Journal of Antimicrobial Chemotherapy最新文献

{"title":"Synergistic antimicrobial activity of lynronne-1 and EDTA against bovine mastitis pathogens.","authors":"Ana Julia S Moreira, Katialaine C de Araújo Domingues, Karine D V Camargo, Nicole A Aulik, Linda B Oyama, Sharon A Huws, Hilario C Mantovani","doi":"10.1093/jac/dkae425","DOIUrl":"https://doi.org/10.1093/jac/dkae425","url":null,"abstract":"<p><strong>Background: </strong>Bovine mastitis is the costliest disease in the dairy sector and the main cause of antibiotic use in dairy cattle, potentially contributing to the antimicrobial resistance crisis. Antimicrobial peptides (AMPs) offer promise as antibiotic alternatives for controlling mastitis pathogens.</p><p><strong>Methods: </strong>The efficacy of five AMPs (Lynronne-1 [Lyn-1], Lynronne-2 [Lyn-2], Bovicin HC5, AMP 660, and AMP 1043) and two bioactive compounds (disodium ethylenediaminetetraacetic acid [EDTA] and glycerol monolaurate) was assessed against a range of 35 mastitis-causing pathogens. The fractional inhibitory concentrations index (FICI) was calculated to determine the interaction effect and values ≤0.5 were indicative of synergism. Time-dependent killing assays were performed to assess bactericidal efficacy of the combination. Cytotoxicity was evaluated using the MTT assay and haemolytic activity was assessed against fresh bovine erythrocytes.</p><p><strong>Results: </strong>Lyn-1 and EDTA exhibited the highest broad spectrum antimicrobial activity and reduced bacterial growth (OD600 nm) by 95.1% and 86.9%, respectively. FICI values ranged from 0.1 to 0.5, indicating synergism. The combination of lyn-1 (0.03 mg/mL) and EDTA (1.02 mg/mL) exhibited higher antimicrobial activity against all bacterial strains, at significantly lower concentrations than each compound individually. Lyn-1-EDTA combination reduced viable population by >10 000-fold within 12 h. The combination was non-haemolytic in concentrations up to 8-fold the established MIC values (P > 0.05), although cytotoxic effects were observed at concentrations above MIC (P < 0.01).</p><p><strong>Conclusions: </strong>These findings highlight the therapeutic potential of Lyn-1 and Lyn-1-EDTA for developing antibiotic-free formulations to combat contagious and environmental mastitis pathogens and treat udder infections.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710276","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":"Efficacy and tolerability of high-dose cefalexin 45 mg/kg/dose (maximum 1.5 g) three times daily in children with bone and joint infections.","authors":"Samar Hikmat, Alison Boast, Nigel Curtis, Amanda Gwee","doi":"10.1093/jac/dkae423","DOIUrl":"https://doi.org/10.1093/jac/dkae423","url":null,"abstract":"<p><strong>Background: </strong>Cefalexin, a first-generation cephalosporin, is commonly used as oral continuation therapy for paediatric bone and joint infections (BJIs). The standard four times daily cefalexin dose makes treatment adherence challenging. A pharmacokinetic modelling study found that a cefalexin dose of 45 mg/kg (maximum 1.5 g) three times daily achieves the same pharmacodynamic target.</p><p><strong>Objectives: </strong>To evaluate the efficacy and tolerability of three times daily cefalexin dosing in children with BJIs.</p><p><strong>Patients and methods: </strong>Retrospective audit of children aged 1-18 years who received cefalexin at a dose of 40-50 mg/kg (maximum 1.5 g) three times daily as oral continuation therapy for a haematogenous BJI at a quaternary paediatric hospital in Australia over a 4 year period (January 2019 to December 2022).</p><p><strong>Results: </strong>Of 149 children with BJIs treated with three times daily cefalexin dosing, the majority (147/149; 99%) achieved cure, with two experiencing recurrence of their infection. Most children tolerated the higher cefalexin dose; 4 children experienced gastrointestinal symptoms and 13 developed neutropenia, which was mild in most cases with no associated complications.</p><p><strong>Conclusions: </strong>A reduced frequency dosing regimen using a high cefalexin dose of 45 mg/kg (maximum 1.5 g) three times daily is effective and well tolerated in most children with BJIs.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681947","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":"Comparative evaluation of eravacycline susceptibility testing methods in 587 clinical carbapenem-resistant Acinetobacter baumannii isolates: broth microdilution, MIC test strip and disc diffusion.","authors":"Qihui Liu, Shirong Li, Xuan Wang, Yijing Lin, Haoqin Jiang, Ning Li","doi":"10.1093/jac/dkae426","DOIUrl":"https://doi.org/10.1093/jac/dkae426","url":null,"abstract":"<p><strong>Objectives: </strong>The study aimed to evaluate the accuracy of different methods for determining carbapenem-resistant Acinetobacter baumannii (CRAB) susceptibility to eravacycline.</p><p><strong>Methods: </strong>We collected 587 CRAB strains from Huashan Hospital affiliated to Fudan University between 2019 and 2023. The broth microdilution (BMD) method served as the reference standard. The susceptibility results were evaluated using the clinical breakpoints established by the Chinese Committee on Antimicrobial Susceptibility Testing (ChinaCAST) (susceptible MIC,  ≤ 1 mg/L; inhibition zone diameter,  ≥ 15 mm). The study compared the reliability of the MIC test strip (MTS) and disc diffusion (DD) methods in detecting CRAB susceptibility to eravacycline.</p><p><strong>Results: </strong>The MICs required to inhibit 50% and 90% of CRAB growth were as follows: BMD, 0.5/1 mg/L; MTS, 0.38/0.75 mg/L. According to the ChinaCAST breakpoints, the BMD method demonstrated a 98.13% (576/587) susceptibility rate, whereas the MTS and DD methods showed susceptibility rates of 97.96% (575/587) and 97.61% (573/587), respectively. The essential agreement rate between the MTS and BMD methods was 94.55%. Categorical agreement (CA) rates for the MTS and DD methods were 99.83% and 99.49%, respectively. The major error (ME) rate for MTS was 0.17%, with no very major errors (VMEs) observed. For the DD method, the ME rate was 0.51%, also with no VMEs.</p><p><strong>Conclusion: </strong>The MTS and DD methods demonstrated strong consistency with the BMD reference method, with CA, ME and VME rates meeting methodological evaluation criteria. Both MTS and DD methods are reliable alternatives for assessing the antibacterial activity of eravacycline in clinical microbiology laboratories.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681943","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":"Outcomes after a virological failure to first-line second-generation INSTI-based therapy in a real-life setting.","authors":"Rebecka Papaioannu Borjesson, Tommaso Clemente, Sara Diotallevi, Riccardo Lolatto, Arianna Forniti, Martina Bottanelli, Laura Galli, Nicola Gianotti, Camilla Muccini, Hamid Hasson, Antonella Castagna, Vincenzo Spagnuolo","doi":"10.1093/jac/dkae420","DOIUrl":"https://doi.org/10.1093/jac/dkae420","url":null,"abstract":"<p><strong>Background: </strong>Virological failures of first-line second-generation (SG) INSTI-based regimens are rare, usually characterized by low viremia and absence of drug resistance mutations.</p><p><strong>Objectives: </strong>To explore the efficacy of rescue regimens introduced after virological failure (VF) to a first-line SG-INSTI therapy.</p><p><strong>Patients and methods: </strong>This was a retrospective study on people living with HIV (PWH) failing a first-line SG-INSTI regimen [DTG/3TC, BIC/FTC/TAF, DTG-based three-drug regimen (DTG-3DR)] between 24 March 2016 and 31 December 2021. Follow-up accrued from the second viral load (VL) ≥ 50 copies/mL under SG-INSTI regimen (baseline) until virological success (VS, achievement of at least one VL < 50 copies/mL after baseline) or last visit. Cumulative probabilities of VS were estimated by Kaplan-Meier curves and compared using a log-rank test.</p><p><strong>Results: </strong>Overall, of 521 naïve PWH who started a first-line SG-INSTI regimen, 45 (8.6%) had VF after a median of 14.9 (IQR = 6.9-25.9) months: 33/395 (8.4%) individuals failed a DTG-3DR, 11/102 (10.8%) a BIC/FTC/TAF and 1/24 (4.2%) failed a DTG/3TC.At baseline, 12/45 (27%) PWH changed antiretroviral therapy [median baseline VL 134 (IQR = 81-233) copies/mL], while 33 (73%) maintained their failing regimen [median baseline VL 75 (IQR = 60-145) copies/mL].During a median follow-up of 5.13 (IQR = 3.8-7.1) months, 34 (75.6%) PWH achieved VS: 25/33 (75.8%) maintaining their failing regimen, 9/12 (75%) switched regimen; the estimated 6- and 12-months probabilities of VS were 59% and 84%, respectively.There was no difference in VS curves between PWH who maintained their failing regimen and those who switched therapy.</p><p><strong>Conclusions: </strong>Most individuals remained on their failing regimen, achieving spontaneous virological suppression in most cases. These data help to understand a real-life VF scenario in the context of the current SG-INSTI era.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681950","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":"Comment on: Skin pharmacokinetics of miltefosine in the treatment of post-kala-azar dermal leishmaniasis in South Asia.","authors":"Marlene Prager, Valentin Al Jalali, Markus Zeitlinger","doi":"10.1093/jac/dkae417","DOIUrl":"10.1093/jac/dkae417","url":null,"abstract":"","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667923","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":"Pretreatment and acquired HIV drug resistance in Belize-results of nationally representative surveys, 2021-22.","authors":"Francis Morey, Amalia Girón-Callejas, Russell Manzanero, Aspiro Urbina, Claudia García-Morales, Job Joseph, Edwin Bolastig, Sandra Jones, Stephanie M Wu, Daniela Tapia-Trejo, Jessica Monreal-Flores, Veronica Ortega, Marvin Manzanero, Aldo Sosa, Giovanni Ravasi, Michael R Jordan, Omar Sued, Santiago Ávila-Ríos","doi":"10.1093/jac/dkae408","DOIUrl":"https://doi.org/10.1093/jac/dkae408","url":null,"abstract":"<p><strong>Background: </strong>The rising prevalence of pretreatment drug resistance (PDR) to non-nucleoside reverse-transcriptase inhibitors threatens the effectiveness of ART. In response, the WHO recommends dolutegravir-based ART regimens due to their high genetic barrier to resistance and better treatment outcomes. This is expected to contribute to achieving the Joint United Nations Programme on HIV/AIDS (UNAIDS) target of 95% viral suppression in people on ART.</p><p><strong>Objectives: </strong>To estimate the prevalence of PDR among adults initiating ART and assess viral suppression and acquired HIV drug resistance (ADR) among individuals receiving ART in Belize.</p><p><strong>Patients and methods: </strong>Nationally representative cross-sectional PDR and ADR surveys were conducted between 2021 and 2022. Sixty-seven adults were included in the PDR survey, and 43 children and adolescents and 331 adults were included in the ADR survey. Demographic and clinic data and blood specimens were collected. HIV drug resistance (HIVDR) was predicted using the Stanford HIVdb tool.</p><p><strong>Results: </strong>The prevalence of PDR to efavirenz or nevirapine in adults was 49.3% (95% CI 42.2%-56.4%) and was significantly higher in those with previous antiretroviral exposure (OR: 7.16; 95% CI 2.71-18.95; P = 0.002). Among children and adolescents receiving ART, 50.0% had viral suppression, with better rates for those receiving dolutegravir-based ART (OR: 5.31; 95% CI 3.02-9.34; P < 0.001). In adults, 79.6% achieved viral suppression. No resistance to integrase inhibitors was observed in those on dolutegravir-based ART.</p><p><strong>Conclusions: </strong>Prioritizing dolutegravir-based ART is critical for achieving HIV epidemic control in Belize. Efforts should focus on retention in care and adherence support to prevent HIVDR.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647561","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":"Insights into interspecies protein binding variability using clindamycin as an example.","authors":"Hifza Ahmed, Michaela Böhmdorfer, Walter Jäger, Markus Zeitlinger","doi":"10.1093/jac/dkae412","DOIUrl":"https://doi.org/10.1093/jac/dkae412","url":null,"abstract":"<p><strong>Background: </strong>In the preclinical development of new drugs, animal models are often employed to predict their efficacy in humans, relying on translational pharmacokinetic/pharmacodynamic (PK/PD) studies. We performed in vitro experiments focusing on the comparison of plasma protein binding (PPB) and bacterial growth dynamics of clindamycin, a commonly used antimicrobial agent, across a range of drug concentrations and plasma environments.</p><p><strong>Methods: </strong>Human, bovine and rat plasma were used for determining PPB of clindamycin at various antibiotic concentrations in buffer and media containing 20% to 70% plasma or pure plasma using ultrafiltration (UF) and equilibrium dialysis (ED). Also bacterial growth and time-kill assays were performed in Mueller-Hinton broth (MHB) containing various percentages of plasma.</p><p><strong>Results: </strong>Protein binding of clindamycin correlated well between UF and ED. Notably, clindamycin exhibited substantially lower protein binding to rat plasma compared with human and bovine plasma. Staphylococcus aureus growth was significantly reduced in 70% human, bovine, and rat plasma after 4, 8 and 24 h compared with standard MHB. Time-kill data demonstrated that bacterial counts at both 20% and 70% plasmas were less when compared with MHB at drug concentrations lower than MIC after 4 and 8 h of incubation. For rat plasma, the difference was maintained over 24 h of incubation. Furthermore, a complete bacterial killing at 16 mg/L was observed after 24 h in 20% and 70% human and bovine plasma, but not for rat plasma.</p><p><strong>Conclusions: </strong>Recognizing interspecies differences in PB might be essential for optimizing the translational relevance of preclinical studies.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647486","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":"Parenteral aciclovir for suspected herpes simplex virus infection in children: 0-18 years.","authors":"Angela Berkhout, Julia E Clark, Cheryl A Jones, Keith Grimwood, Brendan McMullan, Philip N Britton, Pamela Palasanthiran, Selina Lim, Daniel K Yeoh, Shirley Wong, Daryl R Cheng, Amanda Gwee, Jack Cross, Tran Nguyen, Emma Jeffs, Tony Walls, Michelle Mahony, Jennifer Yan, Clare Nourse","doi":"10.1093/jac/dkae411","DOIUrl":"https://doi.org/10.1093/jac/dkae411","url":null,"abstract":"<p><strong>Background: </strong>Variations in neonatal aciclovir prescribing for suspected herpes simplex virus (HSV) disease are well-known, but there are limited data describing aciclovir prescribing in older children.</p><p><strong>Methods: </strong>Medical records of neonates (≤28 days) and children (29 days to 18 years) prescribed intravenous aciclovir for suspected HSV disease (1 January 2019-12 December 2019) in eight Australian and New Zealand hospitals were reviewed. Prescribing indication, HSV testing, aciclovir prescription details, adverse events and discharge diagnosis were recorded.</p><p><strong>Results: </strong>1426 received empirical aciclovir. For neonates (n = 425), the median duration was 1 day (IQR 1-3), 411/425 underwent HSV investigations and 13/425 had HSV disease (two with disseminated encephalitis, four with encephalitis and seven with skin, eye, mouth disease). Of the 1001 children, 906 were immunocompetent. 136/906 suspected of mucocutaneous disease received aciclovir for a median of 2 days (1-2), 121/136 underwent HSV testing, and 69/136 had proven disease. 770/906 received aciclovir for suspected disseminated disease or encephalitis for a median of 1 day (1-2), 556/770 underwent HSV testing, and 5/770 had disseminated disease or encephalitis. Among 95 immunocompromised children, 53/58 with suspected mucocutaneous disease had HSV testing and this was confirmed in 22. Disseminated disease or encephalitis was suspected in 37/95, HSV testing conducted in 23/37 and detected in one. The median aciclovir duration was 3 (2-7) days for immunocompromised children. Nephrotoxicity occurred in 7/1426 and 24/1426 had an extravasation injury.</p><p><strong>Conclusion: </strong>Frequent and often unnecessary intravenous aciclovir prescribing for suspected HSV encephalitis or disseminated disease occurred in children, as evidenced by incomplete HSV investigations and only 5/770 older children having the diagnosis confirmed.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647638","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":"Efficacy of bictegravir/emtricitabine/tenofovir alafenamide versus dolutegravir-based three-drug regimens in people with HIV with varying adherence to antiretroviral therapy.","authors":"Kristen Andreatta, Paul E Sax, David Wohl, Michelle L D'Antoni, Hui Liu, Jason T Hindman, Christian Callebaut","doi":"10.1093/jac/dkae407","DOIUrl":"https://doi.org/10.1093/jac/dkae407","url":null,"abstract":"<p><strong>Objective: </strong>Five Phase 3 bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) clinical studies demonstrated that the efficacy of B/F/TAF was non-inferior to dolutegravir (DTG) + 2 NRTIs. We retrospectively assessed drug adherence and effect on virologic outcomes.</p><p><strong>Methods: </strong>Studies (NCT02607930, NCT02607956, NCT03547908, NCT02603120 and NCT03110380) were double-blind, placebo-controlled and enrolled treatment-naïve or virologically suppressed adults. Adherence was calculated by pill count from returned pill bottles; virologic outcome was assessed by last on-treatment HIV-1 RNA.</p><p><strong>Results: </strong>Altogether, 2622 participants (B/F/TAF: n = 1306; DTG + 2 NRTIs: n = 1316) were categorized as having high (≥95%), intermediate (≥85% to <95%) or low (<85%) adherence. Through Week 48, low adherence was observed in 46 (3.5%) participants in the B/F/TAF group (78% median adherence) and 69 (5.2%) in the DTG + 2 NRTI group (80% median adherence). Overall, 1287 (98.5%) participants in the B/F/TAF group and 1292 (98.2%) in the DTG + 2 NRTI group had virologic suppression (VS; HIV-1 RNA < 50 copies/mL) through Week 48. VS in participants with low adherence versus high or intermediate adherence was similar in the B/F/TAF group, but lower in the DTG + 2 NRTI group (P ≤ 0.002). Similar results were observed at Weeks 96 and 144. Two participants (<95% adherence) in the DTG + 2 NRTI group receiving DTG and abacavir/lamivudine developed M184V; there was no treatment-emergent resistance to B/F/TAF.</p><p><strong>Conclusions: </strong>Participants with suboptimal (<85%) adherence to B/F/TAF maintained high levels of VS, whereas suboptimal DTG + 2 NRTI adherence was associated with lower VS.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647552","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":"Model-informed drug development for antimicrobials: translational pharmacokinetic-pharmacodynamic modelling of apramycin to facilitate prediction of efficacious dose in complicated urinary tract infections.","authors":"Irene Hernández-Lozano, Vincent Aranzana-Climent, Sha Cao, Carina Matias, Jon Ulf Hansen, Edgars Liepinsh, Diarmaid Hughes, Sven N Hobbie, Carina Vingsbo Lundberg, Lena E Friberg","doi":"10.1093/jac/dkae409","DOIUrl":"https://doi.org/10.1093/jac/dkae409","url":null,"abstract":"<p><strong>Objectives: </strong>The use of mouse models of complicated urinary tract infection (cUTI) has usually been limited to a single timepoint assessment of bacterial burden. Based on longitudinal in vitro and in vivo data, we developed a pharmacokinetic-pharmacodynamic (PKPD) model to assess the efficacy of apramycin, a broad-spectrum aminoglycoside antibiotic, in mouse models of cUTI.</p><p><strong>Methods: </strong>Two Escherichia coli strains were studied (EN591 and ATCC 700336). Apramycin exposure-effect relationships were established with in vitro time-kill data at pH 6 and pH 7.4 and in mice with cUTI. Immunocompetent mice were treated with apramycin (1.5-30 mg/kg) starting 24 h post-infection. Kidney and bladder tissue were collected 6-96 h post-infection for cfu determination. A PKPD model integrating all data was developed and simulations were performed to predict bacterial burden in humans.</p><p><strong>Results: </strong>Treatment with apramycin reduced the bacterial load in kidneys and bladder tissue up to 4.3-log compared with vehicle control. In vitro and in vivo tissue time-course efficacy data were integrated into the PKPD model, showing 76%-98% reduction of bacterial net growth and 3- to 145-fold increase in apramycin potency in vivo compared with in vitro. Simulations suggested that an 11 mg/kg daily dose would be sufficient to achieve bacterial stasis in kidneys and bladder in humans.</p><p><strong>Conclusions: </strong>PKPD modelling with in vitro and in vivo PK and PD data enabled simultaneous evaluation of the different components that influence drug effect, an approach that had not yet been evaluated for antibiotics in the cUTI model and that has potential to enhance model-informed drug development of antibiotics.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644194","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}