Antimicrobial Agents and Chemotherapy最新文献

{"title":"Analogs of the anti-malaria drug mefloquine have broad-spectrum antifungal activity and are efficacious in a model of disseminated <i>Candida auris</i> infection.","authors":"Soumitra Guin, Marhiah C Montoya, Xiaoyu Wang, Robert Zarnowski, David R Andes, Marvin J Meyers, Noelle S Williams, Damian J Krysan","doi":"10.1128/aac.01301-24","DOIUrl":"https://doi.org/10.1128/aac.01301-24","url":null,"abstract":"<p><p>Only three classes of antifungal drugs are currently in clinical use. Here, we report that derivatives of the malarial drug mefloquine have broad-spectrum antifungal activity including difficult-to-treat molds and endemic fungi. Pharmacokinetic and efficacy studies of NSC-4377 indicate that it penetrates the central nervous system and is active against <i>Candida auris in vivo</i>. These data strongly support the further development of mefloquine analogs as a potentially new class of antifungal molecules.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370827","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":"High frequency of acquired virulence factors in carbapenemase-producing <i>Klebsiella pneumoniae</i> isolates from a large German university hospital, 2013-2021.","authors":"Janko Sattler, Christoph M Ernst, Janine Zweigner, Axel Hamprecht","doi":"10.1128/aac.00602-24","DOIUrl":"https://doi.org/10.1128/aac.00602-24","url":null,"abstract":"<p><p>Carbapenemase-producing <i>Klebsiella pneumoniae</i> (CP-Kp) isolates are a public health concern as they can cause severe hospital-acquired infections that are difficult to treat. It has recently been shown that CP-Kp can take up virulence factors from hypervirulent <i>K. pneumoniae</i> lineages. In this study, 109 clinical CP-Kp isolates from the University Hospital Cologne were examined for the presence of acquired virulence factors using whole-genome sequencing and phenotypic tests, and results were linked to clinical data. The virulence factor <i>iuc</i> was present in 18/109 of the CP-Kp isolates. Other acquired virulence factors, such as <i>ybt</i>, <i>cbt</i>, <i>iro</i>, <i>rmpA/rmpA2</i>, <i>peg-344</i>, and hypervirulence-associated capsule types were detected in various combinations among these isolates. The <i>iuc</i>-positive isolates produced OXA-232 (<i>n</i> = 7), OXA-48 (<i>n</i> = 6), OXA-48+NDM (<i>n</i> = 3), NDM, and KPC (each <i>n</i> = 1), and 7/18 isolates were resistant to ceftazidime-avibactam, colistin, and/or cefiderocol. Four isolates carried hybrid plasmids that harbored acquired virulence factors alongside the carbapenemase genes <i>bla</i>_NDM-1/5 or <i>bla</i>_OXA-48. In 15/18 patients, <i>iuc</i>-positive CP-Kp were isolated from a clinically manifest infection site. Among these, four patients had osteomyelitis, and four patients died from pneumonia with OXA-232-producing ST231 isolates, three of them as part of an outbreak. In conclusion, acquired virulence factors are frequently detected in various combinations in carbapenemase-producing <i>K. pneumoniae</i> isolates in Germany, warranting continuous monitoring of infections caused by these strains.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370828","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":"Impact of porin deficiency on the synergistic potential of colistin in combination with β-lactam/β-lactamase inhibitors against ESBL- and carbapenemase-producing <i>Klebsiella pneumoniae</i>.","authors":"Lisa Allander, Karin Vickberg, Elin Fermér, Thomas Söderhäll, Linus Sandegren, Pernilla Lagerbäck, Thomas Tängdén","doi":"10.1128/aac.00762-24","DOIUrl":"https://doi.org/10.1128/aac.00762-24","url":null,"abstract":"<p><p>Combinations of colistin and β-lactam/β-lactamase inhibitors (BLBLIs) have shown <i>in vitro</i> synergy against β-lactamase-producing strains. However, data are limited and conflicting, potentially attributed to variations among the examined strains. This study investigated whether loss of porins OmpK35 and OmpK36 impacts the synergistic potential of colistin in combination with ceftazidime-avibactam or meropenem-avibactam against β-lactamase-producing <i>Klebsiella pneumoniae</i>. Genetically modified strains were constructed by introducing <i>bla</i>_CTX-M-15, <i>bla</i>_KPC-2, and <i>bla</i>_OXA-48 chromosomally into <i>K. pneumoniae</i> ATCC 35657, in which the major porin-encoding genes (<i>ompK35</i>, <i>ompK36</i>) were either intact or knocked out. The <i>in vitro</i> activity of colistin in combination with ceftazidime-avibactam or meropenem-avibactam was evaluated by time-lapse microscopy screening and in static time-kill experiments. The deletion of porins in the β-lactamase-producing strains resulted in 2- to 128-fold increases in MICs for the β-lactams and BLBLIs. The activity of avibactam was concentration-dependent, and 4- to 16-fold higher concentrations were required to achieve similar inhibition of the β-lactamases in strains with porin loss. In the screening, synergy was observed for colistin and ceftazidime-avibactam against the CTX-M-15-producing strains and colistin and meropenem-avibactam against the KPC-2- and OXA-48-producing strains. The combination effects were less pronounced in the time-kill experiments, where synergy was rarely detected. No apparent associations were found between the loss of OmpK35 and OmpK36 and combination effects with colistin and BLBLIs, indicating that additional factors determine the synergistic potential of such combinations.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370829","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":"Relative inhibitory activities of newly developed diazabicyclooctanes, boronic acid derivatives, and penicillin-based sulfone β-lactamase inhibitors against broad-spectrum AmpC β-lactamases.","authors":"Christophe Le Terrier, Patrik Mlynarcik, Mustafa Sadek, Patrice Nordmann, Laurent Poirel","doi":"10.1128/aac.00775-24","DOIUrl":"https://doi.org/10.1128/aac.00775-24","url":null,"abstract":"<p><p>The relative inhibitory activities of diazabicyclooctanes (avibactam, relebactam, zidebactam, nacubactam, durlobactam), boronic acid derivatives (vaborbactam, taniborbactam, xeruborbactam), and penicillin-based sulfone derivative enmetazobactam were evaluated against several intrinsic and acquired class C β-lactamases. By contrast to vaborbactam and enmetazobactam, taniborbactam, xeruborbactam, and all diazabicyclooctanes demonstrated effective activities against most AmpC enzymes. Notably, durlobactam exhibited the most pronounced inhibitory effect. Interstingly, the chromosomal AmpC of <i>Acinetobacter baumannii</i> was the least sensitive enzyme to the newly developed β-lactamase inhibitors.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370830","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":"Oral oxaborole MRX-5 exhibits efficacy against pulmonary <i>Mycobacterium abscessus</i> in mouse.","authors":"Binayak Rimal, Ruth A Howe, Chandra M Panthi, Wen Wang, Gyanu Lamichhane","doi":"10.1128/aac.01351-24","DOIUrl":"https://doi.org/10.1128/aac.01351-24","url":null,"abstract":"<p><p><i>Mycobacterium abscessus (Mab</i>) is an opportunistic pathogen common in patients with lung comorbidities and immunosuppression. There are no FDA-approved treatments, and current treatment has a failure rate exceeding 50%. The intravenous oxaborole MRX-6038 is active against <i>Mab</i>. This study evaluated MRX-5, the oral prodrug, against five <i>Mab</i> isolates in a mouse lung infection model. MRX-5 showed dose-dependent efficacy, with 15 and 45 mg/kg doses comparable to the standard of care, supporting progression to clinical trial.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364182","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 glutamate receptor antagonist ifenprodil inhibits hepatitis E virus infection.","authors":"Mara Klöhn, André Gömer, Qiyu He, Richard J P Brown, Daniel Todt, Lin Wang, Eike Steinmann","doi":"10.1128/aac.01035-24","DOIUrl":"https://doi.org/10.1128/aac.01035-24","url":null,"abstract":"<p><p>Infection with hepatitis E virus (HEV) represents a global problem, with over 20 million people infected annually. No specific antiviral drugs are available for treating HEV infection, necessitating the development of novel targeted therapeutics. Here, we report that the N-methyl-D-aspartate receptor (NMDAR) antagonist ifenprodil, a clinically approved drug used to treat idiopathic pulmonary fibrosis (IPF), is an HEV inhibitor in liver-derived cells. <i>In vitro</i> investigation demonstrates that ifenprodil suppresses viral protein expression in a dose-dependent manner in human hepatoma cells by inhibiting early stages of viral infection. We also found that ifenprodil modulates host cell intrinsic biological processes distinct from virus-induced innate immunity, inhibiting HEV RNA accumulation in primary human hepatocytes. Finally, the inhibitory effect of ifenprodil <i>in vivo</i> was also tested in rabbits challenged with the HEV-3ra CHN-BJ-R14 strain. Fecal virus shedding was below the limit of detection in two animals for both ribavirin-treated and ifenprodil-treated rabbits compared to vehicle-treated control animals. Our data demonstrate that ifenprodil is an effective anti-HEV compound with potential as a therapeutic candidate for the treatment of HEV infection.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364183","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":"Intrapulmonary pharmacokinetics of SPR719 following oral administration of SPR720 to healthy volunteers.","authors":"Keith A Rodvold, Mark H Gotfried, Xilla T Ussery, Shekman L Wong, Kamal A Hamed","doi":"10.1128/aac.01103-24","DOIUrl":"https://doi.org/10.1128/aac.01103-24","url":null,"abstract":"<p><p>SPR720 is a phosphate ester prodrug that is converted rapidly <i>in vivo</i> to SPR719, the active moiety, which exhibits potent <i>in vitro</i> activity against clinically relevant mycobacterial species including <i>Mycobacterium avium</i> complex (MAC) and <i>Mycobacterium abscessus</i>. SPR720 is in clinical development for the treatment of nontuberculous mycobacterial pulmonary disease (NTM-PD) due to MAC. This study evaluated the safety and the intrapulmonary pharmacokinetics of SPR719 in healthy volunteers. A total of 30 subjects received oral SPR720 1,000 mg once daily for 7 days followed by bronchoscopy and bronchoalveolar lavage, with blood samples collected for plasma pharmacokinetic assessments. Mean SPR719 area under the concentration-time curve from time 0 to 24 hours (AUC_0-24) and maximum concentration (<i>C</i>_max) for plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) were 52,418 ng·h/mL and 4,315 ng/mL, 59,880 ng·h/mL and 5,429 ng/mL, and 128,105 ng·h/mL and 13,033 ng/mL, respectively. The ratios of ELF to total plasma concentrations of SPR719 based on AUC_0-24 and <i>C</i>_max were 1.14 and 1.26, and the ratios of AM to total plasma concentrations of SPR719 based on AUC_0-24 and <i>C</i>_max were 2.44 and 3.02, respectively. When corrected for protein binding, the ratios of ELF to unbound plasma concentrations of SPR719 for AUC_0-24 and <i>C</i>_max were 19.87 and 21.88, and the ratios of AM to unbound plasma concentrations of SPR719 for AUC_0-24 and <i>C</i>_max were 42.50 and 52.53, respectively. No unexpected safety findings were observed. Results from this study of the intrapulmonary disposition of SPR719 support further investigation of SPR720 as a potential oral agent for the treatment of patients with NTM-PD.</p><p><strong>Clinical trials: </strong>This study is registered with ClinicalTrials.gov as NCT05955586.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339939","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":"Contribution of direct InhA inhibitors to novel drug regimens in a mouse model of tuberculosis.","authors":"Lourdes Encinas, Si-Yang Li, Joaquin Rullas-Trincado, Rokeya Tasneen, Sandeep Tyagi, Heena Soni, Adolfo Garcia-Perez, Jin Lee, Rubén González Del Río, Jaime De Mercado, Verónica Sousa, Izidor Sosič, Stanislav Gobec, Alfonso Mendoza-Losana, Paul J Converse, Khisi Mdluli, Nader Fotouhi, David Barros-Aguirre, Eric L Nuermberger","doi":"10.1128/aac.00357-24","DOIUrl":"https://doi.org/10.1128/aac.00357-24","url":null,"abstract":"<p><p>Isoniazid is an important first-line medicine to treat tuberculosis (TB). Isoniazid resistance increases the risk of poor treatment outcomes and development of multidrug resistance, and is driven primarily by mutations involving <i>katG</i>, encoding the prodrug-activating enzyme, rather than its validated target, InhA. The chemical tractability of InhA has fostered efforts to discover direct inhibitors of InhA (DIIs). In this study, we bridge the gap in understanding the potential contribution of DIIs to novel combination regimens and demonstrate a clear distinction of DIIs, like GSK693 and the newly described GSK138, from isoniazid, based on activity against clinical isolates and contribution to novel drug regimens. The results suggest that DIIs, specifically GSK138 and GSK693, could be promising partners in novel drug regimens, including those used against isoniazid-resistant TB, potentially enhancing their efficacy and/or preventing the selection of resistant mutants and supporting the continued exploration of InhA as a promising target for TB drug development.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339925","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":"Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis.","authors":"Allison A Bauman, Jansy P Sarathy, Firat Kaya, Lisa M Massoudi, Michael S Scherman, Courtney Hastings, Jiuyu Liu, Min Xie, Elizabeth J Brooks, Michelle E Ramey, Isabelle L Jones, Noalani D Benedict, Madelyn R Maclaughlin, Jake A Miller-Dawson, Samanthi L Waidyarachchi, Michelle M Butler, Terry L Bowlin, Matthew D Zimmerman, Anne J Lenaerts, Bernd Meibohm, Mercedes Gonzalez-Juarrero, Michael A Lyons, Veronique Dartois, Richard E Lee, Gregory T Robertson","doi":"10.1128/aac.00716-24","DOIUrl":"https://doi.org/10.1128/aac.00716-24","url":null,"abstract":"<p><p>The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by <i>Mycobacterium tuberculosis</i>. Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. Here, we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models, including mice exhibiting advanced pulmonary disease, can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339943","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":"Prevalence of the cefazolin inoculum effect (CzIE) in nasal colonizing methicillin-susceptible <i>Staphylococcus aureus</i> in patients from intensive care units in Colombia and use of a modified rapid nitrocefin test for detection.","authors":"Lina P Carvajal, Sandra Rincon, Sara I Gomez Villegas, J Manuel Matiz-Gonzalez, Karen Ordoñez, Alejandra Santamaria, Leonardo Ospina Navarro, Jaime Beltran, Fredy Guevara, Yardany R Mendez, Soraya Salcedo, Alexandra Porras, Albert Valencia-Moreno, Haley Greenia, Alexander Deyanov, Rodrigo Baptista, Vincent H Tam, Diana Panesso, Truc T Tran, William R Miller, Cesar A Arias, Jinnethe Reyes","doi":"10.1128/aac.00898-24","DOIUrl":"https://doi.org/10.1128/aac.00898-24","url":null,"abstract":"<p><p>The cefazolin inoculum effect (CzIE) has been associated with poor clinical outcomes in patients with methicillin-susceptible <i>Staphylococcus aureus</i> (MSSA) infections. We aimed to investigate the point prevalence of the CzIE among nasal colonizing MSSA isolates from ICU patients in a multicenter study in Colombia (2019-2023). Patients underwent nasal swabs to assess for <i>S. aureus</i> colonization on admission to the ICU, and some individuals had follow-up swabs. We performed cefazolin MIC by broth microdilution using standard and high inoculum and developed a modified nitrocefin-based rapid test to detect the CzIE. Whole-genome sequencing was carried out to characterize BlaZ types and allotypes, phylogenomics, and Agr-typing. A total of 352 patients were included; 46/352 (13%) patients were colonized with <i>S. aureus</i> and 22% (10/46) and 78% (36/46) with MRSA and MSSA, respectively. Among 36 patients who contributed with 43 MSSA colonizing isolates, 21/36 (58%) had MSSA exhibiting the CzIE. BlaZ type A and BlaZ-2 were the predominant type and allotype in 56% and 52%, respectively. MSSA belonging to CC30 were highly associated with the CzIE, and single-nucleotide polymorphism (SNP) analyses supported possible transmission of MSSA exhibiting the CzIE among some patients of the same unit. The modified nitrocefin rapid test had 100%, 94.4%, and 97.7% sensitivity, specificity, and accuracy, respectively. We found a high point prevalence of the CzIE in MSSA colonizing the nares of critically ill patients in Colombia. A modified rapid test was highly accurate in detecting the CzIE in this patient population.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339942","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}