International Journal of Antimicrobial Agents最新文献

{"title":"A physiologically based pharmacokinetic model of voriconazole in human CNS—Integrating time-dependent inhibition of CYP3A4, genetic polymorphisms of CYP2C19 and possible transporter mechanisms","authors":"Liuhan Dong ,&nbsp;Xiaomei Zhuang ,&nbsp;Tianli Yang ,&nbsp;Kaicheng Yan ,&nbsp;Yun Cai","doi":"10.1016/j.ijantimicag.2024.107310","DOIUrl":"10.1016/j.ijantimicag.2024.107310","url":null,"abstract":"<div><h3>Objectives</h3><p>Voriconazole is a classical antifungal drug that is often used to treat CNS fungal infections due to its permeability through the BBB. However, its clinical use remains challenging because of its narrow therapeutic window and wide inter-individual variability. In this study, we proposed an optimised and validated PBPK model by integrating <em>in vitro, in vivo</em> and clinical data to simulate the distribution and PK process of voriconazole in the CNS, providing guidance for clinical individualised treatment.</p></div><div><h3>Methods</h3><p>The model structure was optimised and tissue-to-plasma partition coefficients were obtained through animal experiments. Using the allometric relationships, the distribution of voriconazole in the human CNS was predicted. The model integrated factors affecting inter-individual variation and drug interactions of voriconazole—polymorphisms in the CYP2C19 gene and auto-inhibition and then was validated using real clinical data.</p></div><div><h3>Results</h3><p>The overall AFE value showing model predicted differences was 1.1420 in the healthy population; and in the first prediction of plasma and CSF in actual clinical patients, 89.5% of the values were within the 2-fold error interval, indicating good predictive performance of the model. The bioavailability of voriconazole varied at different doses (39%-86%), and the optimised model conformed to this pattern (46%–83%).</p></div><div><h3>Conclusions</h3><p>Combined with the relevant pharmacodynamic indexes, the PBPK model provides a feasible way for precise medication in patients with CNS infection and improve the treatment effect and prognosis.</p></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 4","pages":"Article 107310"},"PeriodicalIF":4.9,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017335","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":"Meta-analysis on safety of standard vs. prolonged infusion of beta-lactams","authors":"Hunter Rolain ,&nbsp;Zachary Schwartz ,&nbsp;Raymond Jubrail ,&nbsp;Kevin J. Downes ,&nbsp;Lisa Hong ,&nbsp;Alireza FakhriRavari ,&nbsp;Nathaniel J. Rhodes ,&nbsp;Marc H. Scheetz","doi":"10.1016/j.ijantimicag.2024.107309","DOIUrl":"10.1016/j.ijantimicag.2024.107309","url":null,"abstract":"<div><h3>Background</h3><p>Efficacy for prolonged infusion beta-lactam dosing schemes has been previously described, but there has been less focus on the safety of standard vs. prolonged infusion protocols of beta-lactams. This study explored differences in adverse drug reactions (ADRs) reported for beta-lactams between each of these infusion protocols.</p></div><div><h3>Methods</h3><p>A systematic review of MEDLINE literature databases via PubMed was conducted and references were reviewed. Articles were compiled and assessed with specific inclusion/exclusion criteria. We included randomised and nonrandomised, prospective, and retrospective cohort studies that reported adverse drug reactions (ADRs) due to either standard (30–60 mins) or prolonged (≥3 h) infusions of beta-lactam infusions. Total ADRs between strategies were analysed by infusion methodology. The most consistently reported ADRs were subject to meta-analysis across studies.</p></div><div><h3>Results</h3><p>12 studies met inclusion/exclusion criteria with data for 4163 patients. There was insufficient data to systematically analyse neurotoxicity or cytopenias. Seven studies reported on nephrotoxicity outcomes with no significant difference in event rates between standard (n = 434/2258,19.2%) vs. prolonged infusion (n = 266/1271, 20.9%) of beta-lactams (OR = 1.08, 95% CI [0.91, 1.29]). Six studies observed diarrhoea in a total of 759 patients with no significant difference in patients of standard (n = 18/399, 4.5%) vs. prolonged (n = 19/360, 5.3%) infusion of beta-lactams (OR = 1.14, 95% CI [0.59,2.20]).</p></div><div><h3>Conclusion</h3><p>Prolonged and standard infusion schemes for beta-lactams demonstrated similar adverse event rates. Future research should focus on improved standardisation of adverse effect definitions and a priori aim to study neurotoxicity and cytopenias. Consistent recording of ADRs and standardised definitions of these reactions will be paramount to further study of this subject.</p></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 4","pages":"Article 107309"},"PeriodicalIF":4.9,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017337","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":"Host immunomodulation strategies to combat pandemic-associated antimicrobial-resistant secondary bacterial infections","authors":"Srimathi Raghavan,&nbsp;Kwang-sun Kim","doi":"10.1016/j.ijantimicag.2024.107308","DOIUrl":"10.1016/j.ijantimicag.2024.107308","url":null,"abstract":"<div><p>The incidence of secondary bacterial infections has increased in recent decades owing to various viral pandemics. These infections further increase the morbidity and mortality rates associated with viral infections and remain a significant challenge in clinical practice. Intensive antibiotic therapy has mitigated the threat of such infections; however, overuse and misuse of antibiotics have resulted in poor outcomes, such as inducing the emergence of bacterial populations with antimicrobial resistance (AMR) and reducing the therapeutic options for this crisis. Several antibiotic substitutes have been suggested and employed; however, they have certain limitations and novel alternatives are urgently required. This review highlights host immunomodulation as a promising strategy against secondary bacterial infections to overcome AMR. The definition and risk factors of secondary bacterial infections, features and limitations of currently available therapeutic strategies, host immune responses, and future perspectives for treating such infections are discussed.</p></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 4","pages":"Article 107308"},"PeriodicalIF":4.9,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017336","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":"Dual therapy based on co-formulated darunavir/ritonavir plus lamivudine for initial therapy of HIV infection: The ANDES randomized controlled trial","authors":"M.I. Figueroa ,&nbsp;O. Sued ,&nbsp;D. Cecchini ,&nbsp;M. Sanchez ,&nbsp;M.J. Rolón ,&nbsp;G. Lopardo ,&nbsp;M. Ceschel ,&nbsp;G. Mernies ,&nbsp;M. De Stefano ,&nbsp;P. Patterson ,&nbsp;A. Gun ,&nbsp;V. Fink ,&nbsp;Z. Ortiz ,&nbsp;P. Cahn","doi":"10.1016/j.ijantimicag.2024.107301","DOIUrl":"10.1016/j.ijantimicag.2024.107301","url":null,"abstract":"<div><h3>Background</h3><div>Tenofovir-containing antiretroviral therapy regimens may have long-term toxicity-related side effects. This study aimed to compare the virological efficacy of co-formulated darunavir/ritonavir plus lamivudine with darunavir/ritonavir plus tenofovir and emtricitabine or lamivudine.</div></div><div><h3>Methods</h3><div>The ANDES study was a 48-week, phase 4, randomized, open-label, non-inferiority trial in treatment-naïve adults living with human immunodeficiency virus (HIV). Patients were randomized on a 1:1 basis to receive a daily oral regimen of either dual therapy based on a generic co-formulation of darunavir/ritonavir (800/100 mg) plus a generic lamivudine 300 mg pill, or triple therapy with darunavir/ritonavir plus tenofovir/emtricitabine (300/200 mg) or tenofovir/lamivudine (300/300 mg). The primary endpoint was the proportion of patients with a viral load of &lt;50 copies/mL at week 48 in the intention-to-treat population. The US Food and Drug Administration snapshot algorithm and a non-inferiority margin of -12% were used. The secondary objective was to analyse safety in the per-protocol population. This study has been registered at ClinicalTrials.gov (NCT02770508).</div></div><div><h3>Results</h3><div>Between November 2015 and 31 October 2020, 336 participants were assigned at random to the triple therapy arm (<em>n</em>=165) or the dual therapy arm (<em>n</em>=171). After 48 weeks, 153 patients in the triple therapy group (93%) and 155 patients in the dual therapy group (91%) achieved virological suppression (difference -2.1%, 95% confidence interval -7.0 to 2.9). Drug-related adverse events were more common in the triple therapy group (<em>P</em>=0.04). Two toxicity-related events led to discontinuation in each group.</div></div><div><h3>Interpretation</h3><div>Co-formulated darunavir/ritonavir plus lamivudine showed non-inferiority and a safer toxicity profile compared with the standard-of-care triple therapy regimen including tenofovir in treatment-naïve patients.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 4","pages":"Article 107301"},"PeriodicalIF":4.9,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995710","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":"Verapamil enhances the activity of Caspofungin against Cryptococcus neoformans， coinciding with inhibited Ca2+/CN pathway and damage to cell wall integrity","authors":"Xinyuan Peng ,&nbsp;Qingtao Kong ,&nbsp;Qian Wei ,&nbsp;Shilin Guo ,&nbsp;Qiying Chen ,&nbsp;Min Peng ,&nbsp;Binyi An ,&nbsp;Xiaoyu Wang ,&nbsp;Chen Zhang ,&nbsp;Hong Sang","doi":"10.1016/j.ijantimicag.2024.107303","DOIUrl":"10.1016/j.ijantimicag.2024.107303","url":null,"abstract":"<div><h3>Objectives</h3><p>Given the challenges posed by toxicity and drug resistance in the treatment of cryptococcal infections, we sought to explore the antifungal potential of verapamil (VER), a calcium channel blocker, against <em>Cryptococcus neoformans</em> (<em>C. neoformans</em>), and its potential synergy with antifungals, specifically caspofungin (CAS).</p></div><div><h3>Materials and Methods</h3><p><em>In vitro</em> and <em>in vivo</em> (<em>Galleria mellonella</em>) models were employed to assess VER's antifungal activity and its interaction with CAS. Mechanisms underlying the synergism were explored through analysis of cell wall integrity, membrane permeability, and gene expression related to the calcineurin pathway. Additionally, the influence of Ca²⁺ on chitin deacetylase activity was investigated.</p></div><div><h3>Results</h3><p>VER exhibited a pronounced antifungal effect on <em>C. neoformans</em> and synergized with CAS, enhancing antifungal efficacy in <em>Galleria mellonella</em>. VER reduced chitosan content and disrupted cell wall integrity, evidenced by melanin leakage and fluorescence staining. VER+CAS modified membrane permeability, triggering intracellular ROS accumulation and mitochondrial membrane potential alterations. VER mitigated CAS-induced calcium fluctuations and downregulated calcineurin pathway genes. Furthermore, it was found that the enzyme activity of chitin deacetylase of <em>C. neoformans</em> is significantly influenced by the presence of Ca²⁺, suggesting that the use of VER may affect this activity.</p></div><div><h3>Conclusions</h3><p>The synergistic antifungal effect of VER and CAS represents a promising therapeutic strategy for cryptococcal infections. The multifaceted mechanisms, including disruption of cell wall integrity and modulation of membrane permeability, and regulation of intracellular calcium signaling pathways, offer new insights into antifungal drug development.</p></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 4","pages":"Article 107303"},"PeriodicalIF":4.9,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995711","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":"Predictive performance of multi-model approaches for model-informed precision dosing of piperacillin in critically ill patients","authors":"Lea Marie Schatz ,&nbsp;Sebastian Greppmair ,&nbsp;Alexandra K. Kunzelmann ,&nbsp;Johannes Starp ,&nbsp;Alexander Brinkmann ,&nbsp;Anka Roehr ,&nbsp;Otto Frey ,&nbsp;Stefan Hagel ,&nbsp;Christoph Dorn ,&nbsp;Michael Zoller ,&nbsp;Christina Scharf ,&nbsp;Sebastian G. Wicha ,&nbsp;Uwe Liebchen","doi":"10.1016/j.ijantimicag.2024.107305","DOIUrl":"10.1016/j.ijantimicag.2024.107305","url":null,"abstract":"<div><h3>Objectives</h3><p>Piperacillin (PIP)/tazobactam is a frequently prescribed antibiotic; however, over- or underdosing may contribute to toxicity, therapeutic failure, and development of antimicrobial resistance. An external evaluation of 24 published PIP-models demonstrated that model-informed precision dosing (MIPD) can enhance target attainment. Employing various candidate models, this study aimed to assess the predictive performance of different MIPD-approaches comparing (i) a single-model approach, (ii) a model selection algorithm (MSA) and (iii) a model averaging algorithm (MAA).</p></div><div><h3>Methods</h3><p>Precision, accuracy and expected target attainment, considering either initial (B1) or initial and secondary (B2) therapeutic drug monitoring (TDM)-samples per patient, were assessed in a multicentre dataset (561 patients, 11 German centres, 3654 TDM-samples).</p></div><div><h3>Results</h3><p>The results demonstrated a slight superiority in predictive performance using MAA in B1, regardless of the candidate models, compared to MSA and the best single models (MAA, MSA, best single models: inaccuracy ±3%, ±10%, ±8%; imprecision: &lt;25%, &lt;31%, &lt;28%; expected target attainment &gt;77%, &gt;71%, &gt;73%). The inclusion of a second TDM-sample notably improved precision and target attainment for all MIPD-approaches, particularly within the context of MSA and most of the single models. The expected target attainment is maximized (up to &gt;90%) when the TDM-sample is integrated within 24 h.</p></div><div><h3>Conclusions</h3><p>In conclusion, MAA streamlines MIPD by reducing the risk of selecting an inappropriate model for specific patients. Therefore, MIPD of PIP using MAA implicates further optimisation of antibiotic exposure in critically ill patients, by improving predictive performance with only one sample available for Bayesian forecasting, safety, and usability in clinical practice.</p></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 4","pages":"Article 107305"},"PeriodicalIF":4.9,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0924857924002218/pdfft?md5=d215d933dc422ceff04ee5a5d0e95ad5&pid=1-s2.0-S0924857924002218-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987813","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":"Pharmacodynamics of taniborbactam in combination with cefepime studied in an in vitro model of infection","authors":"A.R. Noel,&nbsp;M. Attwood,&nbsp;K.E. Bowker,&nbsp;A.P. MacGowan","doi":"10.1016/j.ijantimicag.2024.107304","DOIUrl":"10.1016/j.ijantimicag.2024.107304","url":null,"abstract":"<div><h3>Objectives</h3><p>To define the in vitro pharmacodynamics of taniborbactam against Enterobacterales with CTXM-15, KPC, AmpC, and OXA-48 β-lactamases.</p></div><div><h3>Methods</h3><p>An in vitro pharmacokinetic model was used to simulate serum concentrations associated with cefepime 2G by 1 h infusion 8 h. Taniborbactam was given in exposure ranging and fractionation simulations. Reduction in viable count at 24 h (Δ 24) was the primary end point and four strains were used: Escherichia <em>coli</em> expressing CTXM-15 or AmpC and Klebsiella <em>pneumoniae</em> expressing KPC or OXA-48 enzymes.</p></div><div><h3>Results</h3><p>Taniborbactam was administered as continuous infusions; ≥4 log kill was attained with taniborbactam concentrations of ≥0.01 mg/L against CTXM-15 <em>E. coli</em>, ≥0.5 mg/L against KPC- and OXA-48 <em>K. pneumoniae</em>, and ≥4 mg/L against AmpC <em>E. coli</em>. Analyses were conducted to determine the pharmacokinetic/dynamic driver for each strain. For <em>E. coli</em> (CTXM-15) and <em>E. coli</em> (AmpC), area under the concentration-time curve (AUC) was best related to change in viable count (R²0.74 and 0.72, respectively). For <em>K. pneumoniae</em> (KPC) AUC and T &gt; 0.25 mg/L were equally related to bacterial clearance (R²0.72 for both), and for <em>K. pneumoniae</em> (OXA-48) T &gt; 0.25 mg/L was the best predictor (R²0.94). The taniborbactam AUC range to produce a 1-log₁₀ reduction in viable count was 4.4–11.2 mg·h/L. Analysis of data from all strains indicated T &gt; MIC divided by 4 was best related to change in viable count; however, curve fit was poor R² &lt; 0.49.</p></div><div><h3>Conclusions</h3><p>Taniborbactam was effective in combination with cefepime in producing bacterial clearance for B lactam resistant Enterobacterales. The primary pharmacodynamic driver was AUC or time &gt; threshold, both being closely related to antibacterial effect.</p></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 4","pages":"Article 107304"},"PeriodicalIF":4.9,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987812","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":"Advancing research and development of anti-infectives for children: A clinical development perspective","authors":"Ann M. Buchanan ,&nbsp;Adrie Bekker ,&nbsp;Hardik Chandasana ,&nbsp;Ralph DeMasi ,&nbsp;Zrinka Lulic ,&nbsp;Terry Ernest ,&nbsp;Cindy Brothers ,&nbsp;Sherene Min ,&nbsp;Theodore Ruel ,&nbsp;Lionel K. Tan","doi":"10.1016/j.ijantimicag.2024.107306","DOIUrl":"10.1016/j.ijantimicag.2024.107306","url":null,"abstract":"<div><div>The HIV treatment landscape for adults has progressed dramatically in recent decades; however, paediatric populations continue to experience delayed and limited access to effective and safe antiretroviral therapy options. Despite current incentive programmes, formulation research and development and approved drug dosing for children have been limited, particularly for neonates (aged &lt;4 wk). Regulatory approval of drug formulations and dosing in children may lag behind adult approvals by years. Formulation and trial design adjustments complicate paediatric drug development, all of which are vital to accommodate for physiological differences, organ maturation, and rapid weight gain, which are most significant in the youngest children. To facilitate more rapid anti-infective drug development for paediatric populations, regulatory agencies provide guidelines that include extrapolating efficacy and safety data from relevant populations; using pharmacokinetic (PK) bridging and modelling to reduce sample sizes and limit the number of PK studies needed before efficacy analyses; and enrolling age- or weight-based cohorts in parallel rather than sequentially for clinical trials. Ensuring access to approved drugs poses an additional challenge, as uncertainty in demand leads to manufacturing and supply complexity with potentially higher costs that can be a barrier to uptake. Here we summarise challenges in drug development for children living with HIV, which are not unique to antiretrovirals. We aim to propose strategies for how model-based approaches and global partnerships can overcome some of these barriers to accelerate paediatric drug development, with particular reference to HIV, and how lessons learnt from HIV could be extended to other anti-infectives.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 4","pages":"Article 107306"},"PeriodicalIF":4.9,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S092485792400222X/pdfft?md5=44b768261b44a44fd0a44c31f8ad3cc5&pid=1-s2.0-S092485792400222X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987910","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":"Increased risk of adverse drug reactions by higher linezolid dose per weight in multidrug-resistant tuberculosis","authors":"Johanna Kuhlin ,&nbsp;Lina Davies Forsman ,&nbsp;Aisha Osman ,&nbsp;Magdalena Skagerberg ,&nbsp;Jerker Jonsson ,&nbsp;Ramona Groenheit ,&nbsp;Mikael Mansjö ,&nbsp;Jim Werngren ,&nbsp;Jan-Willem Alffenaar ,&nbsp;Thomas Schön ,&nbsp;Judith Bruchfeld","doi":"10.1016/j.ijantimicag.2024.107302","DOIUrl":"10.1016/j.ijantimicag.2024.107302","url":null,"abstract":"<div><h3>Objectives</h3><p>Linezolid treatment has a high risk of toxicity and adverse drug reactions (ADR) are frequent. Few studies have investigated risk factors of major ADRs separately, therefore, we aimed to evaluate major ADRs including peripheral neuropathy in relation to risk factors and drug concentration levels of linezolid in a high-resource setting for multidrug-resistant tuberculosis (MDR-TB).</p></div><div><h3>Methods</h3><p>We conducted a retrospective cohort study including participants treated with a linezolid-containing MDR-TB regimen in Sweden 1992–2018. Data was collected from medical records. ADRs were classified according to Common Terminology Criteria for Adverse Events (version 5.0).</p></div><div><h3>Results</h3><p>Of all participants (n = 132), 43.2% were female and the median age 28 y. The median linezolid treatment was 6.5 months (IQR 3.0–12.7) with a median daily dose of 9.6 mg/kg/d. Any ADR was seen in 58.3% (n = 77) of participants, with 35.6% having peripheral neuropathy (n = 47), 27.3% anaemia (n = 36), 22.0% leukopenia (n = 36) while 6.1% (n = 8) had optic neuritis. The median time for peripheral neuropathy was 3.6 months (IQR 2.1–5.9) and 8.3 months (6.2–10.7) for optic neuritis. A &gt;2.0 mg/L trough concentration (n = 40) was associated with anaemia (<em>P</em> = 0.0038) and thrombocytopenia (<em>P</em> = 0.009) but not with peripheral neuropathy. In multivariable analysis, a dose ≥12 mg/kg/d was associated with time to peripheral neuropathy (HR 2.89, 95% CI 1.08–7.74, <em>P</em> = 0.035), anaemia (HR 6.62, 95% CI 2.22–19.8, <em>P</em> = 0.001) and leukopenia (HR 5.23, 95% CI 1.48–18.5, <em>P</em> = 0.010).</p></div><div><h3>Conclusions</h3><p>Linezolid ADRs were frequent in a high-resource setting. Structured, regular follow-up for ADRs and adjusting dosing according to body weight followed-up by monitoring of drug concentrations early may reduce toxicity.</p></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 4","pages":"Article 107302"},"PeriodicalIF":4.9,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0924857924002188/pdfft?md5=0b7dfcec5eb3a37fd71495fc0ccc05b6&pid=1-s2.0-S0924857924002188-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987911","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":"Neisseria gonorrhoeae ST-1901 in Rio de Janeiro from 2006 to 2022: Phylogeny and antimicrobial resistance evolution of a well-succeeded pathogen","authors":"Raphael Cavalcante de Medeiros ,&nbsp;Késia Thaís Barros dos Santos ,&nbsp;Ana Paula Ramalho Costa-Lourenço ,&nbsp;Larissa Brasil Skaf ,&nbsp;Adriane Meira Mercadante ,&nbsp;Matheus Henrique Banchete Rosa ,&nbsp;Sergio Eduardo Longo Fracalanzza ,&nbsp;Adriana Lúcia Pires Ferreira ,&nbsp;Jennifer L. Reimche ,&nbsp;Kim M. Gernert ,&nbsp;Ellen Neumeister Kersh ,&nbsp;Raquel Regina Bonelli","doi":"10.1016/j.ijantimicag.2024.107299","DOIUrl":"10.1016/j.ijantimicag.2024.107299","url":null,"abstract":"<div><p><em>Neisseria gonorrhoeae</em> is a global threat to public health due to the accumulation of antimicrobial resistance mechanisms. ST-1901 is an internationally important sequence type (ST) because of its high incidence and the usual occurrence of chromosomally determined resistance. In this study, we describe the evolution of the ST-1901 and its single locus variants in Rio de Janeiro from 2006 to 2022. We analyzed 82 <em>N. gonorrhoeae</em> isolates according to antimicrobial susceptibility profile, resistance mechanisms, molecular typing, and phylogenetics. Six different single locus variants were detected. Phylogenetic analysis identified five clades, which share similar characteristics. Resistance rates for penicillin and tetracycline decreased due to the lower occurrence of resistance plasmids, but intermediary resistance to penicillin rose. Resistance to ciprofloxacin remained high throughout all clades and the years of the study. Regarding resistance to azithromycin, alterations in <em>mtrR</em> promoter and gene, and <em>23S rRNA</em> encoding gene <em>rrl</em> were detected, with a notable rise in the incidence of C2611T mutations in more recent years occurring in four of five clades. In contrast, β-lactam resistance associated penA 34 mosaic was found only in one persisting clade (Clade D), and unique G45D and A39T mutations in <em>mtrR</em> gene and its promoter (Nm-Like) were found only in Clade B. Taken together, these data suggest that ST-1901, a persistently circulating lineage of <em>N. gonorrhoeae</em> in Rio de Janeiro, has undergone changes over the years and may evolve to develop resistance to the current recommended dual therapy adopted in Brazil, namely, ceftriaxone and azithromycin.</p></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 4","pages":"Article 107299"},"PeriodicalIF":4.9,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982261","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}