Characterization and Rate of Killing of Conjugated Silver Nanoparticles Against Selected Clinical Bacterial Isolates

The menace of drug resistance, bioavailability and drug delivery to the target sites has motivated researchers to search for new antimicrobial agents from medicinal plants and subsequently use them for the biosynthesis of silver nanoparticles for effective killing of bacteria challenging to kill using crude extracts. The biosynthesis of silver nanoparticles was done using aqueous extract (AQE) of E<i>uphorbia heterophylla</i>, while characterization and the killing rate of conjugated silver nanoparticles (CA_gNP_s) were carried out using standard methods. The maximum wavelength obtained for CA_gNP_s was 410.33 nm, while the size distribution was 237.8 d.nm. The Fourier Transform Infra-Red result showed O-H (3308.94 cm^-1), which is responsible for stabilising and reducing silver ions, while the Transmission Electron Microscopy revealed the presence of monodispersed spherical shapes CA_gNP_s. The Energy Dispersive Spectroscopy confirmed the presence of silver. There were reductions in the clinical bacterial isolates exposed to CA_gNP_s as the exposure time increased. <i>Escherichia coli</i> was killed between 6-7 h while<i> Salmonella typhimurium</i> was killed at the seven has the value of 0.00 log₁₀ CFU/ml was recorded respectively. However, there were increments in the populations of clinical bacterial isolates in control as the time of exposure increased. Therefore, the study suggests that the CA_gNP_s exhibit intense antimicrobial activity and the potential to be developed as an alternative agent to treat bacterial infections, curb multidrug-resistant bacterial infection, and promote speedy drug delivery to the target sites.

Respecting the Patient’s Choice: A Case of Possible Drug-Induced Parkinsonism

This report describes a case of likely drug-induced Parkinsonism (DIP) identified by the pharmacist. A 54-year-old female patient was referred by a physician to the pharmacist in a rural, integrated care team for a comprehensive medication review (CMR) to address the patient’s concerns of possible Parkinson’s disease (PD). While PD may occur over the progression of age, medications that affect dopamine transport can also cause DIP, a secondary form of Parkinson’s disease. Although PD and DIP may be clinically indistinguishable, differentiation may be possible by reviewing a patient’s medication history for any potential causative drugs correlating to the timeline of the onset of symptoms. In this case, the pharmacist reviewed the medication profile and identified medications that could be responsible for causing DIP, specifically bupropion. The pharmacist suggested discontinuing bupropion and identifying another option for treating depression. The patient appreciated the suggestion and education, but ultimately preferred continuing her bupropion therapy instead of discontinuing therapy or changing to an alternative agent. At a follow-up meeting with the pharmacist, not only was the patient still experiencing tremors despite taking carbidopa/levodopa, but additional medications known to be potential inducers of tremors were added to her regimen. Although the pharmacist repeatedly discussed DIP with the patient and believed stopping bupropion would determine whether her Parkinsonism was PD or DIP, ultimately the patient continued taking bupropion because of concerns related to depression severity and the impact on her well-being. The patient’s wishes were respected.

1315. Ceftaroline Versus Vancomycin for the Treatment of Acute Pulmonary Exacerbations of Cystic Fibrosis in Adults

Background Methicillin-resistant Staphylococcus aureus (MRSA) is a prominent colonizer in cystic fibrosis (CF) patients that causes acute pulmonary exacerbation (APE). Vancomycin is the first line treatment for APE of CF; however, optimal alternatives remain poorly defined. The goal of this study was to determine the safety and efficacy of ceftaroline in CF patients presenting with an APE caused by MRSA. Methods This study was a single-center, retrospective cohort study from January 1, 2011 to January 1, 2020. The study included adult CF patients admitted for APE with %FEV1 &gt; 10% lower than the patient’s baseline. A positive MRSA culture within 90 days before or 21 days after hospital admission and receipt of &gt; 7 days of either vancomycin or ceftaroline was required for inclusion. Patients were excluded for receipt of a lung transplant, &gt; 48 hours of alternative MRSA therapy, renal replacement therapy, or an APE secondary to fungal or mycobacterium infection. The primary outcome was the return to &gt; 90% of baseline lung function measured by discharge %FEV1 in comparison to baseline %FEV1. Results Fifty-six patients were included in the analysis (22 ceftaroline; 34 vancomycin). There were no differences in baseline characteristics (Table 1). Eleven (50%) patients in the ceftaroline group and 19 (56%) in the vancomycin group met the primary outcome (P = 0.79) (Figure 1A). FEV1 measurements at baseline, admission, and discharge were not different between treatments (Figure 1B). Patients treated with ceftaroline had a longer length of stay during hospital admission, 14 days (IQR 13-14) vs.10 days (IQR 7-14), P = 0.01. Other secondary outcomes were similar between the ceftaroline and vancomycin groups, respectfully, including 30-day readmission rate, 6 (27%) vs. 12 (35%), P = 0.57; 30-day mortality, 0 (0%) vs. 2 (6%), P = 0.51; neutropenia 3 (12%) vs. 1 (3%), P = 0.29; Clostridioides difficile infection 0 (0%) vs. 1 (3%), P = &gt;0.99; or acute kidney injury 2 (9%) vs. 5 (15%), P = 0.69. Table 1. Baseline characteristics for ceftaroline and vancomycin treated patients 1Lumacaftor/ivacaftor, tezacaftor/ivacaftor; 2Piperacillin/tazobactam, aminoglycoside, furosemide, contrast dye, lisinopril, NSAIDs, colistin, phenylephrine; 3Methimazole, sulfasalazine, trimethoprim/sulfamethoxazole; 4Albuterol, hypertonic saline, dornase alpha, azithromycin, ibuprofen, inhaled aminoglycoside, inhaled colistin, corticosteroid; 5Azithromycin, aminoglycoside, fluroquinolone, cephalosporin, carbapenem, piperacillin/tazobactam. Data represents n (%) unless noted. CFTR=cystic fibrosis transmembrane conductance regulator. Figure 1. %FEV1 trend from baseline to discharge in patients treated with ceftaroline or vancomycin (A) Percentage (%) of patients who met the primary outcome in each group; (B) Mean %FEV1 change between ceftaroline (square) and vancomycin (circle) with error bars representing standard deviations Conclusion This study found no difference in safety and efficacy outcomes between vancomycin and ceftaroline. Our small cohort supports ceftaroline as an alternative agent for the treatment of MRSA mediated APE of CF. Disclosures All Authors: No reported disclosures

1304. Antimicrobial Management of Stenotrophomonas maltophilia Pneumonia: Does TMP-SMX Dose Affect Treatment Failure?

Background Limited literature exists to guide the appropriate antimicrobial choice, dose, and duration for Stenotrophomonas maltophilia (S. maltophilia) pneumonia. Methods This multi-center, retrospective cohort study was conducted in adults diagnosed with S. maltophilia pneumonia in eight hospitals between March 1, 2014 and August 31, 2020. Patients were enrolled into one of two arms: those treated with TMP-SMX and those treated with alternative antibiotics. The primary outcome was a composite of treatment failure, defined as the need for alternative antibiotics with in vitro activity against S. maltophilia, isolation of S. maltophilia on repeat cultures drawn greater than 72 hours from the index culture, or in-hospital mortality. Other clinical outcomes that were accessed include the TMP-SMX dosing regimen, and 30- and 90-day mortality rates. This study was approved by the local Institutional Review Board (IRB). Results Overall, 213 patients were included; 100 (46.9%) received TMP-SMX, and 113 (53.0%) received alternative therapy. Though there was no difference in treatment failure between the two groups, more patients in the “alternative” antibiotic group required mechanical ventilation (57% vs. 31%, respectively; p &lt; 0.001) (Table 1). 74% of patients who received TMP-SMX received a “low-dose” regimen, characterized by &lt; 10 mg/kg/day. When evaluating treatment failure based on “high” or “low-dose” TMP-SMX, there was no difference in treatment failure. However, we noted that physicians were more likely to utilize an alternative agent in addition to TMP-SMX (p=0.001) compared to an alternative agent. When removing this confounder from the composite endpoint, high-dose TMP-SMX was associated with significantly less treatment failure compared to low dose 23% vs. 49%, respectively (p=0.023). The average TMP-SMX dose of patients in the “low-dose” group was 5 + 2.2 mg/kg/day vs. 13.9 + 3.5 mg/kg/day in the “high-dose group. Moreover, when serum creatinine was evaluated at baseline, day 3, day 5, and day 7, no increase was seen in patients who received high dose TMP-SMX (Table 1). Table 1: Clinical Outcomes Conclusion These preliminary results suggest that appropriate dosing of TMP-SMX may be more important for clinical success in patients with S. maltophilia pneumonia than the choice of agent. Disclosures All Authors: No reported disclosures

Supratherapeutic Posaconazole Concentration in a Pediatric Transplant Patient With Confirmed Rhizopus Infection

There are a limited number of studies that guide dosing of posaconazole delayed-release (DR) tablets for the pediatric population. Current FDA-approved doses are only recommended for patients 13 years and older. For younger patients, providers are faced with the challenge of recommending posaconazole doses extrapolated from adult studies or choosing an alternative agent. We report on a case of a 10-year-old patient who experienced a supratherapeutic trough serum concentration and transaminitis after receiving the extrapolated adult dosage of posaconazole DR tablets (300 mg twice daily for the first day, followed by 300 mg daily) for 7 days. In the end, the patient required a smaller dose of 200 mg daily to achieve the desired trough target concentration for the treatment of a Rhizopus neck infection. Our findings highlight the need for additional studies to determine the optimal dosing of posaconazole DR tablets for children.

Drug-Induced QTc Prolongation: What We Know and Where We Are Going

: Drug-induced QTc prolongation is a concerning electrocardiogram (ECG) abnormality. This cardiac disturbance carries a 10% risk of sudden cardiac death due to the malignant arrhythmia, Torsades de Pointes. The Arizona Center for Education and Research on Therapeutics (AzCERT) has classified QTc prolonging therapeutic classes such as antiarrhythmics, antipsychotics, anti-infectives, and others. AzCERT criteria categorizes medications into three risk categories: “known,” “possible,” and “conditional risk” of QTc prolongation and Torsades de Pointes. The list of QTc prolonging medications continues to expand as new drug classes are approved and studied. Risk factors for QTc prolongation can be delineated into modifiable or non-modifiable. A validated risk scoring tool may be utilized to predict the likelihood of prolongation in patients receiving AzCERT classified medication. The resultant risk score may be applied to a clinical decision support system which offers mitigation strategies. Mitigation strategies including discontinuation of possible offending agents with selection of an alternative agent, assessment of potential drug interactions or dose adjustments through pharmacokinetic and pharmacodynamic monitoring, and initiation of both ECG and electrolyte monitoring are essential to prevent a drug-induced arrhythmia. The challenges presented by the COVID-19 pandemic have led to the development of innovative continuous monitoring technology, increasing protection for both patients and healthcare workers. Early intervention strategies may reduce adverse events and improve clinical outcomes in patients identified to be at risk of QTc prolongation.

Tomatidine Suppresses the Destructive Behaviors of Fibroblast-Like Synoviocytes and Ameliorates Type II Collagen-Induced Arthritis in Rats

Fibroblast-like synoviocytes (FLSs) are the prominent non-immune cells in synovium and play a pivotal role in rheumatoid arthritis (RA) pathogenesis. Searching for natural compounds that may suppress the pathological phenotypes of FLSs is important for the development of RA treatment. Tomatidine (Td), a steroidal alkaloid derived from the solanaceae family, has been reported to have anti-inflammatory, anti-tumor and immunomodulatory effects. However, its effect on RA remains unknown. Here, we examined the inhibitory effect of Td on TNFα-induced arthritic FLSs, and subsequently investigated its therapeutic effect on collagen-induced arthritis (CIA) rats. Our results revealed that Td significantly inhibited TNFα-induced proliferation and migration of arthritic FLSs. In addition, we found that Td treatment could efficaciously ameliorate synovial inflammation and joint destruction of rats with CIA. Both in vitro and in vivo studies showed that Td significantly suppressed the production of pro-inflammatory cytokines including IL-1β, IL-6 and TNFα, and downregulated the expression of MMP-9 and RANKL. Further molecular mechanism studies revealed that the inhibitory effect of Td on RA might attribute to the decreased activations of MAPKs (ERK and JNK) and NF-κB. These findings provide evidence that Td has the potential to be developed into a complementary or alternative agent for RA therapy.

Effect of dexmedetomidine on heart rate in neonates with hypoxic ischemic encephalopathy undergoing therapeutic hypothermia

BACKGROUND: Sedation is recommended to optimize neuroprotection in neonates with hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Dexmedetomidine is an alternative agent to opioids, which are commonly used but have adverse effects. Both TH and dexmedetomidine can cause bradycardia. In this study, we describe our experience with dexmedetomidine and fentanyl in neonates undergoing TH for HIE, with a focus on heart rate (HR). METHODS: We performed a retrospective chart review from 2011–2019 at a level IV NICU comparing sedation with dexmedetomidine (n = 14), fentanyl (n = 120), or both (n = 32) during TH for HIE. HR trends were compared based on sedation and gestational age. Neonates were included if they underwent TH and received sedation and were excluded if cooling was initiated past 24 hours(h) of life or required ECMO. RESULTS: Of the 166 neonates included, 46 received dexmedetomidine, 14 as monotherapy and 32 in combination with fentanyl. Mean hourly HR from 12–36 h after birth was significantly lower for infants on dexmedetomidine versus fentanyl monotherapy (91±9 vs. 103±11 bpm, p < 0.002). Dexmedetomidine was decreased or discontinued in 22 (47.8%) neonates, most commonly due to inadequate sedation with a low HR. Lower gestational age was associated with higher HR but no significant difference in dexmedetomidine-related HR trends. CONCLUSIONS: Despite an association with lower HR, dexmedetomidine may be successfully used in neonates with HIE undergoing TH. Implementation of a standardized protocol may facilitate dexmedetomidine titration in this population.

Neuroprotective Potential of Limonene and Limonene Containing Natural Products

Limonene is a monoterpene confined to the family of Rutaceae, showing several biological properties such as antioxidant, anti-inflammatory, anticancer, antinociceptive and gastroprotective characteristics. Recently, there is notable interest in investigating the pharmacological effects of limonene in various chronic diseases due to its mitigating effect on oxidative stress and inflammation and regulating apoptotic cell death. There are several available studies demonstrating the neuroprotective role of limonene in neurodegenerative diseases, including Alzheimer’s disease, multiple sclerosis, epilepsy, anxiety, and stroke. The high abundance of limonene in nature, its safety profile, and various mechanisms of action make this monoterpene a favorable molecule to be developed as a nutraceutical for preventive purposes and as an alternative agent or adjuvant to modern therapeutic drugs in curbing the onset and progression of neurodegenerative diseases. This manuscript presents a comprehensive review of the available scientific literature discussing the pharmacological activities of limonene or plant products containing limonene which attribute to the protective and therapeutic ability in neurodegenerative disorders. This review has been compiled based on the existing published articles confined to limonene or limonene-containing natural products investigated for their neurotherapeutic or neuroprotective potential. All the articles available in English or the abstract in English were extracted from different databases that offer an access to diverse journals. These databases are PubMed, Scopus, Google Scholar, and Science Direct. Collectively, this review emphasizes the neuroprotective potential of limonene against neurodegenerative and other neuroinflammatory diseases. The available data are indicative of the nutritional use of products containing limonene and the pharmacological actions and mechanisms of limonene and may direct future preclinical and clinical studies for the development of limonene as an alternative or complementary phytomedicine. The pharmacophore can also provide a blueprint for further drug discovery using numerous drug discovery tools.

Carvacrol: A Promising Environmentally Friendly Agent to Fight Seeds Damping-Off Diseases Induced by Fungal Species

Background: Gramineae damping-off disease is a growing problem worldwide, which affects a large range of seedlings in nurseries, glasshouses, gardens, crops, forests and untimely generates a heavy economic impact on the agriculture and related sectors. Objectives: The present study was conducted to evaluate the preventive potential of carvacrol on germination of Fusarium oxysporum, Neocosmospora solani, and Microdochium nivale spores as responsible agents for Lolium perenne seeds damping-off disease. Material and methods: Macrodilution method in agar medium, spore germination, spore destruction, and preventive treatment bioassays were used to achieve this goal. Results: The minimum inhibitory concentration (MIC) of carvacrol vs. tested strains existed in the range of 0.25–0.5 mg/mL. Carvacrol used in concentrations ranging from 0.2 to 0.4 mg/mL inhibited the germination of all fungal spores in a dose-dependent manner. Carvacrol showed a very strong sporicidal effect against all studied fungal strains, and this effect was well confirmed by microscopic observations. The percentage of growth inhibition was found to be strictly correlated to carvacrol dose up vs. all strains. Carvacrol increased the emergence of L. perenne seeds when compared to both uninfested and infested seeds. Conclusion: Based on the results obtained, carvacrol fulfills the requirement for being a natural alternative agent to fight Gramineae seedlings’ damping-off caused by fungal species without adverse effects on the plants.