Leonie Feuer, Stefanie Katharina Frenzer, Roswitha Merle, Rasmus Leistner, Wolfgang Bäumer, Astrid Bethe, Antina Lübke-Becker, Babette Klein, Alexander Bartel
Background: MRSA is a major contributor to AMR-related deaths. The WHO's global action plan emphasizes a One Health approach, acknowledging the connection between humans and their companion animals. It is agreed on that comprehensive AMR surveillance is needed.
Objectives: This study provides a large-scale overview of MRSA occurrence in cats and dogs in Germany, serving as a foundation for continuous surveillance.
Methods: The study analysed all results of canine and feline bacterial diagnostic samples from a large laboratory, encompassing samples received from veterinary practices between January 2019 and December 2021. MRSA prevalence between host species, sample types and geographical distribution were compared. Additionally, data were contrasted with human MRSA surveillance data from Germany.
Results: Samples originated from 3491 German veterinary practices, representing 33.1% of practices and clinics nationally. Bacterial examination results from 175 171 samples were analysed, identifying S. aureus in 5526 of these samples (3.2% isolation rate). S. aureus in clinical samples was more prevalent in cats (5.6%) than dogs (2.0%). Methicillin resistance was found in 17.8% of S. aureus samples and was higher in dogs (20.4%, 95%CI 18.9-22.0) than cats (15.6%, 95%CI 14.3-17.0). The highest MRSA prevalence was found in canine wound samples (32%), compared to skin/soft tissue, respiratory tract and other (<23% respectively).
Conclusion: The study reveals a 17.8% MRSA prevalence, which is higher than the human outpatient MRSA prevalence (5.4%). Restriction and regulation of veterinary antibiotic use should be validated with AMR surveillance. Our study shows that this is feasible in companion animals with significant coverage.
{"title":"Prevalence of MRSA in canine and feline clinical samples from one-third of veterinary practices in Germany from 2019-2021.","authors":"Leonie Feuer, Stefanie Katharina Frenzer, Roswitha Merle, Rasmus Leistner, Wolfgang Bäumer, Astrid Bethe, Antina Lübke-Becker, Babette Klein, Alexander Bartel","doi":"10.1093/jac/dkae225","DOIUrl":"10.1093/jac/dkae225","url":null,"abstract":"<p><strong>Background: </strong>MRSA is a major contributor to AMR-related deaths. The WHO's global action plan emphasizes a One Health approach, acknowledging the connection between humans and their companion animals. It is agreed on that comprehensive AMR surveillance is needed.</p><p><strong>Objectives: </strong>This study provides a large-scale overview of MRSA occurrence in cats and dogs in Germany, serving as a foundation for continuous surveillance.</p><p><strong>Methods: </strong>The study analysed all results of canine and feline bacterial diagnostic samples from a large laboratory, encompassing samples received from veterinary practices between January 2019 and December 2021. MRSA prevalence between host species, sample types and geographical distribution were compared. Additionally, data were contrasted with human MRSA surveillance data from Germany.</p><p><strong>Results: </strong>Samples originated from 3491 German veterinary practices, representing 33.1% of practices and clinics nationally. Bacterial examination results from 175 171 samples were analysed, identifying S. aureus in 5526 of these samples (3.2% isolation rate). S. aureus in clinical samples was more prevalent in cats (5.6%) than dogs (2.0%). Methicillin resistance was found in 17.8% of S. aureus samples and was higher in dogs (20.4%, 95%CI 18.9-22.0) than cats (15.6%, 95%CI 14.3-17.0). The highest MRSA prevalence was found in canine wound samples (32%), compared to skin/soft tissue, respiratory tract and other (<23% respectively).</p><p><strong>Conclusion: </strong>The study reveals a 17.8% MRSA prevalence, which is higher than the human outpatient MRSA prevalence (5.4%). Restriction and regulation of veterinary antibiotic use should be validated with AMR surveillance. Our study shows that this is feasible in companion animals with significant coverage.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gert-Jan Wijnant, Perrin Ngougni Pokem, Marie Coessens, Eleonora Cottone, Julian Ermtraud, Lieven Goeman, Steven Vervaeke, Sebastian G Wicha, Françoise Van Bambeke
Objectives: Temocillin, a carbapenem-sparing β-lactam antibiotic, is commonly used at the standard 4 g/day dosage for treating complicated urinary tract infections (cUTIs). However, pharmacokinetic/pharmacodynamic (PK/PD) data supporting this regimen is limited. This study evaluated the plasma pharmacokinetics (PK) and PTA of temocillin in non-critically ill cUTI patients with varying degrees of renal insufficiency (RI).
Methods: In this single-centre clinical study, 22 cUTI patients received a fixed 4 g/day (2 g q12h, intravenously) temocillin dose, irrespective of renal function (no RI: n = 5, mild RI: n = 8, moderate RI: n = 9). Plasma samples were collected post-dosing for LC-MS analysis of total and unbound temocillin levels. Monte Carlo simulations were performed based on the established PK/PD target of ≥35% fT > MIC (minimal inhibitory concentration).
Results: Among patients, the highest plasma drug exposure and PK/PD target attainment were observed in those with moderate RI (median AUC0-12h = 1143 h.mg/L and %fT > MIC = 68%), followed by mild RI patients (median AUC0-12h = 918 h.mg/L and %fT > MIC = 34%), and the lowest in those with healthy kidney function (median AUC0-12h = 692 h.mg/L and %fT > MIC = 26%). Simulations indicated that the 4 g/day temocillin dose achieves 90% PTA only for glomerular filtration rate < 60 mL/min and MIC ≤ 8 mg/L.
Conclusion: The standard temocillin dose may need to be increased from 4 to 6 g/day to treat non-critically ill cUTI patients, in line with recent EUCAST recommendations. For patients with moderate RI, who experience higher exposure due to reduced renal drug clearance, 4 g/day temocillin remains appropriate.
{"title":"Pharmacokinetics and pharmacological target attainment of standard temocillin dosing in non-critically ill patients with complicated urinary tract infections.","authors":"Gert-Jan Wijnant, Perrin Ngougni Pokem, Marie Coessens, Eleonora Cottone, Julian Ermtraud, Lieven Goeman, Steven Vervaeke, Sebastian G Wicha, Françoise Van Bambeke","doi":"10.1093/jac/dkae215","DOIUrl":"10.1093/jac/dkae215","url":null,"abstract":"<p><strong>Objectives: </strong>Temocillin, a carbapenem-sparing β-lactam antibiotic, is commonly used at the standard 4 g/day dosage for treating complicated urinary tract infections (cUTIs). However, pharmacokinetic/pharmacodynamic (PK/PD) data supporting this regimen is limited. This study evaluated the plasma pharmacokinetics (PK) and PTA of temocillin in non-critically ill cUTI patients with varying degrees of renal insufficiency (RI).</p><p><strong>Methods: </strong>In this single-centre clinical study, 22 cUTI patients received a fixed 4 g/day (2 g q12h, intravenously) temocillin dose, irrespective of renal function (no RI: n = 5, mild RI: n = 8, moderate RI: n = 9). Plasma samples were collected post-dosing for LC-MS analysis of total and unbound temocillin levels. Monte Carlo simulations were performed based on the established PK/PD target of ≥35% fT > MIC (minimal inhibitory concentration).</p><p><strong>Results: </strong>Among patients, the highest plasma drug exposure and PK/PD target attainment were observed in those with moderate RI (median AUC0-12h = 1143 h.mg/L and %fT > MIC = 68%), followed by mild RI patients (median AUC0-12h = 918 h.mg/L and %fT > MIC = 34%), and the lowest in those with healthy kidney function (median AUC0-12h = 692 h.mg/L and %fT > MIC = 26%). Simulations indicated that the 4 g/day temocillin dose achieves 90% PTA only for glomerular filtration rate < 60 mL/min and MIC ≤ 8 mg/L.</p><p><strong>Conclusion: </strong>The standard temocillin dose may need to be increased from 4 to 6 g/day to treat non-critically ill cUTI patients, in line with recent EUCAST recommendations. For patients with moderate RI, who experience higher exposure due to reduced renal drug clearance, 4 g/day temocillin remains appropriate.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Daniel Kiiza, Danial Rostami-Hochaghan, Yussif Alhassan, Kay Seden, Helen Reynolds, Julian P Kaboggoza, Miriam Taegtmeyer, Tao Chen, Elizabeth Challenger, Thokozile Malaba, Duolao Wang, Laura Else, Faye Hern, Jo Sharp, Megan Neary, Sujan Dilly Penchala, Catriona Waitt, Catherine Orrell, Angela Colbers, Landon Myer, Andrew Owen, Steve Rannard, Saye Khoo, Mohammed Lamorde
Background: We investigated the impact of Drug-Drug Interactions (DDIs) on virologic control among HIV-positive pregnant women initiating antiretroviral therapy while identifying drivers for Traditional Medicine (TM) use and exploring the nature and extent of TM-related DDIs.
Methods: Employing a three-pronged approach, we examined DDIs arising from comedication, including TM, in ART. The DolPHIN-2 trial (NCT03249181) randomized 268 HIV-positive pregnant women in Uganda and South Africa to dolutegravir (DTG)-based (135) or efavirenz-based (133) regimens while systematically recording comedications and screening for DDIs. We used Cox regression models to compare time-to-virologic control between participants with and without DDIs. We conducted in-depth interviews and focus group discussions among 37 and 67 women with and without HIV, respectively, to explore reasons for TM use during pregnancy. Additionally, in-vitro and in-vivo studies evaluated the composition and impact of clay-based TM, mumbwa, on DTG plasma exposure.
Results: The baseline prevalence of DDIs was 67.2%, with TM use prevalent in 34% of participants, with mumbwa being the most frequent (76%, 69/91). There was no difference in virologic response between participants with and without DDIs. Fetal health and cultural norms were among the reasons cited for TM use. Analysis of mumbwa rods confirmed significant amounts of aluminium (8.4%-13.9%) and iron (4%-6%). In Balb-C mice, coadministration of mumbwa led to a reduction in DTG exposure observed in the AUC0-24 (-21%; P = 0.0271) and C24 (-53%; P = 0.0028).
Conclusions: The widespread use of clay-based TM may compromise HIV treatment, necessitating medication screening and counselling to manage DDIs in pregnant women.
{"title":"Clinical, pharmacological, and qualitative characterization of drug-drug interactions in pregnant women initiating HIV therapy in Sub-Saharan Africa.","authors":"Daniel Kiiza, Danial Rostami-Hochaghan, Yussif Alhassan, Kay Seden, Helen Reynolds, Julian P Kaboggoza, Miriam Taegtmeyer, Tao Chen, Elizabeth Challenger, Thokozile Malaba, Duolao Wang, Laura Else, Faye Hern, Jo Sharp, Megan Neary, Sujan Dilly Penchala, Catriona Waitt, Catherine Orrell, Angela Colbers, Landon Myer, Andrew Owen, Steve Rannard, Saye Khoo, Mohammed Lamorde","doi":"10.1093/jac/dkae232","DOIUrl":"10.1093/jac/dkae232","url":null,"abstract":"<p><strong>Background: </strong>We investigated the impact of Drug-Drug Interactions (DDIs) on virologic control among HIV-positive pregnant women initiating antiretroviral therapy while identifying drivers for Traditional Medicine (TM) use and exploring the nature and extent of TM-related DDIs.</p><p><strong>Methods: </strong>Employing a three-pronged approach, we examined DDIs arising from comedication, including TM, in ART. The DolPHIN-2 trial (NCT03249181) randomized 268 HIV-positive pregnant women in Uganda and South Africa to dolutegravir (DTG)-based (135) or efavirenz-based (133) regimens while systematically recording comedications and screening for DDIs. We used Cox regression models to compare time-to-virologic control between participants with and without DDIs. We conducted in-depth interviews and focus group discussions among 37 and 67 women with and without HIV, respectively, to explore reasons for TM use during pregnancy. Additionally, in-vitro and in-vivo studies evaluated the composition and impact of clay-based TM, mumbwa, on DTG plasma exposure.</p><p><strong>Results: </strong>The baseline prevalence of DDIs was 67.2%, with TM use prevalent in 34% of participants, with mumbwa being the most frequent (76%, 69/91). There was no difference in virologic response between participants with and without DDIs. Fetal health and cultural norms were among the reasons cited for TM use. Analysis of mumbwa rods confirmed significant amounts of aluminium (8.4%-13.9%) and iron (4%-6%). In Balb-C mice, coadministration of mumbwa led to a reduction in DTG exposure observed in the AUC0-24 (-21%; P = 0.0271) and C24 (-53%; P = 0.0028).</p><p><strong>Conclusions: </strong>The widespread use of clay-based TM may compromise HIV treatment, necessitating medication screening and counselling to manage DDIs in pregnant women.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141599914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Penetration of isavuconazole into the epithelial lining fluid of patients with pulmonary fungal infections. Comment on: 'Pharmacokinetics of isavuconazole at different target sites in healthy volunteers after single and multiple intravenous infusions'.","authors":"Alexis Maillard, Léo Froelicher Bournaud, Jean Pastre, Benjamin Planquette, Perrine Parize, Fanny Lanternier, Camille Rasmussen, Camille Chenevier-Gobeaux, Cherifa Cheurfa, Sihem Benaboud, Caroline Charlier, Etienne Canouï","doi":"10.1093/jac/dkae258","DOIUrl":"10.1093/jac/dkae258","url":null,"abstract":"","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: β-lactam antibiotics, which inhibit penicillin-binding protein 3 (PBP3) that is required for cell division, play a key role in treating P. aeruginosa infections. Some sequence variations in PBP3 have been associated with β-lactam resistance but the effects of variations on antibiotic susceptibility and on cell division have not been quantified. Antibiotic efflux can also reduce susceptibility.
Objectives: To quantify the effects of PBP3 variations on β-lactam susceptibility and cell morphology in P. aeruginosa.
Methods: Nineteen PBP3 variants were expressed from a plasmid in the reference strain P. aeruginosa PAO1 and genome engineering was used to construct five mutants expressing PBP3 variants from the chromosome. The effects of the variations on β-lactam minimum inhibitory concentration (MIC) and cell morphology were measured.
Results: Some PBP3 variations reduced susceptibility to a variety of β-lactam antibiotics including meropenem, ceftazidime, cefepime and ticarcillin with different variations affecting different antibiotics. None of the tested variations reduced susceptibility to imipenem or piperacillin. Antibiotic susceptibility was further reduced when PBP3 variants were expressed in mutant bacteria overexpressing the MexAB-OprM efflux pump, with some variations conferring clinical levels of resistance. Some PBP3 variations, and sub-MIC levels of β-lactams, reduced bacterial growth rates and inhibited cell division, causing elongated cells.
Conclusions: PBP3 variations in P. aeruginosa can increase the MIC of multiple β-lactam antibiotics, although not imipenem or piperacillin. PBP3 variations, or the presence of sub-lethal levels of β-lactams, result in elongated cells indicating that variations reduce the activity of PBP3 and may reduce bacterial fitness.
{"title":"Penicillin-binding protein 3 sequence variations reduce susceptibility of Pseudomonas aeruginosa to β-lactams but inhibit cell division.","authors":"Karl A Glen, Iain L Lamont","doi":"10.1093/jac/dkae203","DOIUrl":"10.1093/jac/dkae203","url":null,"abstract":"<p><strong>Background: </strong>β-lactam antibiotics, which inhibit penicillin-binding protein 3 (PBP3) that is required for cell division, play a key role in treating P. aeruginosa infections. Some sequence variations in PBP3 have been associated with β-lactam resistance but the effects of variations on antibiotic susceptibility and on cell division have not been quantified. Antibiotic efflux can also reduce susceptibility.</p><p><strong>Objectives: </strong>To quantify the effects of PBP3 variations on β-lactam susceptibility and cell morphology in P. aeruginosa.</p><p><strong>Methods: </strong>Nineteen PBP3 variants were expressed from a plasmid in the reference strain P. aeruginosa PAO1 and genome engineering was used to construct five mutants expressing PBP3 variants from the chromosome. The effects of the variations on β-lactam minimum inhibitory concentration (MIC) and cell morphology were measured.</p><p><strong>Results: </strong>Some PBP3 variations reduced susceptibility to a variety of β-lactam antibiotics including meropenem, ceftazidime, cefepime and ticarcillin with different variations affecting different antibiotics. None of the tested variations reduced susceptibility to imipenem or piperacillin. Antibiotic susceptibility was further reduced when PBP3 variants were expressed in mutant bacteria overexpressing the MexAB-OprM efflux pump, with some variations conferring clinical levels of resistance. Some PBP3 variations, and sub-MIC levels of β-lactams, reduced bacterial growth rates and inhibited cell division, causing elongated cells.</p><p><strong>Conclusions: </strong>PBP3 variations in P. aeruginosa can increase the MIC of multiple β-lactam antibiotics, although not imipenem or piperacillin. PBP3 variations, or the presence of sub-lethal levels of β-lactams, result in elongated cells indicating that variations reduce the activity of PBP3 and may reduce bacterial fitness.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603671","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}
Leah M C Mcgee, Alemao G Carpinteyro Sanchez, Marina Perieteanu, Kaveh Eskandari, Yan Bian, Logan Mackie, Louise Young, Rebecca Beveridge, Colin J Suckling, Craig W Roberts, Fraser J Scott
Background: Acanthamoeba spp. is the causative agent of Acanthamoeba keratitis and granulomatous amoebic encephalitis. Strathclyde minor groove binders (S-MGBs) are a promising new class of anti-infective agent that have been shown to be effective against many infectious organisms.
Objectives: To synthesize and evaluate the anti-Acanthamoeba activity of a panel of S-MGBs, and therefore determine the potential of this class for further development.
Methods: A panel of 12 S-MGBs was synthesized and anti-Acanthamoeba activity was determined using an alamarBlue™-based trophocidal assay against Acanthamoeba castellanii. Cross-screening against Trypanosoma brucei brucei, Staphylococcus aureus and Escherichia coli was used to investigate selective potency. Cytotoxicity against HEK293 cells allowed for selective toxicity to be measured. DNA binding studies were carried out using native mass spectrometry and DNA thermal shift assays.
Results and discussion: S-MGB-241 has an IC50 of 6.6 µM against A. castellanii, comparable to the clinically used miltefosine (5.6 µM) and negligible activity against the other organisms. It was also found to have an IC50 > 100 µM against HEK293 cells, demonstrating low cytotoxicity. S-MGB-241 binds to DNA as a dimer, albeit weakly compared to other S-MGBs previously studied. This was confirmed by DNA thermal shift assay with a ΔTm = 1 ± 0.1°C.
Conclusions: Together, these data provide confidence that S-MGBs can be further optimized to generate new, potent treatments for Acanthameoba spp. infections. In particular, S-MGB-241, has been identified as a 'hit' compound that is selectively active against A. castellanii, providing a starting point from which to begin optimization of DNA binding and potency.
背景:阿卡阿米巴属是阿卡阿米巴角膜炎和肉芽肿阿米巴脑炎的病原体。斯特拉斯克莱德小沟结合剂(S-MGBs)是一类很有前途的新型抗感染剂,已被证明对许多感染性生物有效:目的:合成并评估一组S-MGB的抗阿卡他米巴活性,从而确定该类药物进一步开发的潜力:方法:合成了一组 12 种 S-MGB,并使用基于氨溴蓝(alamarBlue™)的滋养层杀菌法测定了它们对卡氏棘阿米巴的抗卡氏棘阿米巴活性。针对布氏锥虫、金黄色葡萄球菌和大肠杆菌的交叉筛选被用来研究其选择性效力。对 HEK293 细胞的细胞毒性可用于测量选择性毒性。使用原生质谱法和 DNA 热转移测定法进行了 DNA 结合研究:S-MGB-241 对 A. castellanii 的 IC50 值为 6.6 µM,与临床使用的米替福新(5.6 µM)相当,对其他生物的活性可忽略不计。研究还发现,它对 HEK293 细胞的 IC50 > 100 µM,显示出较低的细胞毒性。S-MGB-241 以二聚体形式与 DNA 结合,尽管与以前研究过的其他 S-MGB 相比,其结合力较弱。DNA 热转移测定证实了这一点,ΔTm = 1 ± 0.1°C:总之,这些数据让人相信,S-MGBs 可以进一步优化,以产生新的、强效的方法来治疗 Acanthameoba 感染。特别是,S-MGB-241 已被确定为一种 "命中 "化合物,对卡斯特氏疟原虫具有选择性活性,为开始优化 DNA 结合力和效力提供了一个起点。
{"title":"Strathclyde minor groove binders (S-MGBs) with activity against Acanthamoeba castellanii.","authors":"Leah M C Mcgee, Alemao G Carpinteyro Sanchez, Marina Perieteanu, Kaveh Eskandari, Yan Bian, Logan Mackie, Louise Young, Rebecca Beveridge, Colin J Suckling, Craig W Roberts, Fraser J Scott","doi":"10.1093/jac/dkae221","DOIUrl":"10.1093/jac/dkae221","url":null,"abstract":"<p><strong>Background: </strong>Acanthamoeba spp. is the causative agent of Acanthamoeba keratitis and granulomatous amoebic encephalitis. Strathclyde minor groove binders (S-MGBs) are a promising new class of anti-infective agent that have been shown to be effective against many infectious organisms.</p><p><strong>Objectives: </strong>To synthesize and evaluate the anti-Acanthamoeba activity of a panel of S-MGBs, and therefore determine the potential of this class for further development.</p><p><strong>Methods: </strong>A panel of 12 S-MGBs was synthesized and anti-Acanthamoeba activity was determined using an alamarBlue™-based trophocidal assay against Acanthamoeba castellanii. Cross-screening against Trypanosoma brucei brucei, Staphylococcus aureus and Escherichia coli was used to investigate selective potency. Cytotoxicity against HEK293 cells allowed for selective toxicity to be measured. DNA binding studies were carried out using native mass spectrometry and DNA thermal shift assays.</p><p><strong>Results and discussion: </strong>S-MGB-241 has an IC50 of 6.6 µM against A. castellanii, comparable to the clinically used miltefosine (5.6 µM) and negligible activity against the other organisms. It was also found to have an IC50 > 100 µM against HEK293 cells, demonstrating low cytotoxicity. S-MGB-241 binds to DNA as a dimer, albeit weakly compared to other S-MGBs previously studied. This was confirmed by DNA thermal shift assay with a ΔTm = 1 ± 0.1°C.</p><p><strong>Conclusions: </strong>Together, these data provide confidence that S-MGBs can be further optimized to generate new, potent treatments for Acanthameoba spp. infections. In particular, S-MGB-241, has been identified as a 'hit' compound that is selectively active against A. castellanii, providing a starting point from which to begin optimization of DNA binding and potency.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563404","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":"Correction to: Extrapolation of lung pharmacokinetics of antitubercular drugs from preclinical species to humans using PBPK modelling.","authors":"","doi":"10.1093/jac/dkae251","DOIUrl":"10.1093/jac/dkae251","url":null,"abstract":"","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579735","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}
Alex Howard, Peter L Green, Anoop Velluva, Alessandro Gerada, David M Hughes, Charlotte Brookfield, William Hope, Iain Buchan
Background: Estimates of the prevalence of antimicrobial resistance (AMR) underpin effective antimicrobial stewardship, infection prevention and control, and optimal deployment of antimicrobial agents. Typically, the prevalence of AMR is determined from real-world antimicrobial susceptibility data that are time delimited, sparse, and often biased, potentially resulting in harmful and wasteful decision-making. Frequentist methods are resource intensive because they rely on large datasets.
Objectives: To determine whether a Bayesian approach could present a more reliable and more resource-efficient way to estimate population prevalence of AMR than traditional frequentist methods.
Methods: Retrospectively collected, open-source, real-world pseudonymized healthcare data were used to develop a Bayesian approach for estimating the prevalence of AMR by combination with prior AMR information from a contextualized review of literature. Iterative random sampling and cross-validation were used to assess the predictive accuracy and potential resource efficiency of the Bayesian approach compared with a standard frequentist approach.
Results: Bayesian estimation of AMR prevalence made fewer extreme estimation errors than a frequentist estimation approach [n = 74 (6.4%) versus n = 136 (11.8%)] and required fewer observed antimicrobial susceptibility results per pathogen on average [mean = 28.8 (SD = 22.1) versus mean = 34.4 (SD = 30.1)] to avoid any extreme estimation errors in 50 iterations of the cross-validation. The Bayesian approach was maximally effective and efficient for drug-pathogen combinations where the actual prevalence of resistance was not close to 0% or 100%.
Conclusions: Bayesian estimation of the prevalence of AMR could provide a simple, resource-efficient approach to better inform population infection management where uncertainty about AMR prevalence is high.
背景:对抗菌药物耐药性(AMR)流行率的估计是有效开展抗菌药物管理、预防和控制感染以及优化抗菌药物使用的基础。通常情况下,AMR 的流行率是根据真实世界的抗菌药物敏感性数据确定的,这些数据有时间限制、稀少,而且往往存在偏差,可能导致有害和浪费的决策。频数法依赖于大型数据集,因此需要大量资源:目的:确定贝叶斯方法是否比传统的频数法更可靠、更节省资源,可用于估算 AMR 在人群中的流行率:方法:利用回顾性收集的、开源的、现实世界中的化名医疗数据,结合从文献背景回顾中获得的先验AMR信息,开发出一种贝叶斯方法来估算AMR的流行率。使用迭代随机抽样和交叉验证来评估贝叶斯方法与标准频数法相比的预测准确性和潜在资源效率:结果:贝叶斯估算AMR流行率的极端估算错误少于频数估算方法[n = 74 (6.4%)对n = 136 (11.8%)],在50次迭代交叉验证中,平均每种病原体需要更少的抗菌药物敏感性观察结果[平均值 = 28.8 (SD = 22.1) 对平均值 = 34.4 (SD = 30.1)]来避免任何极端估算错误。对于实际抗药性流行率不接近 0% 或 100% 的药物病原体组合,贝叶斯方法具有最大的有效性和效率:贝叶斯法对 AMR 流行率的估计可以提供一种简单、节省资源的方法,从而在 AMR 流行率不确定性较高的情况下为人群感染管理提供更好的信息。
{"title":"Bayesian estimation of the prevalence of antimicrobial resistance: a mathematical modelling study.","authors":"Alex Howard, Peter L Green, Anoop Velluva, Alessandro Gerada, David M Hughes, Charlotte Brookfield, William Hope, Iain Buchan","doi":"10.1093/jac/dkae230","DOIUrl":"10.1093/jac/dkae230","url":null,"abstract":"<p><strong>Background: </strong>Estimates of the prevalence of antimicrobial resistance (AMR) underpin effective antimicrobial stewardship, infection prevention and control, and optimal deployment of antimicrobial agents. Typically, the prevalence of AMR is determined from real-world antimicrobial susceptibility data that are time delimited, sparse, and often biased, potentially resulting in harmful and wasteful decision-making. Frequentist methods are resource intensive because they rely on large datasets.</p><p><strong>Objectives: </strong>To determine whether a Bayesian approach could present a more reliable and more resource-efficient way to estimate population prevalence of AMR than traditional frequentist methods.</p><p><strong>Methods: </strong>Retrospectively collected, open-source, real-world pseudonymized healthcare data were used to develop a Bayesian approach for estimating the prevalence of AMR by combination with prior AMR information from a contextualized review of literature. Iterative random sampling and cross-validation were used to assess the predictive accuracy and potential resource efficiency of the Bayesian approach compared with a standard frequentist approach.</p><p><strong>Results: </strong>Bayesian estimation of AMR prevalence made fewer extreme estimation errors than a frequentist estimation approach [n = 74 (6.4%) versus n = 136 (11.8%)] and required fewer observed antimicrobial susceptibility results per pathogen on average [mean = 28.8 (SD = 22.1) versus mean = 34.4 (SD = 30.1)] to avoid any extreme estimation errors in 50 iterations of the cross-validation. The Bayesian approach was maximally effective and efficient for drug-pathogen combinations where the actual prevalence of resistance was not close to 0% or 100%.</p><p><strong>Conclusions: </strong>Bayesian estimation of the prevalence of AMR could provide a simple, resource-efficient approach to better inform population infection management where uncertainty about AMR prevalence is high.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368424/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141758872","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}
Alexandra David, Daniel Golparian, Susanne Jacobsson, Caleb Stratton, Pham Thi Lan, Ken Shimuta, Pam Sonnenberg, Nigel Field, Makoto Ohnishi, Christopher Davies, Magnus Unemo
Objectives: The novel dual-target triazaacenaphthylene, gepotidacin, recently showed promising results in its Phase III randomized controlled trial for the treatment of gonorrhoea. We investigated alterations in the gepotidacin GyrA and ParC targets in gonococci by in silico mining of publicly available global genomes (n = 33 213) and determined gepotidacin MICs in isolates with GyrA A92 alterations combined with other GyrA and/or ParC alterations.
Methods: We examined gonococcal gyrA and parC alleles available at the European Nucleotide Archive. MICs were determined using the agar dilution method (gepotidacin) or Etest (four antimicrobials). Models of DNA gyrase and topoisomerase IV were obtained from AlphaFold and used to model gepotidacin in the binding site.
Results: GyrA A92 alterations were identified in 0.24% of genomes: GyrA A92P/S/V + S91F + D95Y/A/N (0.208%), A92P + S91F (0.024%) and A92P (0.003%), but no A92T (previously associated with gepotidacin resistance) was found. ParC D86 alterations were found in 10.6% of genomes: ParC D86N/G (10.5%), D86N + S87I (0.051%), D86N + S88P (0.012%) and D86G + E91G (0.003%). One isolate had GyrA A92P + ParC D86N alterations, but remained susceptible to gepotidacin (MIC = 0.125 mg/L). No GyrA plus ParC alterations resulted in a gepotidacin MIC > 4 mg/L. Modelling of gepotidacin binding to GyrA A92/A92T/A92P suggested that gepotidacin resistance due to GyrA A92T might be linked to the formation of a new polar contact with DNA.
Conclusions: In silico mining of 33 213 global gonococcal genomes (isolates from 1928 to 2023) showed that A92 is highly conserved in GyrA, while alterations in D86 of ParC are common. No GyrA plus ParC alterations caused gepotidacin resistance. MIC determination and genomic surveillance of potential antimicrobial resistance determinants are imperative.
{"title":"In silico gepotidacin target mining among 33 213 global Neisseria gonorrhoeae genomes from 1928 to 2023 combined with gepotidacin MIC testing of 22 gonococcal isolates with different GyrA and ParC substitutions.","authors":"Alexandra David, Daniel Golparian, Susanne Jacobsson, Caleb Stratton, Pham Thi Lan, Ken Shimuta, Pam Sonnenberg, Nigel Field, Makoto Ohnishi, Christopher Davies, Magnus Unemo","doi":"10.1093/jac/dkae217","DOIUrl":"10.1093/jac/dkae217","url":null,"abstract":"<p><strong>Objectives: </strong>The novel dual-target triazaacenaphthylene, gepotidacin, recently showed promising results in its Phase III randomized controlled trial for the treatment of gonorrhoea. We investigated alterations in the gepotidacin GyrA and ParC targets in gonococci by in silico mining of publicly available global genomes (n = 33 213) and determined gepotidacin MICs in isolates with GyrA A92 alterations combined with other GyrA and/or ParC alterations.</p><p><strong>Methods: </strong>We examined gonococcal gyrA and parC alleles available at the European Nucleotide Archive. MICs were determined using the agar dilution method (gepotidacin) or Etest (four antimicrobials). Models of DNA gyrase and topoisomerase IV were obtained from AlphaFold and used to model gepotidacin in the binding site.</p><p><strong>Results: </strong>GyrA A92 alterations were identified in 0.24% of genomes: GyrA A92P/S/V + S91F + D95Y/A/N (0.208%), A92P + S91F (0.024%) and A92P (0.003%), but no A92T (previously associated with gepotidacin resistance) was found. ParC D86 alterations were found in 10.6% of genomes: ParC D86N/G (10.5%), D86N + S87I (0.051%), D86N + S88P (0.012%) and D86G + E91G (0.003%). One isolate had GyrA A92P + ParC D86N alterations, but remained susceptible to gepotidacin (MIC = 0.125 mg/L). No GyrA plus ParC alterations resulted in a gepotidacin MIC > 4 mg/L. Modelling of gepotidacin binding to GyrA A92/A92T/A92P suggested that gepotidacin resistance due to GyrA A92T might be linked to the formation of a new polar contact with DNA.</p><p><strong>Conclusions: </strong>In silico mining of 33 213 global gonococcal genomes (isolates from 1928 to 2023) showed that A92 is highly conserved in GyrA, while alterations in D86 of ParC are common. No GyrA plus ParC alterations caused gepotidacin resistance. MIC determination and genomic surveillance of potential antimicrobial resistance determinants are imperative.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616477","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}
Emmanuelle Gras, Tommaso Francesco Aiello, Mariana Chumbita, Antonio Gallardo-Pizarro, Patricia Monzó-Gallo, Christian Teijón-Lumbreras, Maria Suárez-Lledó, Laura Magnano, Montse Tuset, Maria Ángeles Marcos, Alex Soriano, Carolina Garcia-Vidal
Objectives: To describe the management of haematological patients experiencing prolonged SARS-CoV-2 viral shedding, as the optimal management strategy for this condition remains undetermined.
Methods: We conducted a retrospective evaluation of our prospectively followed cohort of haematological patients treated with remdesivir for more than 10 days. Starting January 2023, upon COVID-19 diagnosis, the treatment strategy was based on symptoms and PCR cycle threshold (Ct) as follows: (i) when Ct was 25 or less or if the patient had symptoms, a course of remdesivir for at least 10 days, nirmatrelvir/ritonavir for 5 days (whenever possible) and convalescent plasma was administered; and (ii) when the patient was asymptomatic and had a PCR Ct of more than 25, when possible, a course of 5 days of nirmatrelvir/ritonavir was administered. The patient was considered to have achieved viral clearance and, thus, remdesivir was stopped, in either of these cases: (i) PCR negativity, or (ii) subgenomic RNA negativity.
Results: From January to November 2023, 18 patients benefited from a safe extended remdesivir administration, resulting in detection of SARS-CoV-2 viral clearance in a median time of 3.5 weeks (IQR 2.6-3.9) (min-max 1.6-8.0). No clinical or biological side effects were detected. No patient died or needed further treatment for their COVID-19 episode.
Conclusions: The extended course of remdesivir, combined with other active therapies for COVID-19 infection, was well tolerated. Cure and virus negativity were obtained in all these high-risk patients.
{"title":"Extended remdesivir administration in haematological patients with malignancies and COVID-19 during the Omicron era: safety and outcomes.","authors":"Emmanuelle Gras, Tommaso Francesco Aiello, Mariana Chumbita, Antonio Gallardo-Pizarro, Patricia Monzó-Gallo, Christian Teijón-Lumbreras, Maria Suárez-Lledó, Laura Magnano, Montse Tuset, Maria Ángeles Marcos, Alex Soriano, Carolina Garcia-Vidal","doi":"10.1093/jac/dkae237","DOIUrl":"10.1093/jac/dkae237","url":null,"abstract":"<p><strong>Objectives: </strong>To describe the management of haematological patients experiencing prolonged SARS-CoV-2 viral shedding, as the optimal management strategy for this condition remains undetermined.</p><p><strong>Methods: </strong>We conducted a retrospective evaluation of our prospectively followed cohort of haematological patients treated with remdesivir for more than 10 days. Starting January 2023, upon COVID-19 diagnosis, the treatment strategy was based on symptoms and PCR cycle threshold (Ct) as follows: (i) when Ct was 25 or less or if the patient had symptoms, a course of remdesivir for at least 10 days, nirmatrelvir/ritonavir for 5 days (whenever possible) and convalescent plasma was administered; and (ii) when the patient was asymptomatic and had a PCR Ct of more than 25, when possible, a course of 5 days of nirmatrelvir/ritonavir was administered. The patient was considered to have achieved viral clearance and, thus, remdesivir was stopped, in either of these cases: (i) PCR negativity, or (ii) subgenomic RNA negativity.</p><p><strong>Results: </strong>From January to November 2023, 18 patients benefited from a safe extended remdesivir administration, resulting in detection of SARS-CoV-2 viral clearance in a median time of 3.5 weeks (IQR 2.6-3.9) (min-max 1.6-8.0). No clinical or biological side effects were detected. No patient died or needed further treatment for their COVID-19 episode.</p><p><strong>Conclusions: </strong>The extended course of remdesivir, combined with other active therapies for COVID-19 infection, was well tolerated. Cure and virus negativity were obtained in all these high-risk patients.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}