Evaluation of Sequential Oral Versus Intravenous Antibiotic Treatment of Enterococcus faecalis Bloodstream Infections.

BACKGROUND: Intravenous (IV) antibiotics have historically been considered standard of care for treatment of bloodstream infections (BSIs). Recent literature has shown sequential oral (PO) therapy to be noninferior to IV antibiotics for certain pathogens and disease states. However, a gap exists in the literature for BSI caused by Enterococcus faecalis. OBJECTIVE: To compare outcomes of definitive sequential PO therapy to definitive IV therapy in patients with E faecalis BSI. METHODS: Multicenter, retrospective, matched cohort study of adult patients with at least one blood culture positive for E faecalis from January 2017 to November 2022. Patients with polymicrobial BSI, concomitant infections requiring prolonged IV antibiotic therapy, those who did not receive antibiotic therapy, and those who died within 72 hours of index culture were excluded. Subjects were matched based on source of infection in a 2:1 (IV:PO) ratio. The primary outcome was a composite of all-cause mortality and treatment failure. Secondary outcomes included hospital length of stay (LOS), antibiotic duration, and 30-day readmission rate. RESULTS: Of the 186 patients who met criteria for inclusion, there was no statistically significant difference in the primary composite outcome for PO compared to IV therapy (14.5% vs 21.8%; OR 0.53 [0.23-1.25]) or 30-day readmission (17.5% vs 29%; OR 0.53 [0.25-1.13]). Hospital LOS was significantly longer in patients receiving IV-only therapy (6 days vs 14 days; P < 0.001). CONCLUSION AND RELEVANCE: Sequential oral therapy for E faecalis BSI had similar outcomes compared to IV-only treatment and may be considered in eligible patients.

Ascorbic Acid for Methemoglobinemia Treatment: A Case Report and Literature Review.

PURPOSE: Ascorbic acid has been proposed as an alternative treatment for methemoglobinemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, its efficacy has never been compared to that of methylene blue given the inability of patients with G6PD deficiency to receive methylene blue. We present a case of methemoglobinemia treated with ascorbic acid in a patient without G6PD deficiency who had previously received methylene blue. SUMMARY: A 66-year-old male was treated for methemoglobinemia deemed to be secondary to benzocaine throat spray. He received intravenous (IV) methylene blue but had a severe reaction: diaphoresis, lightheadedness, and hypotension. The infusion was stopped prior to completion. Approximately 6 days later he presented with methemoglobinemia following an additional overconsumption of benzocaine and was treated with ascorbic acid. In both instances his methemoglobin levels were >30% on arterial blood gas on admission and decreased to 6.5% and 7.8%, respectively, after administration of methylene blue and ascorbic acid. CONCLUSION: Ascorbic acid had a similar effect on decreasing the concentration of methemoglobin compared to methylene blue. Further research into use of ascorbic acid as a recommended agent for treatment of methemoglobinemia is warranted.

EPR Spectroscopy as a Method for ROS Quantification in the Skin.

Electron paramagnetic resonance (EPR) spectroscopy is an established method for the measurement of free radicals. Solar radiation is essential for human life as it stimulates vitamin D synthesis and well-being. However, an excessive dose of solar radiation leads to the formation of free radicals. Here, we describe an EPR method for measuring the amount of radicals induced by UVA irradiation in excised skin. For the first time, a wavelength stable UVA LED (365 nm) was used. The method allows the quantitative determination of radicals in skin before, during, and after UVA irradiation. A dose-dependent radical production could be demonstrated, independent of the yielded power.

Kinetics of the carotenoid concentration degradation of smoothies and their influence on the antioxidant status of the human skin in vivo during 8 weeks of daily consumption.

The antioxidant status of the skin shows constant alterations depending on nutrition and other lifestyle factors. Carotenoids can serve as marker substances for the antioxidant status of the epidermis in vivo. The carotenoid concentration of 2 homemade green smoothies and a commercial green smoothie, all containing fruits and vegetables, was assessed by resonance Raman spectroscopy. Furthermore, a pilot study was conducted to investigate changes of the cutaneous carotenoid concentration of 20 healthy volunteers under the daily intake of either a homemade smoothie or the commercial smoothie in vivo using reflectance spectroscopy. We hypothesized that higher carotenoid concentrations in the homemade smoothies compared to those of the commercial one would lead to a faster increase of the cutaneous carotenoid concentration in healthy volunteers. The measurements of the homemade smoothies showed notably higher initial carotenoid concentrations (7.6 ±0.8)*10-4arbitrary units (a.u.) (smoothie A) and (10.4 ± 0.6)*10-4 a.u. (smoothie B) compared to the commercial smoothie (5.8 ± 0.2)*10-4 a.u. Nevertheless, the commercial smoothie showed a higher stability of carotenoids over 24 hours. 8 weeks after daily consumption of the homemade smoothies, volunteers showed an insignificant increase of cutaneous carotenoids from (4.5 ± 0.1)*10-4 a.u. at baseline to (4.8 ± 0.3)*10-4 a.u. (means ± standard error of the mean). The volunteers consuming the commercial smoothie showed an insignificant increase of cutaneous carotenoids from (4.3 ± 0.2)*10-4 a.u. to (4.7 ± 0.2)*10-4 a.u. after 8 weeks. The observed increase of cutaneous carotenoid concentrations could be classified as a strong tendency. Fresh homemade smoothies can exhibit a higher carotenoid concentration compared to commercial smoothies but need to be consumed immediately after preparation.

Practices Involved in the Enteral Delivery of Drugs.

PURPOSE OF REVIEW: While the delivery of medications through enteral tubes is common in critically ill patients, there are complications and a lack of unified practices between institutions. The purpose of this review is to evaluate current practices and literature evidence regarding this administration route. The effect of this administration on the medication's efficacy, safety, tolerability, and pharmacokinetics was examined, as well as other considerations to ensure that this route of delivery is both safe and effective for patients. RECENT FINDINGS: Studies have found crushed oral tablets are the most frequent cause of obstructed feeding tubes. Complications such as this are primarily due to inadequate personnel training and failure to properly access medications before enteral administration. There are many factors that should be considered in order to effectively administer drugs via enteral tubes. Formal training and use of a multi-disciplinary approach that includes pharmacists and dieticians has been shown to reduce tube obstructions and administration errors.

Insight into the redox status of inflammatory skin equivalents as determined by EPR spectroscopy.

Atopic dermatitis (AD) is a chronic inflammatory skin disease whose pathogenesis is still not fully understood. Since inflammatory processes correlate with oxidative stress, the redox status may play a key role in AD. In this study, electron paramagnetic resonance (EPR) spectroscopy was mainly used to investigate the redox status in normal and inflammatory skin equivalents mimicking characteristics of AD in vitro using EPR spin probes (TEMPO, PCA) and a spin trap (DMPO). The total antioxidant status in the hydrophilic and lipophilic compartments of skin (microenvironment) showed no differences between the skin equivalents. In the inflammatory skin equivalents, a decreased glutathione concentration in the epidermis and an increased metabolic radical production could be observed compared to normal skin equivalents. The induction of external stress by simulated solar irradiation (UVB-NIR) resulted in the same amount and type of radicals in normal and inflammatory skin equivalents. For the first time, the antioxidant and oxidant status of inflammatory in vitro skin equivalents was analyzed by EPR to elucidate their redox status using different methods which focus on various microenvironments. Our investigations suggested that the redox status in atopic skin could be different, but this should be investigated more comprehensively, because the results can vary depending on the used methods and where the investigations take place.

pH-sensitive Eudragit® L 100 nanoparticles promote cutaneous penetration and drug release on the skin.

Nanoparticles (NPs) are promising carriers for dermal and transdermal drug delivery. However, the underlying dynamics of drug release from the NPs, especially, how the physiological changes of diseased skin influence the drug release, remain poorly understood. We utilized electron paramagnetic resonance (EPR) and confocal laser scanning microscopy (CLSM) to comprehensively investigate the penetration behavior of a spin-labeled dexamethasone (DxPCA)-loaded pH-sensitive Eudragit® L 100 NP on intact and barrier-disrupted skins. The EPR investigation showed that a rapid in vitro DxPCA release from the NPs was triggered above pH 5.9. It also demonstrated that the NPs considerably improved the cutaneous penetration of the model drug in comparison to a commercial cream. Besides, as compared to the intact skin, a faster drug release and a higher drug penetration into the viable skin layers were obtained with barrier-disrupted skin. In accordance, CLSM studies confirmed that the NPs enhanced the penetration of the lipophilic model drug Nile red (NR) across the skin, whose penetration depth into glabrous skin was 160 µm. Moreover, a significant transfollicular penetration of NR from the NPs was observed. In conclusion, the pH-sensitive Eudragit® L 100 NPs improved the cutaneous penetration and controlled the release of a lipophilic drug, especially on barrier-disrupted skin. This may allow targeted drug delivery to lesional skin, avoiding side effects.

Quantification and characterization of radical production in human, animal and 3D skin models during sun irradiation measured by EPR spectroscopy.

Sun radiation is indispensable to our health, however, a long term and high exposure could lead to erythema, premature skin aging and promotion of skin tumors. An underlying pathomechanism is the formation of free radicals. First, reactive oxygen species (*OH, *O2-) and then, secondary lipid oxygen species (C centered radicals, CCR) are formed. A high amount of free radicals results in oxidative stress with subsequent cell damage. In dermatological research different skin models are used, however, comparative data about the cutaneous radical formation are missing. In this study, the radical formation in porcine-, (SKH-1) murine-, human- ex vivo skin and reconstructed human skin (RHS) were investigated during simulated sun irradiation (305-2200 nm), with X-band EPR spectroscopy. The amount of radical formation was investigated with the spin probe PCA exposed to a moderate sun dose below one minimal erythema dose (MED, ~25 mJ/cm2 UVB) in all skin models. Furthermore, the *OH and *CCR radical concentrations were measured with the spin trap DMPO within 0-4 MED (porcine-, human skin and RHS). The highest amount of radicals was found in RHS followed by murine and porcine, and the lowest amount in human ex vivo skin. In all skin models, more *OH than CCR radicals were found at 0-4 MED. Additionally, this work addresses the limitations in the characterization with the spin trap DMPO. The measurements have shown that the most comparable skin model to in vivo human skin could differ depending on the focus of the investigation. If the amount of radial production is regarded, RHS seems to be in a similar range like in vivo human skin. If the investigation is focused on the radical type, porcine skin is most comparable to ex vivo human skin, at an irradiation dose not exceeding 1 MED. Here, no comparison to in vivo human skin is possible.

From UV Protection to Protection in the Whole Spectral Range of the Solar Radiation: New Aspects of Sunscreen Development.

Sunscreens have been constantly improving in the past few years. Today, they provide an efficient protection not only in the UVB but also in the UVA spectral region of the solar radiation. Recently it could be demonstrated that 50% of all free radicals induced in the skin due to solar radiation are formed in the visible and infrared spectral region. The good protective efficacy of sunscreens in the UV region prompts people to stay much longer in the sun than if they had left their skin unprotected. However, as no protection in the visible and infrared spectral region is provided, high amounts of free radicals are induced here that could easily exceed the critical radical concentration. This chapter describes how the effect of sunscreens can be extended to cover also the visible and infrared spectral region of the solar radiation by adding pigments and antioxidants with high radical protection factors to the sunscreen formulations.

Radical-Scavenging Activity of a Sunscreen Enriched by Antioxidants Providing Protection in the Whole Solar Spectral Range.

BACKGROUND/AIM: The main reason for extrinsic skin aging is the negative action of free radicals. The formation of free radicals in the skin has been associated with ultraviolet (UV) exposure and also to visible (VIS) and near-infrared (NIR) irradiations. The aim of the present study was to evaluate the efficacy of a sunscreen in the whole solar range. METHODS: The radical-scavenging activity of a sunscreen in the UV, VIS, and NIR ranges was evaluated using electron paramagnetic resonance spectroscopy. Ex vivo penetration profiles were determined using confocal Raman microscopy on porcine ear skin at different time points after application. RESULTS: Compared to the untreated skin, the sunscreen decreased the skin radical formation in the UV and VIS regions. Additional protection in the VIS and NIR ranges was observed for the sunscreen containing antioxidants (AO). The penetration depth of the cream was less than 11.2 ± 3.0 µm for all time points. CONCLUSION: A sunscreen containing AO improved the photoprotection in the VIS and NIR ranges. The sunscreen was retained in the stratum corneum. Therefore, these results show the possibility of the development of effective and safer sunscreen products.

Effects on detection of radical formation in skin due to solar irradiation measured by EPR spectroscopy.

In various research projects, oxidative stress in irradiated skin was investigated by measuring the production of free radical using EPR spectroscopy. However, comparison of the obtained measuring results proved to be difficult as different preparation parameters were used for those measurements. In the present study the influence of the preparation parameters on the detected radical production was methodically investigated. For this purpose, porcine skin was exposed in situ to UV and VIS-NIR radiation, respectively, while being measured in an X band EPR spectrometer. Prior to the measurements, the skin had been treated with the spin trap N-tert-Butyl-α-phenylnitrone (PBN) and the spin marker 3-(Carboxyl)-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (PCA). The two methods were investigated for quantitative comparability, for advantages and disadvantages and for errors potentially affecting the evaluation of the results. A significant influence of the preparation parameters (concentration and amount of substance) on the detected radical formations could be found. This influence had a nonlinear effect on the detected radical production. 120µl of incubated amount for 1M PBN and for PCA at a concentration of 0.6 and 1.5mM were determined to be the optimum parameters. The incubated skin samples were 1cm in diameter and 300µm thick. Between 22 and 37°C the incubation temperature showed no significant influence on the detected radical production. For the first time it could be demonstrated for PCA-incubated skin that the radiation-induced radical production depends exclusively on the irradiation dose, provided the preparation parameters and the spectral region are kept constant. In addition, the radical production in the UVB-UVA and VIS-NIR spectral regions was measured in PCA- and PBN-treated excised porcine skin. It was found that PBN and PCA provide comparable results for the relative quantity and kinetics of radical production.

Free radicals induced by sunlight in different spectral regions - in vivo versus ex vivo study.

Sunlight represents an exogenous factor stimulating formation of free radicals which can induce cell damage. To assess the effect of the different spectral solar regions on the development of free radicals in skin, in vivo electron paramagnetic resonance (EPR) investigations with human volunteers and ex vivo studies on excised human and porcine skin were carried out. For all skin probes, the ultraviolet (UV) spectral region stimulates the most intensive radical formation, followed by the visible (VIS) and the near infrared (NIR) regions. A comparison between the different skin models shows that for UV light, the fastest and highest production of free radicals could be detected in vivo, followed by excised porcine and human skin. The same distribution pattern was found for the VIS/NIR spectral regions, whereby the differences in radical formation between in vivo and ex vivo were less pronounced. An analysis of lipid composition in vivo before and after exposure to UV light clearly showed modifications in several skin lipid components; a decrease of ceramide subclass [AP2] and an increase of ceramide subclass [NP2], sodium cholesterol sulphate and squalene (SQ) were detectable. In contrast, VIS/NIR irradiation led to an increase of ceramides [AP2] and SCS, and a decrease of SQ. These results, which are largely comparable for the different skin models investigated in vivo and ex vivo, indicate that radiation exposure in different spectral regions strongly influences radical production in skin and also results in changes in skin lipid composition, which is essential for barrier function.

The calcitonin gene-related peptide receptor antagonist MK-8825 decreases spinal trigeminal activity during nitroglycerin infusion.

BACKGROUND: Calcitonin gene-related peptide (CGRP) and nitric oxide (NO) are regarded as key mediators in migraine and other primary headaches. Migraineurs respond to infusion of nitroglycerin with delayed headaches, and inhibition of CGRP receptors has been shown to be effective in migraine therapy. In animal experiments nitrovasodilators like nitroglycerin induced increases in spinal trigeminal activity, which were reversed after inhibition of CGRP receptors. In the present study we asked if CGRP receptor inhibition can also prevent spinal trigeminal activity induced by nitroglycerin. METHODS: In isoflurane anaesthetised rats extracellular recordings were made from neurons in the spinal trigeminal nucleus with meningeal afferent input. The non-peptide CGRP receptor inhibitor MK-8825 (5 mg/kg) dissolved in acidic saline (pH 3.3) was slowly infused into rats one hour prior to prolonged glyceryl trinitrate (nitroglycerin) infusion (250 µg/kg/h for two hours). RESULTS: After infusion of MK-8825 the activity of spinal trigeminal neurons with meningeal afferent input did not increase under continuous nitroglycerin infusion but decreased two hours later below baseline. In contrast, vehicle infusion followed by nitroglycerin was accompanied by a transient increase in activity. CONCLUSIONS: CGRP receptors may be important in an early phase of nitroglycerin-induced central trigeminal activity. This finding may be relevant for nitroglycerin-induced headaches.

Calcitonin gene-related peptide receptors in rat trigeminal ganglion do not control spinal trigeminal activity.

Calcitonin gene-related peptide (CGRP) is regarded as a key mediator in the generation of primary headaches. CGRP receptor antagonists reduce migraine pain in clinical trials and spinal trigeminal activity in animal experiments. The site of CGRP receptor inhibition causing these effects is debated. Activation and inhibition of CGRP receptors in the trigeminal ganglion may influence the activity of trigeminal afferents and hence of spinal trigeminal neurons. In anesthetized rats extracellular activity was recorded from neurons with meningeal afferent input in the spinal trigeminal nucleus caudalis. Mechanical stimuli were applied at regular intervals to receptive fields located in the exposed cranial dura mater. α-CGRP (10(-5) M), the CGRP receptor antagonist olcegepant (10(-3) M), or vehicle was injected through the infraorbital canal into the trigeminal ganglion. The injection of volumes caused transient discharges, but vehicle, CGRP, or olcegepant injection was not followed by significant changes in ongoing or mechanically evoked activity. In animals pretreated intravenously with the nitric oxide donor glyceryl trinitrate (GTN, 250 µg/kg) the mechanically evoked activity decreased after injection of CGRP and increased after injection of olcegepant. In conclusion, the activity of spinal trigeminal neurons with meningeal afferent input is normally not controlled by CGRP receptor activation or inhibition in the trigeminal ganglion. CGRP receptors in the trigeminal ganglion may influence neuronal activity evoked by mechanical stimulation of meningeal afferents only after pretreatment with GTN. Since it has previously been shown that olcegepant applied to the cranial dura mater is ineffective, trigeminal activity driven by meningeal afferent input is more likely to be controlled by CGRP receptors located centrally to the trigeminal ganglion.

Significantly improved accuracy of diagnosis of early Lyme disease by peptide enzyme-linked immunosorbent assay based on the borreliacidal antibody epitope of Borrelia burgdorferi OspC.

Highly specific borreliacidal antibodies are induced by infection with Borrelia burgdorferi, and the immunodominant response during early Lyme disease is specific for an epitope within the 7 amino acids nearest the C terminus of OspC. We evaluated the ability of an enzyme-linked immunosorbent assay (ELISA) based on a synthetic peptide (OspC7) that matched the region to detect the response and compared the sensitivity during early Lyme disease to that for an FDA-approved Western blot. When the optical density value was adjusted to 98% specificity based on the results from testing normal or uncharacterized sera (n = 236) or sera from patients with blood factors or illnesses that commonly produce antibodies that cross-react with B. burgdorferi antigens (n = 77), 115 (73%) of 157 sera from patients likely to have early Lyme disease were positive for immunoglobulin M (IgM) antibodies and 17 (11%) also had IgG antibodies. In addition, the IgM ELISA reactivities and the titers of antibodies detected by a flow cytometric borreliacidal antibody test correlated closely (r = 0.646). Moreover, the IgM ELISA was significantly more sensitive (P < 0.001) than the Western blot procedure. The findings therefore confirmed that the peptide IgM ELISA detected OspC borreliacidal antibodies and provided strong evidence that the test can eliminate the necessity for confirming early Lyme disease by a supplementary test such as Western blotting.