JAC-Antimicrobial Resistance最新文献

{"title":"Paediatricians' knowledge, perceptions, preparedness and involvement towards paediatric antimicrobial stewardship in Pakistan: findings and the implications.","authors":"Zia Ul Mustafa, Amer Hayat Khan, Muhammad Salman, Sabariah Noor Harun, Johanna C Meyer, Brian Godman","doi":"10.1093/jacamr/dlae193","DOIUrl":"10.1093/jacamr/dlae193","url":null,"abstract":"<p><strong>Introduction: </strong>Antibiotics are frequently prescribed for neonates and children. However, this can be excessive with inappropriate prescribing leading to increased antimicrobial resistance (AMR). Paediatricians are key initiators of antibiotics. Consequently, their awareness, perceptions, readiness and potential barriers towards hospital-based antimicrobial stewardship programmes are of considerable importance, especially in Pakistan with high rates of AMR.</p><p><strong>Materials and methods: </strong>A web-based cross-sectional survey among paediatricians from June to August 2023 using a validated questionnaire. Paediatricians from all four Provinces and the capital territory of Pakistan were invited from randomly selected public and private sector hospitals.</p><p><strong>Results: </strong>383 paediatricians participated (79.8% response rate). Most were male (87.7%), aged 35 years or less (55.4%), working in tertiary care hospitals (68.4%) and undertaking 51-100 child consultations every day (45%). Only 15% reported obtaining training on antibiotic usage, AMR and/or antimicrobial stewardship. Only 7.6% confirmed functional antimicrobial stewardship programmes in their institutions. Most had adequate knowledge of antibiotic use and AMR. However, key issues were not fully understood with only 27.4% believing antibiotics were being overused among children. Paediatricians with less experience, and who undertook fewer consultations per day, had significantly lower knowledge scores. Most participants were prepared to initiate antimicrobial stewardship programmes; however, perceived barriers included a lack of online learning sources, treatment guidelines and support from hospital administration.</p><p><strong>Discussion: </strong>Paediatricians had appropriate knowledge about antibiotic use and AMR although concerns with antibiotic use. Important barriers to integrating antimicrobial stewardship programmes were identified, which need addressing for these to become routine.</p>","PeriodicalId":14594,"journal":{"name":"JAC-Antimicrobial Resistance","volume":"6 6","pages":"dlae193"},"PeriodicalIF":3.7,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11631149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clearance of archived integrase strand transfer inhibitors resistance mutations in people with virologically suppressed HIV infection.","authors":"Basma Abdi, Romain Palich, Sophie Seang, Antoine Fauchois, Théophile Cocherie, Antoine Faycal, Sophie Sayon, Elisa Teyssou, Sanaa Saliba, Cathia Soulie, Marc Antoine Valantin, Valérie Pourcher, Christine Katlama, Vincent Calvez, Anne-Geneviève Marcelin, Marc Wirden","doi":"10.1093/jacamr/dlae194","DOIUrl":"10.1093/jacamr/dlae194","url":null,"abstract":"<p><strong>Introduction: </strong>We assessed the kinetics of the clearance of integrase strand transfer inhibitors resistance mutations (INSTIs-RMs) and associated factors from people living with HIV (PWH) displaying suppressed viral replication after virological failure (VF) on an INSTI regimen.</p><p><strong>Patients and methods: </strong>We included PWH with HIV-RNA viral loads ≤20 copies/mL for at least 5 years in whom INSTIs-RM had been identified at least once in a prior RNA resistance genotyping test. HIV DNAs were sequenced by Sanger sequencing (SS) and ultra-deep sequencing (UDS; detection threshold: 5%) every year over the preceding 5 years.</p><p><strong>Results: </strong>We included 39 PWH in the study. Most (95%) had experienced VF on a raltegravir-containing regimen. The past INSTIs-RMs were not detected in the peripheral blood mononuclear cells of 35 of the 39 (90%) PWH by SS at the end of follow-up. In a longitudinal analysis (2017-21) based on UDS, the previously detected INSTIs-RMs were not detected in 29 of the 35 (83%) PWH. In multivariable analysis, the duration of viral replication and the level of HIV-RNA during prior VF were significantly associated with the persistence of INSTIs-RM, with odds ratios of 1.05 per week of replication (95% CI, 1.00-1.11; <i>P </i>= 0.024) and 8.26 per log₁₀ copies/mL (95% CI, 1.46-46.59; <i>P </i>= 0.017).</p><p><strong>Conclusions: </strong>We observed a clear trend towards the clearance of archived INSTIs-RM after a long period of virological control leading to changes in the resistance profile in cellular DNA, raising the possibility of studies assessing the recycling of INSTI classes even in the presence of a history of resistance.</p>","PeriodicalId":14594,"journal":{"name":"JAC-Antimicrobial Resistance","volume":"6 6","pages":"dlae194"},"PeriodicalIF":3.7,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11630525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The 'Other' in AWaRe.","authors":"Areeb Arshad, Clark D Russell, Barbara Moore, Simon Dewar","doi":"10.1093/jacamr/dlae196","DOIUrl":"10.1093/jacamr/dlae196","url":null,"abstract":"","PeriodicalId":14594,"journal":{"name":"JAC-Antimicrobial Resistance","volume":"6 6","pages":"dlae196"},"PeriodicalIF":3.7,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11630521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A review of antimicrobial stability testing guidance for outpatient parenteral antimicrobial therapy programmes: is it time for global harmonization of testing frameworks?","authors":"Saiyuri Naicker, Jason A Roberts, Vesa Cheng, Suzanne L Parker, R Andrew Seaton, Mark Gilchrist, Fekade B Sime","doi":"10.1093/jacamr/dlae186","DOIUrl":"10.1093/jacamr/dlae186","url":null,"abstract":"<p><p>Antimicrobial stability is an important consideration for treatment planning and service delivery in outpatient parenteral antimicrobial therapy (OPAT) programmes. Regulation of stability assessment varies by region, and conflicting guidance and standards exist. This leads to disparity of equity in access and limits availability of certain antimicrobials for managing infections in the outpatient setting. This review discusses the degree to which the international regulatory bodies have reached consensus on the regulation of antimicrobial stability testing, specifically for OPAT, and describes the variation in antimicrobial recommendations across regulatory bodies. The three major findings in this review are (i) variation in antimicrobial stability testing guidance, particularly in relation to temperature; (ii) lack of regulatory guidance, specifically in that some regions did not have OPAT guidelines; and (iii) only the UK's NHS has provided non-regulatory OPAT-specific advice on antimicrobial stability testing. In conclusion, harmonization of antimicrobial stability testing to form a global OPAT-specific regulatory framework, particularly considering 'areas of variation' amongst current guidance, is required. We call for the development of a global OPAT antimicrobial stability testing framework with consensus from accepted antimicrobial stability criteria, expert opinion and pharmacopoeial best practice.</p>","PeriodicalId":14594,"journal":{"name":"JAC-Antimicrobial Resistance","volume":"6 6","pages":"dlae186"},"PeriodicalIF":3.7,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11606649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142768964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AmpC β-lactamases detected in Southeast Asian <i>Escherichia coli</i> and <i>Klebsiella pneumoniae</i>.","authors":"Tamalee Roberts, Clare L Ling, Wanitda Watthanaworawit, Chanvoleak Cheav, Amphonesavanh Sengduangphachanh, Joy Silisouk, Jill Hopkins, Koukeo Phommasone, Elizabeth M Batty, Paul Turner, Elizabeth A Ashley","doi":"10.1093/jacamr/dlae195","DOIUrl":"10.1093/jacamr/dlae195","url":null,"abstract":"<p><strong>Objectives: </strong>AmpC β-lactamases are neglected compared with ESBL as a cause of third-generation cephalosporin (3GC) resistance in Enterobacterales in low- and middle-income countries and the burden is unknown. The aim of this study was to investigate the presence of AmpC β-lactamase-producing <i>Escherichia coli</i> and <i>Klebsiella pneumoniae</i> in clinical specimens from three clinical research laboratories in Southeast Asia.</p><p><strong>Methods: </strong>Stored clinical isolates of <i>E. coli</i> and <i>K. pneumoniae</i> resistant to ceftriaxone or ceftazidime or cefpodoxime and ESBL confirmation test negative were screened using MASTDISCS AmpC, ESBL and Carbapenemase Detection Set-D72C. Short-read WGS was performed to identify <i>ampC</i> genes.</p><p><strong>Results: </strong>Of 126 isolates collected between 2010 and 2020, 31 (24.6%) and 16 (12.7%) were phenotypically AmpC and inducible AmpC positive by MASTDISCS testing, respectively. All inducible AmpC isolates were ceftriaxone susceptible and 97.7% of AmpC/inducible AmpC isolates tested against cefoxitin were resistant. Through WGS, 17 and eight different STs were detected for the AmpC/inducible AmpC <i>E. coli</i> and <i>K. pneumoniae</i> isolates, respectively. Twelve different β-lactamase resistance genes were detected, with <i>bla</i> _CMY-2 most commonly in AmpC-positive isolates (20/31; 64.5%; 15 chromosomal, five plasmid). All inducible AmpC-positive isolates had the <i>bla</i> _DHA-1 gene (seven chromosomal, nine plasmid).</p><p><strong>Conclusions: </strong>Though uncommon, AmpC and inducible AmpC β-lactamases in <i>E. coli</i> and <i>K. pneumoniae</i> are an important cause of infection in Southeast Asia. With current testing methods, these infections may be going undetected, resulting in patients receiving suboptimal treatment.</p>","PeriodicalId":14594,"journal":{"name":"JAC-Antimicrobial Resistance","volume":"6 6","pages":"dlae195"},"PeriodicalIF":3.7,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11604056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-typhoidal <i>Salmonella</i> in humans in India, Vietnam, Bangladesh and Sri Lanka: a systematic review.","authors":"Reshma Raju, Luke O'Neil, Charlotte Kerr, Burhan Lehri, Sudipta Sarkar, Twinkle Soni, Patrick Nguipdop-Djomo, Anne Conan, Nguyen Dong Tu, Tran Thi Mai Hung, Melanie Hay, Jane Falconer, Fiona Tomley, Damer Blake, Guillaume Fournié, Sitara Swarna Rao Ajjampur, Punam Mangtani, Richard Stabler","doi":"10.1093/jacamr/dlae190","DOIUrl":"10.1093/jacamr/dlae190","url":null,"abstract":"<p><strong>Objectives: </strong>Non-typhoidal <i>Salmonella</i> (NTS) commonly causes a self-limiting illness but invasive disease (iNTS) can be life-threatening. Antimicrobial resistance (AMR) increases the risk of mortality. This systematic review aimed to estimate the proportion of NTS isolated in those attending healthcare services, serovar burden, AMR, serovar-specific AMR, and case fatality rate (CFR) in India, Bangladesh, Sri Lanka and Vietnam.</p><p><strong>Methods: </strong>The review included quantitative studies on NTS and AMR from 1980 to 2020 but excluded studies unrelated to humans or selected countries. Data were extracted from articles identified from Ovid SP, Web of Science, Wiley Cochrane Library, Elsevier Scopus and WHO Global Index Medicus. The Joanna Briggs Institute Critical Appraisal Tools Checklist for Prevalence Studies was used for risk-of-bias assessment. Meta-analyses were performed for the proportion of NTS isolated, the proportion of specific serovars isolated, percentage of AMR and CFR.</p><p><strong>Results: </strong>Six thousand and twenty-six isolates (79 serovars) were identified from 73 studies, with <i>Salmonella enterica</i> serovar Typhimurium being the most common. Of the 73 selected studies, 46% were hospital/laboratory surveillance studies, examining the aetiology of invasive or non-invasive infections. The pooled proportion estimate for non-iNTS was 2.1% (95% CI: 1.2%-3.2%) and for iNTS was 0.3% (95% CI: 0.1%-0.5%). The pooled CFR was 14.9% (95% CI: 4.0%-29.6%). Pooled resistance estimates for ampicillin, ceftriaxone, chloramphenicol, ciprofloxacin, co-trimoxazole, nalidixic acid and azithromycin were calculated. MDR iNTS was less prevalent in India [22.3% (95% CI: 0.0%-66.8%)] than in Vietnam [41.2% (95% CI: 33.6%-49.3%)]. Heterogeneity of studies was high as the majority were observational surveillance studies.</p><p><strong>Conclusions: </strong>Despite data scarcity in some countries, this review highlights the continued contribution of NTS infection to disease burden, compounded by high AMR rates.</p>","PeriodicalId":14594,"journal":{"name":"JAC-Antimicrobial Resistance","volume":"6 6","pages":"dlae190"},"PeriodicalIF":3.7,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11589464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142728669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urinary tract infections: a retrospective cohort study of (mis)matching antimicrobial therapy and clinical outcome among Finnish adults.","authors":"Anu Patjas, T Sakari Jokiranta, Anu Kantele","doi":"10.1093/jacamr/dlae188","DOIUrl":"10.1093/jacamr/dlae188","url":null,"abstract":"<p><strong>Objectives: </strong>With the global spread of antimicrobial resistance, treating urinary tract infections (UTIs) is becoming more challenging. Clinical data on UTI outcomes are scarce in cases with antimicrobial treatment mismatching the uropathogens' <i>in vitro</i> susceptibility profiles. We explored the association of (mis)matching antimicrobial treatment and clinical outcomes among patients with either ESBL-producing Enterobacterales (ESBL-PE) or non-ESBL-PE identified in urine samples.</p><p><strong>Patients and methods: </strong>In 2015-2019, we recruited 18-65-year-old patients with laboratory-confirmed, community-acquired ESBL-PE (<i>n</i> = 130) or non-ESBL-PE (<i>n</i> = 187) UTI. Our study involved collecting data on <i>in vitro</i> susceptibility profiles, antimicrobial therapy (microbiological match/mismatch) and clinical outcomes, and a follow-up of relapses/reinfections.</p><p><strong>Results: </strong>Non-beta-lactam co-resistance was found more frequent among ESBL-PE than non-ESBL-PE isolates. The initial antimicrobial matched the <i>in vitro</i> susceptibility for 91.6% (164/179) of those with non-ESBL-PE and 46.9% (38/81) with ESBL-PE UTI (<i>P</i> < 0.001). The clinical cure rates in the non-ESBL-PE and ESBL-PE UTI groups were 82.6% (142/172) and 62.2% (74/119) (<i>P</i> < 0.001) for all, 87.3% (131/150) and 83.3% (30/36) for those treated with matching antimicrobials, and 33.3% (5/15) and 41.9% (18/43) for those given mismatching antimicrobials, respectively. Mismatching antimicrobial therapy was not associated with relapse/reinfection over the 3-month follow-up (<i>P</i> = 0.943).</p><p><strong>Conclusions: </strong>In our data, (mis)matching microbiological susceptibility is only partially associated with the clinical outcome of UTI: microbiological matching appears to predict clinical cure better than mismatching predicts clinical failure.</p>","PeriodicalId":14594,"journal":{"name":"JAC-Antimicrobial Resistance","volume":"6 6","pages":"dlae188"},"PeriodicalIF":3.7,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11589465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142728672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of cefiderocol resistance prevalence and resistance mechanisms in carbapenem-resistant <i>Pseudomonas aeruginosa</i>, Germany 2019-21.","authors":"Kaan Kocer, Sébastien Boutin, Maximilian Moll, Dennis Nurjadi","doi":"10.1093/jacamr/dlae183","DOIUrl":"10.1093/jacamr/dlae183","url":null,"abstract":"<p><strong>Background: </strong>Cefiderocol, a novel siderophore cephalosporin, is a promising therapeutic option for infections caused by multidrug-resistant <i>Pseudomonas aeruginosa</i>. We evaluated the activity of cefiderocol against carbapenem-resistant <i>P. aeruginosa</i> (Cr-Pa) isolates and investigated the potential mechanisms involved in resistance.</p><p><strong>Methods: </strong>108 CR-Pa isolates collected from patients without prior exposure to the substance were studied. MICs of cefiderocol were determined by broth microdilution using iron-depleted cation-adjusted Mueller-Hinton broth. Whole genome sequencing was performed to investigate the potential resistance mechanisms by comparing resistant and susceptible <i>P. aeruginosa</i> isolates and identifying unique mutations in the resistant group.</p><p><strong>Results: </strong>Of the 108 isolates, nine were resistant to cefiderocol with MIC values ranging from 4 to 32 mg/L. The genetic analysis revealed a broad spectrum of mutations in the resistant isolates associated with iron uptake systems, efflux pumps, AmpC β-lactamase and penicillin-binding proteins. The most frequently observed mutations among the resistant isolates were located in <i>fptA</i>, <i>fpvB</i> and <i>chtA</i>. Notably, the presence of carbapenemases did not correlate with cefiderocol resistance.</p><p><strong>Conclusions: </strong>Our findings show the low prevalence of cefiderocol resistance among CR-Pa isolates, showing its potential as an effective treatment option. However, the complex genetic landscape of resistance mechanisms, particularly mutations affecting iron transport and other TonB-dependent receptors, requires continuous monitoring and functional analyses to identify and manage potential resistance mechanisms. This study provides a foundation for future research to improve antimicrobial resistance prediction and develop targeted therapies against CR-Pa.</p>","PeriodicalId":14594,"journal":{"name":"JAC-Antimicrobial Resistance","volume":"6 6","pages":"dlae183"},"PeriodicalIF":3.7,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11584512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Medical school ranking and provider outpatient Medicare Part D claims for antibiotics among older patients in the USA.","authors":"Mayar Al Mohajer, David Slusky, David Nix, Catia Nicodemo","doi":"10.1093/jacamr/dlae191","DOIUrl":"10.1093/jacamr/dlae191","url":null,"abstract":"<p><strong>Background: </strong>Our study aimed to assess whether there was a relationship between graduating from higher-ranked medical schools and the rate of prescribing antibiotics among Medicare Part D providers in the USA.</p><p><strong>Methods: </strong>The study obtained data from the Medicare Part D Prescribers (FY2013-2021) and the Doctor and Clinicians National repositories. A regression model was fitted to assess the relationship between provider medical school ranking and the rate of antibiotic days supplied per 100 beneficiaries at the provider level.</p><p><strong>Results: </strong>A total of 197 540 providers were included. No association was found between the medical school ranking and the rate of antibiotics days supplied per 100 beneficiaries. Instead, the type of provider is associated with the prescription rates. Hospitalists and Emergency Medicine providers had fewer days supplied per 100 beneficiaries than Family Medicine providers. In contrast, students, more experienced providers (>20 years since medical school graduation) and females had more days supplied per 100 beneficiaries.</p><p><strong>Conclusion: </strong>Our study highlights the need for robust outpatient stewardship interventions and incorporating an outcome-based approach to antibiotic stewardship curricula in medical and mid-level provider schools.</p>","PeriodicalId":14594,"journal":{"name":"JAC-Antimicrobial Resistance","volume":"6 6","pages":"dlae191"},"PeriodicalIF":3.7,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11584510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the effects of ivacaftor exposure on <i>Staphylococcus aureus</i> small colony variant development and antibiotic tolerance.","authors":"Gretchen E Bollar, Kendall M Shaffer, Johnathan D Keith, Ashley M Oden, Alexander E Dowell, Kevin J Ryan, Edward P Acosta, Jennifer S Guimbellot, Megan R Kiedrowski, Susan E Birket","doi":"10.1093/jacamr/dlae185","DOIUrl":"10.1093/jacamr/dlae185","url":null,"abstract":"<p><strong>Background: </strong>Ivacaftor exhibits anti-staphylococcal properties but does not clear <i>Staphylococcus aureus</i> from the lungs of people with cystic fibrosis (pwCF). We assessed whether exposure to therapeutic concentrations of ivacaftor could allow <i>S. aureus</i> to form small colony variants (SCVs), a phenotype commonly associated with bacterial persistence.</p><p><strong>Methods: </strong>Humanized G551D-CFTR (hG551D) rats were treated with ivacaftor for 7 days. Concentrations in the plasma, epithelial lining fluid and lung tissue lysate were measured using LC-MS/MS. Survival of <i>S. aureus</i> during ivacaftor treatment was assessed in an hG551D rat model of lung infection. <i>S. aureus</i> adaptation to therapeutic concentrations of ivacaftor was investigated <i>in vitro</i> by serial passage in the presence of 10 µM ivacaftor. Bacterial survival in the presence of antimicrobials was evaluated using growth curves and density assays.</p><p><strong>Results: </strong>Ivacaftor plasma concentrations of treated hG551D rats reached 3.488 ± 1.118 µM, with more variable concentrations in the epithelial lining fluid and lung tissue lysate. During <i>S. aureus</i> infection, ivacaftor-treated hG551D rats returned similar numbers of bacteria from the lung, compared with vehicle-treated controls. Exposure of <i>S. aureus</i> to ivacaftor <i>in vitro</i> led to the formation of ivacaftor-tolerant SCVs with an unstable phenotype and increased antibiotic tolerance.</p><p><strong>Conclusions: </strong>Treatment with ivacaftor did not alter <i>S. aureus</i> burden in the cystic fibrosis rat and led to the formation of tolerant SCVs <i>in vitro</i>, suggesting that development of an SCV phenotype may allow <i>S. aureus</i> to persist in the cystic fibrosis lung during ivacaftor therapy.</p>","PeriodicalId":14594,"journal":{"name":"JAC-Antimicrobial Resistance","volume":"6 6","pages":"dlae185"},"PeriodicalIF":3.7,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11630538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}