Antimicrobial Agents and Chemotherapy最新文献

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Harnessing the effect of iron deprivation to attenuate the growth of opportunistic pathogen Acinetobacter baumannii. 利用缺铁效应减弱条件致病菌鲍曼不动杆菌的生长。
IF 4.1 2区 医学
Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-09 DOI: 10.1128/aac.01689-24
Sujata Saha, Debasrita RoyChowdhury, Ali Hossain Khan, Sukhendu Mandal, Kunal Sikder, Dipak Manna, Amit Ranjan Maity, Soumyananda Chakraborti, Arnab Basu
{"title":"Harnessing the effect of iron deprivation to attenuate the growth of opportunistic pathogen <i>Acinetobacter baumannii</i>.","authors":"Sujata Saha, Debasrita RoyChowdhury, Ali Hossain Khan, Sukhendu Mandal, Kunal Sikder, Dipak Manna, Amit Ranjan Maity, Soumyananda Chakraborti, Arnab Basu","doi":"10.1128/aac.01689-24","DOIUrl":"10.1128/aac.01689-24","url":null,"abstract":"<p><p><i>Acinetobacter baumannii</i> is an opportunistic pathogen having high infectivity among immunocompromised patients. The bacteria are resistant to major first-line antibiotics and have become a serious concern in the aspect of nosocomial and community-acquired infections. To overcome this dire situation, the necessity of introducing new approaches is undeniable, which can bypass the need for conventional antibiotic therapy. In this article, we have pinpointed the importance of iron in <i>A. baumannii.</i> Iron is an essential micronutrient in all bacteria. Loss of iron acquisition leads to membrane destabilization, and change in the expression of iron-transporting or -metabolizing genes causes death of the bacteria. Iron scavenging was primarily mediated by different chelators, and β-thujaplicin showed the best antibacterial efficacy with respect to time killing assay and CFU analysis. When iron (Fe<i><sup>2+</sup></i>) was supplemented after initial deficiency, the growth of the bacteria was seen to be restored. Iron deprivation also disintegrates the biofilm matrix, a major cause of bacterial resistance against different types of antibiotics. Moreover, iron scavenging promotes inhibition of biofilm sessile persister cells, the root cause of recalcitrant and chronic infection. As a part of antimicrobial therapy, β-thujaplicin was treated alongside colistin and chloramphenicol at an amount significantly lower than its MIC value. Our results indicated that β-thujaplicin nicely complemented those antibiotics to potentiate their antimicrobial action. In a nutshell, iron chelating agents are potential alternative therapeutics that can be used alongside different antibiotics to circumvent the resistance of different nosocomial pathogens.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0168924"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810323","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}
引用次数: 0
Statins do not reduce the parasite burden during experimental Trypanosoma cruzi infection. 他汀类药物不能减轻实验性克氏锥虫感染期间的寄生虫负担。
IF 4.1 2区 医学
Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-14 DOI: 10.1128/aac.00135-25
Sarah Razzaq, Francisco Olmo, Suresh B Lakshminarayana, Chen Ying-Bo, Shiromani Jayawardhana, Srinivasa P S Rao, John M Kelly, Francisco A F
{"title":"Statins do not reduce the parasite burden during experimental <i>Trypanosoma cruzi</i> infection.","authors":"Sarah Razzaq, Francisco Olmo, Suresh B Lakshminarayana, Chen Ying-Bo, Shiromani Jayawardhana, Srinivasa P S Rao, John M Kelly, Francisco A F","doi":"10.1128/aac.00135-25","DOIUrl":"https://doi.org/10.1128/aac.00135-25","url":null,"abstract":"<p><p>Cardiomyopathy is the most common pathology associated with <i>Trypanosoma cruzi</i> infection. Reports that statins have both cardioprotective and trypanocidal activity have generated interest in their potential as a therapeutic treatment. Using a highly sensitive bioluminescent mouse model, we show that a 5-day treatment with statins has no significant impact on parasite load. The free systemic concentrations fail to reach the level required for potency. Hence, clinical trials to investigate the trypanocidal activity of statins lack experimental justification.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":"69 5","pages":"e0013525"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952572","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}
引用次数: 0
A small regulatory RNA controls antibiotic adaptation in Staphylococcus aureus by modulating efflux pump expression. 一种小的调控RNA通过调节外排泵的表达来控制金黄色葡萄球菌对抗生素的适应。
IF 4.1 2区 医学
Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-03 DOI: 10.1128/aac.01176-24
Kam Pou Ha, Etornam Kofi Kumeko, Philippe Bouloc
{"title":"A small regulatory RNA controls antibiotic adaptation in <i>Staphylococcus aureus</i> by modulating efflux pump expression.","authors":"Kam Pou Ha, Etornam Kofi Kumeko, Philippe Bouloc","doi":"10.1128/aac.01176-24","DOIUrl":"10.1128/aac.01176-24","url":null,"abstract":"<p><p><i>Staphylococcus aureus</i> is an opportunistic pathogen that poses a considerable burden to healthcare settings worldwide, aided by its ability to thrive in different environmental growth conditions and survive exposure to antibiotics. Small regulatory RNAs (sRNAs) are decisive in enhancing bacterial fitness by modulating gene expression in response to changing environmental conditions. We investigated the role of sRNAs in the adaptation of <i>S. aureus</i> to antibiotics. By assessing the fitness of a library of sRNA mutants, we identified that RsaA sRNA is required for optimal bacterial growth when exposed to low concentrations of fluoroquinolone, a class of antibiotics targeting DNA replication. We also found that in the absence of RsaA, <i>S. aureus</i> is less susceptible to β-lactam antibiotics, which act on the cell wall. RsaA has been reported to prevent the expression of MgrA, a master regulatory protein controlling the expression of efflux pumps. Here, we show that RsaA affects the sensitivity of <i>S. aureus</i> to fluoroquinolone and β-lactam antibiotics through MgrA. RsaA has two forms, a short one commonly referred to in RsaA studies, and a long form about twice the length, of which less is known. Interestingly, our phenotype was only restored when complemented with the long form of the gene or when it was supplied in two parts, the short form and the missing part to obtain the long form. This work demonstrates the role of regulatory RNAs in the adaptation of <i>S. aureus</i> to antibiotic resistance and highlights their value as potential therapeutic targets for manipulating individual sRNA responses to promote the efficacy of existing antibiotics.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0117624"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770902","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}
引用次数: 0
Identification and characterization of a novel major facilitator superfamily (MFS) efflux pump conferring multidrug resistance in Staphylococcus aureus and Staphylococcus epidermidis. 金黄色葡萄球菌和表皮葡萄球菌多重耐药的新型主促进剂超家族外排泵的鉴定和表征
IF 4.1 2区 医学
Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-07 DOI: 10.1128/aac.01739-24
Honghao Huang, Yiyi Chen, Lingxuan Zhang, Peng Wan, Yan Chen, Yafei Li, Zhenling Zeng
{"title":"Identification and characterization of a novel major facilitator superfamily (MFS) efflux pump conferring multidrug resistance in <i>Staphylococcus aureus</i> and <i>Staphylococcus epidermidis</i>.","authors":"Honghao Huang, Yiyi Chen, Lingxuan Zhang, Peng Wan, Yan Chen, Yafei Li, Zhenling Zeng","doi":"10.1128/aac.01739-24","DOIUrl":"10.1128/aac.01739-24","url":null,"abstract":"<p><p>A novel major facilitator superfamily (MFS) efflux pump in <i>Staphylococcus</i>, designated Nms, was identified via topology prediction. The secondary structure indicated the presence of 12 transmembrane segments (TMSs) and characteristic motif A of MFS efflux pumps. Experimental verification of efflux activity was conducted using ethidium bromide accumulation and efflux assays and biofilm formation assays. Antimicrobial susceptibility testing and efflux pump inhibition confirmed that Nms effectively effluxed various antimicrobial agents to confer multidrug resistance. Comprehensive genomic analyses were used to assess the prevalence and possible origins of the <i>nms</i> gene. The results revealed that the <i>nms</i> gene was present in <i>Staphylococcus aureus</i> ST398/ST541 and <i>Staphylococcus epidermidis</i> ST570/ST1166 strains from global isolates. The transmission of <i>nms</i> was associated with the prevalence of <i>S. aureus</i> ST398-t571 in swine-derived samples from China. Phylogenetic analysis revealed that <i>nms-</i>positive strains formed a distinct clade separate from other <i>S. aureus</i> ST398 strains. Genetic analysis of the <i>nms</i> gene revealed a significant presence of plasmid-related mobile genetic elements, with extended nucleotide sequences containing circular intermediates exhibiting high homology with those found in an <i>S. aureus</i> plasmid. These findings suggested that the <i>nms</i> gene likely initially originated from plasmids and subsequently integrated into chromosomes. In conclusion, Nms is a novel MFS efflux pump that confers multidrug resistance to <i>S. aureus</i> and has been carried predominantly by ST398-t571 isolates in recent years. Ongoing surveillance is essential to elucidate the origin of <i>nms</i> in <i>S. aureus</i>, particularly MRSA ST398-t571, and to understand the transmission among humans, animals, and the environment.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0173924"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794352","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}
引用次数: 0
Novel Plasmodium falciparum Kelch13 polymorphisms in Cameroon with structural and physicochemical impact. 喀麦隆新型恶性疟原虫Kelch13多态性及其结构和物理化学影响
IF 4.1 2区 医学
Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-14 DOI: 10.1128/aac.00884-24
Loick P Kojom Foko, Jahnvi Jakhan, Geetika Narang, Joseph Hawadak, Carole E Eboumbou Moukoko, Vineeta Singh
{"title":"Novel <i>Plasmodium falciparum Kelch13</i> polymorphisms in Cameroon with structural and physicochemical impact.","authors":"Loick P Kojom Foko, Jahnvi Jakhan, Geetika Narang, Joseph Hawadak, Carole E Eboumbou Moukoko, Vineeta Singh","doi":"10.1128/aac.00884-24","DOIUrl":"https://doi.org/10.1128/aac.00884-24","url":null,"abstract":"<p><p>The recent emergence of <i>Plasmodium falciparum</i> (<i>Pf</i>) parasites resistant to artemisinin-based combination therapies (ACT) in Africa has outlined the need for continuous molecular surveillance of artemisinin partial resistance. Here, the genetic polymorphism in the <i>Kelch</i> 13 gene (<i>pfk13</i>) and its structural impact were analyzed. <i>Pf</i>DNA was extracted from dried blood spots of symptomatic and asymptomatic individuals living in different epidemiological facets of Cameroon. The <i>pfk13</i> gene was amplified by nested polymerase chain reaction, and amplicons were sequenced to detect single nucleotide polymorphisms (SNPs). The evolutionary history and the impact of the polymorphisms on physicochemical properties, structure, and function of the pfK13 protein were appraised using various <i>in silico</i> models. A total of ten SNPs were identified in this study, of which five non-synonymous SNPs have not been previously reported (L647<b><u>F</u></b>, D648<b><u>V</u></b>, N657<b><u>S</u></b>, K658<b><u>R</u></b>, and L663<b><u>P</u></b>). The genetic diversity of <i>pfk13</i> sequences was low, and the <i>pfk13</i> gene evolved under the neutral model. Some mutations, especially L663<b><u>P</u></b>, appeared to affect the function and structure of the pfK13 protein. Analysis of the physicochemical properties of the Cameroonian pfK13 protein sequences revealed slight changes in the solvent-accessible surface area, isoelectric point, and hydrophobicity. The results support the ongoing use of ACTs in the study areas, given the absence of validated SNPs associated with artemisinin partial resistance. Computational findings suggest a possible deleterious effect of some novel SNPs on the pfK13 structure and/or function.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":"69 5","pages":"e0088424"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958452","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}
引用次数: 0
Evaluation of phenotypic and genotypic methods for detecting KPC variants. 检测KPC变异的表型和基因型方法的评价。
IF 4.1 2区 医学
Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-03 DOI: 10.1128/aac.00082-25
Yasmine Benhadid-Brahmi, Claire Amaris Hobson, Lydia Abdelmoumene, Ella Jaouen, Mélanie Magnan, Maud Gits-Muselli, Mathilde Lescat, Olivier Tenaillon, Stéphane Bonacorsi, André Birgy
{"title":"Evaluation of phenotypic and genotypic methods for detecting KPC variants.","authors":"Yasmine Benhadid-Brahmi, Claire Amaris Hobson, Lydia Abdelmoumene, Ella Jaouen, Mélanie Magnan, Maud Gits-Muselli, Mathilde Lescat, Olivier Tenaillon, Stéphane Bonacorsi, André Birgy","doi":"10.1128/aac.00082-25","DOIUrl":"10.1128/aac.00082-25","url":null,"abstract":"<p><p><i>Klebsiella pneumoniae</i> carbapenemases (KPCs) have spread and diversified extensively. To date, 242 clinical variants have been identified and harbor different hydrolytic capacities, thereby interfering with rapid diagnostic tests. The accurate detection of KPC variants is crucial to guide treatment and control measures in healthcare settings. We constructed KPC variants to assess the mutational impact on detection capacities of resistance-based tests. KPC variants (<i>n</i> = 45) were characterized phenotypically and used to measure the detection sensitivity of KPC detection methods (two lateral flow immunoassays [LFIAs], three hydrolysis tests, three selective culture media, and two PCR-based tests). We identified four antibiotic susceptibility patterns: \"KPC-like\" (23/45; 51%), \"extended-spectrum beta-lactamase-like\" (6/45; 13%), \"ceftazidimase\" (9/45; 20%), and outlier variants with \"mixed-profiles\" (5/45; 11%). These phenotypes had different impacts on the detection capabilities of hydrolysis tests (0%-100%), LFIA (44%-100%), and selective culture media (0%-100%), highlighting a risk of misdiagnosis for some KPC variants. All variants were detected with PCR-based tests. To detect the maximum of KPC variants, fecal carriage screening requires a combination of selective media targeting resistance to carbapenems, third-generation cephalosporins, and ceftazidime-avibactam. From antibiotic susceptibility testing, resistance to ceftazidime ± avibactam and specific phenotypic profiles should be used as warnings to track the presence of KPC variants. We recommend LFIA as a first-line test, owing to its high sensitivity in detecting KPC variants. Nevertheless, using a combination of tests may remain wise in some situations. The spread of KPC variants remains a significant concern, particularly as reversion to ancestral phenotype could restore carbapenem resistance and lead to therapeutic failure.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0008225"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770912","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}
引用次数: 0
Spectrum of cefepime-taniborbactam coverage against 190 β-lactamases defined in engineered isogenic Escherichia coli strains. 头孢吡肟-taniborbactam对工程等基因大肠杆菌菌株中190种β-内酰胺酶的覆盖谱。
IF 4.1 2区 医学
Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-01 DOI: 10.1128/aac.01699-24
Tsuyoshi Uehara, Cassandra L Chatwin, Brittany Miller, Mitchell Edwards, Annie Stevenson, Jenna Colombo, David A Six, Denis M Daigle, Greg Moeck, Steven A Boyd, Daniel C Pevear
{"title":"Spectrum of cefepime-taniborbactam coverage against 190 β-lactamases defined in engineered isogenic <i>Escherichia coli</i> strains.","authors":"Tsuyoshi Uehara, Cassandra L Chatwin, Brittany Miller, Mitchell Edwards, Annie Stevenson, Jenna Colombo, David A Six, Denis M Daigle, Greg Moeck, Steven A Boyd, Daniel C Pevear","doi":"10.1128/aac.01699-24","DOIUrl":"10.1128/aac.01699-24","url":null,"abstract":"<p><p>Cefepime-taniborbactam is a β-lactam/β-lactamase inhibitor combination in clinical development for the treatment of Enterobacterales and <i>Pseudomonas</i> infections, including carbapenem-resistant Enterobacterales and multidrug-resistant <i>Pseudomonas aeruginosa</i>. Taniborbactam is a novel cyclic boronate with direct inhibitory activity against clinically relevant Ambler class A, B, C, and D β-lactamases. To further characterize the spectrum of β-lactamase coverage by cefepime-taniborbactam, we constructed 190 isogenic strains of <i>Escherichia coli</i> that constitutively expressed a different β-lactamase. Synthetic codon-optimized genes encoding the mature periplasmic protein linked to the TEM-1 signal sequence were used for optimized expression and periplasmic localization of the β-lactamase. The repertoire of β-lactamases consisted of 50 Ambler class A, 34 class B (metallo), 48 class C, and 58 class D enzymes known to mediate β-lactam resistance in the clinical isolates of Enterobacterales and <i>P. aeruginosa</i>. Overall, in the 190 isogenic strains, the MIC<sub>50</sub>/MIC<sub>90</sub> values were 8/128 µg/mL for cefepime and >128/>128 µg/mL for ceftazidime. Cefepime-taniborbactam (MIC<sub>50</sub>/MIC<sub>90</sub> of 0.25/8 µg/mL) showed greater activity than ceftazidime-avibactam (MIC<sub>50</sub>/MIC<sub>90</sub> of 4/>128 µg/mL) and similar activity to aztreonam-avibactam (MIC<sub>50</sub>/MIC<sub>90</sub> of 0.5/4 µg/mL). Cefepime-taniborbactam inhibited strains overproducing metallo-β-lactamases, including clinically important NDM and VIM enzymes, whereas ceftazidime-avibactam showed no coverage. Among the 129 β-lactamase-overproducing strains with increased cefepime MIC ≥16-fold relative to the control strain, taniborbactam potentiated cefepime MIC by ≥8-fold for 113 strains overexpressing β-lactamases (42 Ambler class A, 24 B, 23 C, and 24 D). Cefepime-taniborbactam demonstrated broader activity relative to ceftazidime-avibactam and comparable activity with aztreonam-avibactam in the overall coverage of both serine- and metallo-β-lactamases from all four Ambler classes.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0169924"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750846","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}
引用次数: 0
The effect of pregnancy on the population pharmacokinetics of levofloxacin in South Africans with rifampicin-resistant tuberculosis. 妊娠对南非利福平耐药结核病患者左氧氟沙星药代动力学的影响。
IF 4.1 2区 医学
Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-01 DOI: 10.1128/aac.01626-24
Sharon Sawe, Lufina Tsirizani, Richard Court, Kamunkhwala Gausi, Asanda Poswa, Tasnim Badat, Lubbe Wiesner, Marian Loveday, Gary Maartens, Francesca Conradie, Paolo Denti
{"title":"The effect of pregnancy on the population pharmacokinetics of levofloxacin in South Africans with rifampicin-resistant tuberculosis.","authors":"Sharon Sawe, Lufina Tsirizani, Richard Court, Kamunkhwala Gausi, Asanda Poswa, Tasnim Badat, Lubbe Wiesner, Marian Loveday, Gary Maartens, Francesca Conradie, Paolo Denti","doi":"10.1128/aac.01626-24","DOIUrl":"10.1128/aac.01626-24","url":null,"abstract":"<p><p>Levofloxacin is a key drug in the prevention and treatment of rifampicin-resistant tuberculosis (RR-TB). There are limited data describing the effect of pregnancy on the pharmacokinetics of levofloxacin. We aimed to characterize the pharmacokinetics of levofloxacin in adults with RR-TB, including the effect of pregnancy. We pooled data from two studies conducted in adult participants treated for RR-TB in South Africa. Treatment regimens in both studies included levofloxacin dosed at 750/1000 mg daily, depending on body weight. We analyzed data from 47 participants, 31 (66%) living with HIV, using nonlinear mixed-effects modeling in NONMEM v7.5.1. Out of 33 female participants, 21 were pregnant, of whom 12 contributed matched antepartum and postpartum pharmacokinetic profiles. Levofloxacin followed one-compartment pharmacokinetics with first-order elimination and absorption with transit absorption compartments. The clearance and volume of distribution for a typical non-pregnant participant (weight: 58 kg; age: 32 years; serum creatinine: 56.2 µmol/L) were 6.06 (95% confidence interval [CI], 5.47 to 6.53) L/h and 85.9 (95% CI, 80.6 to 91.7) L, respectively. Higher serum creatinine levels were associated with lower levofloxacin clearance using a power function with an exponent of -0.367 (95% CI, -0.493 to -0.104). Pregnancy increased levofloxacin clearance by 38.1% (95% CI, 23.4% to 57.1%), with substantially lower exposures in pregnant compared with non-pregnant participants receiving equivalent weight-based doses. To achieve non-pregnant equivalent exposures of levofloxacin, an additional 250 mg tablet may be required, although further study is needed to assess the safety implications of a higher recommended dose in pregnant women.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0162624"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750848","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}
引用次数: 0
A novel pan-fungal screening platform for antifungal drug discovery: proof of principle study. 一种新的抗真菌药物发现的泛真菌筛选平台:原理验证研究。
IF 4.1 2区 医学
Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-01 DOI: 10.1128/aac.01328-24
Rebecca Inman, Adilia Warris, Elaine Bignell
{"title":"A novel pan-fungal screening platform for antifungal drug discovery: proof of principle study.","authors":"Rebecca Inman, Adilia Warris, Elaine Bignell","doi":"10.1128/aac.01328-24","DOIUrl":"10.1128/aac.01328-24","url":null,"abstract":"<p><p>Broad-spectrum activity is a desirable property of novel antifungal drugs, but relevant <i>in vitro</i> testing is complicated by differential nutritional requirements and growth dynamics of fungal pathogens. Many screens for novel drugs are initiated against individual species or genera, with hit compounds later tested for \"pan-fungal\" activity. Hypothesizing that an optimized pan-fungal methodology would enhance the efficiency of early-stage drug discovery, a standardized assay was developed for a selection of World Health Organization-defined critical and high-priority fungal pathogens. Instead of using the standard susceptibility testing broth RPMI, an enriched media \"fungal RPMI\" (fRPMI), including multiple additional fungal growth-enhancing nutrients, was utilized. To assess utility for pan-fungal growth assessments, growth in fRPMI was compared to RPMI medium for 12 fungal pathogens. Growth was significantly improved in 7/12 species in fRPMI after 24 and/or 48 hours. For our proof-of-principle study, 500 chemical fragments from the Maybridge Ro3 Fragment library were screened at concentrations of 0.1 or 1 mM against five fungal pathogens: <i>Aspergillus fumigatus</i>, <i>Candida albicans</i>, <i>Candida auris</i>, <i>Cryptococcus neoformans</i>, and <i>Nakaseomyces glabratus</i>. Assay quality was assessed using <i>z</i>-factor analysis, and hits were normalized using a standard <i>z</i>-score to identify outliers. All assays achieved a high-quality <i>z</i>-factor (≥0.5) with readings at ≤24 hours, allowing the identification of 23 compounds with antifungal activity against at least one fungal species. From these, five compounds were identified as having pan-assay interference or broadly toxic properties. In conclusion, hits identified from pan-fungal phenotypic growth-based assays demonstrate reproducibility in all fungal species tested with carefully optimized conditions and precise timing.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0132824"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750839","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}
引用次数: 0
Population pharmacokinetic analysis of tobramycin in serum and ELF using data from patients with pneumonia. 肺炎患者血清和ELF中妥布霉素的人群药代动力学分析。
IF 4.1 2区 医学
Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-14 DOI: 10.1128/aac.00908-24
Scott A Van Wart, Michael Trang, M Courtney Safir, Andrew R Santulli, Christopher M Rubino, Sujata M Bhavnani
{"title":"Population pharmacokinetic analysis of tobramycin in serum and ELF using data from patients with pneumonia.","authors":"Scott A Van Wart, Michael Trang, M Courtney Safir, Andrew R Santulli, Christopher M Rubino, Sujata M Bhavnani","doi":"10.1128/aac.00908-24","DOIUrl":"https://doi.org/10.1128/aac.00908-24","url":null,"abstract":"<p><p>Population pharmacokinetic analyses were undertaken to characterize epithelial lining fluid (ELF) penetration for tobramycin in pneumonia patients. A two-compartment model with zero-order intravenous input and first-order elimination linked to an effect site ELF compartment was utilized to determine the steady-state ELF penetration ratio of 0.51 for tobramycin. These results are useful to account for effect site exposure when performing analyses to support recommendations for aminoglycoside dosing regimens and interpretive criteria for <i>in vitro</i> susceptibility testing.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":"69 5","pages":"e0090824"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966762","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}
引用次数: 0
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