Clinical Pharmacokinetics and Pharmacodynamics of Dalbavancin.

Dalbavancin is a synthetic lipoglycopeptide that exerts its antimicrobial activity through two distinct modes of action, inhibition of cell wall synthesis and an anchoring mechanism. Compared with previous glycopeptide antibiotics, dalbavancin demonstrates improved antibacterial potency against Gram-positive organisms and a long half-life of approximately 1 week, which is longer in tissues (e.g., skin, bone) than plasma. These factors facilitated the development of single-dose or once-weekly dosing regimens to treat acute bacterial skin and skin structure infections (ABSSSI). Dalbavancin exhibits dose-proportional pharmacokinetics and is highly protein bound (93%). Despite being highly protein bound, it has a steady-state volume of distribution >10 L and distributes widely into the skin, bone, peritoneal space, and epithelial lining fluid, but not cerebrospinal fluid. Dalbavancin elimination occurs via a combination of renal (approximately 45%) and non-renal clearance, with dose adjustments recommended only in patients with a creatinine clearance <30 mL/min not receiving any form of dialysis. The established pharmacokinetic/pharmacodynamic index associated with bacterial kill is free area under the concentration-time curve over the minimum inhibitory concentration (fAUC/MIC), with a goal 24-h fAUC/MIC of at least 27.1 for Staphylococcus aureus infections. Recent data suggest usefulness in the treatment of infections beyond ABSSSI, with convenient dosing and redosing strategies for complicated infections requiring extended treatment durations. Additional studies are needed to confirm these preliminary findings.

A Severe Case of Diabetic Ketoacidosis and New-Onset Type 1 Diabetes Mellitus Associated with Anti-Glutamic Acid Decarboxylase Antibodies Following Immunotherapy with Pembrolizumab.

BACKGROUND Immune checkpoint inhibitors (ICIs) are a novel class of antibodies, which have been increasingly utilized in cancer immunotherapies. Pembrolizumab is a humanized IgG4 monoclonal antibody, which acts against programmed cell death (PD)-1 receptors to help restore the body's T-cell and immune response. CASE REPORT In this case, we present a 51-year-old woman with a past medical history of lung adenocarcinoma and triple-positive breast cancer who was actively receiving therapy with pembrolizumab. Following her second chemotherapy cycle, she developed a severe case of diabetic ketoacidosis (DKA), with concern for new-onset autoimmune type 1 diabetes mellitus (T1DM), secondary to her recent ICI therapy. The patient was initiated on a high-dose insulin infusion for rapid glycemic control and was successfully transitioned to a subcutaneous regimen approximately 24 h after presentation. She additionally developed other autoimmune-related complications, including hepatoxicity, duodenitis, and a maculopapular rash, which all resolved upon discontinuation of the ICI treatment. Her laboratory test results were consistent with positive anti-glutamic acid decarboxylase (anti-GAD) antibodies and undetectable c-peptides, illustrating the uniqueness of an ICI potentially precipitating an autoimmune T1DM. CONCLUSIONS Immune-related adverse events from ICI therapy warrant further investigation to acknowledge the risk of potentially life-threatening adverse reactions, such as the development of DKA. Patients receiving ICI therapy should be educated on signs and symptoms of hyperglycemia, and routine measurements of blood glucose levels should be completed during each chemotherapy cycle. Future research in assessing potential biomarkers of beta cell dysfunction, such as anti-GAD antibodies and c-peptides, is of interest, particularly for patients receiving ICI therapies.

Ribavirin and cellular ribavirin-triphosphate concentrations in blood and bronchoalveolar lavage fluid in two lung transplant patients with respiratory syncytial virus.

Respiratory syncytial virus (RSV) is responsible for significant morbidity and mortality in the lung transplant population. Oral and aerosolized ribavirin may improve outcomes in lung transplant patients with RSV; however, data relating ribavirin concentrations in plasma and intracellular ribavirin triphosphate (iRTP) concentrations in blood and bronchoalveolar lavage (BAL) fluid cells with efficacy and safety are lacking. We describe ribavirin and iRTP concentrations within various compartments in two adult lung transplant recipients with RSV who were sampled throughout successful treatment courses with oral and inhaled ribavirin. In patient 1, iRTP BAL concentrations decreased by 45% over 3 days after changing inhaled ribavirin to oral (6.32 to 3.43 pmol/106 cells). In patient 2, iRTP BAL concentrations were 103 pmol/106 cells after 5 days of oral followed by 5 days of inhaled ribavirin. Further study is needed to describe ribavirin pharmacokinetics in the respiratory compartment to inform clinical use of ribavirin for respiratory viruses.

Hydroxocobalamin Versus Methylene Blue for Vasoplegic Syndrome in Cardiothoracic Surgery: A Retrospective Cohort.

OBJECTIVE: To compare methylene blue with hydroxocobalamin as a rescue therapy for vasoplegic syndrome. DESIGN: Retrospective cohort. SETTING: Academic medical center. PARTICIPANTS: Patients undergoing cardiothoracic surgery treated for vasoplegic syndrome. INTERVENTIONS: Thirty-five patients were treated with methylene blue (n = 16) or hydroxocobalamin (n = 19). MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure, systemic vascular resistance, and vasopressor exposures were recorded before and after medication administration. Change in time-averaged norepinephrine equivalents in the hour after administration was the primary outcome. The average norepinephrine equivalent observed at baseline in this cohort was 0.347 µg/kg/min. Methylene blue patients had greater Acute Physiological Assessment and Chronic Health Evaluation II scores (29.8 v 22.2; p = 0.01) and trended toward greater European System for Cardiac Operative Risk Evaluation II values (26.8% v 15.1%; p = 0.07). Methylene blue and hydroxocobalamin were associated with increased mean arterial pressure and systemic vascular resistance 1 hour after administration (10.6 mmHg and 192 dyn*sec/cm5; p = 0.01 and p = 0.01, respectively; 11.8 mmHg and 254 dyn*sec/cm5; p = 0.002 and p = 0.015, respectively). Hemodynamic changes were not different between the rescue therapy groups (p = 0.79 and p = 0.53, respectively). No significant differences were observed within the 1-hour change in time-averaged norepinephrine equivalents for either agent or when methylene blue and hydroxocobalamin were compared (0.012 ± 0.218 µg/kg/min v -0.037 ± 0.027 µg/kg/min; p = 0.46, respectively). When compared with baseline time-averaged norepinephrine equivalent (0.326 ± 0.106 µg/kg/min), only hydroxocobalamin was associated with decreased vasopressor requirements at the 1-hour (0.255 ± 0.129 µg/kg/min; p = 0.03) and 4-hour time points (0.247 ± 0.180 µg/kg/min; p = 0.04) post-administration. CONCLUSION: Methylene blue and hydroxocobalamin increased mean arterial pressures and systemic vascular resistance without significantly decreasing time-averaged norepinephrine exposure in the hour after administration.

Oral Vancomycin Prophylaxis as Secondary Prevention Against Clostridioides difficile Infection in the Hematopoietic Stem Cell Transplantation and Hematologic Malignancy Population.

Clostridioides difficile infection (CDI) is a common complication in the hematopoietic stem cell transplantation (HSCT) and hematologic malignancy (HM) population. CDI is associated with increased hospital length of stay, health care and societal costs, morbidity, and mortality. Identifying strategies for secondary prevention of CDI is of extreme importance in the HSCT/HM population. In this study, our primary objective was to evaluate the effectiveness and safety of an oral vancomycin prophylaxis (OVP) protocol for secondary prevention of CDI in a retrospective cohort of adult autologous/allogeneic HSCT recipients and patients with HM who did not undergo HSCT with a first CDI episode treated with concomitant broad-spectrum antibiotics (BSA). Patients were diagnosed and treated for CDI as inpatients and/or outpatients and were divided into 2 groups based on a preprotocol versus postprotocol analysis: the OVP group, comprising patients who received planned monotherapy with oral vancomycin 125 mg every 6 hours for 14 days for a first episode of CDI and subsequently received OVP posttreatment and a no OVP (NOVP) group, comprising patients who received planned monotherapy with oral vancomycin 125 mg every 6 hours for 14 days for a first episode of CDI and subsequently did not receive OVP posttreatment. OVP was defined as vancomycin 125 mg every 12 hours for up to 7 days after BSA discontinuation. The primary endpoint was recurrent CDI (rCDI), defined as symptoms of loose stools/diarrhea with high clinical suspicion for CDI prompting empiric therapy within 60 days of completion of treatment/prophylaxis for the first CDI episode. The incidence of vancomycin-resistant enterococcal (VRE) infection and 60-day mortality were also compared between the 2 groups. Multivariate logistic regression was created from associated variables to identify independent associations with rCDI. A total of 50 patients were included, 21 in the OVP group (42%) and 29 in the NOVP group (58%). The mean patient age was 58 years, and the cohort was 60% male and 86% Caucasian. HSCT was performed in 60% of the patients, and 76% of CDI cases were diagnosed during hospitalization. The rate of rCDI was significantly lower in the OVP group compared with the NOVP group (5% [1 of 21] versus 35% [10 of 29]; P= .016), with no subsequent increase in VRE infection rate (14% [3 of 21] versus 10% [3 of 29]; P = .686). By multivariable logistic regression, rCDI was inversely associated with OVP (odds ratio [OR], .14; 95% confidence interval [CI], .007 to .994; P = .049) and directly associated with outpatient CDI diagnosis (OR, 8.72; 95% CI, 1.816 to 49.158; P = .007). No between-group differences were found in 60-day mortality (10% [2 of 21] for OVP versus 7% [2 of 29] for NOVP; P > 0.999). OVP appears to be safe and effective for secondary prevention of CDI in the HSCT/HM population. Prospective trials are needed to validate the effectiveness of OVP in this vulnerable population to prevent rCDI.

Early administration of infliximab for severe ipilimumab-related diarrhea in a critically ill patient.

OBJECTIVE: To report a case of ipilimumab-associated life-threatening diarrhea responding quickly to a single dose of infliximab. CASE SUMMARY: A 67-year-old man presented 3 weeks after his second dose of ipilimumab with severe diarrhea, acute kidney injury, and hypotension. After 2 days of high-dose corticosteroids and supportive care, he continued to have 2.8 L of stool output per day (grade 4 National Cancer Institute Common Terminology Criteria for Adverse Events). The patient was transferred to the medical intensive care unit requiring endotracheal intubation because of concerns of worsening mental status, metabolic acidosis, and increased work of breathing, with a serum bicarbonate concentration of <5 mmol/L. Despite aggressive fluid resuscitation and a sodium bicarbonate infusion, he remained hypotensive and hyponatremic with persistent premature ventricular contractions. On the evening of day 3, infliximab (5 mg/kg) was given, resulting in a rapid decrease in diarrhea. After 48 hours, the acidosis was corrected and electrolytes, renal function, and fluid status were improving. At discharge, diarrhea, acute kidney injury, and acidosis had resolved, and he was discharged on a slow steroid taper. DISCUSSION: Autoimmune colitis is a described immune-related adverse event of ipilimumab. Prompt recognition, initiation of steroids, and supportive therapy are key to the management of diarrhea. Infliximab should be considered early in steroid-nonresponsive or life-threatening diarrhea. CONCLUSION: Infliximab is a life-saving intervention in patients with ipilimumab-induced diarrhea.

Xanthine oxidase inhibition attenuates endothelial dysfunction caused by chronic intermittent hypoxia in rats.

BACKGROUND: Xanthine oxidase is a major source of superoxide in the vascular endothelium. Previous work in humans demonstrated improved conduit artery function following xanthine oxidase inhibition in patients with obstructive sleep apnea. OBJECTIVES: To determine whether impairments in endothelium-dependent vasodilation produced by exposure to chronic intermittent hypoxia are prevented by in vivo treatment with allopurinol, a xanthine oxidase inhibitor. METHODS: Sprague-Dawley rats received allopurinol (65 mg/kg/day) or vehicle via oral gavage. Half of each group was exposed to intermittent hypoxia (FIO(2) = 0.10 for 1 min, 15×/h, 12 h/day) and the other half to normoxia. After 14 days, gracilis arteries were isolated, cannulated with micropipettes, and perfused and superfused with physiological salt solution. Diameters were measured before and after exposure to acetylcholine (10(-6)M) and nitroprusside (10(-4)M). RESULTS: In vehicle-treated rats, intermittent hypoxia impaired acetylcholine-induced vasodilation compared to normoxia (+4 ± 4 vs. +21 ± 6 µm, p = 0.01). Allopurinol attenuated this impairment (+26 ± 6 vs. +34 ± 9 µm for intermittent hypoxia and normoxia groups treated with allopurinol, p = 0.55). In contrast, nitroprusside-induced vasodilation was similar in all rats (p = 0.43). Neither allopurinol nor intermittent hypoxia affected vessel morphometry or systemic markers of oxidative stress. Urinary uric acid concentrations were reduced in allopurinol- versus vehicle-treated rats (p = 0.02). CONCLUSIONS: These data confirm previous findings that exposure to intermittent hypoxia impairs endothelium-dependent vasodilation in skeletal muscle resistance arteries and extend them by demonstrating that this impairment can be prevented with allopurinol. Thus, xanthine oxidase appears to play a key role in mediating intermittent hypoxia-induced vascular dysfunction.

Neuromuscular blockade resistance during therapeutic hypothermia.

OBJECTIVE: To report a case of neuromuscular blockade resistance to multiple agents during therapeutic hypothermia and discuss possible mechanisms of this resistance. CASE SUMMARY: A 64-year-old man with stage IV non-small-cell lung cancer and respiratory distress developed cardiac arrest in the emergency department. The man was quickly resuscitated and treated with therapeutic hypothermia. A chest tube was inserted for pleural drainage of a large right-sided effusion that collapsed the right lung; this was unsuccessful in reinflating the lung. A bronchopleural fistula developed and independent lung ventilation was initiated due to persistent hypoxemia. Neuromuscular blockade was initiated after sedation and analgesia did not control shivering and was continued due to patient-ventilator dyssynchrony and persistent hypoxemia. Despite large doses of 3 different neuromuscular blocking agents and negligible response to train-of-four tests, clinical neuromuscular blockade, represented by ventilator synchrony, was not achieved until the patient was warmed. DISCUSSION: Resistance to neuromuscular blocking agents has been reported in critically ill patients. Our case of neuromuscular blockade resistance occurred in a patient treated with therapeutic hypothermia, which generally requires a dose reduction of neuromuscular blocking agents. Resistance to neuromuscular blockade was quickly reversed upon warming of the patient as patient-ventilator synchrony was achieved at lower neuromuscular blocking agent doses. CONCLUSIONS: Clinicians should be aware of a potential blunted response to neuromuscular blocking agents during therapeutic hypothermia and difficulty with paralysis monitoring since train-of-four response may correlate poorly with clinical neuromuscular blockade during hypothermia. Further research is needed to elucidate the mechanism of this interaction, identify patients at risk, and evaluate alternative strategies to neuromuscular blockade for controlling shivering in patients undergoing therapeutic hypothermia.