ACPHS Research Commons (Albany College of Pharmacy and Health Sciences)
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Review of the In Vitro Microbiological Activity of Mecillinam Against Common Uropathogens in Uncomplicated Urinary Tract Infection: Focus on Resistant Pathogens.
No full textClick on the Resource Link to access the article (may not be free).Antimicrobial resistance in uropathogens commonly causing urinary tract infections (UTIs) is a growing problem internationally. Pivmecillinam, the oral prodrug of mecillinam, has been used for over 40 years, primarily in Northern Europe and Canada. It is recommended in several countries as a first-line agent for the treatment of uncomplicated UTIs (uUTIs) and is now approved in the United States. We performed a structured literature search to review the available evidence on susceptibility of common uUTI-causing uropathogens to mecillinam. Among 38 studies included in this literature review, susceptibility rates for to mecillinam-including resistant phenotypes such as extended-spectrum β-lactamase-producing -exceed 90% in most studies. High rates of susceptibility were also reported among many other uropathogens including spp., spp., and spp. In the current prescribing climate within the United States, pivmecillinam represents a viable first-line treatment option for patients with uUTI.https://doi.org/10.1093/ofid/ofae296http://www.ncbi.nlm.nih.gov/pmc/articles/pmc11167674
Retrospective, propensity score--matched study examining the relationship between frailty and Clostridioides difficile infection in a national cohort of US veterans
No full textClick on the Resource Link to access the article (may not be free).Background: Frailty is often more predictive of disease and mortality compared with chronological age. This study determined the impact of frailty on Clostridioides difficile infection (CDI) risk and outcomes in a national veteran population.Methods: This was a retrospective cohort study of CDI and control veteran inpatients and outpatients from fiscal year 2003 to 2018. Baseline frailty was presented as the Veterans Affairs (VA) Frailty Index. Propensity score--matched analyses were conducted to compare CDI risk, CDI health outcomes, and 1-year new-onset frailty-associated conditions.Results: A total of 11,451 CDI and 11,451 matched control patients were included. Baseline frailty conditions were more common among CDI patients, especially involuntary weight loss (6.0% vs 3.4%, P < .001) and anemia (24.6% vs 18.7%, P < .001). VA Frailty Index was significantly higher for CDI patients (0.13 vs 0.11, P = .019). Frail CDI patients were more likely to experience 30-day mortality (11.3% vs 1.1%, P < .001) and 60-day CDI recurrence (20.4% vs 16.3%, P < .001) compared with non-/prefrail CDI patients. At 1year, CDI patients were significantly more likely to be categorized as frail (19.6% vs 17.0%, P < .001).https://doi.org/10.1016/j.ajic.2024.08.02
Clinical Utility of Free Drug Monitoring
No full textClick on the resource link to find the book in the ACPHS catalog.https://doi.org/10.1016/B978-0-443-18649-3.00008-
Combination therapy with IV fosfomycin for adult patients with serious Gram-negative infections: a review of the literature.
No full textClick on the resource link (may not be free).Treatment of patients with serious infections due to resistant Gram-negative bacteria remains highly problematic and has prompted clinicians to use existing antimicrobial agents in innovative ways. One approach gaining increased therapeutic use is combination therapy with IV fosfomycin. This article reviews the preclinical pharmacokinetic/pharmacodynamic (PK/PD) infection model and clinical data surrounding the use of combination therapy with IV fosfomycin for the treatment of serious infections caused by resistant Gram-negative bacteria. Data from dynamic in vitro and animal infection model studies of highly resistant Enterobacterales and non-lactose fermenters are positive and suggest IV fosfomycin in combination with a β-lactam, polymyxin or aminoglycoside produces a synergistic effect that rivals or surpasses that of other aminoglycoside- or polymyxin-containing regimens. Clinical studies performed to date primarily have involved patients with pneumonia and/or bacteraemia due to Klebsiella pneumoniae, Pseudomonas aeruginosa or Acinetobacter baumannii. Overall, the observed success rates with fosfomycin combination regimens were consistent with those reported for other combination regimens commonly used to treat these patients. In studies in which direct treatment comparisons can be derived, the results suggest that patients who received fosfomycin combination therapy had similar or improved outcomes compared with other therapies and combinations, especially when it was used in combination with a β-lactam that (1) targets PBP-3 and (2) has exceptional stability in the presence of β-lactamases. Collectively, the data indicate that combination therapy with IV fosfomycin should be considered as a potential alternative to aminoglycoside or polymyxin combinations for patients with antibiotic-resistant Gram-negative infections when benefits outweigh risks.Zavante Therapeutics, Inc., Delaware, USAhttps://doi.org/10.1093/jac/dkae25
Piperacillin/tazobactam Susceptibility Test Interpretive Criteria for Enterobacterales: Recommendations from the United States Committee on Antimicrobial Susceptibility Testing.
No full textClick on the Resource Link to access the article (may not be free).The in vitro susceptibility testing interpretive criteria (STIC) for TZP against Enterobacterales were recently updated by the Food and Drug Administration (FDA), Clinical & Laboratory Standards Institute (CLSI), and European Committee on Antimicrobial Susceptibility Testing (EUCAST). The United States Committee on Antimicrobial Susceptibility Testing (USCAST) also recently reviewed TZP STIC for Enterobacterales and arrived at different STIC for Enterobacterales and herein we explain our recommendations and rationale behind them. Based on our review of the available data, USCAST does not recommend TZP STIC for certain Enterobacterales species that have a moderate to high likelihood of clinically significant AmpC production (E. cloacae, C. freundii, and K. aerogenes only) or for third-generation cephalosporin-non-susceptible (3GC-NS) Enterobacterales. USCAST recommends a TZP susceptibility breakpoint of ≤ 16/4 mg/L for third-generation cephalosporin-susceptible (3GC-S) Enterobacterales but only endorses the use of extended infusion TZP regimens for patients with infections due to these pathogens.https://doi.org/10.1093/cid/ciae32
Dosing Adjustments in Cases of Altered Plasma Protein Binding are Most Needed for Drugs with a Volume of Distribution Below 1.3 L/kg.
No full textClick on the Resource Link to access the article (may not be free).Background: The present literature offers conflicting views on the importance of changes in plasma protein binding in clinical therapeutics. Furthermore, there are no methods to calculate a new dosing regimen when such changes occur.
Methods: Previous models developed by Balaz et al. and Greenblat et al. were used to calculate a plasma protein binding (PPB) score for individual drugs based on the volume of distribution for total concentration and the bound fraction of drug. The models were further used to calculate a new drug dosing interval for cases of altered plasma protein binding. The equations apply best for drugs with fast absorption and fast distribution; they can be used as approximations for drugs with slow distribution by using the volume of distribution at steady state and the rate constant of the elimination phase.
Results: The newly developed equations show that changes in plasma protein binding are relevant only for drugs with a positive PPB score; such drugs must have a volume of distribution for total concentration below 1.3 L/kg and high protein binding. It is further shown that the drug dosing interval should be reduced when the remaining fraction of plasma protein binding is below the PPB score.
Conclusion: A new method to rank drugs according to the impact of changes in plasma protein binding on their pharmacokinetic profile was developed. The new method was applied to show that drugs with high PPB scores need reductions in their dosing interval when the level of protein binding decreasesGrant Funded1R15GM126510/Foundation for the National Institutes of Healthhttps://doi.org/10.1007/s40262-024-01403-
Critical role of growth medium for detecting drug interactions in Gram-negative bacteria that model responses.
No full textThe rise in infections caused by multidrug-resistant (MDR) bacteria has necessitated a variety of clinical approaches, including the use of antibiotic combinations. Here, we tested the hypothesis that drug-drug interactions vary in different media, and determined which in vitro models best predict drug interactions in the lungs. We systematically studied pair-wise antibiotic interactions in three different media, CAMHB, (a rich lab medium standard for antibiotic susceptibility testing), a urine mimetic medium (UMM), and a minimal medium of M9 salts supplemented with glucose and iron (M9Glu) with three Gram-negative ESKAPE pathogens, Acinetobacter baumannii (Ab), Klebsiella pneumoniae (Kp), and Pseudomonas aeruginosa (Pa). There were pronounced differences in responses to antibiotic combinations between the three bacterial species grown in the same medium. However, within species, PaO1 responded to drug combinations similarly when grown in all three different media, whereas Ab17978 and other Ab clinical isolates responded similarly when grown in CAMHB and M9Glu medium. By contrast, drug interactions in Kp43816, and other Kp clinical isolates poorly correlated across different media. To assess whether any of these media were predictive of antibiotic interactions against Kp in the lungs of mice, we tested three antibiotic combination pairs. In vitro measurements in M9Glu, but not rich medium or UMM, predicted in vivo outcomes. This work demonstrates that antibiotic interactions are highly variable across three Gram-negative pathogens and highlights the importance of growth medium by showing a superior correlation between in vitro interactions in a minimal growth medium and in vivo outcomes.
Importance: Drug-resistant bacterial infections are a growing concern and have only continued to increase during the SARS-CoV-2 pandemic. Though not routinely used for Gram-negative bacteria, drug combinations are sometimes used for serious infections and may become more widely used as the prevalence of extremely drug-resistant organisms increases. To date, reliable methods are not available for identifying beneficial drug combinations for a particular infection. Our study shows variability across strains in how drug interactions are impacted by growth conditions. It also demonstrates that testing drug combinations in tissue-relevant growth conditions for some strains better models what happens during infection and may better inform combination therapy selection.Grant FundedK12 GM133314/GM/NIGMS NIH HHS/United StatesT32 AI007422/AI/NIAID NIH HHS/United StatesR01 AI169786/AI/NIAID NIH HHS/United Stateshttps://doi.org/10.1128/mbio.00159-24http://www.ncbi.nlm.nih.gov/pmc/articles/pmc10936441
Pharmacy Intern Involvement in COVID-19 Immunization Practices in New York State.
No full textClick on the Resource Link to access the article (may not be free).Background: Pharmacists and pharmacy interns were instrumental in vaccination efforts during the COVID-19 pandemic. Objectives: To identify pharmacy intern involvement in COVID-19 immunization practices in New York State (NYS) and explore interns' perceptions of experiences.
Methods: A 34-item survey was developed and administered at 5 pharmacy programs in NYS. Data collected included: perceptions of immunization readiness, participation in immunizations, description of experiences, and perceptions on the role of pharmacists. Respondents also reported on their preparedness to participate in the immunization process and the types of questions received from patients. Data were analyzed using descriptive statistics and thematic analysis. Questions regarding student experiences before and after participating in immunization efforts were analyzed using a two-sample t test.
Results: A total of 460 interns participated in the survey with 398 (87%) reporting participation in COVID-19 immunizations. Of those, 231 (58%) participated at work, 146 (36.7) during experiential rotations, and 98 (24.6%) during volunteer experiences. Respondents participated in various components of vaccine delivery including administration (n = 246, 61.8%). Respondents administered an estimated 57,100 COVID-19 vaccines from December 2020 to April 2021 resulting in significantly higher mean scores for comfort level (5-point Likert scale) administering vaccines after participation (mean score 4.08 ± 1.31) compared to before (mean score 3.61 ± 1.42) (p < .0001). Themes which emerged regarding student perceptions of their experience are described.
Conclusion: Pharmacy intern involvement in NYS COVID-19 immunization practices contributed to public health vaccination efforts. Additionally, interns improved comfort levels with immunization administration and recognized pharmacists' emerging roles within the U.S. healthcare system.https://doi.org/10.1177/08971900231164748http://www.ncbi.nlm.nih.gov/pmc/articles/pmc10031270
Inhibition of sulfated glycans on the binding of dengue virus envelope protein to heparin.
No full textClick on the resource link to access the article (may not be free)Dengue viruses (DENV) are transmitted to humans through mosquito bites and infect millions globally. DENV uses heparan sulfate (HS) for attachment and cell entry by binding the envelope protein to highly sulfated HS on target cells. Therefore, inhibiting the binding between DENV and HS could be a promising strategy for preventing DENV infection. In the current study, the interactions between DENV envelope protein (from Type 2 DENV) and heparin (a surrogate for HS) were analyzed using competition solution SPR. Results demonstrate that heparin binds to DENV envelope protein with high affinity (K = 8.83 nM). Competitive Solution SPR assays using surface-immobilized heparin and a series of naturally-sourced and semi-synthetic sulfated glycans demonstrated significant inhibitory activity against the binding of DENV envelope proteins to heparin. This study of molecular interactions could provide insights into the development of therapeutics for DENV infection.Grant FundedNIH [S10OD028523 and R21AI156573 (R.J.L, F.Z.), 1P20GM130460-01A1-7936 and 1R03NS110996-01A1, R01 AG069039-01/GF/NIH HHS/United Stateshttps://doi.org/10.1007/s10719-024-10172-
Synthesis of bioengineered heparin chemically and biologically similar to porcine-derived products and convertible to low MW heparin.
No full textClick on the Resource Link to access the article (may not be free).Heparins have been invaluable therapeutic anticoagulant polysaccharides for over a century, whether used as unfractionated heparin or as low molecular weight heparin (LMWH) derivatives. However, heparin production by extraction from animal tissues presents multiple challenges, including the risk of adulteration, contamination, prion and viral impurities, limited supply, insecure supply chain, and significant batch-to-batch variability. The use of animal-derived heparin also raises ethical and religious concerns, as well as carries the risk of transmitting zoonotic diseases. Chemoenzymatic synthesis of animal-free heparin products would offer several advantages, including reliable and scalable production processes, improved purity and consistency, and the ability to produce heparin polysaccharides with molecular weight, structural, and functional properties equivalent to those of the United States Pharmacopeia (USP) heparin, currently only sourced from porcine intestinal mucosa. We report a scalable process for the production of bioengineered heparin that is biologically and compositionally similar to USP heparin. This process relies on enzymes from the heparin biosynthetic pathway, immobilized on an inert support and requires a tailored -sulfoheparosan with -sulfo levels similar to those of porcine heparins. We also report the conversion of our bioengineered heparin into a LMWH that is biologically and compositionally similar to USP enoxaparin. Ultimately, we demonstrate major advances to a process to provide a potential clinical and sustainable alternative to porcine-derived heparin products.NA/Heparin Applied Research Centerhttps://doi.org/10.1073/pnas.2315586121http://www.ncbi.nlm.nih.gov/pmc/articles/pmc10998570