Dalbavancin Use in Persons Who Use Drugs May Increase Adherence Without Increasing Cost.

Background: Dalbavancin (DAL) may obviate concerns regarding misuse of IV access in persons who use drugs (PWUD) completing treatment for infections in an outpatient setting. However, hesitancy to adopt its use exists due to the cost-prohibitive nature of DAL and perceived issues with insurance reimbursement. Our study looks to determine the financial impact of DAL use in actual, measured cost, and health care utilization, data as well as the effect on treatment completion rates. Methods: This is a retrospective cohort comparing cost information and treatment completion rates of patients who received DAL to a random sample of patients with Staphylococcus aureus bacteremia prior to the institutional availability of DAL. Results: From June 2020 to January 2022, 29 PWUD received DAL. Dalbavancin use resulted in the completion of intended duration in 19 patients (66%) compared with 11 (55%) without DAL. The contribution margin with DAL use was $7180 compared with $6655 without; this was not statistically significant (P = 0.47). Conclusion: Dalbavancin use in PWUD may increase treatment completion, with no statistically significant difference in contribution margins.

Impact of California Statute on Naloxone Availability and Opioid Overdose Rates.

Introduction: Ensuring that people at risk of overdosing on opioids have easy access to naloxone is an essential part of the fight against the opioid crisis. This study evaluates the impact of the 2016 California law (CA AB1535) permitting pharmacies to dispense this life-saving medication without a physician's prescription. Methods: California counties were categorized on the basis of population density (rural, suburban, urban), rate of opioid-related deaths by population density (high, medium, low), and rate of opioid prescriptions by population density (high, medium, low). Ten diverse pharmacies from each category were selected for inclusion. In a brief 1-minute interview conducted between July and August 2021, pharmacists from 146 California pharmacies were surveyed regarding their knowledge of CA AB1535, their practice of dispensing naloxone without a physician's prescription, and whether they normally stock naloxone. Chi-square tests were used to compare responses. Results: Although almost all pharmacies interviewed (94%) were aware of the law and most of them (64%) dispensed naloxone without a physician's prescription, few statistically significant differences were found between surveyed categories. There were no significant relationships between naloxone availability at pharmacies and overdose death rates. Conclusions: Our results suggest that the number of California pharmacies dispensing naloxone without a physician's prescription has continued to increase since the implementation of CA AB1535. However, despite increased access to naloxone at pharmacies, opioid overdose rates have continued to rise since 2016, indicating the need for a multifaceted harm reduction approach.

Safety and Efficacy of Sildenafil for Group 2 Pulmonary Hypertension in Left Heart Failure.

Pulmonary hypertension (PH) is a multifactorial, progressive disease with poor outcomes. Group 2 PH is defined by pulmonary vascular disease with elevated pulmonary capillary wedge pressure including both left-sided obstructive lesions and diastolic heart failure (HF). Sildenafil was historically discouraged in this population as pulmonary vasodilation can lead to pulmonary edema. However, evidence suggests that sildenafil can help to treat the precapillary component of PH. This is a single center, retrospective pilot study of pediatric PH patients with left-sided HF who were treated with sildenafil for ≥ 4 weeks. HF patients without mechanical support (HF group) and HF patients with a left ventricular assist device (HF-VAD) were analyzed. The exploratory analysis described the safety and side effects of the drug. Echocardiographic parameters were compared before and after sildenafil treatment in a paired analysis. The changes in medical therapy during treatment, mechanical support, and mortality was reported; 19/22 patients tolerated sildenafil. Pulmonary edema in two patients resolved upon discontinuation of sildenafil. In the HF group, both the right atrial volume and right ventricular diastolic area decreased, and the tricuspid regurgitation (TR) S/D ratio decreased after therapy (p = 0.02). Across both the groups, four patients weaned off milrinone and seven weaned off inhaled nitric oxide. Of the thirteen HF patients, four received a transplant, and all of the nine HF-VAD patients received a transplant. Sildenafil can be safely used in carefully selected patients with HF and mixed pre/postcapillary PH with judicious titration and inpatient surveillance, with patients showing improvements in echocardiographic parameters.

Assessment of an online calculator's vancomycin dosing and exposure appropriateness in persons who inject drugs with methicillin-resistant Staphylococcus aureus bloodstream infections.

WHAT IS KNOWN AND OBJECTIVE: While the gold standard for calculating AUC involves two steady-state concentrations, online calculators can empirically estimate AUC and other pharmacokinetic (PK) parameters. In patients with potentially altered PK, such as persons who inject drugs (PWID), the reliability of these predictions is unclear. Our objectives were to characterize the PK of vancomycin in PWID with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) and to assess the impact of these PK parameters on dosing regimens when compared to regimens generated by an online calculator. METHODS: This descriptive pilot study included a retrospective chart review of 48 inpatient PWID with MRSA BSI from 30 April 2018 through 31 August 2020. Demographic and clinical data along with vancomycin dosing and serum concentrations were collected. Patient-specific PK parameters were used to calculate the AUC of each empiric regimen compared with the originally predicted AUC. RESULTS AND DISCUSSION: The study population had a median volume of distribution of 0.74 L/kg, clearance of 0.081 L/kg/h, elimination rate constant of 0.110/h and half-life of 6.3 h. The online calculator empirically predicted 6 subtherapeutic and 42 appropriate AUC values with its recommended empiric dosing regimens. Using the actual patient-specific PK parameters, the empiric vancomycin regimens actually resulted in 21 (43.75%) underexposures, 24 (50%) appropriate exposures and 3 (6.25%) overexposures. WHAT IS NEW AND CONCLUSIONS: In PWID, empiric vancomycin dosing strategies suggested by an online calculator frequently resulted in lower-than-predicted vancomycin exposures. These findings suggest that PWID with MRSA BSI may require higher and/or more frequent vancomycin doses than those empirically recommended by the population-based methods of an online calculator.

Clinical failure of dalbavancin for MRSA bacteremia in patient with severe obesity and history of IVDU.

Dalbavancin is a lipoglycopeptide antibiotic used off-label to treat serious gram-positive infections, including infections secondary to methicillin-resistant Staphylococcus aureus (MRSA). Dalbavancin has unique pharmacokinetic parameters and has a role in therapy for treating vulnerable patients, including intravenous drug users, who have challenges complying with typical care plans for serious infections. While there is data indicating successful clinical use of dalbavancin in patients with history of intravenous drug use as well as pharmacokinetic-pharmacodynamic data assessing dalbavancin in obesity, there is a lack of information regarding clinical effects of dalbavancin in patients with extreme obesity, especially in patients with concomitant drug use. This case report describes a 40-year-old morbidly obese female actively using intravenous drugs who developed prolonged MRSA bacteremia without a recognizable focus. Despite partial treatment with dalbavancin, the patient developed osteomyelitis and discitis of the spine with associated epidural phlegmon, likely complications of the MRSA bacteremia.

Pharmacokinetics of flucytosine in a critically ill patient on continuous venovenous hemodiafiltration.

PURPOSE: To describe the pharmacokinetics of flucytosine in a critically ill patient undergoing continuous venovenous hemodiafiltration (CVVHDF) treated for cryptococcal meningitis. SUMMARY: A 20-year-old female weighing 93.4 kg with a body mass index of 34.3 kg/m2 with a past medical history of systemic lupus erythematous with diffuse proliferative lupus nephritis (class IV) was admitted to the hospital after several months of worsening dyspnea, fatigue, myalgia, vomiting, and diarrhea. The patient developed worsening renal function and volume overload requiring CVVHDF on hospital day 7. She was diagnosed with cryptococcal meningitis on hospital day 8, and flucytosine 2,500 mg enterally every 12 hours and liposomal amphotericin B 500 mg intravenously every 24 hours were initiated. Flucytosine serum concentrations were collected on day 4 of therapy, and pharmacokinetics were performed on 2 sequential levels. Pharmacokinetic calculations displayed an elimination rate constant of 0.0338 h-1, a volume of distribution between 0.42 and 0.43 L/kg, a half-life of 20.5 hours, and a total drug clearance between 1.32 and 1.36 L/h while on CVVHDF. The nonsequential levels displayed good correlation, and no further monitoring or dosage adjustment was required. The patient completed therapy, with clinical resolution of her infection, and no toxicities due to flucytosine were noted. CONCLUSION: Flucytosine dosed at 25 mg/kg of actual body weight every 12 hours during CVVHDF conferred therapeutic levels with no appreciable toxicities. Because of its narrow therapeutic index and risk of toxicity, additional pharmacokinetic studies are needed to determine optimal drug dosing of this medication in patients requiring renal replacement therapy.

Intravenous Olanzapine in a Critically Ill Patient: An Evolving Route of Administration.

Purpose: The purpose of the article is to describe the successful use of parenteral olanzapine intravenously (IV) in a critically ill patient with severe agitated delirium. Summary: A 70-year-old man was admitted to the medical intensive care unit requiring plasmapheresis with platelet counts consistently below 20 000/µL secondary to thrombotic thrombocytopenic purpura (TTP). The patient had experienced agitated delirium requiring treatment, which was complicated by electrocardiogram (EKG) findings of a prolonged QTc interval. The antipsychotics the patient was receiving were believed to be responsible and, as such, the team desired an option that would have a lesser chance of worsening QTc (baseline-corrected QT) interval. Olanzapine was chosen and given IV versus the U.S. Food and Drug Administration (FDA)-approved parenteral route of intramuscular (IM) due to concern of bleeding. The patient's delirious state responded to treatment to varying degrees and showed no increase in EKG abnormalities. To our knowledge, there is a paucity of published literature regarding this route of administration. Conclusion: Intramuscular olanzapine used IV may be a safe and effective option for the treatment of acutely agitated, delirious, critically ill patient.

In vitro activity of ampicillin and ceftriaxone against ampicillin-susceptible Enterococcus faecium.

OBJECTIVES: To assess activity of the combination of ceftriaxone and ampicillin against clinical isolates of ampicillin-susceptible Enterococcus faecium. METHODS: Ampicillin-susceptible E. faecium (n = 29) and Enterococcus faecalis (n = 10) collected from locations in the USA and France were used for this analysis. Susceptibility testing was performed by gradient diffusion strip (GDS) and broth microdilution (BMD). Synergy with the combination of ceftriaxone and ampicillin was assessed in all isolates using GDS crossing and double disc diffusion methods. Selected isolates (nine E. faecium and three E. faecalis) were assessed for synergy in time-kill studies using ampicillin alone and in combination with ceftriaxone. RESULTS: In isolates of E. faecium, the median (range) ampicillin MIC by BMD was 0.5 (0.25-4) mg/L and by GDS it was 2 (1-8) mg/L. In E. faecalis, the median (range) ampicillin MIC by BMD was 0.5 (0.5-1) mg/L and by GDS it was 2 (0.75-3) mg/L. A total of 24/29 (82.8%) isolates of E. faecium displayed synergy by GDS and 22/29 (75.9%) by double disc diffusion. Seven of 10 (70%) isolates of E. faecalis displayed synergy by GDS and 4/10 (40%) by double disc diffusion. Time-kill studies found synergy in 3/9 (33.3%) E. faecium and 3/3 (100%) E. faecalis. CONCLUSIONS: In contrast to the demonstrated synergy in time-kill models of ceftriaxone and ampicillin for E. faecalis, this combination does not appear to provide uniform synergy in E. faecium. Antagonism was not observed. Clinical correlation is necessary and caution should be used when considering ampicillin and ceftriaxone for the treatment of infections caused by ampicillin-susceptible E. faecium.

What's new in the treatment of multidrug-resistant gram-negative infections?

Eradicating multi-drug resistant (MDR) organisms has been a major challenge in healthcare settings worldwide. Newly approved drugs and those currently in the pipeline may have a promising solution to this issue. The purposes of this review are to describe the various resistance mechanisms of Gram-negative bacteria and to provide a summary of the current literature available on the newer agents, such as ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, and other emerging agents used for the treatment of MDR Gram-negative infections. Given that MDR organisms confer resistance to treatment by various methods, including enzymatic degradation, efflux pumps, and porin mutation, an understanding of mechanisms of bacterial resistance combined with information on newer antimicrobial agents against MDR Gram-negative bacteria will further assist clinicians in determining the best suitable therapy for the treatment of various complicated infections.

Corneal keratin aggresome (CKAGG) formation and clearance by proteasome activation.

PURPOSE: To understand the mechanism of corneal keratin expression and clearance in corneal epithelium with Limbal Stem Cell Deficiency (LSCD). The hypothesis is that LSCD-induced proteasome dysfunction is a contributing factor to keratin aggregation, causing corneal keratin aggresome (CKAGG) formation. METHOD: LSCD was surgically induced in rabbit corneas. LSCD corneal epithelial cells (D-CEC) were collected to investigate keratin K4 and K13 expression and CKAGG formation. Oral mucosal epithelial cells (OMECS) were isolated and cultured to study K4 and K13 expression. Cultured cells were treated with proteasome inhibitor to induce CKAGG formation. RESULTS: K4 and K13 were strongly expressed in D-CEC, with additional higher molecular weight bands of K4 and K13, suggesting CKAGG formation. Double staining of K4/K13 and ubiquitin showed co-localization of these keratins with ubiquitin in D-CEC. Proteasome inhibition also showed K4/K13 modification and accumulation in cultured OMECS, similar to D-CEC. Proteasome activation was then performed in cultured OMEC. There was no accumulation of keratins, and levels of unmodified keratins were found significantly reduced. CONCLUSION: Results showed an abnormal expression of K4 and K13 after LSCD-induced proteasome dysfunction, which coalesce to form CKAGG in Corneal Epithelial Cells (CEC). We propose that CKAGG formation may be one of the causative factors of morphological alterations in the injured corneal epithelium, and that CKAGG could potentially be cleared by enhancing proteasome activity.

Impact of a Combination Antibiotic Bag on Compliance With Surviving Sepsis Campaign Goals in Emergency Department Patients With Severe Sepsis and Septic Shock.

BACKGROUND: Severe sepsis and septic shock represent common presentations in the emergency department (ED) and have high rates of mortality. Guideline-recommended goals of care have been shown to benefit these patients, but can be difficult to provide. OBJECTIVE: To determine whether the use of a premixed bag consisting of 2 g cefepime and 1 g vancomycin in 1000 mL of normal saline increases the probability of patients receiving Surviving Sepsis Campaign (SSC) recommendations for the initiation of antimicrobials and fluid challenge. METHODS: This was a 6-month retrospective analysis conducted to determine the impact of an intervention on time to antimicrobials and fluid administration in patients with severe sepsis and septic shock. Patients presenting to the ED who received a diagnosis of severe sepsis or septic shock and were administered 2 antibiotics were eligible for inclusion. The primary outcome assessed was compliance with SSC recommendations for antibiotic and fluid goals within 3 hours of ED arrival. RESULTS: A total of 160 patients were included. In the intervention group, 63.8% of patients met the primary outcome compared with 22.5% in the historical group (odds ratio = 2.32; 95% CI = 1.67-3.23). Time to administration of antibiotics was less with the combination antibiotic bag (CAB: median (IQR) = 72 (48-115) minutes; non-CAB: median (IQR) = 135 (102-244) minutes; P ≤ 0.001). CONCLUSION: This intervention significantly increased the proportion of patients provided with SSC goals of care. Such interventions have not been reported previously and could be meaningful in the management of severe sepsis and septic shock.

Seasonal Pacing - Match Importance Affects Activity in Professional Soccer.

This research explores the influence of match importance on player activity in professional soccer. Therefore, we used an observational approach and analyzed 1,211 matches of German Bundesliga and 2nd Bundesliga. The importance measurement employed is based on post season consequences of teams involved in a match. This means, if a match result could potentially influence the final rank, and this rank would lead to different consequences for a team, such as qualification for Champions League opposed to qualification for Europe League, then this match is classified as important; otherwise not. Activity was quantified by TOTAL DISTANCE COVERED, SPRINTS, FAST RUNS, DUELS, FOULS and ATTEMPTS. Running parameters were recorded using a semi-automatic optical tracking system, while technical variables were collected by professional data loggers. Based on our importance classification, low important matches occurred at the beginning of round 29. A two-way ANOVA indicates significantly increased FAST RUNS (+4%, d = 0.3), DUELS (+16%, d = 1.0) and FOULS (+36%, d = 1.2) in important matches compared to low important ones. For FAST RUNS and FOULS, this effect only exists in Bundesliga. A comparison of the two leagues show that TOTAL DISTANCE COVERED (+3%, d = 0.9), SPRINTS (+25%, d = 1.4) and FAST RUNS (+15%, d = 1.4) are higher compared to 2nd Bundesliga, whilst FOULS is less in Bundesliga (-7%, d = 0.3). No difference in player activity was found between matches at the beginning of a season (round 1-6) and at the end of a season (round 29-34). We conclude that match importance influences player activity in German professional soccer. The most reasonable explanation is a conscious or unconscious pacing strategy, motivated by preserving abilities or preventing injury. Since this tendency mainly exists in Bundesliga, this may suggest that more skilled players show a higher awareness for the need of pacing.

Corneal stromal elasticity and viscoelasticity assessed by atomic force microscopy after different cross linking protocols.

The purpose of this study was to evaluate elasticity and viscoelasticity in the anterior and deeper stromal regions of the cornea after cross linking with three different protocols using atomic force microscopy (AFM) through indentation. A total of 40 porcine corneas were used in this study and were divided into 4 groups (10 corneas per group): control (no treatment), Dresden (corneal epithelial debridement, riboflavin pretreatment for 30 min and a 3mw/cm(2) for 30 min UVA irradiation), accelerated (corneal epithelial debridement, riboflavin pretreatment for 30 min and a 30mw/cm(2) for 3 min UVA irradiation), and genipin (corneal epithelial debridement and submersion of anterior surface in a 1% genipin solution for 4 h). Elasticity and viscoelasticity were quantified using AFM through indentation for all corneas, for the anterior stroma and at a depth of 200 µm. For the control, Dresden, accelerated, and genipin groups, respectively, the average Young's modulus for the anterior stromal region was 0.60 ± 0.58 MPa, 1.58 ± 1.04 MPa, 0.86 ± 0.46 MPa, and 1.71 ± 0.51 MPa; the average for the 200 µm stromal depth was 0.08 ± 0.06 MPa, 0.08 ± 0.04 MPa, 0.08 ± 0.04 MPa, and 0.06 ± 0.01 MPa. Corneas crosslinked with the Dresden protocol and genipin were significantly stiffer than controls (p < 0.05) in the anterior region only. For the control, Dresden, Accelerated, and genipin groups, respectively, the average calculated apparent viscosity for the anterior stroma was 88.2 ± 43.7 kPa-s, 8.3 ± 7.1 kPa-s, 8.1 ± 2.3 kPa-s, and 9.5 ± 3.8 kPa-s; the average for the 200 µm stromal depth was 35.0 ± 3.7 kPa-s, 49.6 ± 35.1 kPa-s, 42.4 ± 17.6 kPa-s, and 41.8 ± 37.6 kPa-s. All crosslinking protocols resulted in a decrease in viscosity in the anterior region only (p < 0.05). The effects of cross-linking seem to be limited to the anterior corneal stroma and do not extend to the deeper stromal region. Additionally, the Dresden and genipin protocols seem to produce a stiffer anterior corneal stroma when compared to the accelerated protocol.

Surface quality of human corneal lenticules after SMILE assessed using environmental scanning electron microscopy.

PURPOSE: To assess the cut quality of the anterior and posterior surfaces of intrastromal refractive lenticules removed during small incision lenticule extraction (SMILE). METHODS: The VisuMax femtosecond laser (500 kHz; Carl Zeiss Meditec, Dublin, CA) was used to perform SMILE on 8 eyes of 5 individuals to correct only myopia (no cylinder). The cut energy index was 26 (equivalent to an energy of 130 nJ) with a 2.5 × 2.5 µm spot/track separation. The lenticule diameter was 6.5 mm with a minimum edge thickness of 15 µm and the cap diameter was 7.3 mm with an intended thickness of 120 µm. After laser treatment, the lenticule was loosened with a spatula and removed with forceps. The extracted lenticules were placed in 2% formalin and sent for imaging with an environmental scanning electron microscope. Images of the anterior and posterior surfaces of the lenticules were obtained at multiple magnifications (100×, 250×, and 500×). Surface quality was evaluated by an investigator who specializes in electron microscopy using three criteria: overall surface regularity, percent of surface irregularity, and position of irregular area. RESULTS: Both the anterior and posterior surfaces of the extracted lenticules were smooth and absent of surface irregularities. The cut edges also appeared uniform. Jagged edges were seen in several images, but were clearly caused by the forceps during extraction. CONCLUSIONS: Using the VisuMax laser to perform SMILE produces smooth cuts absent of surface irregularities.

A person based formula for allocating commissioning funds to general practices in England: development of a statistical model.

OBJECTIVES: To develop a formula for allocating resources for commissioning hospital care to all general practices in England based on the health needs of the people registered in each practice DESIGN: Multivariate prospective statistical models were developed in which routinely collected electronic information from 2005-6 and 2006-7 on individuals and the areas in which they lived was used to predict their costs of hospital care in the next year, 2007-8. Data on individuals included all diagnoses recorded at any inpatient admission. Models were developed on a random sample of 5 million people and validated on a second random sample of 5 million people and a third sample of 5 million people drawn from a random sample of practices. SETTING: All general practices in England as of 1 April 2007. All NHS inpatient admissions and outpatient attendances for individuals registered with a general practice on that date. SUBJECTS: All individuals registered with a general practice in England at 1 April 2007. MAIN OUTCOME MEASURES: Power of the statistical models to predict the costs of the individual patient or each practice's registered population for 2007-8 tested with a range of metrics (R(2) reported here). Comparisons of predicted costs in 2007-8 with actual costs incurred in the same year were calculated by individual and by practice. RESULTS: Models including person level information (age, sex, and ICD-10 codes diagnostic recorded) and a range of area level information (such as socioeconomic deprivation and supply of health facilities) were most predictive of costs. After accounting for person level variables, area level variables added little explanatory power. The best models for resource allocation could predict upwards of 77% of the variation in costs at practice level, and about 12% at the person level. With these models, the predicted costs of about a third of practices would exceed or undershoot the actual costs by 10% or more. Smaller practices were more likely to be in these groups. CONCLUSIONS: A model was developed that performed well by international standards, and could be used for allocations to practices for commissioning. The best formulas, however, could predict only about 12% of the variation in next year's costs of most inpatient and outpatient NHS care for each individual. Person-based diagnostic data significantly added to the predictive power of the models.