Antimicrobial Agents and Chemotherapy最新文献

{"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}

{"title":"Molecular epidemiology of β-lactamases in ceftriaxone-resistant Enterobacterales bloodstream infections in the mid-Atlantic United States.","authors":"Dariusz A Hareza, Yehudit Bergman, Emily Jacobs, Jennifer Lu, Nancy D Hanson, Rick Conzemius, Sara E Cosgrove, Anthony D Harris, Patricia J Simner, Pranita D Tamma","doi":"10.1128/aac.01258-24","DOIUrl":"10.1128/aac.01258-24","url":null,"abstract":"<p><p>Ceftriaxone-resistant Enterobacterales remain a public health threat; contemporary data investigating their molecular epidemiology are limited. Five hundred consecutive ceftriaxone-resistant (MIC ≥ 4 µg/mL) Enterobacterales bloodstream isolates were collected between 2018 and 2022 from three Maryland hospitals. Broth microdilution confirmed antibiotic susceptibilities. Whole-genome sequencing identified extended-spectrum β-lactamase (ESBL) and <i>ampC</i> genes both in bacterial chromosomes (c-<i>ampC</i>) and on plasmids (p-<i>ampC</i>). Mutations in promoter or attenuator regions of the <i>Escherichia coli</i> c-<i>ampC</i> gene (i.e., <i>bla</i>_EC gene) with the potential to result in <i>ampC</i> derepression were investigated. The presence of ESBL or <i>ampC</i> genes was confirmed in 497 (99.4%) isolates. Two hundred seventy-nine (55.8%) isolates had both ESBL and <i>ampC</i> genes. ESBL families were identified among 398 (80%) patients: <i>bla</i>_CTX-M (<i>n</i> = 370), <i>bla</i>_SHV (<i>n</i> = 17), <i>bla</i>_OXY (<i>n</i> = 14), and <i>bla</i>_VEB (<i>n</i> = 5). Ceftriaxone-resistant Enterobacterales species carrying ESBL genes included the following: <i>E. coli</i> (67%), <i>Klebsiella pneumoniae</i> (24%), <i>Klebsiella oxytoca</i> (4%), <i>Proteus mirabilis</i> (2%), <i>Enterobacter cloacae</i> complex (2%), <i>Klebsiella aerogenes</i> (1%), <i>Providencia stuartii</i> (<1%), and <i>Serratia marcescens</i> (<1%). c-<i>ampC</i> genes were identified in 374 (75%) of the 500 isolates. Only 7% of <i>E. coli</i> isolates with mutations in the promoter or attenuator region of the c-<i>ampC</i> gene exhibited resistance to cefoxitin, a proxy for increased AmpC production. Two p-<i>ampC</i> genes were confirmed in 25 (5%) of the 500 isolates: <i>bla</i>_CMY-59 (72%) and <i>bla</i>_DHA-1 (28%; confined to <i>E. coli</i> [92%] and <i>K. pneumoniae</i> [8%]). Until comprehensive β-lactamase molecular testing is available, the species-specific prevalence of ESBL and <i>ampC</i> genes in ceftriaxone-resistant Enterobacterales should be considered to promote effective albeit judicious antibiotic prescribing. Mutations in promoter or attenuator regions of the <i>E. coli</i> c-<i>ampC</i> gene do not appear to contribute significantly to increased AmpC production in this species.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0125824"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045210","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":"Population pharmacokinetics and pulmonary modeling of eravacycline and the determination of microbiological breakpoint and cutoff of PK/PD.","authors":"Xi-Wei Ji, Wen Yao Mak, Feng Xue, Wen-Yu Yang, Isabelle Hui-San Kuan, Xiao-Qiang Xiang, Yun Li, Xiao Zhu","doi":"10.1128/aac.01065-24","DOIUrl":"10.1128/aac.01065-24","url":null,"abstract":"<p><p>Eravacycline is a broad-spectrum fluorocycline currently approved for complicated intra-abdominal infections (cIAIs). In lung-infection models, it is effective against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and tetracycline-resistant MRSA. As such, we aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model to evaluate eravacycline's pulmonary distribution and kinetics. Data were extracted from a Phase I study (NCT01989949) which assessed the bronchopulmonary disposition of intravenous eravacycline to construct the population PK model that could adequately describe the drug's pulmonary kinetics. Eravacycline lung PK was best described by a three-compartment model with allometric scaling, with the epithelial lining fluid (ELF) component parameterized as the ELF distribution ratio ([Formula: see text], unbound concentration in ELF over central compartment). The estimated ELF distribution ratio was 8.26 (95% confidence interval = 6.8-9.8). Besides allometrically scaled weight, no other significant covariate was found. MIC₉₀ was 0.5 mg/L (<i>Escherichia coli</i>), 2 mg/L (<i>Klebsiella pneumoniae</i>), 0.5 mg/L (<i>Acinetobacter baumannii</i>), and 0.12 mg/L (<i>S. aureus</i>). At the approved cIAI dosage or higher (1 mg/kg or 1.5 mg/kg q12h), a PK/PD cutoff value of 2 mg/L was appropriate for <i>E. coli</i>, while a lower value of 1 mg/L was selected for <i>K. pneumoniae</i>, <i>A. baumannii</i>, and <i>S. aureus</i>. For lower doses, the cutoff value was reduced to 0.5 mg/L for <i>K. pneumoniae</i>, <i>A. baumannii</i>, and <i>S. aureus</i>. The study showed eravacycline was widely distributed into the lungs with promising antibacterial efficacy, thus justifying further investigations into its uses for pulmonary infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0106524"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057850","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":"Assessing the threat of <i>Yersinia pestis</i> harboring a multi-resistant IncC plasmid and the efficacy of an antibiotic targeting LpxC.","authors":"Nadine Lemaitre, Amélie Dewitte, Faniry Rakotomanimana, David Gooden, Eric Toone, Minoarisoa Rajerison, Pei Zhou, Florent Sebbane","doi":"10.1128/aac.01497-24","DOIUrl":"10.1128/aac.01497-24","url":null,"abstract":"<p><p>Self-transmissible IncC plasmids rapidly spread multidrug resistance in many medically important pathogens worldwide. A large plasmid of this type (pIP1202, ~80 Kb) has been isolated in a clinical isolate of <i>Yersinia pestis</i>, the agent of plague. Here, we report that pIP1202 was highly stable in <i>Y. pestis-</i>infected mice and fleas and did not reduce <i>Y. pestis</i> virulence in these animals. Although pIP1202 inflicted a fitness cost in fleas (but not in mice) when the insects fed on blood containing a mixture of plasmid-free and plasmid-bearing strains, such a co-infection scenario has never been reported in nature, indicating that pIP1202 could persist in <i>Y. pestis</i> strains. Despite being resistant to commonly used antibiotic treatments, we show that plague caused by <i>Y. pestis</i> harboring the pIP1202 plasmid is effectively cured by LPC-233-a potent inhibitor of the essential LpxC enzyme in the lipid A biosynthetic pathway. Taken as a whole, our data highlight the alarming threat posed by <i>Y. pestis</i> harboring multidrug-resistant IncC plasmids that may persist in wild animals as a reservoir for long periods without antibiotic pressure and illuminate the impact of antibiotics with a novel mode of action against such a biothreat.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0149724"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063382","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":"Cefepime-taniborbactam and ceftibuten-ledaborbactam maintain activity against KPC variants that lead to ceftazidime-avibactam resistance.","authors":"Cullen L Myers, Annie Stevenson, Brittany Miller, Denis M Daigle, Tsuyoshi Uehara, Daniel C Pevear","doi":"10.1128/aac.01511-24","DOIUrl":"10.1128/aac.01511-24","url":null,"abstract":"<p><p><i>Klebsiella pneumoniae</i> carbapenemases (KPCs) are widespread β-lactamases that are a major cause of clinical non-susceptibility of Gram-negative bacteria to carbapenems and other β-lactam antibiotics. Ceftazidime combined with the β-lactamase inhibitor avibactam (CAZ-AVI) has been effective in treating infections by KPC-producing bacteria, but emerging KPC variants confer resistance to the combination. Taniborbactam and ledaborbactam are bicyclic boronate β-lactamase inhibitors currently under development with cefepime and ceftibuten, respectively, to treat carbapenem-resistant bacterial infections. Here, we assessed the effects of clinically important KPC-2 and KPC-3 variants (V240G, D179Y, and D179Y/T243M) on the antibacterial activity of cefepime-taniborbactam (FEP-TAN) and ceftibuten-ledaborbactam (CTB-LED) and examined catalytic activity and inhibition of these variants. Unlike CAZ-AVI, FEP-TAN and CTB-LED were highly active against <i>Escherichia coli</i> strains expressing these KPC variants. Experiments with purified enzymes showed that FEP and CTB were poorly hydrolyzed by the KPC variants and had weak affinity for variants containing D179Y. In addition, the D179Y substitution in KPC-2 reduced inhibition by TAN and LED, but inactivation efficiencies (<i>k</i>₂/<i>K</i>) for these inhibitors were significantly higher than those for AVI. <i>K</i>₂/<i>K</i> was less affected for D179Y-containing KPC-3 variants, and robust inhibition was observed by TAN, LED, and AVI. Together, the findings illustrate a biochemical basis for FEP-TAN and CTB-LED efficacy in KPC variant-mediated CAZ-AVI resistance backgrounds, whereby the boronate inhibitors have sufficient inhibitory activity, while FEP and CTB are poor substrates and bind to the variant enzymes with reduced affinity.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0151124"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381638","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":"Restoring cefepime activity against multidrug-resistant KPC-producing <i>Klebsiella pneumoniae</i> by combination with boronic acid inhibitors, MB076 and S02030.","authors":"Laura J Rojas, Travis B Nielsen, Paul Pantapalangkoor, Magdalena A Taracila, Maria L Introvigne, Rajnikant Sharma, Shekhar Yeshwante, Maria F Mojica, Krisztina M Papp-Wallace, Andrea M Hujer, Fabio Prati, Emilia Caselli, Brad Spellberg, Philip N Rather, Gauri G Rao, Robert A Bonomo","doi":"10.1128/aac.00964-24","DOIUrl":"10.1128/aac.00964-24","url":null,"abstract":"<p><p>Foremost in the design of new β-lactamase inhibitors (BLIs) are the boronic acid transition state inhibitors (BATSIs). Two highly potent BATSIs being developed are S02030 and MB076 strategically designed to be active against cephalosporinases and carbapenemases, especially KPC. When combined with cefepime, S02030 and MB076 demonstrated potent antimicrobial activity against laboratory and clinical strains of <i>Enterobacterales</i> expressing a variety of class A and class C β-lactamases, including <i>bla</i>_KPC-2 and <i>bla</i>_KPC-3. Static time-kill assays revealed the bactericidal activity of cefepime in combination with S02030 and MB076 against a multidrug-resistant KPC-producing <i>K. pneumoniae</i> (KPC-<i>Kpn</i>-1), in which a ≥ 3-log₁₀ decrease in the bacterial density was observed by 6 h. <i>In vivo</i> efficacy of MB076 in combination with cefepime was evaluated in a lung infection model where male C57BL/6 mice were infected intranasally with KPC-<i>Kpn</i>-1. Cefepime alone administered at 2 h post infection resulted in a 1.07 log₁₀ CFU reduction at 24 h, while cefepime in combination with MB076 resulted in an enhanced reduction of 2.70 log₁₀ CFU (<i>P</i> < 0.0001) compared to the no treatment control group. In a survival analysis where mice were infected via the tail vein with KPC-<i>Kpn</i>-1<i>,</i> all mice treated with placebo or cefepime alone (100 mg/kg) died, whereas those treated with a 1:4 molar ratio of cefepime-MB076 survived. Our data demonstrate bactericidal activity and <i>in vivo</i> efficacy of cefepime-MB076 comparable to ceftazidime-avibactam and support the continued development of this combination as a new treatment option for infections caused by class A carbapenemase producing <i>Enterobacterales,</i> particularly KPC-<i>Kpn</i>.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0096424"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051417","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":"Artemisinin pressure in field isolates can select highly resistant <i>Plasmodium falciparum</i> parasites with unconventional phenotype and no K13 mutation.","authors":"Lucie Paloque, Luana Mathieu, Marion Laurent, Romain Coppée, Stéphanie Blandin, Pascal Campagne, Jean-Michel Augereau, Lise Musset, Françoise Benoit-Vical","doi":"10.1128/aac.01541-24","DOIUrl":"10.1128/aac.01541-24","url":null,"abstract":"<p><p>Artemisinin resistance, which poses a serious threat to malaria control efforts, is monitored in the field by delayed parasite clearance in patients, elevated parasite survival rate in the ring-stage survival assay, and mutations in the <i>Plasmodium falciparum kelch13</i> gene. However, sporadic cases of artemisinin-resistant malaria do not meet all of these criteria, highlighting that our understanding of artemisinin resistance is still incomplete. Here, we selected for artemisinin resistance <i>in vitro</i> in nine <i>P. falciparum</i> field isolates from Africa, Asia, and South America. Artemisinin pressure selected highly resistant parasites in all lineages, but only one acquired a validated <i>pfkelch13</i> mutation. Phenotypic tests evidenced an unconventional response of selected parasites that can be artemisinin-resistant only at an advanced ring age, making them undetectable by the standard \"0-3 h\" test used to monitor resistance. These results highlight the need for broader approaches to artemisinin resistance monitoring.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0154124"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187620","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":"Double carbapenemases in <i>Klebsiella pneumoniae</i> blood isolates: dissemination in a single medical center via multiple plasmids and a variety of highly efficient clones.","authors":"Anastasia Rigatou, Ayorinde O Afolayan, Elizabeth-Barbara Tatsi, Ioannis Deliolanis, Athanasios Michos, Sandra Reuter, George L Daikos","doi":"10.1128/aac.01462-24","DOIUrl":"10.1128/aac.01462-24","url":null,"abstract":"<p><p>Acquisition of multiple carbapenemase genes by <i>Klebsiella pneumoniae</i> (Kp) is an emerging public health threat. Here, we aim to elucidate the population structure of Kp blood isolates carrying two different carbapenemase genes and identify the mechanism facilitating their dissemination. The study was conducted in a tertiary healthcare center between 2014 and 2022. Twenty-four patients with bacteremia caused by Kp carrying two different carbapenemase genes were identified. All 24 blood isolates were analyzed by short-read genome sequences supplemented by long reads in a selected number of isolates. All isolates carried <i>bla</i>_KPC (23 <i>bla</i>_KPC-2, 1 <i>bla</i>_KPC-3) and <i>bla</i>_VIM-1 genes, along with a variety of antimicrobial resistance determinants. The isolates were clustered in six clonal lineages (ST39, ST147, ST323, ST258, ST3035, and ST340). Long-read genome sequences demonstrated that each carbapenemase gene was located in a separate group of plasmids: the <i>bla</i>_KPC-2 on a fusion of IncFIB(pQil) and IncFII(K) plasmids, the <i>bla</i>_KPC-3 on IncX3, the <i>bla</i>_VIM-1 on IncC, or a fusion of the IncFIB(pNDM-Mar) and IncHI1B(pNDM-MAR) plasmids. Comparison of plasmid content of eight isolates carrying a single carbapenemase gene from a previous study with eight isolates carrying two carbapenemase genes from the present study, matched by clonal lineages, revealed that the second carbapenemase gene was acquired by addition of another plasmid. Identical plasmids were found within the same lineage and across lineages. These findings suggest that dissemination of carbapenemase genes in our hospital setting was driven by multiple plasmids across a variety of highly efficient clones.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0146224"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078442","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":"Prediction of higher ceftazidime-avibactam concentrations in the human renal interstitium compared with unbound plasma using a minimal physiologically based pharmacokinetic model developed in rats and pigs through microdialysis.","authors":"Maxime Vallée, Vincent Aranzana-Climent, Jérémy Moreau, Isabelle Lamarche, Théo Fontanier, Céline Barc, Nathalie Kasal-Hoc, Céline Debiais-Delpech, Hélène Mirfendereski, Jérémy Pezant, Anne Pinard, Jonathan Clarhaut, William Couet, France Cazenave-Roblot, Sandrine Marchand","doi":"10.1128/aac.01518-24","DOIUrl":"10.1128/aac.01518-24","url":null,"abstract":"<p><p>Last resort antibiotics, like ceftazidime-avibactam (CZA), were used to treat urinary tract infections caused by multidrug-resistant bacteria. However, no data on tissue distribution were available. Our aim was to describe the <i>in vivo</i> kidney distribution of CZA in healthy rats and pigs using a physiologically based pharmacokinetic model (PBPK). Microdialysis probes were inserted into the blood, muscle, and kidney of both species. The experiment started with a retrodialysis by drug period. An i.v. single dose of CZA was administered. Samples were collected for 3 h in rats and 7 h in pigs. A PBPK model was developed to describe tissue and blood CZA pharmacokinetics in animals and to predict human concentrations. The PBPK model adequately described CZA rat and pig data in each tissue and blood. In both species, the concentration profiles of CZA in muscle and blood were almost superimposed, with muscle-to-plasma area under the curve (AUC) ratios close to one. However, kidney CZA concentrations were higher than those in blood, as indicated by kidney-to-plasma AUC ratios exceeding one (respectively 2.27 in rats and 2.63 in pigs for ceftazidime [CAZ]; 2.7 in rats and 4.5 in pigs for avibacam [AVI]). Prediction of human concentrations led to same observations. This study demonstrated an excellent penetration of CZA into the renal parenchyma of rats and pigs. Our PBPK model adequately described the data, and AUCs were higher in the renal cortex interstitium compared with unbound plasma. Our data suggested that the joint PK/PD target for CZA in humans could be attained with reduced CZA doses.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0151824"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254536","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":"Enhanced suppression of <i>Stenotrophomonas maltophilia</i> by a three-phage cocktail: genomic insights and kinetic profiling.","authors":"Alisha N Monsibais, Olivia Tea, Pooja Ghatbale, Sage J B Dunham, Mirjam Zünd, Jennifer Phan, Karen Lam, McKenna Paulson, Natalie Tran, Diana S Suder, Alisha N Blanc, Cyril Samillano, Joy Suh, Hanna Atif, Ethan Vien, Ryan Nguyen, Allene Vo, Shane Gonen, David Pride, Katrine Whiteson","doi":"10.1128/aac.01162-24","DOIUrl":"10.1128/aac.01162-24","url":null,"abstract":"<p><p><i>Stenotrophomonas maltophilia</i> is an understudied, gram-negative, aerobic bacterium that is widespread in the environment and increasingly a cause of opportunistic infections. Treating <i>S. maltophilia</i> remains difficult, leading to an increase in disease severity and higher hospitalization rates in people with cystic fibrosis, cancer, and other immunocompromised health conditions. The lack of effective antibiotics has led to renewed interest in phage therapy; however, there remains a great need for well-characterized phages, especially against <i>S. maltophilia</i>. In response to an oncology patient with a sepsis infection, we collected 18 phages from Southern California wastewater influent that exhibit different plaque morphology against <i>S. maltophilia</i> host strain B28B. We hypothesized that, when combined into a cocktail, genetically diverse phages would give rise to distinct lytic infection kinetics that would enhance bacterial killing when compared to the individual phages alone. We identified three genetically distinct clusters of phages, and a representative from each group was further investigated and screened for potential therapeutic use. The results demonstrated that the three-phage cocktail significantly suppressed bacterial growth compared with individual phages when observed for 48 h. We also assessed the lytic impacts of our three-phage cocktail against a collection of 46 <i>S</i>. <i>maltophilia</i> strains to determine if a multi-phage cocktail has an expanded host range. Our phages remained strain-specific and infected >50% of tested strains. In six clinically relevant <i>S. maltophilia</i> strains, the multi-phage cocktail has enhanced suppression of bacterial growth. These findings suggest that specialized phage cocktails may be an effective avenue of treatment for recalcitrant <i>S. maltophilia</i> infections resistant to current antibiotics.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0116224"},"PeriodicalIF":4.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999068","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}