Antimicrobial Agents and Chemotherapy最新文献

{"title":"Clinical outcomes and pharmacokinetics/pharmacodynamics of intravenous polymyxin B treatment for various site carbapenem-resistant gram-negative bacterial infections: a prospective observational multicenter study.","authors":"Zhenwei Yu, Huangdu Hu, Xiaofen Liu, Jieqiong Liu, Lingyan Yu, Anqi Wei, Chuanwei Xin, Yongxiong Gan, Shu Lei, Li Zhuang, Yanfei Shen, Xiaoxing Du, Jianping Zhu, Yi Yang, Gang Liang, Feng Guo, Jing Zhang, Yunsong Yu","doi":"10.1128/aac.01859-24","DOIUrl":"https://doi.org/10.1128/aac.01859-24","url":null,"abstract":"<p><p>Polymyxin B, a last resort for carbapenem-resistant gram-negative bacteria (CRGNB) infections, has infection site-specific pharmacokinetic/pharmacodynamic (PK/PD) properties. However, there is little clinical evidence to support optimal exposures of polymyxin B for different site infections. We performed a prospective, observational, multicenter study to evaluate the clinical outcomes and PK/PD of intravenous polymyxin B treatment for various site CRGNB infections. The main clinical outcomes were 14-day all-cause mortality and nephrotoxicity, and the secondary outcomes were 28-day mortality and clinical response. The area under curves (AUCs) of polymyxin B were determined, and their associations with clinical outcomes were analyzed by stratification based on the infection site. A total of 312 patients were ultimately enrolled from 10 research centers. The overall 14-day mortality was 29.5%, and those of patients with lower respiratory tract infection (LRTI), intra-abdominal infection (IAI), and bloodstream infection (BSI) were 32.3%, 19.7%, and 30.3%, respectively. The 28-day mortality rate was 38.1%, while LRTI patients had the highest mortality (41.4%) and IAI patients lowest (34.8%). The clinical response rate was 46.2%, which was similar among the subgroups. The overall AKI rate was 60.9%. An AUC greater than 50 mg∙h/L was related to lower mortality in IAI patients but not in LRTI patients, which led to a lower but not significant difference in the overall analysis. The AUC of polymyxin B was an independent risk factor for 14-day mortality in IAI patients, and the cutoff value was 76 mg∙h/L. The results would be helpful for personalized dosing and monitoring of polymyxin B.CLINICAL TRIALSThis study is registered with the Chinese Clinical Trial Registry as ChiCTR2200056667.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0185924"},"PeriodicalIF":4.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565863","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 susceptibility of <i>Stenotrophomonas maltophilia</i> from United States medical centers (2019-2023).","authors":"Helio S Sader, Mariana Castanheira, S J Ryan Arends, Timothy B Doyle","doi":"10.1128/aac.00124-25","DOIUrl":"https://doi.org/10.1128/aac.00124-25","url":null,"abstract":"<p><p>We evaluated the antimicrobial susceptibility of 1,400 clinical isolates of <i>Stenotrophomonas maltophilia</i> consecutively collected from United States medical centers in 2019-2023. Aztreonam-avibactam (MIC_50/90, 2/4 µg/mL; 99.6% inhibited at ≤8 µg/mL) was the most active compound, followed by trimethoprim-sulfamethoxazole (MIC_50/90, ≤0.12/0.5 µg/mL; 96.9% susceptible), minocycline (MIC_50/90, 0.5/2 µg/mL; 89.2% susceptible), and levofloxacin (MIC_50/90, 1/8 µg/mL; 78.9% susceptible). Aztreonam-avibactam retained potent activity against isolates not susceptible to trimethoprim-sulfamethoxazole, minocycline, and/or levofloxacin (99.3%-100.0% inhibited at ≤8 µg/mL).</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0012425"},"PeriodicalIF":4.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565862","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 stress-protectant molecule trehalose mediates fluconazole tolerance in <i>Candida glabrata</i>.","authors":"Qingjuan Zhu, Stefanie Wijnants, Regina Feil, Wouter Van Genechten, Rudy Vergauwen, Odessa Van Goethem, John E Lunn, Mieke Van Ende, Patrick Van Dijck","doi":"10.1128/aac.01349-24","DOIUrl":"10.1128/aac.01349-24","url":null,"abstract":"<p><p>The incidence of non-<i>albicans Candida</i> infections has witnessed a substantial rise in recent decades. <i>Candida glabrata (Nakaseomyces glabratus</i>), an opportunistic human fungal pathogen, is accountable for both superficial mucosal and life-threatening bloodstream infections, particularly in immunocompromised individuals. Distinguished by its remarkable resilience to environmental stressors, <i>C. glabrata</i> exhibits intrinsic tolerance to azoles and a high propensity to swiftly develop azole resistance during treatment. The molecular mechanism for the high tolerance is not fully understood. In this work, we investigated the possible role of trehalose in this tolerance. We generated mutants in the <i>C. glabrata TPS1</i>, <i>TPS2</i>, and <i>NTH1</i> genes, encoding trehalose 6-phosphate synthase (Tps1), trehalose 6-phosphate phosphatase (Tps2), and neutral trehalase (Nth1), respectively. As expected, the <i>tps1∆</i> strain cannot grow on glucose. The <i>tps2</i>∆ strain demonstrated diminished trehalose accumulation and very high levels of trehalose 6-phosphate (T6P), the biosynthetic intermediate, in comparison to the wild-type (WT) strain. Whereas these higher T6P levels did not affect growth, the lower trehalose levels clearly resulted in lower environmental stress tolerance and a lower susceptibility to fluconazole. More interestingly, the <i>tps2∆</i> strain completely lost tolerance to fluconazole, characterized by the absence of slow growth at supra-MIC concentrations of this drug. All these phenotypes are reversed in the <i>nth1</i>∆ strain, which accumulates high levels of trehalose. Our findings underscore the role of trehalose in enabling tolerance toward fluconazole in <i>C. glabrata</i>. We further show that the change in tolerance is a result of the effect that trehalose has on the sterol pattern in the cell.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0134924"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single- and multiple-dose pharmacokinetics and safety of the SARS-CoV-2 3CL protease inhibitor RAY1216: a phase 1 study in healthy participants.","authors":"Yue Hu, Haijun Li, Kun Wang, Dandan Wu, Hong Zhang, Yanhua Ding, Junyan Wu, Suiwen Ye, Yun Peng, Li Liu","doi":"10.1128/aac.01450-24","DOIUrl":"10.1128/aac.01450-24","url":null,"abstract":"<p><p>Coronavirus disease 2019, which leads to pneumonia, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RAY1216 is a 3C-like protease inhibitor that targets SARS-CoV-2. The aim of our study was to assess the pharmacokinetics (PK) and safety of RAY1216 in healthy volunteers. This was a randomized, placebo-controlled, double-blind study consisting of four components: a single ascending dose study, a drug-drug interaction study, a multiple ascending dose study, and a food-effect study. All participants were randomly assigned to receive either a single dose or multiple doses of RAY1216 or placebo. A total of 88 healthy adult participants (male-to-female ratio of 1:1) aged 18-50 years were enrolled. A total of 37 participants (42%) experienced at least one adverse event (AE). All AEs were mild or moderate and were resolved without additional treatment. The most commonly reported adverse drug reactions were hypertriglyceridemia, hyperuricemia, and elevated serum creatinine levels. RAY1216 was well-absorbed after administration with exposure increasing in a dose-dependent manner. Food appeared to increase exposure and delay the absorption of RAY1216. Ritonavir significantly inhibited drug metabolism, and increased drug exposure increased the associated safety risks. RAY1216 was found to be well tolerated and safe in healthy participants. On the basis of preclinical results, PK characteristics, and the safety profile of RAY1216, a dosage of 400 mg three times daily was selected, thereby establishing a foundation for future research and for the clinical application of RAY1216.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT05829551.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0145024"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Xpert MTB/RIF Ultra-resistant and MTBDR<i>plus-</i>susceptible rifampicin results in people with tuberculosis: utility of FluoroType MTBDR and deep sequencing.","authors":"Yonas Ghebrekristos, Aysha Ahmed, Natalie Beylis, Sarishna Singh, Christoffel Opperman, Fahd Naufal, Megan Folkerts, David Engelthaler, Erick Auma, Rouxjeane Venter, Ghowa Booley, John Metcalfe, Robin Warren, Grant Theron","doi":"10.1128/aac.01671-24","DOIUrl":"10.1128/aac.01671-24","url":null,"abstract":"<p><p>Xpert MTB/RIF Ultra (Ultra)-detected rifampicin-resistant tuberculosis (TB) is often programmatically confirmed using MTBDR<i>plus</i>. There are limited data on discordant results, including when re-tested using newer methods, like FluoroType MTBDR (FT-MTBDR) and targeted deep sequencing. MTBDR<i>plus</i> rifampicin-susceptible isolates from people with Ultra rifampicin-resistant sputum were identified from a South African programmatic laboratory. FT-MTBDR and single molecule-overlapping reads (SMOR; <i>rpoB</i>, <i>inhA</i>, <i>katG</i>) on isolate DNA were done (SMOR was used as a reference standard). Between 1 April 2021 and 30 September 2022, 8% (109/1347) of Ultra rifampicin-resistant specimens were MTBDR<i>plus</i>-susceptible. Of 89% (97/109) isolates with a sequenceable <i>rpoB</i>, SMOR resolved most in favor of Ultra (79% [77/97]). Sputum with lower mycobacterial load was associated with Ultra false-positive resistance (46% [11/24] of \"very low\" Ultra had false resistance vs 12% [9/73; <i>P</i> = 0.0004] of ≥\"low\"), as were Ultra heteroresistance calls (all wild-type probes, ≥1 mutant probe) (62% [23/37 vs 25% 15/60] for Ultra without heteroresistance calls; <i>P</i> = 0.0003). Of the 91% (88/97) of isolates successfully tested by FT-MTBDR, 55% (48/88) were FT-MTBDR rifampicin-resistant and 45% (40/88) susceptible, translating to 69% (47/68) sensitivity and 95% (19/20) specificity. In the 91% (99/109) of isolates with <i>inhA</i> and <i>katG</i> sequenced, 62% (61/99) were SMOR isoniazid-susceptible. When Ultra and MTBDR<i>plus</i> rifampicin results are discordant, Ultra is more likely to be correct, and FT-MTBDR agrees more with Ultra than MTBDR<i>plus</i>; however, lower load and the Ultra heteroresistance probe pattern were risk factors for Ultra false rifampicin-resistant results. Most people with Ultra-MTBDR<i>plus</i> discordant resistance results were isoniazid-susceptible. These data have implications for drug-resistant TB diagnosis.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0167124"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic analyses reveal high diversity and rapid evolution of <i>Pichia kudriavzevii</i> within a neonatal intensive care unit in Delhi, India.","authors":"Kusum Jain, Yue Wang, Peeyush Jain, Barsha Kalita, Raju Shivarathri, Manju Chauhan, Hardeep Kaur, Neeraj Chauhan, Jianping Xu, Anuradha Chowdhary","doi":"10.1128/aac.01709-24","DOIUrl":"10.1128/aac.01709-24","url":null,"abstract":"<p><p><i>Pichia kudriavzevii</i> causes life-threatening infections in immunocompromised hosts, including hospitalized neonates. This pathogen is intrinsically resistant to fluconazole, while uncommon <i>P. kudriavzevii</i> strains resistant to multiple antifungal drugs, including voriconazole, amphotericin B, and echinocandins, have also been reported from healthcare environments. Thus, understanding how <i>P. kudriavzevii</i> spread, persist, and adapt to healthcare settings could help us develop better infection management strategies. In this study, whole genome sequencing identifies multiple outbreaks of bloodstream infections in a single neonatal intensive care unit (NICU) over 5 years caused by genetically diverse strains of <i>P. kudriavzevii</i>. Interestingly, two genetically distinct clusters of <i>P. kudriavzevii</i> strains showed frequent loss of heterozygosity (LOH) events between two temporal samples. The first outbreak cluster (2015-2016) showed LOH at chromosomes 1, 4, and 5, and the other outbreak cluster (2020) exhibited LOH at chromosome 2. The circulation of two separate strain clusters of <i>P. kudriavzevii</i> suggests nosocomial transmission in the NICU in different time periods. Furthermore, we compared the transcriptomic profiles of three isolates of clusters I and II that exhibited distinct fluconazole and itraconazole MICs. While no significant difference in gene expression was found at the azole-target gene <i>ERG11</i> or the ATP-binding cassette (ABC) transporter genes, such differences were found in genes involved in cell division and filamentation, such as <i>SIR2</i> (sirtuin deacetylase) and <i>RFA1</i> (replication factor A). Interestingly, increased filamentation was observed in clade I isolate exhibiting high fluconazole MICs. Together, our study indicates significant diversity, persistence, and rapid evolution of <i>P. kudriavzevii</i> within a single NICU.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0170924"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of switching from entecavir to tenofovir alafenamide in chronic hepatitis B patients with low-level viremia: a real-world 48-week extension study.","authors":"Meng-Wen He, Li Cui, Dan-Dan Chen, Yun Zhao, Wen-Zhao Luo, Yun-Fei Jia, Jie Zhou, Qing-Juan He, Ying Dai, Wei-Hua Zhang, Zhao-Xia Yu, Wen-Chang Wang, Chang Guo, Yi-Ming Fu, Wu-Cai Yang, Xu-Yang Li, Yi-Fan Guo, Chun-Yan Wang, Jian-Jun Wang, Ping Li, Bing Qiao, Dong Ji, Zhong-Bin Li","doi":"10.1128/aac.01827-24","DOIUrl":"10.1128/aac.01827-24","url":null,"abstract":"<p><p>Chronic hepatitis B (CHB) patients receiving entecavir (ETV) treatment might develop low-level viremia (LLV), which is proven to be associated with worse clinical outcomes, such as risk of drug-related mutations, progression to cirrhosis, and even hepatocellular carcinoma. This real-world prospective study evaluated the efficacy and safety of switching from ETV to tenofovir alafenamide fumarate (TAF) in CHB patients with LLV. From August 2020 to August 2023, 351 ETV-experienced CHB patients with LLV were enrolled from eight hospitals. Patients either continued ETV or switched to TAF. The primary efficacy endpoint was the complete virological response (CVR) at week 48; the safety endpoint was the first occurrence of any clinical adverse event during the treatment; and the renal safety and change in blood lipids were also assessed. Inverse probability treatment weighting (IPTW) generated 350.9 cases in the ETV group and 351.4 cases in the TAF group. After the 48-week treatment, the CVR and ALT normalization rates in the TAF group were 75.3% and 67.8%, which were significantly higher than 11.4% and 17.1% in the ETV group (<i>P</i> < 0.001). The two strategies showed comparable impact on renal function and lipid profiles, regarding low-density lipoprotein (LDL) cholesterol and the total cholesterol to high-density lipoprotein (TC/HDL) ratio. Therefore, for ETV-treated patients with LLV, switching to TAF is superior compared with continuing ETV treatment in terms of virological and biochemical response, with non-inferior renal safety and lipid profiles.CLINICAL TRIALSThis study is registered with the Chinese Clinial Trial Registry as ChiCTR2400089257.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0182724"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-Lactamase diversity in <i>Pseudomonas aeruginosa</i>.","authors":"Andrew R Mack, Andrea M Hujer, Maria F Mojica, Magdalena A Taracila, Michael Feldgarden, Daniel H Haft, William Klimke, Arjun B Prasad, Robert A Bonomo","doi":"10.1128/aac.00785-24","DOIUrl":"10.1128/aac.00785-24","url":null,"abstract":"<p><p><i>Pseudomonas aeruginosa</i> is a clinically important Gram-negative pathogen responsible for a wide variety of serious nosocomial and community-acquired infections. Antibiotic resistance is a major concern, as this organism has a wide variety of resistance mechanisms, including chromosomal class C (<i>bla</i>_PDC) and D (<i>bla</i>_OXA-50 family) β-lactamases, efflux pumps, porin channels, and the ability to readily acquire additional β-lactamases. Surveillance studies can reveal the diversity and distribution of β-lactamase alleles but are difficult and expensive to conduct. Herein, we apply a novel approach, using publicly available data derived from whole genome sequences, to explore the diversity and distribution of β-lactamase alleles across 30,452 <i>P</i>. <i>aeruginosa</i> isolates. The most common alleles were <i>bla</i>_PDC-3, <i>bla</i>_PDC-5, <i>bla</i>_PDC-8, <i>bla</i>_OXA-488, <i>bla</i>_OXA-50, and <i>bla</i>_OXA-486. Interestingly, only 43.6% of assigned <i>bla</i>_PDC alleles were encountered, and the 10 most common <i>bla</i>_PDC and intrinsic <i>bla</i>_OXA alleles represent approximately 75% of their respective total alleles, while many other assigned alleles were extremely uncommon. As anticipated, differences were observed over time and geography. Surprisingly, more distinct unassigned alleles were encountered than distinct assigned alleles. Understanding the diversity and distribution of β-lactamase alleles helps to prioritize variants for further research, select targets for drug development, and may aid in selecting therapies for a given infection.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0078524"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isolation and characterization of <i>Plasmodium falciparum</i> blood-stage persisters by improved selection protocols using dihydroartemisinin alone.","authors":"Daniel Kiboi, Juliana M Sá, Akshaykumar Nayak, Chiara E Micchelli, Shuchi N Amin, Alexander G Burbelo, Sasha A Abielmona, Brian Xi, Lucia A Mulei, Noah M Onchieku, Caroline M Percopo, Jianbing Mu, Thomas E Wellems","doi":"10.1128/aac.00053-24","DOIUrl":"10.1128/aac.00053-24","url":null,"abstract":"<p><p>Artemisinin-based combination therapies (ACTs) are vital for malaria treatment, but these are threatened by blood-stage persisters-dormant forms of <i>Plasmodium</i> parasites that can survive drug exposure and cause recrudescent infections. Here, we present improved protocols for efficient preparation of pure <i>Plasmodium falciparum</i> persister populations without the need for magnetically activated columns, sorbitol exposure, or prolonged manipulations. Our protocols transformed actively replicating parasites into persister populations by exposing mixed blood-stage parasites to three or four consecutive daily 6 h pulses of 700 nM or 200 nM dihydroartemisinin (DHA). In micrographs of Giemsa-stained cells, we observed different persister morphologies: Type I persisters containing a rounded magenta-stained nucleus accompanied by a local region of blue-stained cytoplasm; and the more-prevalent Type II persisters characterized by a dark round or irregular-appearing nucleus and faded or no detectable cytoplasm. We also observed cells with disorganized nuclear and cytoplasmic structure, suggesting possible autophagic processes of destruction and remodeling. Recrudescence of actively replicating parasites to starting parasitemia or higher occurred around 17-22 days after initial DHA exposure. Differential expression patterns of the acetyl CoA carboxylase (<i>acc</i>) and skeleton binding protein 1 (<i>sbp1</i>) genes during DHA treatment, dormancy, and recrudescence highlighted the evolution of physiologic states and metabolic changes underlying persister formation and recovery. Our findings suggest hypotheses and questions for further research to understand the cellular pathways of dormancy and uncover strategies to thwart parasite survival after drug exposure.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0005324"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and bioequivalence of a molnupiravir tablet formulation compared with the molnupiravir capsule formulation in healthy adult participants-a randomized, open-label, three-period, crossover study.","authors":"Julie L Fiore, Yoon Jin, Tycho Heimbach, Shruti R Patel, Tian Zhao, Catherine Z Matthews, Sandra Pagnussat, Brian M Maas, Mickie H Cheng, S Aubrey Stoch","doi":"10.1128/aac.01434-24","DOIUrl":"10.1128/aac.01434-24","url":null,"abstract":"<p><p>Molnupiravir, a prodrug of β-D-N⁴-hydroxycytidine (NHC), is administered orally as four 200 mg capsules twice daily for 5 days to treat COVID-19. This randomized, open-label, four-treatment sequence, three-period crossover study (NCT06615869) evaluated the bioequivalence of a new single 400 mg oral dose of the molnupiravir tablet Formulation 1 (F1) to a 400 mg oral dose of the currently authorized molnupiravir capsule formulation (administered as two 200 mg capsules) by comparing the plasma pharmacokinetics of NHC following administration to healthy participants. The effect of food on the plasma NHC pharmacokinetics following the administration of the molnupiravir F1 tablet, safety and tolerability of a single oral 400 mg dose of molnupiravir, and pharmacokinetics of a separate molnupiravir tablet Formulation 2 (F2) with a slower <i>in vitro</i> dissolution rate were also evaluated. The geometric mean ratio and 90% confidence intervals ([1 × 400-mg F1 tablet]/[2 × 200 mg reference capsules]) for plasma NHC area under the concentration-time curve (AUC) from time 0-infinity, AUC from time 0-last measurable time point, and maximum plasma concentration were 1.00 (0.97, 1.03), 1.00 (0.97, 1.03), and 0.98 (0.93, 1.03), respectively. All estimates were within prespecified limits (0.80, 1.25), demonstrating bioequivalence of the molnupiravir F1 tablet and reference capsules. Administration of the F1 tablet with a high-fat meal did not meaningfully impact the rate or extent of absorption. The pharmacokinetics of the F2 tablet were similar to the reference capsules. Administered in either formulation, molnupiravir was generally safe and well tolerated. In conclusion, a single 400 mg tablet of molnupiravir is bioequivalent to the reference capsule formulation in healthy adults.CLINICAL TRIALSThis study was registered at ClinicalTrials.gov as NCT06615869.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0143424"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}