Pharmacotherapy最新文献

{"title":"Creation and validation of an extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) clinical risk scoring tool for select Enterobacterales in non-urinary isolates.","authors":"Jordan Jones, Taylor Morrisette, Aaron Hamby, Krutika Mediwala Hornback, Rachel Burgoon","doi":"10.1002/phar.4646","DOIUrl":"10.1002/phar.4646","url":null,"abstract":"<p><strong>Background: </strong>Infections caused by extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) are increasing in the United States. Although many risk factor scoring tools exist, many are specific to bloodstream isolates and may not represent all patient populations. The purpose of this study was to create and validate an institution-specific scoring tool for select ESBL-E of non-urinary origin based on previously identified risk factors.</p><p><strong>Methods: </strong>This retrospective, case-control analysis included inpatient adults at an academic medical center from July 2021 through August 2023 with a documented ESBL-E or non-ESBL-E infection of non-urinary origin. Patients with ESBL-E isolates were matched in a 1:1 ratio to non-ESBL-E isolates by organism and specimen type. Points for each risk factor were assigned by dividing their respective regression coefficient by half of the smallest regression coefficient and rounding to the nearest integer (prior ESBL-E within the past 12 months: 6 points, urinary catheter: 3 points, central venous catheter: 2 points, cirrhosis: 2 points). Sensitivities, specificities, positive predictive values (PPV), and negative predictive values (NPV) were calculated for each score, and discriminatory power was assessed via the receiver operating characteristic (ROC)-area under the curve (AUC).</p><p><strong>Results: </strong>Of the 1139 identified cultures, 140 patients met the criteria for inclusion into the ESBL-E case arm, thus 140 patients with non-ESBL-E cultures were matched as controls. Baseline characteristics were relatively similar between the groups. A score of 0 was associated with low risk of ESBL-E (PPV 0.31, NPV 0.36), whereas scores between 2 and 5 were considered moderate risk (PPV 0.56, NPV 0.55), and scores ≥6 were associated with high risk (PPV 0.91, NPV 0.56). The ROC curve AUC was 0.705.</p><p><strong>Conclusions: </strong>The majority of ESBL-E risk factor scoring tools are specific to isolates causing bloodstream infections. This institution-specific scoring tool may be used to tailor empiric antimicrobial regimens and decrease unnecessary exposure to carbapenems in non-ESBL-E infections of non-urinary origin.</p>","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":" ","pages":"87-93"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of carbamazepine, a strong CYP3A inducer, on the pharmacokinetics of zongertinib in healthy male volunteers.","authors":"Xiaofan Tian, Habib Esmaeili, David Minich, Friedeborg Seitz, Philipp M Roessner, Sven Wind, Rolf Grempler, Guanfa Gan, Tom S Chan, Mazyar Mahmoudi, Behbood Sadrolhefazi, Fabian Müller","doi":"10.1002/phar.4641","DOIUrl":"10.1002/phar.4641","url":null,"abstract":"<p><strong>Introduction: </strong>Zongertinib (BI 1810631) is a potent, selective, and epidermal growth factor receptor (EGFR) wild-type sparing human epidermal growth factor receptor 2 (HER2) inhibitor. Based on in vitro data, the oxidative hepatic metabolism of zongertinib is principally driven by cytochrome P450 (CYP) 3A4/5. Therefore, zongertinib may be affected by strong CYP3A inducers, like carbamazepine.</p><p><strong>Objective: </strong>This study aimed to investigate the effect of multiple oral doses of carbamazepine on the pharmacokinetics of a single oral dose of zongertinib in healthy male subjects.</p><p><strong>Methods: </strong>This open-label, two-period, fixed-sequence clinical drug-drug interaction study examined the pharmacokinetics of a single 60-mg oral dose of zongertinib in the absence or presence of multiple oral doses of carbamazepine. The extent of drug-drug interaction was estimated using the adjusted geometric mean ratios (and 90% confidence intervals [CIs]) for the test treatment (zongertinib in the presence of carbamazepine) versus the reference treatment (zongertinib alone) for areas under the plasma concentration-time curve from time 0 to infinity and to the last quantifiable time point (AUC_0-∞, AUC_0-tz) and maximum measured plasma concentration (C_max).</p><p><strong>Results: </strong>Sixteen subjects (all Caucasian males) received zongertinib alone in Study Period 1, and 15 of them received both zongertinib and carbamazepine in Study Period 2. Upon co-administration with carbamazepine in Study Period 2, AUC_0-∞ and AUC_0-tz of zongertinib were both reduced to 36.5% (90% CI: 32.0%-41.6% for AUC_0-∞ and 31.9%-41.7% for AUC_0-tz). The C_max of zongertinib was reduced to 56.4% (90% CI: 45.1%-70.6%).</p><p><strong>Conclusion: </strong>Zongertinib exposure was reduced by 63.5% when coadministered with the strong CYP3A inducer, carbamazepine.</p>","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":" ","pages":"94-103"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unsupervised machine learning analysis to identify patterns of ICU medication use for fluid overload prediction.","authors":"Kelli Henry, Shiyuan Deng, Xianyan Chen, Tianyi Zhang, John W Devlin, David J Murphy, Susan E Smith, Brian Murray, Rishikesan Kamaleswaran, Amoreena Most, Andrea Sikora","doi":"10.1002/phar.4642","DOIUrl":"10.1002/phar.4642","url":null,"abstract":"<p><strong>Background: </strong>Fluid overload (FO) in the intensive care unit (ICU) is common, serious, and may be preventable. Intravenous medications (including administered volume) are a primary cause for FO but are challenging to evaluate as a FO predictor given the high frequency and time-dependency of their use and other factors affecting FO. We sought to employ unsupervised machine learning methods to uncover medication administration patterns correlating with FO.</p><p><strong>Methods: </strong>This retrospective cohort study included 927 adults admitted to an ICU for ≥72 h. FO was defined as a positive fluid balance ≥7% of admission body weight. After reviewing medication administration record data in 3-h periods, medication exposure was categorized into clusters using principal component analysis (PCA) and Restricted Boltzmann Machine (RBM). Medication regimens of patients with and without FO were compared within clusters to assess their temporal association with FO.</p><p><strong>Results: </strong>FO occurred in 127 (13.7%) of 927 included patients. Patients received a median (interquartile range) of 31(13-65) discrete intravenous medication administrations over the 72-h period. Across all 47,803 intravenous medication administrations, 10 unique medication clusters, containing 121 to 130 medications per cluster, were identified. The mean number of Cluster 7 medications administered was significantly greater in the FO cohort compared with patients without FO (25.6 vs.10.9, p < 0.0001). A total of 51 (40.2%) of 127 unique Cluster 7 medications were administered in more than five different 3-h periods during the 72-h study window. The most common Cluster 7 medications included continuous infusions, antibiotics, and sedatives/analgesics. Addition of Cluster 7 medications to an FO prediction model including the Acute Physiologic and Chronic Health Evaluation (APACHE) II score and receipt of diuretics improved model predictiveness from an Area Under the Receiver Operation Characteristic (AUROC) curve of 0.719 to 0.741 (p = 0.027).</p><p><strong>Conclusions: </strong>Using machine learning approaches, a unique medication cluster was strongly associated with FO. Incorporation of this cluster improved the ability to predict FO compared to traditional prediction models. Integration of this approach into real-time clinical applications may improve early detection of FO to facilitate timely intervention.</p>","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":" ","pages":"76-86"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142922584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intravenous thrombolysis for patients with acute ischemic stroke while receiving a direct oral anticoagulant: A systematic review and meta-analysis.","authors":"Megan Z Roberts, Spencer H Durham, Nathan A Pinner, Jessica A Starr","doi":"10.1002/phar.4644","DOIUrl":"10.1002/phar.4644","url":null,"abstract":"<p><p>Recent guidelines for acute ischemic stroke (AIS) indicate administration of intravenous thrombolysis (IVT) in patients receiving direct oral anticoagulants (DOAC) is not firmly established and may be harmful unless certain potential parameters are met. This systematic review and meta-analysis explores safety outcomes and other clinical parameters from the growing number of publications describing patients taking a DOAC who experience an AIS that is treated acutely with IVT alone. Embase, International Pharmaceutical Abstracts, and PubMed were searched up to January 9, 2024 for studies including adult patients taking a DOAC who experienced an AIS treated with IVT and did not undergo endovascular therapy (EVT), regardless of the use of an anticoagulation reversal agent. Primary safety outcomes evaluated included symptomatic intracranial hemorrhage (sICH), any intracranial hemorrhage, and in-hospital mortality. A total of 873 patients from 78 studies, primarily case reports or case series of patients receiving dabigatran with or without idarucizumab reversal (n = 340), were included in the review. The rate of sICH during the index hospitalization was 3.3%. Seven high-quality studies with low risk of bias included outcomes for patients on DOAC and comparator groups of either patients not taking an oral anticoagulant (no OAC) or patients taking a vitamin K antagonist (VKA) with INR primarily <1.7 at the time of AIS. No significant difference was observed in the incidence of sICH among patients receiving DOAC vs. no OAC (odds ratio [OR] 0.8, 95% confidence interval [CI]: 0.48-1.33) or among patients receiving DOAC vs. VKA (OR 1.02, 95% CI 0.59-1.75). Similar findings of no difference were observed for other safety outcomes. Findings from this study suggest that utilization of IVT as sole recanalization therapy for AIS may be safe in patients taking a DOAC; however, further studies are needed to elucidate specific parameters that differentiate timepoints and variables to ensure safe, optimal treatment.</p>","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":" ","pages":"111-123"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of lamotrigine disposition changes during and after pregnancy in women with epilepsy.","authors":"Ashwin Karanam, Page B Pennell, Kimford J Meador, Yuhan Long, Angela K Birnbaum","doi":"10.1002/phar.4640","DOIUrl":"10.1002/phar.4640","url":null,"abstract":"<p><strong>Background: </strong>Lamotrigine clearance can change drastically in pregnant women with epilepsy (PWWE) making it difficult to assess the need for dosing adjustments. Our objective was to characterize lamotrigine pharmacokinetics in PWWE during pregnancy and postpartum along with a control group of nonpregnant women with epilepsy (NPWWE).</p><p><strong>Methods: </strong>The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study was a prospective, observational, 20 site, cohort study conducted in the United States (December 2012 and February 2016). Inclusion criteria included patients aged 14-45 years, gestational age <20 weeks at the time of recruitment, IQ >70 points, and receiving lamotrigine. PWWE participated throughout pregnancy and 18 months postpartum with NPWWE having matched visit intervals. Plasma drug and hormone concentrations were measured at each of the seven visits. A population mixed-effects modeling approach was used to describe lamotrigine clearance change.</p><p><strong>Results: </strong>221 (170 PWWE, 51 NPWWE) women were included. Baseline apparent clearance (clearance for NPWWE and when not pregnant for PWWE) was identical between the two groups (2.79 L/hour. with 36% between-subject variability). Two subpopulations were identified in PWWE: ~91% of PWWE had a maximum increase to 275% of baseline clearance with 50% of the maximum increase reached at 12 weeks gestational age and ~9% had no significant change in clearance during gestation. Following delivery, a first-order mono-exponential decline (1.27 weeks^-1) in clearance as a function of postpartum week described a return of clearance to baseline. The use of estrogen-based medication and enzyme-inducing antiseizure medications increased nonpregnant clearance by a further 0.33-fold and 0.84-fold, respectively.</p><p><strong>Discussion: </strong>During pregnancy, 91% of PWWE experience a 275% change from nonpregnant baseline in lamotrigine clearance whereas the remaining PWWE experience little to no change. Nonpregnant baseline lamotrigine clearance was higher in both PWWE and NPWWE with the administration of oral estrogen-containing medications. Our results are of clinical importance as they indicate a subpopulation without the need for substantial dose changes during pregnancy and a source of potential difference across nonpregnant individuals.</p>","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":"45 1","pages":"33-42"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11755693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of methotrexate Pharmacogenomic variation to predict acute neurotoxicity in children with acute lymphoblastic leukemia.","authors":"Rachel D Harris, Olga A Taylor, M Monica Gramatges, Amy E Hughes, Mark Zobeck, Sandi Pruitt, M Brooke Bernhardt, Ashley Chavana, Van Huynh, Kathleen Ludwig, Laura Klesse, Kenneth Heym, Timothy Griffin, Rodrigo Erana, Juan Carlos Bernini, Ashley Choi, Yuu Ohno, Melissa A Richard, Alanna C Morrison, Han Chen, Bing Yu, Philip J Lupo, Karen Rabin, Michael E Scheurer, Austin L Brown","doi":"10.1002/phar.4638","DOIUrl":"10.1002/phar.4638","url":null,"abstract":"<p><strong>Background: </strong>Methotrexate is an important component of curative therapy in childhood acute lymphoblastic leukemia (ALL), but the role of genetic variation influencing methotrexate clearance and transport in toxicity susceptibility in children with ALL is not well established. Therefore, we evaluated the association between suspected methotrexate pharmacogenomic variants and methotrexate-related neurotoxicity.</p><p><strong>Methods: </strong>This study included children (aged 2-20 years) diagnosed with ALL (2005-2019) at six treatment centers in the southwest United States. Clinical information was abstracted from medical records. Suspected neurotoxic events occurring within 21 days of intravenous and/or intrathecal methotrexate delivered between the end of induction and start of maintenance therapy were independently reviewed by at least two pediatric oncologists. Germline DNA was genotyped and 97 methotrexate pharmacogenomic variants of interest with at least grade 3 evidence were identified using the Pharmacogenomics Knowledge Base. Associations between variants and neurotoxicity were assessed by logistic regression. Data were randomly split (80/20) and random forest was constructed to estimate the ability of the variants to correctly classify neurotoxicity.</p><p><strong>Results: </strong>Of the 763 patients included in the study, 8.2% (n = 63) developed methotrexate-associated neurotoxicity. In logistic models, none of the 97 available pharmacogenomic variants reached adjusted statistical significance. However, two variants, rs17222723 (odds ratio [OR] = 2.83 [ref. = T allele], 95% confidence interval [CI]: 1.20-6.15) in ABCC2 and rs1045642 (OR = 0.66 [ref. = minor A allele], 95% CI: 0.44-0.98) in ABCB1, were nominally associated (p-value < 0.05) with neurotoxicity susceptibility. The addition of pharmacogenomic variants did not improve the predictive performance of random forest model (AUC = 0.73) compared to clinical information alone (AUC = 0.74).</p><p><strong>Conclusion: </strong>Overall, our results suggest that associations between neurotoxicity susceptibility and methotrexate pharmacogenomic variants are generally modest and these variants do not significantly improve neurotoxicity risk stratification among children with ALL.</p>","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":" ","pages":"4-11"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to comment on \"Delirium event and associated treatment modifications among older adults with Alzheimer's disease: An interrupted time-series analysis of Medicare data\".","authors":"Rajender R Aparasu, Ashna Talwar","doi":"10.1002/phar.4637","DOIUrl":"https://doi.org/10.1002/phar.4637","url":null,"abstract":"","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":"45 1","pages":"71"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of atrial fibrillation with lamotrigine: An observational cohort study.","authors":"Sodam Kim, Landon Welch, Bertha De Los Santos, Przemysław B Radwański, Mark A Munger, Kibum Kim","doi":"10.1002/phar.4633","DOIUrl":"10.1002/phar.4633","url":null,"abstract":"<p><strong>Background: </strong>Drug-induced atrial fibrillation (AF) is recognized as an important causal association. Lamotrigine (LTG) is a widely prescribed neurological agent with Class IB antiarrhythmic properties at therapeutically relevant concentrations. The United States Food and Drug Administration has issued a warning for a higher risk of LTG proarrhythmic events in patients with structural heart disease (SHD) and/or myocardial ischemia. This study evaluated the incidence of AF with LTG use.</p><p><strong>Methods: </strong>A retrospective observational study was performed using a large healthcare claims database of adult participants analyzing 2 years AF incidence. The analytic cohort included adult participants with bipolar I disorder (BPD), partial seizures (PSZ), or generalized tonic-clonic seizures (GTSZ). Exposure to LTG was compared with commonly prescribed alternative agents as the control comparators (CTR). Participants were free from supraventricular or ventricular arrhythmias during the 6 months baseline period prior to the index LTG or CTR date. Kaplan-Meier estimator calculated 2 years cumulative AF incidence, with participants censored at last enrollment, treatment switching, or discontinuation. The AF association hazard ratios (HR) for LTG versus CTR were adjusted for baseline characteristics.</p><p><strong>Results: </strong>The analytic cohort with BPD, PSZ, and GTSZ consisted, respectively, of 150,470 LTG versus 204,704 CTR, 9565 LTG versus 21,595 CTR, and 5505 LTG versus 15,513 CTR patients. In a predominantly middle-aged female population at baseline, the prevalence of cardiovascular conditions was low. The 12 months cumulative incidence of AF for LTG versus CTR was 0.764% versus 0.642% among BPD, 0.833% versus 0.646% among PSZ, and 0.585% versus 0.338% among GTSZ, respectively. The adjusted 365-day HR [95% confidence interval CI] of AF for LTG versus CTR in the BPD, PSZ, and CTSZ groups was 1.257 [1.088-1.453], 1.651 [1.104-2.468], and 1.451 [0.770-2.734], respectively.</p><p><strong>Conclusions: </strong>In adult AF-naïve participants, LTG has a strong association with increased AF risk compared with commonly prescribed alternatives.</p>","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":" ","pages":"20-32"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comment on \"Delirium event and associated treatment modifications among older adults with Alzheimer's disease: An interrupted time-series analysis of Medicare data\".","authors":"Shih-Jie Wang, Lien-Chung Wei, Hsien-Jane Chiu","doi":"10.1002/phar.4636","DOIUrl":"https://doi.org/10.1002/phar.4636","url":null,"abstract":"","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":"45 1","pages":"70"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of cefiderocol in a patient with carbapenem-resistant Acinetobacter baumannii ventriculitis: A case report.","authors":"Natalie A Finch, Alejandro Granillo, Nazanin Pouya, Adarsh Bhimraj, William R Miller, Vincent H Tam","doi":"10.1002/phar.4632","DOIUrl":"10.1002/phar.4632","url":null,"abstract":"<p><strong>Objective: </strong>Cefiderocol is a novel antibiotic used to treat multidrug-resistant bacterial infections. However, there is limited data on its effectiveness for ventriculitis. The objective of this study was to evaluate cefiderocol concentrations in both serum and cerebrospinal fluid (CSF) during the treatment of ventriculitis.</p><p><strong>Method: </strong>A 54-year-old patient with carbapenem-resistant Acinetobacter baumannii ventriculitis was given cefiderocol intravenously 2 g every 6 h (each dose administered over 3 h). Serial samples were obtained over a dosing interval at steady state, and cefiderocol concentrations in serum and CSF were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Cefiderocol serum concentration-time profile was characterized by a one-compartment model with zero-order input. Penetration into CSF was estimated as the CSF AUC/unbound serum AUC ratio.</p><p><strong>Results: </strong>Observed total serum concentrations ranged between 24.6 and 76.7 mg/L, while CSF concentrations were approximately 10.0 mg/L. The AUC_0-6 of the free drug in serum and CSF were 181.6 and 60.2 mg h/L, respectively.</p><p><strong>Conclusion: </strong>We observed minimal fluctuation of cefiderocol concentrations in CSF, questioning the conventional reliance on CSF/serum area under the curve (AUC) ratio as a measure of CNS penetration. Our experience suggests that a single CSF concentration (random or trough) could be directly compared to the minimum inhibitory concentration, offering a potentially simpler approach to evaluate dosing adequacy.</p>","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":" ","pages":"66-69"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11757030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142771233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}