Antimicrobial Agents and Chemotherapy最新文献

{"title":"The extended recovery ring-stage survival assay is a scalable alternative for artemisinin susceptibility phenotyping of fresh <i>Plasmodium falciparum</i> isolates.","authors":"Martin Okitwi, Douglas A Shoue, Lisa A Checkley, Stephen Orena, Frida G Ceja, Yoweri Taremwa, Patrick K Tumwebaze, Thomas Katairo, Oswald Byaruhanga, Mackenzie A C Sievert, Shreeya Garg, Oriana K Kreutzfeld, Jennifer Legac, Jeffrey A Bailey, Sam L Nsobya, Melissa D Conrad, Philip J Rosenthal, Michael T Ferdig, Roland A Cooper","doi":"10.1128/aac.01183-24","DOIUrl":"https://doi.org/10.1128/aac.01183-24","url":null,"abstract":"<p><p>Artemisinin partial resistance (ART-R) has emerged in eastern Africa, necessitating regular surveillance of susceptibility of <i>Plasmodium falciparum</i> to artemisinins. The microscopy-based ring-stage survival assay (RSA) provides a laboratory correlate of ART-R but is limited by low throughput and subjectivity of microscopic counts of viable parasites. The extended recovery ring-stage survival assay (eRRSA) replaces microscopy with efficient quantitative PCR (qPCR) readouts but has been studied only with culture-adapted <i>P. falciparum</i> clones. We measured susceptibility to dihydroartemisinin (DHA) after a 6-h incubation with 700-nM DHA, followed by culture without drug, by comparing survival with that of untreated controls by microscopy (the RSA) or qPCR (the eRRSA) and also performed standard growth inhibition (half-maximal inhibitory concentration [IC₅₀]) assays for 122 <i>P. falciparum</i> isolates freshly collected in eastern and northern Uganda from March to July 2022. The median values for RSA survival, eRRSA fold change, and DHA IC₅₀ were 3.0%, 46.2, and 3.2 nM, respectively. RSA percent survival and eRRSA fold changes correlated strongly (Spearman correlation coefficient [<i>r</i>_<i>s</i>] = -0.7411, <i>P</i> < 0.0001), with modest associations between the presence of validated <i>P. falciparum</i> Kelch13 ART-R mutations (C469Y or A675V) and RSA (median survival 2.6% for wild type [WT] vs 4.1% for mutant, <i>P</i> = 0.01), or eRRSA (median fold change 63.4 for WT vs 30.9 for mutant, <i>P</i> = 0.003) results. Significant correlations were also observed between DHA IC₅₀ values and both RSA percent survival (<i>r_s</i> = 0.4235, <i>P</i> < 0.0001) and eRRSA fold changes (<i>r_s</i> = -0.4116, <i>P</i> < 0.0001). The eRRSA is a scalable alternative for phenotyping fresh <i>P. falciparum</i> isolates, providing similar results with improved throughput.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638202","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":"Mutant prevention concentrations, <i>in vitro</i> resistance evolution dynamics, and mechanisms of resistance to imipenem and imipenem/relebactam in carbapenem-susceptible <i>Klebsiella pneumoniae</i> isolates showing ceftazidime/avibactam resistance.","authors":"Tania Blanco-Martín, Lucía González-Pinto, Pablo Aja-Macaya, Salud Rodríguez-Pallares, Lucía Sánchez-Peña, Eva Gato, María Del Carmen Fernández-López, Michelle Outeda-García, Arianna Rodríguez-Coello, Rosa Pedraza-Merino, Isaac Alonso-García, Juan Carlos Vázquez-Ucha, Luis Martínez-Martínez, Jorge Arca-Suárez, Alejandro Beceiro, Germán Bou","doi":"10.1128/aac.01120-24","DOIUrl":"https://doi.org/10.1128/aac.01120-24","url":null,"abstract":"<p><p><i>Klebsiella pneumoniae</i> carbapenemase (KPC) variants selected during ceftazidime/avibactam treatment usually develop susceptibility to carbapenems and carbapenem/β-lactamase inhibitors, such as imipenem and imipenem/relebactam. We analyzed imipenem and imipenem/relebactam single-step mutant frequencies, resistance development trajectories and differentially selected resistance mechanisms using two representative <i>K. pneumoniae</i> isolates that had developed ceftazidime/avibactam resistance during therapy (ST512/KPC-31 and ST258/KPC-35). Mutant frequencies and mutant prevention concentrations were measured in Mueller-Hinton agar plates containing incremental concentrations of imipenem or imipenem/relebactam. Resistance dynamics were determined after incubation for 7 days in 10 mL MH tubes containing incremental concentrations of each antibiotic or combination, up to 64 times their baseline MIC. Two colonies per strain from each experiment were characterized by antimicrobial susceptibility testing and whole genome sequencing. The impact of KPC variants identified in resistant mutants on β-lactam resistance was investigated by cloning experiments. Imipenem/relebactam suppressed the emergence of resistant mutants at lower concentrations than imipenem, slowed down resistance development for both strains, and the resulting mutants yielded lower MICs of carbapenems and carbapenem/β-lactamase inhibitors than those selected with imipenem alone. Characterization of resistant mutants revealed that imipenem resistance was mainly caused by inactivation of OmpK36 and mutations in the KPC β-lactamase. Imipenem/relebactam-resistant mutants also maintained OmpK36 alterations, but mutations in KPC were much less frequent compared with those selected with imipenem alone. Genetic and biochemical characterization of the KPC derivatives identified in the resistant mutants confirmed their role in carbapenem resistance. Our data positions imipenem/relebactam as an attractive therapeutic option for combating ceftazidime/avibactam-resistant KPC-producing <i>K. pneumoniae</i> infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638200","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":"Neural network-based predictions of antimicrobial resistance phenotypes in multidrug-resistant <i>Acinetobacter baumannii</i> from whole genome sequencing and gene expression.","authors":"Huiqiong Jia, Xinyang Li, Yilu Zhuang, Yuye Wu, Shasha Shi, Qingyang Sun, Fang He, Shanyan Liang, Jianfeng Wang, Mohamed S Draz, Xinyou Xie, Jun Zhang, Qing Yang, Zhi Ruan","doi":"10.1128/aac.01446-24","DOIUrl":"https://doi.org/10.1128/aac.01446-24","url":null,"abstract":"<p><p>Whole genome sequencing (WGS) potentially represents a rapid approach for antimicrobial resistance genotype-to-phenotype prediction. However, the challenge still exists to predict fully minimum inhibitory concentrations (MICs) and antimicrobial susceptibility phenotypes based on WGS data. This study aimed to establish an artificial intelligence-based computational approach in predicting antimicrobial susceptibilities of multidrug-resistant <i>Acinetobacter baumannii</i> from WGS and gene expression data. Antimicrobial susceptibility testing (AST) was performed using the broth microdilution method for 10 antimicrobial agents. <i>In silico</i> multilocus sequence typing (MLST), antimicrobial resistance genes, and phylogeny based on cgSNP and cgMLST strategies were analyzed. High-throughput qPCR was performed to measure the expression level of antimicrobial resistance (AMR) genes. Most isolates exhibited a high level of resistance to most of the tested antimicrobial agents, with the majority belonging to the IC2/CC92 lineage. Phylogenetic analysis revealed undetected transmission events or local outbreaks. The percentage agreements between AMR phenotype and genotype ranged from 70.08% to 89.96%, with the coefficient of agreement (κ) extending from 0.025 and 0.881. The prediction of AST employed by deep neural network models achieved an accuracy of up to 98.64% on the testing data set. Additionally, several linear regression models demonstrated high prediction accuracy, reaching up to 86.15% within an error range of one gradient, indicating a linear relationship between certain gene expressions and the corresponding antimicrobial MICs. In conclusion, neural network-based predictions could be used as a tool for the surveillance of antimicrobial resistance in multidrug-resistant <i>A. baumannii</i>.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613876","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":"Safety, outcomes, and pharmacokinetics of isavuconazole as a treatment for invasive fungal diseases in pediatric patients: a non-comparative phase 2 trial.","authors":"Heidi Segers, Jaime G Deville, William J Muller, Angela Manzanares, Amit Desai, Michael Neely, Victoria Bordon, Benjamin Hanisch, Alvaro Lassaletta, Brian T Fisher, Julie Autmizguine, Andreas H Groll, Shamim Sinnar, Rodney Croos-Dabrera, Marc Engelhardt, Mark Jones, Laura L Kovanda, Antonio C Arrieta","doi":"10.1128/aac.00484-24","DOIUrl":"https://doi.org/10.1128/aac.00484-24","url":null,"abstract":"<p><p>Invasive aspergillosis (IA) and mucormycosis (IM) cause significant morbidity and mortality in immunocompromised and/or hospitalized patients. Isavuconazonium sulfate, a prodrug of the antifungal triazole isavuconazole, has been approved for treatment of IA and IM in adults; and was recently approved in children. This study describes the outcomes, safety, and pharmacokinetics of isavuconazole for the treatment of proven, probable, or possible IA or IM in children. In this phase 2, open-label, non-comparative study, patients aged 1 to <18 years with at least possible invasive mold disease were enrolled across 10 centers in the US, Spain, and Belgium from 2019 to 2022. Patients received 10 mg/kg isavuconazonium sulfate daily (maximum 372 mg; equivalent to 5.4 mg/kg or 200 mg isavuconazole) for up to 84 (IA) or 180 days (IM). Outcomes included rates of all-cause case fatality, overall response, treatment-emergent adverse events (TEAEs), and pharmacokinetics. Of 31 patients enrolled, 61.3% were 1-<12 years old; 58.1% had underlying hematologic malignancies. The successful overall response rate at the end of treatment was 54.8%. Day 42 all-cause case fatality was 6.5%; 93.5% experienced TEAEs, and two patients discontinued treatment due to drug-related TEAEs. Dosing at 10 mg/kg (maximum dose: 372 mg) met the pre-defined exposure threshold of above the 25th percentile for the area under the concentration-time curve (≥60 mg·h/L). Simulated doses of 15 mg/kg improved drug exposures in patients aged 1-<3 years. Isavuconazole was well tolerated in children, with exposure consistent with adult studies. Successful response was documented in 54.8% of patients.CLINICAL TRIALSThis study is registered at ClinicalTrials.gov as NCT03816176.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613882","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":"Targeted antimicrobial regimens for Gram-negative prosthetic joint infections: a prospective multicenter study.","authors":"Jaap L J Hanssen, Robert J P van der Wal, Rachid Mahdad, Stefan Keizer, Nathalie M Delfos, Joris C T van der Lugt, Karin Ellen Veldkamp, Peter A Nolte, Masja Leendertse, Luc B S Gelinck, Femke P N Mollema, Emile F Schippers, Hanke G Wattel-Louis, Rob G H H Nelissen, Henk Scheper, Mark G J de Boer","doi":"10.1128/aac.01232-24","DOIUrl":"https://doi.org/10.1128/aac.01232-24","url":null,"abstract":"<p><p>Fluoroquinolones (FQs) are considered the most effective antimicrobial treatment for Gram-negative prosthetic joint infection (GN-PJI). Alternatives are needed due to increasing FQ resistance and side effects. We aimed to compare different targeted antimicrobial strategies for GN-PJI managed by debridement, antibiotics, and implant retention (DAIR) or one-stage revision surgery (1SR) and to review the literature of oral treatment options for GN-PJI. In this prospective, multicenter, registry-based study, all consecutive patients with a PJI caused by a Gram-negative microorganism (including mixed infections with Gram-positive microorganisms), managed with DAIR or 1SR from 2015 to 2020, were included. Minimum follow-up was 1 year. Patients underwent targeted therapy with oral FQ, oral cotrimoxazole, or intravenous or oral β-lactams. Survival analysis was performed with use of Kaplan-Meier and Cox proportional hazards models to identify factors potentially associated with treatment failure. Seventy-four patients who received either FQ (<i>n</i> = 47, 64%), cotrimoxazole (<i>n</i> = 13, 18%), or β-lactams (<i>n</i> = 14, 18%) were included. Surgical strategy consisted of DAIR (<i>n</i> = 72) or 1SR (<i>n</i> = 2). Median follow-up was 449 days (interquartile range 89-738 days). Failure free survival did not differ between the FQ (72%) and cotrimoxazole (92%) groups (log rank, <i>P</i> = 0.13). This outcome did not change when excluding all pseudomonal PJI in the FQ group. Cotrimoxazole is a potential effective targeted antimicrobial therapy for patients with GN-PJI. A randomized controlled trial is needed to confirm the findings of this study.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613886","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":"LiaR-dependent gene expression contributes to antimicrobial responses in group A <i>Streptococcus</i>.","authors":"Luis Alberto Vega, Misú Sanson-Iglesias, Piyali Mukherjee, Kyle D Buchan, Gretchen Morrison, Anne E Hohlt, Anthony R Flores","doi":"10.1128/aac.00496-24","DOIUrl":"https://doi.org/10.1128/aac.00496-24","url":null,"abstract":"<p><p>The ability to sense and respond to host defenses is essential for pathogen survival. Some mechanisms involve two-component systems (TCSs) that respond to host molecules, such as antimicrobial peptides (AMPs), and activate specific gene regulatory pathways to aid in survival. Alongside TCSs, bacteria coordinate cell division proteins, chaperones, cell wall sortases, and secretory translocons at discrete locations within the cytoplasmic membrane, referred to as functional membrane microdomains (FMMs). In group A <i>Streptococcus</i> (GAS), the FMM or \"ExPortal\" coordinates protein secretion, cell wall synthesis, and sensing of AMP-mediated cell envelope stress <i>via</i> the LiaFSR three-component system. Previously, we showed that GAS exposure to a subset of AMPs (α-defensins) activates the LiaFSR system by disrupting LiaF and LiaS co-localization in the ExPortal, leading to increased LiaR phosphorylation, expression of the transcriptional regulator SpxA2, and altered GAS virulence gene expression. The mechanisms by which LiaFSR integrates cell envelope stress with responses to AMP activity and virulence are not fully elucidated. Here, we show the LiaFSR regulon is comprised of genes encoding SpxA2 and three membrane-associated proteins: a PspC domain-containing protein (PCP), the lipoteichoic acid-modifying protein LafB, and the membrane protein insertase YidC2. Our data support that phosphorylated LiaR induces transcription of these genes <i>via</i> a conserved operator, whose disruption attenuates GAS virulence and increases susceptibility to AMPs in a manner primarily dependent on differential expression of SpxA2. Our work expands our understanding of the LiaFSR regulatory network in GAS and identifies targets for further investigation of mechanisms of cell envelope stress tolerance contributing to GAS pathogenesis.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613868","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":"Geo-classification of drug-resistant travel-associated <i>Plasmodium falciparum</i> using <i>Pfs47</i> and <i>Pfcpmp</i> gene sequences (USA, 2018-2021).","authors":"Edwin Pierre-Louis, Julia Kelley, Dhruviben Patel, Christina Carlson, Eldin Talundzic, David Jacobson, Joel Leonard Nicholas Barratt","doi":"10.1128/aac.01203-24","DOIUrl":"https://doi.org/10.1128/aac.01203-24","url":null,"abstract":"<p><p>Travel-related malaria is regularly encountered in the United States, and the U.S. Centers for Disease Control and Prevention (CDC) characterizes <i>Plasmodium falciparum</i> drug-resistance genotypes routinely for travel-related cases. An important aspect of antimalarial drug resistance is understanding its geographic distribution. However, specimens submitted to CDC laboratories may have missing, incomplete, or inaccurate travel data. To complement genotyping for drug-resistance markers <i>Pfcrt</i>, <i>Pfmdr1</i>, <i>Pfk13</i>, <i>Pfdhps</i>, <i>Pfdhfr</i>, and <i>PfcytB</i> at CDC, amplicons of <i>Pfs47</i> and <i>Pfcpmp</i> are also sequenced as markers of geographic origin. Here, a bi-allele likelihood (BALK) classifier was trained using <i>Pfs47</i> and <i>Pfcpmp</i> sequences from published <i>P. falciparum</i> genomes of known geographic origin to classify clinical genotypes to a continent. Among <i>P. falciparum</i>-positive blood samples received at CDC for drug-resistance genotyping from 2018 to 2021 (<i>n</i> = 380), 240 included a travel history with the submission materials, though 6 were excluded due to low sequence quality. Classifications obtained for the remaining 234 were compared to their travel histories. Classification results were over 96% congruent with reported travel for clinical samples, and with collection sites for field isolates. Among travel-related samples, only two incongruent results occurred; a specimen submitted citing Costa Rican travel classified to Africa, and a specimen with travel referencing Sierra Leone classified to Asia. Subsequently, the classifier was applied to specimens with unreported travel histories (<i>n</i> = 140; 5 were excluded due to low sequence quality). For the remaining 135 samples, geographic classification data were paired with results generated using CDC's Malaria Resistance Surveillance (MaRS) protocol, which detects single-nucleotide polymorphisms in and generates haplotypes for <i>Pfcrt</i>, <i>Pfmdr1</i>, <i>Pfk13</i>, <i>Pfdhps</i>, <i>Pfdhfr</i>, and <i>PfcytB</i>. Given the importance of understanding the geographic distribution of antimalarial drug resistance, this work will complement domestic surveillance efforts by expanding knowledge on the geographic origin of drug-resistant <i>P. falciparum</i> entering the USA.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613864","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}