Antimicrobial Agents and Chemotherapy最新文献

{"title":"TBAJ-587, a novel diarylquinoline, is active against <i>Mycobacterium abscessus</i>.","authors":"Junsheng Fan, Zhili Tan, Siyuan He, Anqi Li, Yaping Jia, Juan Li, Zhemin Zhang, Bing Li, Haiqing Chu","doi":"10.1128/aac.00945-24","DOIUrl":"10.1128/aac.00945-24","url":null,"abstract":"<p><p>Nontuberculous mycobacteria (NTM) infections are extremely difficult to treat due to a natural resistance to many antimicrobials. TBAJ-587 is a novel diarylquinoline, which shows higher anti-tuberculosis activity, lower lipophilicity, and weaker inhibition of hERG channels than bedaquiline (BDQ). The susceptibilities of 11 NTM reference strains and 194 clinical <i>Mycobacterium abscessus</i> isolates to TBAJ-587 were determined by the broth microdilution assay. The activity of TBAJ-587 toward the growth of <i>M. abscessus</i> in macrophages was also evaluated. Minimum bactericidal concentration and time-kill kinetic assays were conducted to distinguish between the bactericidal and bacteriostatic activities of TBAJ-587. The synergy between TBAJ-587 and eight clinically important antibiotics was determined using a checkerboard assay. TBAJ-587 was highly effective against <i>M. abscessus</i> by targeting its F-ATP synthase <i>c</i> chain. The antimicrobial activities of TBAJ-587 and BDQ toward intracellular <i>M. abscessus</i> were comparable. The <i>in vivo</i> activities of TBAJ-587 and BDQ in an immunocompromised mouse model were also comparable. TBAJ-587 expressed bactericidal activity and was compatible with eight anti-NTM drugs commonly used in clinical practice; no antagonism was discovered. As such, TBAJ-587 represents a potential candidate for the treatment of NTM infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0094524"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520821","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":"Exploration of novel mechanisms of azole resistance in <i>Candida auris</i>.","authors":"Jizhou Li, Danielle Brandalise, Alix T Coste, Dominique Sanglard, Frederic Lamoth","doi":"10.1128/aac.01265-24","DOIUrl":"10.1128/aac.01265-24","url":null,"abstract":"<p><p><i>Candida auris</i> is a pathogenic yeast of particular concern because of its ability to cause nosocomial outbreaks of invasive candidiasis (IC) and to develop resistance to all current antifungal drug classes. Most <i>C. auris</i> clinical isolates are resistant to fluconazole, an azole drug that is used for the treatment of IC. Azole resistance may arise from diverse mechanisms, such as mutations of the target gene (<i>ERG11</i>) or upregulation of efflux pumps via gain of function mutations of the transcription factors <i>TAC1</i> and/or <i>MRR1</i>. To explore novel mechanisms of azole resistance in <i>C. auris</i>, we applied an <i>in vitro</i> evolutionary protocol to induce azole resistance in a <i>TAC1A</i>/<i>TAC1B</i>/<i>MRR1</i> triple-deletion strain. Azole-resistant isolates without <i>ERG11</i> mutations were further analyzed. In addition to a whole chromosome aneuploidy of chromosome 5, amino acid substitutions were recovered in the transcription factor Upc2 (N592S, L499F), the ubiquitin ligase complex consisting of Ubr2 (P708T, H1275P) and Mub1 (Y765*), and the mitochondrial protein Mrs7 (D293H). Genetic introduction of these mutations in an azole-susceptible wild-type <i>C. auris</i> isolate of clade IV resulted in significantly decreased azole susceptibility. Real-time reverse transcription PCR analyses were performed to assess the impact of these mutations on the expression of genes involved in azole resistance, such as <i>ERG11</i>, the efflux pumps <i>CDR1</i> and <i>MDR1</i> or the transcription factor <i>RPN4</i>. In conclusion, this work provides further insights in the complex and multiple pathways of azole resistance of <i>C. auris</i>. Further analyses would be warranted to assess their respective role in azole resistance of clinical isolates.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0126524"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543322","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":"Analysis of <i>Acinetobacter</i> P-type type IV secretion system-encoding plasmid diversity uncovers extensive secretion system conservation and diverse antibiotic resistance determinants.","authors":"Mosopefoluwa T Oke, Kailey Martz, Mădălina Mocăniță, Sara Knezevic, Vanessa M D'Costa","doi":"10.1128/aac.01038-24","DOIUrl":"10.1128/aac.01038-24","url":null,"abstract":"<p><p><i>Acinetobacter baumannii</i> is globally recognized as a multi-drug-resistant pathogen of critical concern due to its capacity for horizontal gene transfer and resistance to antibiotics. Phylogenetically diverse <i>Acinetobacter</i> species mediate human infection, including many considered as important emerging pathogens. While globally recognized as a pathogen of concern, pathogenesis mechanisms are poorly understood. P-type type IV secretion systems (T4SSs) represent important drivers of pathogen evolution, responsible for horizontal gene transfer and secretion of proteins that mediate host-pathogen interactions, contributing to pathogen survival, antibiotic resistance, virulence, and biofilm formation. Genes encoding a P-type T4SS were previously identified on plasmids harboring the carbapenemase gene <i>bla_NDM-1</i> in several clinically problematic <i>Acinetobacter</i>; however, their prevalence among the genus, geographical distribution, the conservation of T4SS proteins, and full capacity for resistance genes remain unclear. Using systematic analyses, we show that these plasmids belong to a group of 53 P-type T4SS-encoding plasmids in 20 established <i>Acinetobacter</i> species, the majority of clinical relevance, including diverse <i>A. baumannii</i> sequence types and one strain of <i>Providencia rettgeri</i>. The strains were globally distributed in 14 countries spanning five continents, and the conjugative operon's T4SS proteins were highly conserved in most plasmids. A high proportion of plasmids harbored resistance genes, with 17 different genes spanning seven drug classes. Collectively, this demonstrates that P-type T4SS-encoding plasmids are more widespread among the <i>Acinetobacter</i> genus than previously anticipated, including strains of both clinical and environmental importance. This research provides insight into the spread of resistance genes among <i>Acinetobacter</i> and highlights a group of plasmids of importance for future surveillance.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0103824"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566601","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 of cabotegravir following intramuscular thigh injections in adults with and without HIV.","authors":"Kelong Han, Ronald D D'Amico, William R Spreen, Susan L Ford","doi":"10.1128/aac.00880-24","DOIUrl":"10.1128/aac.00880-24","url":null,"abstract":"<p><p>Cabotegravir intramuscular gluteal injection is approved for HIV treatment (with rilpivirine) and prevention. Thigh muscle is a potential alternative injection site. We aim to characterize cabotegravir pharmacokinetics and its association with demographics following intramuscular thigh injection in comparison with gluteal injection using population pharmacokinetic (PPK) analysis. Fourteen HIV-negative participants received 600 mg single thigh injection in phase 1 study 208832 and 118 participants with HIV received thigh injections 400 mg monthly 4× or 600 mg once-every-2-months 2× after ≥3 years of gluteal injections in phase 3b study ATLAS-2M provided 1,249 cabotegravir concentrations from 366 thigh injections and 1,998 concentrations from 1,618 gluteal injections. The established gluteal PPK model was modified by adding thigh injection compartment and fit to pharmacokinetic data following both gluteal and thigh injections, enabling within-person comparison in ATLAS-2M. Gluteal parameters were fixed. Similar to the gluteal absorption rate constant (KA_gluteal), the thigh absorption rate constant (KA_thigh) was slower in females than males and in participants with higher BMI. KA_thigh was strongly correlated with KA_gluteal (correlation coefficient 0.766), best described by the additive linear relationship KA_thigh = KA_gluteal + 0.0002527 h^-1. Terminal half-life of thigh injection was 26% (male) and 39% (female) shorter than gluteal injection. Relative bioavailability of thigh to gluteal was estimated to be 89.9%. The impact of covariates on cabotegravir exposure following thigh injections was ≤35%. In conclusion, cabotegravir absorption following thigh injection was correlated with, faster than, and 10% less bioavailable than gluteal injection, and correlated with sex and BMI. The cabotegravir thigh PPK model can inform dosing strategies and future study design.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0088024"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493543","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":"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":"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":" ","pages":"e0118324"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619366/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and characterization of thiamine analogs with antiplasmodial activity.","authors":"Imam Fathoni, Terence C S Ho, Alex H Y Chan, Finian J Leeper, Kai Matuschewski, Kevin J Saliba","doi":"10.1128/aac.01096-24","DOIUrl":"10.1128/aac.01096-24","url":null,"abstract":"<p><p>Thiamine is metabolized into thiamine pyrophosphate (TPP), an essential enzyme cofactor. Previous work has shown that oxythiamine, a thiamine analog, is metabolized by thiamine pyrophosphokinase (TPK) into oxythiamine pyrophosphate within the malaria parasite <i>Plasmodium falciparum</i> and then inhibits TPP-dependent enzymes, killing the parasite <i>in vitro</i> and <i>in vivo</i>. To identify a more potent antiplasmodial thiamine analog, 11 commercially available compounds were tested against <i>P. falciparum</i> and <i>P. knowlesi</i>. Five active compounds were identified, but only N3-pyridyl thiamine (N3PT), a potent transketolase inhibitor and candidate anticancer lead compound, was found to suppress <i>P. falciparum</i> proliferation with an IC₅₀ value 10-fold lower than that of oxythiamine. N3PT was active against <i>P. knowlesi</i> and was >17 times less toxic to human fibroblasts, as compared to oxythiamine. Increasing the extracellular thiamine concentration reduced the antiplasmodial activity of N3PT, consistent with N3PT competing with thiamine/TPP. A transgenic <i>P. falciparum</i> line overexpressing TPK was found to be hypersensitized to N3PT. Docking studies showed an almost identical binding mode in TPK between thiamine and N3PT. Furthermore, we show that [³H]thiamine accumulation, resulting from a combination of transport and metabolism, in isolated parasites is reduced by N3PT. Treatment of <i>P. berghei</i>-infected mice with 200 mg/kg/day N3PT reduced their parasitemia, prolonged their time to malaria symptoms, and appeared to be non-toxic to mice. Collectively, our studies are consistent with N3PT competing with thiamine for TPK binding and inhibiting parasite proliferation by reducing TPP production, and/or being converted into a TPP antimetabolite that inhibits TPP-dependent enzymes.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0109624"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520814","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":"Novel plasmid-mediated CMY variant (CMY-192) conferring ceftazidime-avibactam resistance in multidrug-resistant <i>Escherichia coli</i>.","authors":"Tingting Xu, Weiyuan Wu, Lili Huang, Bin Liu, Qiaodong Zhang, Jingjie Song, Jialong Liu, Bing Li, Zhao Li, Kai Zhou","doi":"10.1128/aac.00906-24","DOIUrl":"10.1128/aac.00906-24","url":null,"abstract":"<p><p>The rapid rise of multidrug resistance (MDR) among Gram-negative bacteria has accelerated the development of novel therapies. Ceftazidime-avibactam (CZA) is a novel β-lactam/β-lactamase inhibitor recently approved for the treatment of limited infectious diseases. Here, we describe a novel CMY variant, CMY-192, that confers high-level resistance to CZA. This gene was detected in a clinical MDR <i>Escherichia coli</i> strain (Ec73552) isolated from an outpatient with a community-acquired urinary tract infection who had not received prior CZA treatment. Ec73552 was typed as O101:H9-ST10, a high-risk clone associated with human and animal diseases. Ec73552 was able to colonize the bladder in a mouse model, suggesting that this strain was uropathogenic. CMY-192 shared the highest amino acid identity (98.95%) with CMY-172 and conferred at least a 32-fold increase in CZA MIC (from ≤0.125/4 to 8/4 mg/L) when cloned into a CZA-susceptible <i>E. coli</i> DH5α strain. Knockout of CMY-192 in Ec73552 resulted in a 256-fold reduction in CZA MIC (from 64/4 to 0.25/4 mg/L). CMY-192 was encoded on an IncB/O/K/Z-type plasmid (pCMY192). Conjugation assays confirmed that pCMY192 was self-transmissible, resulting in a 256-fold increase in the CZA MIC of the recipient. Notably, pCMY192 cured in Ec73552 did not confer a growth advantage, while the conjugant exhibited reduced biomass and growth rate, indicating that fitness costs imposed by pCMY192 may have been compensated in Ec73552. Our findings highlight the importance of continuous monitoring of CZA susceptibility to prevent the spread of resistance in clinical settings.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0090624"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520819","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":"Are the pharmacokinetic data of meropenem studied in CSF of a mixed population composed of patients with cerebral infections and patients with extracerebral infections really helpful for clinicians treating CNS infections?","authors":"Milo Gatti, Federico Pea","doi":"10.1128/aac.01453-24","DOIUrl":"10.1128/aac.01453-24","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0145324"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581240","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":"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":"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":" ","pages":"e0123224"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619448/pdf/","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":"OA","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":"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":" ","pages":"e0112024"},"PeriodicalIF":4.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619344/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}