Albany College of Pharmacy and Health Sciences

BACKGROUND:Time to bloodstream clearance is a critical prognostic indicator in various infections, yet limited data exist on the relationship between time to mycological clearance and outcomes in candidemia. This study aimed to assess the association between the duration of candidemia and outcomes in adult, hospitalized patients receiving empiric echinocandin treatment across US hospitals. METHODS:A retrospective, multicenter study using the PINCI AI Healthcare Database (1/2016-4/2019) was conducted. Inclusion criteria: hospitalized adults (≥18 years) with Candida spp. identified on a clinical blood culture who received empiric echinocandin therapy (±2 days of index Candida spp. blood culture) for ≥3 days. Outcomes assessed were in-hospital mortality, length of stay, and hospital costs. The associations between increasing duration of candidemia relative to a single day of candidemia and outcomes were examined. RESULTS:A total of 867 patients met the criteria. Multivariable analysis showed that patients with candidemia lasting more than 1 day had significantly higher mortality, longer length of stay, and higher hospital costs compared to those with only 1 day of candidemia. For each additional day of candidemia, the adjusted odds of in-hospital mortality increased by 3%, the adjusted median hospital length of stay after index collection day increased by 1.0 days, and the adjusted median total costs after index collection day increased by $3006. CONCLUSIONS:Prolonged candidemia is associated with worse patient outcomes and higher healthcare costs. Further large-scale studies are needed to confirm these findings given the exploratory and observational nature of this study.

Ceftolozane/tazobactam (C/T) and ceftazidime/avibactam (C/A) are frequently used for the treatment of multidrug-resistant Pseudomonas aeruginosa (MDR-PSA) pneumonia. However, comparative "real-world" effectiveness data are limited. We performed a retrospective cohort study within the U.S. Veterans Health Administration (VHA; 2015-2019, 2022-2024), including adults with microbiologically confirmed MDR-PSA pneumonia receiving C/T or C/A within ≤5 days of index culture. Inverse probability of treatment weighting (IPTW) was applied to balance baseline covariates. The primary outcome was 30-day all-cause mortality, and secondary outcomes were 60-day mortality, 90-day mortality, and 30-, 60-, and 90-day MDR-PSA recurrence and all-cause hospital readmission. A prespecified sensitivity analysis examined the effect of early treatment initiation ≤72 h. Among 260 patients (C/T, n = 132; C/A, n = 128), C/T recipients demonstrated more extensive prior antimicrobial exposure and substantially longer time-to-therapy (median, 56 versus 19 h; P < 0.001). After IPTW, balance improved across most prespecified covariates, although residual imbalance persisted for age and geographic region. No statistically significant between-group differences were observed in 30-day mortality (adjusted risk ratio [aRR], 1.02; 95% confidence interval [CI], 0.56-1.83; P = 0.944) or in other clinical outcomes. Among patients with early treatment within 72 h (n = 175), no significant differences in 30-day mortality (aRR, 1.18; 95% CI, 0.47-2.93; P = 0.724) or other mortality, recurrence, or readmission outcomes were observed between C/T and C/A. In this national VHA cohort, C/T and C/A demonstrated comparable clinical, microbiologic, and healthcare utilization outcomes. These findings support consideration of either C/T or C/A for MDR-PSA pneumonia when used at appropriate doses.

Complicated urinary tract infections (cUTIs) and acute pyelonephritis (AP) often require hospitalization and intravenous (IV) antibiotics. Patients may complete treatment in hospital (IV complete), be discharged with outpatient parenteral antibiotic therapy (IV-to-OPAT) in settings such as home health or skilled nursing facilities, or transition to oral antibiotics (IV-to-PO). Understanding differences in length of stay (LOS) and costs between these strategies is critical for optimizing care and resource use. This retrospective cohort study used Optum’s de-identified electronic health record-linked-claims data (Optum Market Clarity) between 10/01/2015 and 09/30/2023, for hospitalized adults with cUTI/AP receiving IV antibiotics. Hospital admission was defined as the index date. Patients were categorized by the timing of urine culture collection – community-onset (-/+2 days index) versus hospital-onset (≥ +3 days index) – and stratified by Charlson Comorbidity Index score (CCI: 0, 1─2, 3─4, ≥ 5). LOS and costs were compared across treatment strategies (IV-to-PO, IV-to-OPAT, IV complete) and CCI risk groups. Among 54,216 community-onset cases, 50.6% were IV-to-PO, 25.4% IV-to-OPAT, and 24% IV complete. Among 7390 hospital-onset cases, 34.3% were IV-to-PO, 21% IV-to-OPAT, and 44.7% IV complete. Demographics and clinical characteristics are described in Table 1. For community-onset, IV-to-PO had the shortest LOS (mean 5.7 days) and lowest mean cost ($27,905) versus IV-to-OPAT (6.6 days; $35,082) and IV complete (11 days; $53,359). LOS increased with comorbidity; median LOS for community-onset ranged from 4 days (CCI 0) to 7 days (CCI ≥ 5; Tables 2 and 3). Hospital-onset cases showed similar patterns: IV-to-PO (18.4 days; $95,419), IV-to-OPAT (26.5 days; $124,895), IV complete (32.0 days; $149,387). Median LOS for hospital-onset ranged from 17 days (CCI 0) to 20 days (CCI ≥ 5; Tables 2 and 4). Patients that transitioned from IV-to-PO antibiotics had both shorter LOS and lower costs than those managed solely on IV antibiotics (either in OPAT or hospital settings). Higher LOS in IV complete and IV-to-OPAT groups may be influenced by disease complexity, frailty and non-treatment related factors. Funding: GSK study 221141. Thomas Lodise, Jr., PharmD, PhD, GSK: Advisor/Consultant Amy G. Edgecomb, PharmD, MPH, GSK: Employee|GSK: Stocks/Bonds (Public Company) Fanny S. Mitrani-Gold, MPH, GSK: Employee|GSK: Stocks/Bonds (Public Company) Jeffrey J. Ellis, PharmD, MS, GSK: Employee|GSK: Stocks/Bonds (Public Company) Alin Kalayjian, PharmD, MS, MBA, GSK: Previous employment|Penumbra, Inc.: Employee|Penumbra, Inc.: Stocks/Bonds (Public Company) Lindsey Parker, PharmD, GSK: Employee|GSK: Stocks/Bonds (Public Company) Benjamin Chastek, MS, Optum (UnitedHealth Group): Stocks/Bonds (Public Company) Timothy Barnes, MHI, MBA, Optum (UnitedHealth Group): Employee|Optum (UnitedHealth Group): Stocks/Bonds (Public Company) Aaron Lucas, MD, GSK: Advisor/Consultant|Optum (UnitedHealth Group): Advisor/Consultant

Abstract Background Few treatment options exist for serious infections caused by MBL-PSA. While ATM retains activity against some MBL-PSA, isolates often constitutively produce PDCs, resulting in resistance. I/R is a new β-lactam/β-lactamase inhibitor with expanded activity against constitutive PDC-producing PSA, but has no standalone activity against MBL-PSA. This study aimed to evaluate the effect of I/R plus ATM against PDC- and MBL-producing PSA in the HFIM. Methods Two isogenic, constitutive PDC-and MBL-producing PSA isolates (MB10480: IMP-1; MB10620: VIM-1) were studied at a starting inoculum of 8 log10 colony forming units (CFU)/mL in the HFIM over 96 hrs. Humanized exposures of I/R (500/250mg q6h as a 0.5 hr infusion) were evaluated alone and in combination with 3 ATM regimens (1.5g q6h; 2g q8h; 2g q6h as 2 hr infusions). Combination regimens were tested in triplicate with inoculum (log10 cfu/mL) averaged across runs. MIC testing with ATM and relebactam (set at 4 mg/L) was conducted on isolates recovered from the model at 96 hrs. Results Monotherapy arms mirrored the growth control for MB10620 (ATM/relebactam MIC: 4/4 mg/L); combination arms resulted in bacteriostasis through 96 hrs. Maximal killing of each regimen (∼2 log10 CFU/mL; all units log10 cfu/mL change vs. baseline) was achieved through 32 hrs, followed by regrowth across all regimens (Figure 1). Bacterial counts at 96 hrs were similar to the starting inoculum for all combinations, but lowest for I/R plus ATM 2g q6h (I/R plus ATM 1.5g q6h: +1.75 CFU/mL; 2g q8h: +1.74 CFU/mL; 2g q6h: -0.20 CFU/mL;). Similar results were observed with MB10480 (ATM/relebactam MIC: 8/4 mg/L) (Figure 2). Maximal killing was achieved through 56 hrs (∼2 log10 CFU/mL), followed by regrowth across all combination regimens (I/R plus ATM 1.5g q6h: +0.19 CFU/mL; 2g q8h: -0.34 CFU/mL; 2g q6h: -0.35 cfu/mL). Across combination regimens for both isolates, 2 morphologies of PSA were recovered. Retested isolate MICs were occasionally, but not consistently, elevated by >2 dilutions (MB10620: 10/18; MB10480: 4/18). Conclusion I/R plus ATM resulted in initial killing followed by regrowth over 96 hrs for constitutive PDC- and MBL-producing PSA isolates. Further study is needed to evaluate optimal dosing and suppression of regrowth in the HFIM. Disclosures J Nicholas O'Donnell, Pharm.D., Merck and Co, Inc.: Grant/Research Support Thomas Lodise, Jr., Pharm.D., PhD, merck: Grant/Research Support|merck: Honoraria

HFIMs are the gold standard pre-clinical PK/PD model for studying humanized antibiotic exposure-response relationships. Standard HFIM cartridges (Fibercell C2011) use 20 kD MWCO fibers, which retain β-lactamases from lysed bacteria. Newer cartridges (Fibercell C7011) have larger 0.03 µm pores and are less prone to β-lactamase retention. We evaluated whether bacterial killing differs between I/R and I/R + ATM in PSA HFIM studies using C2011 vs. C7011 cartridges.Figure 1.Hollow fiber infection models evaluating bacterial killing against P. aeruginosa CL 5701 at standard (a) and high (b) starting inoculaI/R, imipenem/relebactamFigure 2.Hollow fiber infection models evaluating bacterial killing against P. aeruginosa MB 10480 at standard (a) and high (b) starting inoculaATM, aztreonam; I/R, imipenem/relebactam HFIMs using previously described PSA isolates [CL 5701 (constitutive PDC producer, OprD deleted) and MB 14080 (daughter isolate, IMP-1-producer)] were performed. Simulated exposures of the FDA-approved I/R regimen (0.5/0.5/0.25g q6h, 0.5 h infusion) was evaluated against CL 5701 while I/R + ATM (2g q6h, 2 h infusion) was evaluated against MB 14080. Each regimen was tested in duplicate at starting inocula of 6 log10 cfu/mL (standard) and 7.5 log10 cfu/mL (high). Each set of HFIM experiments was performed using paired C2011 and C7011 cartridges (same syringe, DuetTM, and peristaltic pumps for each pair). Changes in bacterial density from baseline were evaluated at hours 24 and 96. For CL 5701, bacterial killing was limited in the C2011 HFIM at the standard inoculum HFIM studies and regrowth observed after 24 hours. In contrast, bactericidal activity was observed at hours 24 and 96 (-3.53 and -4.55 log10 cfu/mL, respectively) with C7011. In the high inoculum HFIM of CL 5701, no notable differences in killing were observed between cartridges at hours 24 (C2011:-0.74 and C7011: -1.26 log10 cfu/mL) and 96 (-1.05 vs -0.85 log10 cfu/mL). For HFIM of MB10480 at the standard inoculum, bacterial killing was greater in C7011 relative to C2011 at hours 24 (-1.46 vs -2.29 log10 cfu/mL) and 96 (-1.72 vs -2.00 log10 cfu/mL). In high inoculum MB 10480 HFIM studies, killing was greater in C2011 relative to C7011 at hour 24 (-1.27 vs -0.35 log10 cfu/mL), however there was more pronounced killing and less regrowth with C7011 vs C2011 at hour 96 (-0.85 vs -1.76 log10 cfu/mL). Differences in bacterial killing were apparent when comparing the effect of I/R and I/R+ATM in HFIM of PSA with different infection cartridges, likely due to more β-lactamase retention in less porous standard cartridges (C2011). J Nicholas O'Donnell, Pharm.D., MSc, Merck and Co., Inc: Grant/Research Support Nicole L. Shakerley, PhD, Merck and Co., Inc: Grant/Research Support Katherine Young, M.S., Merck & Co., Inc.: Stocks/Bonds (Public Company) Thomas Lodise, Jr., PharmD, PhD, GSK: Advisor/Consultant