>bla</em>_GES) and 15.3% of isolates (71/463) contained hypervirulent genes (<em>iucA</em> or <em>iroB</em>). Correlation analysis indicated <em>mcr</em>-<em>1</em>/<em>8</em>/<em>9</em> genes were positively correlated with specific genomic elements that were rarely described, including <em>mcr</em>-<em>1</em> with <em>iucABC</em> and <em>iutA; mcr</em>-<em>8</em> with <em>oqxB; mcr-9</em> with <em>dfrA19</em>; and IS<em>Esa</em> and repA (R absolute value &gt; 0.3; <em>p</em> &lt; 0.01). The population of <em>K. pneumoniae</em> can be classified into 6 clusters, some isolates co-harbouring <em>mcr</em> and carbapenemase genes exhibited high level of genetic similarity and dispersed in several countries, indicating the possibility of clonal transmission. <em>mcr</em>-<em>9</em> gene was introduced into <em>K. pneumoniae</em> in 1978 before the time of <em>mcr</em>-<em>1</em> gene in 1988 and <em>mcr</em>-<em>8</em> gene in 1993. We found <em>mcr</em>-<em>1</em>/<em>8</em>/<em>9</em> genes in <em>K. pneumoniae</em> evolved high-risk lineages in specific geographical location (China, Thailand and the United Kingdom) that most isolates typically contained <em>iucA, bla</em>_NDM or <em>bla</em>_KPC.</div></div><div><h3>Conclusions</h3><div>This study highlighted that continuous surveillance for the evolution of <em>mcr</em>-positive <em>K. pneumoniae</em> harbouring <em>iucA</em> or carbapenemase genes is essential.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 3","pages":"Article 107533"},"PeriodicalIF":4.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Title Page & Editorial Board","authors":"","doi":"10.1016/S0924-8579(25)00086-X","DOIUrl":"10.1016/S0924-8579(25)00086-X","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 1","pages":"Article 107529"},"PeriodicalIF":4.9,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of different resistance mechanisms on bacterial response to meropenem, ciprofloxacin, and their combination described by next-generation mechanism-based modelling","authors":"Alice E. Terrill ,&nbsp;Jessica R. Tait ,&nbsp;Kate E. Rogers ,&nbsp;Wee L. Lee ,&nbsp;Carla López-Causapé ,&nbsp;Xiaoyu Wang ,&nbsp;Jiangning Song ,&nbsp;Roger L. Nation ,&nbsp;Antonio Oliver ,&nbsp;Cornelia B. Landersdorfer","doi":"10.1016/j.ijantimicag.2025.107528","DOIUrl":"10.1016/j.ijantimicag.2025.107528","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to investigate the effects of different bacterial resistance mechanisms on the response of isogenic strains of <em>Pseudomonas aeruginosa</em> to meropenem and ciprofloxacin, in monotherapy and combination.</div></div><div><h3>Methods</h3><div>Seven isogenic <em>P. aeruginosa</em> strains were used: the PAO1 wild-type reference parent strain, PAΔAD (AmpC overexpression), PAOD1 (OprD porin loss), PAΔmexR (MexAB-OprM overexpression), and strains with two of these mutations (PAΔDMxR, PAOD1MxR, PAOD1ΔD). Each strain was exposed to constant meropenem and/or ciprofloxacin concentrations over 72 h. Pharmacokinetic/pharmacodynamic indices, i.e. the percentage of time the free meropenem concentration exceeded the MIC of the pathogen (%<em>f</em>T_˃MIC) and the ratio of the area under the free ciprofloxacin concentration-time curve over 24 h to MIC (<em>f</em>AUC/MIC), were calculated. A novel mechanism-based mathematical model was developed to describe the bacterial count profiles over time.</div></div><div><h3>Results</h3><div>The antibiotic exposures in monotherapy required to suppress regrowth varied between isogenic strains, even when strains had the same MIC; highlighting limitations of relying solely on MIC to inform dosing. Combination therapies, which cannot be predicted by pharmacokinetic/pharmacodynamic indices, were both synergistic and bactericidal at 72 h in five of the seven strains. All viable counts across all strains with monotherapies, combinations, and controls (<em>n</em> = 292 curves) were simultaneously modelled. The model accounted for different resistance mechanisms present across strains, while keeping all drug effect parameters the same between strains. The responses of strains with two resistance mutations were well described by the model developed from strains with a single mutation.</div></div><div><h3>Conclusions</h3><div>Overall, the mechanism-based mathematical model was predictive for &gt;96% of treatments.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"66 3","pages":"Article 107528"},"PeriodicalIF":4.9,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}