Eugene Applebaum College of Pharmacy and Health Sciences

PurposeDaptomycin-approved dosing is based on actual body weight (ABW). However, the pharmacokinetics and pharmacodynamics of daptomycin are altered in obese patients, leading to increased daptomycin exposure owing to incomplete distribution into excess body tissues. Data regarding the use of alternative weight descriptors for daptomycin dosing are limited. This study aimed to investigate the effectiveness and safety of daptomycin in obese patients by using adjusted body weight (AdjBW).MethodsThis retrospective multicenter cohort study in Saudi Arabia compared the outcomes of obese patients who received daptomycin based on AdjBW with those of obese and non-obese patients who received daptomycin based on ABW. The main outcomes included clinical cure, overall in-hospital mortality, and 30-day mortality. The safety outcomes were evaluated. Multivariate logistic regression was used to control for confounding variables.ResultsA total of 293 patients met the inclusion: 43 patients in AdjBW group, 54 in the ABW group, and 196 in the non-obese group. When comparing the AdjBW and ABW obese groups, no statistically significant difference was observed in clinical cure (83.7% vs 77.8%; p = 0.461; OR, 0.1.47; 95% CI, 0.52–4.12), overall in-hospital mortality (23.3% vs 35.2%; p = 0.200; OR, 0.56; 95% CI, 0.23–1.37), or 30-day mortality (16.3% vs 27.8%; p = 0.174; OR, 0.51; 95% CI, 0.19–1.38). Creatine phosphokinase elevation (8.6% vs 6%; p = 0.651) was similar between the two groups. Similar outcomes were observed when comparing the AdjBW and non-obese groups.ConclusionTreatment with daptomycin based on AdjBW in obese patients had similar effectiveness and safety outcomes as treatment with daptomycin based on ABW in obese and non-obese patients. Therefore, future prospective studies are warranted.

Wastewater surveillance (WWS) is a valuable tool for monitoring circulating and emerging pathogens, and emerging variants, providing an early warning system for potential epidemics. Its use for key viral diarrheal pathogens like Rotavirus (RV), Norovirus (NoV), and Hepatitis A Virus (HAV) remains underexplored in the Middle East and North African (MENA) region. This systematic review aims to advance available data on the use of wastewater to monitor RV, NoV and HAV in countries of the MENA region. A systematic search of six databases (PubMed, Medline, EMBASE, Scopus, Cochrane, and Web of science) was conducted for studies published between 2014 and 2024 in the MENA region following PRISMA guidelines. Eligible studies reported on the use of wastewater to detect RV, NoV, and HAV. Articles on unrelated pathogens, wastewater treatment efficiency, or insufficient sampling data were excluded. Risk of bias assessment was conducted. We retrieved 11 studies meeting our predefined inclusion criteria and were used to extract full data. These studies were from Egypt, Tunisia, Bahrain, and Jordan. RV was the most studied virus (64%), followed by HAV (45%) and NoV (18%). Most studies (73%) had a moderate risk of bias. All studies sampled wastewater treatment plants. The sampling period, frequency, and sample size varied substantially between studies. Positivity rates for RV, NoV, and HAV showed high variability, ranging between no detection and 100%. The predominantly reported genotypes were GI and P[8] for RV, GI for NoV, and IA for HAV. This review reveals significant gaps in WWS coverage across the MENA region for RV, NoV, and HAV, highlighting the need for investing in and expanding the use of WWS in the region. Effective surveillance of these viruses is pivotal to better understand the burden of these diseases and guide national public health interventions in the MENA region.

Carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CR-PA) continue to pose a significant threat to human health. Furthermore, the prevalence of metallo-β-lactamase (MBL)-producing CRE and CR-PA is increasing, which are capable of hydrolyzing nearly all β-lactam antibiotics. Cefepime-taniborbactam (FTB) is a novel bicyclic boronate β-lactam-β-lactamase inhibitor combination with direct inhibitory activity against MBLs (Ambler Class B), in addition to Ambler Class A, C, and D serine-β-lactamases. FTB has demonstrated high invitro activity against CRE and CR-PA, including isolates producing NDM, VIM, KPC, AmpC, OXA-48, and extended-spectrum β-lactamases (ESBLs). Furthermore, FTB has demonstrated invitro activity against Stenotrophomonas maltophilia and Burkholderia cepacia complex. Resistance to FTB is observed in isolates producing IMP, as well as MBL variants NDM-9, NDM-30, and VIM-83. FTB remains susceptible to non-β-lactamase resistance mechanisms, including penicillin-binding protein 3 (PBP3) target mutations. The pharmacodynamic driver of taniborbactam efficacy is the ratio of the area under the curve to the minimum inhibitory concentration (AUC/MIC), and the study dose of FTB 2 g/0.5 g every 8 h infused over 2 h achieves sufficient serum and tissue exposures to maintain therapeutic efficacy. Both components are primarily renally eliminated as unchanged drug; therefore, dose adjustments for renal impairment are required. The clinical efficacy of FTB was demonstrated in the phase III Cefepime Rescue with Taniborbactam in Complicated Urinary Tract Infection (CERTAIN-1) trial, where it demonstrated both non-inferiority and superiority (prespecified analysis) to meropenem in the composite of clinical and microbiologic success at the test of cure for the treatment of complicated urinary tract infection. The safety of FTB was demonstrated throughout its clinical development. Thirteen percent of patients experienced a treatment-related adverse drug event in the phase III clinical trial, with 3% of patients requiring discontinuation of the study agent. Cefepime-taniborbactam appears to be a promising addition to the antibiotic arsenal, particularly as the prevalence of infections caused by MBL-producing organisms continues to rise.

Background: The rise of bacterial resistance has driven the exploration of novel therapies, such as bacteriophage-antibiotic cocktails (PACs), which have shown in vitro promise against resistant pathogens, including daptomycin non-susceptible (DNS-MRSA) strains. While daptomycin has been a cornerstone for treating MRSA bacteremia and vancomycin-refractory infective endocarditis, the emergence of DNS-MRSA presents a significant challenge due to high morbidity, mortality, and rapid intrinsic resistance development. Methods: Phages Intesti13 and Sb-1, were selected for their unique host ranges and activity against sixteen DNS-MRSA strains. Synergy with antibiotics was assessed via growth suppression curves and 24-hour time-kill assays (TKAs) across administration sequences and MIC increments. Selected regimens were further assessed in an ex-vivo simulated endocardial vegetation (SEV) models, with pharmacokinetic analyses confirming target antibiotic concentrations. Results: In the ex-vivo SEV model, simultaneous PAC administration using daptomycin±phage, showed superior bactericidal activity over sequential treatments in isolate C6 (p<0.01). Similarly, in the same model, C2 reached detection limits within 48h and remained suppressed for 120h (p<0.0037). Sequential outcomes varied by phage-antibiotic order and antibiotic choice. Simultaneous and phage-first regimens outperformed antibiotic-first, especially in 24h TKAs, but showed variability at lower MICs and between in-vitro and ex-vivo settings. Conclusion: This study highlights PAC's potential for DNS-MRSA treatment, emphasizing the importance of administration timing. The observed differences across clinical strains emphasize the need for strain-specific evaluations and a deeper understanding of phage-antibiotic interactions to optimize therapy. Future research must focus on expanding phage diversity, refining protocols, and clinically validating sequential strategies to enhance PAC efficacy.

Endothelial cell dysfunction is a crucial feature of diabetic wound healing. The underlying molecular mechanisms are poorly understood. We investigated how G protein-coupled receptor 35 (GPR35) inhibition accelerates diabetic wound healing. We found that GPR35 modulated endothelial cell behavior invitro and identified oxidative stress responsive 1 as its target. Inhibiting GPR35 rescued the healing process in animals with hyperglycemia. This study uncovers novel molecular mechanisms underlying the benefit of GPR35 inhibition on endothelial cell angiogenesis and provides proof-of-concept evidence for therapeutic strategies targeting GPR35 in the endothelium as a potential therapy for diabetic wound care.

This study benchmarked gender trends in research authorship in the physician associate (PA) profession. A bibliometric analysis was conducted of the Journal of Physician Assistant Education and the Journal of the American Academy of Physician Associates from January 2014 to September 2022. We collected data on instances of PA first, last, and solo authorship of clinical or research articles. Author gender was verified through professional websites. Simple proportions and the Mann-Kendall test are reported. Among 1,315 collected instances of PA authorship, women represented 65.6% (n = 863) of the population, comprising 67.8% of first authors and 60.7% of last authors. The proportion of authors categorized as women increased over time ( P = .04). Women were more likely to have only one publication compared with men. Although positive signs of increased research authorship by women are evident, women still lag behind men in overall publication numbers and in senior authorship roles compared with their representation in the PA profession.

Limited evidence exists regarding the use of factor Xa inhibitors for the treatment of venous thromboembolism (VTE) in patients with severe renal impairment. Notably, these patients were excluded from clinical trials.The goal of this study was to examine the safety and effectiveness of apixaban versus warfarin for the treatment of acute VTE in patients with severe renal impairment.This retrospective cohort study was conducted across 36 Ascension Health sites between 2014 and 2024. Adult patients receiving apixaban or warfarin for VTE treatment with severe renal impairment were included. The primary outcome was time to composite bleeding event within six months.This study included 1200 patients receiving apixaban and 600 patients receiving warfarin. Overall, 23.4% of the study population had ESRD requiring renal replacement therapy. Among patients not requiring renal replacement therapy, stage IV CKD was most common (43.8%). No difference in time to composite bleeding events (HR 1.01; 95% CI 0.74-1.38, p = 0.97) or recurrent VTE (HR 1.24; 95% CI 0.70-2.18, p = 0.46) were noted after controlling for confounders. Furthermore, major bleeding (4.7% vs. 7.5%, p = 0.43) and clinically-relevant non-major bleeding (4.3% vs. 6.2%, p = 0.08) were similar between groups. Apixaban was associated with a significantly reduced incidence of anticoagulation-related ED admission (6.8% vs. 9.8%, p = 0.02) compared to warfarin. Anticoagulation-related readmission (7.4% vs. 8%, p = 0.66) and time to all-cause mortality (5.2% vs. 6.2%, p = 0.38) were similar between groups.No differences in safety or effectiveness were noted between apixaban and warfarin, providing encouraging evidence to support the use of apixaban for treatment of acute VTE in patients with severe renal impairment.

BackgroundCACTUS is a retrospective, matched, multicenter study comparing the efficacy of C/T and CZA for treatment of bacteremia or pneumonia due to MDR P. aeruginosa. We found that treatment with C/T resulted in higher rates of clinical success compared to CZA after controlling for baseline differences between cohorts. The objective of this study is to determine the impact of patient subgroups on the overall findings.MethodsC/T and CZA patients were matched 1:1 within each study site based on severity of illness, infection type, and time to treatment initiation. The primary outcome was clinical success at day 30, defined as survival, resolution of signs/symptoms of infection with the intended treatment course, and absence of recurrent infection. For subgroups of interest, the proportion with clinical success in each group was compared using an unadjusted odds ratio (OR) and 95% confidence interval.ResultsAmong 420 cases from 28 sites, 60.95% (128/210) of C/T- and 51.9% (109/210) of CZA-treated patients experienced clinical success. Groups were overall well-balanced by matching; however, CT-treated patients were older, more likely to have immunocompromising conditions, and to receive suboptimal dosing (Table 1). After conditional logistic regression, the adjusted OR for clinical success with C/T treatment was 1.97 (95% CI: 1.11 – 3.49; P=0.02).Unadjusted OR for patient subgroups are listed in Table 2. Overall, the effect size was consistent across all subgroups. Key factors are highlighted in Figure 1. Significantly higher rates of clinical success were found for treatment with C/T compared to CZA for patients with pneumonia, SOFA ≤7, mechanical ventilation, and optimal dosing. Table 3 displays comparative 30-day mortality rates. Higher mortality rates were identified in both C/T- and CZA-treated patients who were critically-ill, received suboptimal dosing, and were treated within 72 hours of index culture (Table 3); rates did not vary by treatment.ConclusionThe consistency of the results in this subgroup analysis of CACTUS reinforces the primary finding of higher rates of clinical success for patients with MDR P. aeruginosa pneumonia or bacteremia treated with C/T compared to CZA.Disclosuresjason M. Pogue, PharmD, Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Venatorx: Advisor/Consultant Samuel L. Aitken, PharmD, MPH, Basilea: Advisor/Consultant|bioMerieux: Advisor/Consultant|Melinta: Advisor/Consultant|Shionogi: Advisor/Consultant Ahmed Babiker, MBBS, Beckman Coulter Inc.: Advisor/Consultant Kimberly C. Claeys, PharmD, PhD, bioMérieux: Advisor/Consultant|bioMérieux: Honoraria Kate DeSear, PharmD, BCIDP, AAHIVP, FIDSA, AbbVie Inc: Advisor/Consultant|Basilea Pharmaceutica: Advisor/Consultant|GSK: Advisor/Consultant|La Jolla (Entasis): Advisor/Consultant|Melinta Therapuetics: Advisor/Consultant Alan E. Gross, PharmD, Becton Dickinson Co: Advisor/Consultant Keith S. Kaye, MD, MPH, Allecra: Advisor/Consultant|CARB-X: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant Wesley D. Kufel, Pharm.D., BCPS, BCIDP, Merck & Co.: Grant/Research Support|Shionogi, Inc: Grant/Research Support Conan MacDougall, PharmD, MAS, Merck: Grant/Research Support Erin K. McCreary, PharmD, Abbvie: Advisor/Consultant|Basilea: Advisor/Consultant|Ciadara: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|GSK: Honoraria|Melinta: Advisor/Consultant|Merck: Advisor/Consultant|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria William R. Miller, M.D., Merck: Grant/Research Support|UptoDate: Royalties Jeffrey C. Pearson, PharmD, inflarx: Advisor/Consultant Michael J. Satlin, MD, AbbVie: DSMB participant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Selux Diagnostics: Grant/Research Support|SNIPRBiome: Grant/Research Support David van Duin, MD, PhD, Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support

Abstract Background The duration of therapy for hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) due to non-lactose fermenter Gram-negatives bacilli including Pseudomonas aeruginosa (PsA) remains a topic of debate. Our study aimed to compare the efficacy of short-duration (≤8 days) to long-duration ( >8 days) therapy for HAP/VAP due to multi-drug resistant (MDR) or difficult-to-treat (DTR) PsA infection. Methods A two-center, retrospective cohort study was conducted from 5/2010 to 12/2022. We included all patients ≥18 years old with HAP or VAP due to MDR- or DTR-PsA in respiratory cultures who were treated for ≥72 hours. The primary outcome was a 30-day recurrence from the index culture, and the secondary outcomes were a 60-day recurrence, 30-day, and 60-day mortality from the index culture. Results Overall, 203 patients (short duration, n=91 and long duration, n=112) were included. Sixty-nine percent were male, and 58.6% were of African American descent. The mean (SD) for age and APACHE II score were 58.5 (15.8) and 23.9 (7.9), respectively. The common comorbidities were diabetes (39.9%), cerebrovascular disease (28.6%), and chronic obstructive pulmonary disease (24.1%). The primary admission source was a nursing home (44.8%). VAP was diagnosed in 53.0% of patients, with DTR-PsA accounting for 58.1% of all infections. Polymicrobial infection was present in 20.1% of the cases with Enterobactarales species present in all cases. Ceftazidime-avibactam and ceftolozane-tazobactam were used for treatment in 33.0% and 47.8%, respectively; combination therapy was used for 11.8% of cases. The 30-day recurrence was significantly lower in the long-duration therapy compared with the short-duration (5.4% vs. 15.9%, p = 0.017). Similarly, there was a lower 60-day recurrence rate in the long-duration group vs. short-duration group (8.9% vs. 24.4%, p=0.026). There were no significant differences in 30-day and 60-day mortality rates observed. Conclusion Prolonged duration ( >8 days) has resulted in lower recurrence rates of HAP/VAP caused by MDR/DTR PsA infection at 30 and 60 days. Although our study is insightful, a larger-scale study is necessary, and logistic regression should be conducted to determine the predictors of the significant differences in the primary outcome. Disclosures Kaylee E. Caniff, PharmD, BCIDP, T2Biosystems: Honoraria Michael J. Rybak, PharmD, PhD, MPH, Abbvie, Melinta, Sionogi, Merck, T2Biosystems: Advisor/Consultant|Abbvie, Melinta, Sionogi, Merck, T2Biosystems: Grant/Research Support|Abbvie, Melinta, Sionogi, Merck, T2Biosystems: Speaker