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646. Clinical and microbiological outcomes of omadacycline for pulmonary Mycobacterium abscessus complex
(Oxford University Press, 2025-01-29) Al Musawa, Mohammed; Vemula, Raaga; Mammadova, Mehriban; Wadle, Carly; Muscarella, Anahit; Cimino, Christo; Zeuli, John; Howard, Catessa A.; Butt, Saira; Mejia-Chew, Carlos; Hamad, Yasir; Ong, Aaron; Cohen, Keira A.; Kaip, Emily A.; Tupayachi-Ortiz, Maria G.; Fiske, Christina T.; Judd, Chloe; Caniff, Kaylee E.; Rybak, Michael J.; Medicine, School of Medicine
Background:
Mycobacterium abscessus complex (MABC) is a difficult-to-treat infection due to antibiotic resistance. Our study aimed to assess omadacycline’s (OMC) clinical and microbiological outcomes for the treatment of pulmonary MABC.
Methods:
A retrospective study was carried out across 12 US medical institutions from 1/2018-4/2023 to examine the clinical outcomes, and tolerability of OMC treatment for pulmonary MABC. Patients aged ≥ 18 years who were treated with OMC for ≥ 3 months were included. The primary outcome was clinical success at 3, 6, and 12 months. The secondary outcomes were sputum culture conversion rate, adverse effects, and clinical success by subspecies and macrolide susceptibility.
Results:
Thirty-five patients were included in this analysis. Most patients were female (74.3%) and Caucasian (74.3%), with a median (IQR) age of 61 years (51–70). Subspeciation was performed for 22 isolates with predominant M. abscessus subspecies (77.3%). Moreover, coinfection with other NTM species was present in 28.6% of cases where Mycobacterium avium complex was present in 8 cultures. Sixty-eight percent of the MABC isolates were confirmed to be macrolide resistance; half (12/24, 50.0%) were evident by the presence of functional erm gene, while the other half by antimicrobial susceptibility (Table 3). Of the remaining isolates, 14% were macrolide-susceptible, while no information was reported in 17%. The median (IQR) treatment duration of OMC was 8 months (3.9 – 15.7). The most commonly co-administered antibiotics were intravenous amikacin, imipenem/cilastatin, inhaled amikacin and clofazimine with the same percentage (42.9%) (Table 1). Overall, MABC clinical success was observed in 71.4%, 89.7%, and 90.9% in 3-, 6- and 12 months, respectively (Table 3). Adverse effects reported in 34.3%. The most common side effects were gastrointestinal intolerance (25.7%) and hepatoxicity (11.4%), which led to drug discontinuation in 22.9%.
Conclusion:
OMC treatment showed clinical success in > 70% of patients with pulmonary MABC including patients with macrolide resistant strains for more than 3 months. However, larger studies are needed to validate the outcomes beyond 12 months.
211. Defining Optimal Sampling Times for Cefepime Therapeutic Drug Monitoring in Clinical Practice
(Oxford University Press, 2025-01-29) Rhodes, Nathaniel J.; Smith, Brandon; Shields, Ryan K.; Pan, Samantha; Weslander, Erin; Galvin, Shannon; Hughes, Jasmine; Hughes, Maria-Stephanie; Sime, Fekade B.; Roberts, Jason A.; Kiel, Patrick J.; Neely, Michael N.; Scheetz, Marc H.; Medicine, School of Medicine
Background:
Clinicians performing beta-lactam therapeutic drug monitoring (TDM) lack evidence on when levels should ideally be drawn after a dose. Herein, we define the optimal timing (i.e., optimal sampling) for cefepime using real-world TDM data to validate our approach.
Methods:
De-identified data from two centers performing routine cefepime TDM were extracted by InsightRX and served as an external validation cohort. Plasma cefepime was quantified using validated LC-MS/MS assays for TDM and dosing was protocolized at each site. CRRT and ECMO patients were included but other dialysis patients were not. Bias (MPE) and precision (RMSE) of a non-parametric prior were assessed. Multiple-model optimal (MM-opt) sampling strategies were estimated for the first 24 hours of treatment. To mirror clinical practice, one- and two-sample designs were evaluated. Dose and covariate values informed optimal sampling times. Bayesian PK exposures were compared using all samples, trough-only sampling, or using a single optimally timed sample. AUCs were calculated from the posteriors. For fT >MIC analysis, the MIC was fixed at 8 mg/L. We used Pmetrics 2.1.1 for R.
Results:
116 patients (42% female; median age, CRCL, and weight: 62 years, 76 mL/min, and 80 kg, respectively) contributed 235 levels. The PK model demonstrated acceptable bias and precision (-6% MPE, 30.9 RMSE) as a prior for estimating exposures from the TDM data (Fig1). For a one-sample approach, the most common MM-opt sampling times varied (Fig2) but were often a mid-point or trough. In the two-sample approach, sample one was often a mid-point and sample two was often a trough (Fig3). First 24-hr AUC and fT>MIC did not significantly differ using all available samples for analysis vs. limiting sampling to a single optimized time point vs. limiting sampling to a trough-only approach (P >0.05 for all comparisons; Fig4).
Conclusion:
Optimal cefepime sampling times depended on dosing regimen, and renal disposition. When limited to a single sample, optimal sampling times for cefepime TDM were often midpoint/trough levels, but when two samples were obtained the optimal sampling times were often a mid-point followed by a trough. Estimation of PK and PK/PD exposures was not significantly worse when using a validated Bayesian prior and a trough-only sampling approach.
P-581. Racial/Ethnic Disparities of Renal Outcomes in People with HIV (PWH) on Tenofovir Alafenamide (TAF) Based Antiretroviral Treatment (ART) Regimens in the Real World
(Oxford University Press, 2025-01-29) Gupta, Samir K.; Canada, Robert; Naik, Sarjita; Huang, Xiwen; Weinberg, Amy; Temme, Lauren; Tao, Li; Chiang, Betty; Chokkalingam, Anand; Slim, Jihad; Medicine, School of Medicine
Background:
The risk of chronic kidney disease (CKD) is higher in PWH than HIV-negative persons. Black communities are not only disproportionately affected by HIV but also more at risk for kidney disease than other races. Despite Black PWH generally being underrepresented in clinical trials, the BRAAVE trial showed switching to bictegravir/emtricitabine/TAF demonstrated non-inferior efficacy and similar tolerability, including renal safety, compared to prior ART regimens in this group. With this analysis, we aim to assess whether these trial results translate to the real-world setting among Black PWH using a retrospective cohort analysis.
Methods:
The descriptive analysis was conducted using IQVIA ambulatory electronic medical record (EMR) database (November 2015 – July 2023). The study population included PWH (≥ 18 years) who were newly prescribed with ART regimens. Study endpoints evaluated the incidence of azotemia, Fanconi syndrome, renal tubular acidosis (RTA), renal toxicity, acute kidney injury (AKI), and CKD stages using diagnosis codes, stratified by racial group (Black and non-Black) and treatment with TAF-based regimens using prescription codes. Incidence rates were reported. The analysis was conducted using ATLAS Version 2.12.1.
Results:
Overall, 4,562 Black and 5,946 non-Black PWH were identified on TAF-containing regimen, with 7,933 and 10,198 person-years of follow-up, respectively (Table 1). Compared to non-Black PWH, Black PWH were more likely to be female, have diabetes and hypertension. Black PWH on TAF had a higher incidence of advanced CKD and similar incidence rates of azotemia, renal toxicity, AKI, and RTA compared to non-Black PWH on TAF (Table 2). When stratified by baseline hypertension, no significant differences in the incidence of renal disease were observed between Black and non-Black PWH. There were no cases of Fanconi syndrome in the study cohort.
Conclusion:
Despite the inherent limitations of real-world data, this analysis included a large cohort of Black PWH on TAF-containing ART and showed a low incidence of RTA and AKI, despite predisposition to increased rates of renal decline or safety outcomes in Black PWH starting ART.
Sex and APOE ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease
(Wiley, 2025) Peterson, Amalia; Sathe, Aditi; Zaras, Dimitrios; Yang, Yisu; Durant, Alaina; Deters, Kacie D.; Shashikumar, Niranjana; Pechman, Kimberly R.; Kim, Michael E.; Gao, Chenyu; Khairi, Nazirah Mohd; Li, Zhiyuan; Yao, Tianyuan; Huo, Yuankai; Dumitrescu, Logan; Gifford, Katherine A.; Wilson, Jo Ellen; Cambronero, Francis E.; Risacher, Shannon L.; Beason-Held, Lori L.; An, Yang; Arfanakis, Konstantinos; Erus, Guray; Davatzikos, Christos; Tosun, Duygu; Toga, Arthur W.; Thompson, Paul M.; Mormino, Elizabeth C.; Habes, Mohamad; Wang, Di; Zhang, Panpan; Schilling, Kurt; Alzheimer's Disease Neuroimaging Initiative (ADNI); BIOCARD Study Team; Alzheimer's Disease Sequencing Project (ADSP); Albert, Marilyn; Kukull, Walter; Biber, Sarah A.; Landman, Bennett A.; Johnson, Sterling C.; Schneider, Julie; Barnes, Lisa L.; Bennett, David A.; Jefferson, Angela L.; Resnick, Susan M.; Saykin, Andrew J.; Hohman, Timothy J.; Archer, Derek B.; Radiology and Imaging Sciences, School of Medicine
Introduction: The effects of sex and apolipoprotein E (APOE)-Alzheimer's disease (AD) risk factors-on white matter microstructure are not well characterized.
Methods: Diffusion magnetic resonance imaging data from nine well-established longitudinal cohorts of aging were free water (FW)-corrected and harmonized. This dataset included 4741 participants (age = 73.06 ± 9.75) with 9671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex and APOE ε4 carrier status.
Results: Sex differences in FAFWcorr in projection tracts and APOE ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced.
Discussion: There are prominent differences in white matter microstructure by sex and APOE ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted.
Highlights: Sex and apolipoprotein E (APOE) ε4 carrier status relate to white matter microstructural integrity. Females generally have lower free water-corrected fractional anisotropy compared to males. APOE ε4 carriers tended to have higher free water than non-carriers.
Amyloid‐PET in patients with a clinical diagnosis of sporadic early‐ versus late‐onset AD: comparison of the LEADS and ADNI cohorts
(Wiley, 2025-01-09) Lagarde, Julien; Maiti, Piyush; Schonhaut, Daniel R.; Zhang, Jiaxiuxiu; Soleimani-meigooni, David N.; Zeltzer, Ehud; Windon, Charles; Raya, Maison Abu; Vrillon, Agathe; Hammers, Dustin B.; Dage, Jeffrey L.; Nudelman, Kelly N.; Eloyan, Ani; Koeppe, Robert A.; Landau, Susan M.; Carrillo, Maria C.; Touroutoglou, Alexandra; Vemuri, Prashanthi; Dickerson, Bradford C.; Apostolova, Liana G.; Rabinovici, Gil D.; La Joie, Renaud; LEADS Consortium, Alzheimer’s Disease Neuroimaging Initiative; Neurology, School of Medicine
Background:
Large‐scale studies comparing sporadic early‐onset AD (EOAD, age<65) and late‐onset AD (LOAD, age≥65) are lacking. We compared amyloid‐PET outcomes (positivity rate and amyloid burden) between patients clinically diagnosed with sporadic EOAD vs LOAD, leveraging data from the Longitudinal Early‐Onset AD Study (LEADS) and the Alzheimer’s Disease Neuroimaging Initiative 3 (ADNI3).
Method:
731 patients meeting the 2011 NIA‐AA criteria for AD dementia or MCI were included (505 early‐onset from LEADS, 226 late‐onset from ADNI3, Table 1). All participants underwent amyloid‐PET with [18F]Florbetaben or [18F]Florbetapir. Amyloid positivity was centrally determined by a process involving a visual read by a trained expert and PET‐only quantification; in case of a discrepancy, a read from an independent physician acted as a tiebreaker. Logistic regressions in each cohort examined relations between amyloid positivity and age, sex, MMSE and APOE4 genotype. Amyloid burden was independently quantified in Centiloids using an MRI‐based pipeline. Mean Centiloids in LEADS and ADNI were compared with two‐way ANOVA, for visually positive and visually negative scans.
Result:
Amyloid positivity rate was higher in LEADS (76%) than ADNI (64%, p<0.001, Figure 1A). Lower MMSE and APOE4 genotype increased odds of amyloid positivity in both cohorts, although the APOE4 effect was stronger in ADNI than LEADS (OR=10.1 versus 2.4, p=0.007, Table 2). Amyloid positivity was more common in females across cohorts, but this effect was only statistically significant in LEADS (Table 2). Centiloids were bimodally distributed in both cohorts, although the separation between positive and negative scans was more prominent in LEADS (Figure 1B). Visually positive scans had significantly higher Centiloids in LEADS than in ADNI, whereas no cohort difference was observed for visually negative scans (Figure 1C). Sensitivity analyses showed that this effect was driven by patients with MCI (CDR≤0.5; Figure 1D‐E).
Conclusion:
The lower amyloid positivity rate in ADNI might be due to AD‐mimicking pathologies being more common at an older age. The higher amyloid burden in early‐onset, amyloid‐positive patients could reflect younger patients being diagnosed later in the disease course compared to typical, late‐onset patients. Alternatively, younger patients might tolerate higher neuropathology burden due to higher brain reserve or fewer co‐pathologies.