Case report: Twice-daily tolvaptan dosing regimen in a challenging case of hyponatremia due to SIAD.

Background: Syndrome of inappropriate antidiuresis (SIAD) is one of the most frequent causes of euvolemic hyponatremia (serum sodium levels < 135 mEq/L) and it represents more than 35% of hyponatremia cases in hospitalized patients. It is characterized by an inappropriate vasopressin (AVP)/antidiuretic hormone (ADH) secretion, which occurs independently from effective serum osmolality or circulating volume, leading to water retention via its action on type 2 vasopressin receptor in the distal renal tubules. Corpus callosum agenesis (CCA) is one of the most common congenital brain defects, which can be associated to alterations in serum sodium levels. This report presents a rare case of chronic hyponatremia associated with SIAD in a woman with CCA, whose correction of serum sodium levels only occurred following twice-daily tolvaptan administration. Case presentation: A 30-year-old female was admitted to our hospital for non-acute hyponatremia with dizziness, headache, distal tremors, and concentration deficits. She had profound hyponatremia (Na 121 mmol/L) with measured plasma hypo-osmolality (259 mOsm/Kg) and urinary osmolality greater than 100 mOsm/Kg (517 mOsm/Kg). She presented clinically as normovolemic. After the exclusion of other causes of normovolemic hyponatremia, such as hypothyroidism and adrenal insufficiency, a diagnosis of SIAD was established. We have ruled out paraneoplastic, inflammatory, and infectious causes, as well as ischemic events. Her medical history showed a CCA and frontal teratoma. We administered tolvaptan initially at a low dosage (15 mg once a day) with persistence of hyponatremia. Therefore, the dosage was first doubled (30 mg once a day) and then increased to 45 mg once a day with an initial improvement in serum sodium levels, although not long-lasting. We therefore tried dividing the 45 mg tolvaptan administration into two doses of 30 mg and 15 mg respectively, using an off-label treatment schedule, thus achieving long-lasting serum sodium levels in the low-normal range associated with a general clinical improvement. Conclusions: This report underlines the importance of the correct diagnosis, management and treatment of SIAD, as well as the need for further studies about the pharmacokinetics and pharmacodynamics of vasopressin receptor antagonists.

Cefiderocol- Compared to Colistin-Based Regimens for the Treatment of Severe Infections Caused by Carbapenem-Resistant Acinetobacter baumannii.

Cefiderocol may represent a therapeutic option for carbapenem-resistant Acinetobacter baumannii (CRAB) infections, but clinical data are limited. This is an observational retrospective study conducted in the University Hospital of Pisa including consecutive patients with CRAB infections (January 2020 to August 2021). Patients were divided in two study groups according to the antibiotic treatment received: cefiderocol- and colistin-containing regimens. The primary outcome was the 30-day mortality. A Cox regression analysis was performed to identify factors independently associated with 30-day mortality. A propensity score analysis using inverse probability of treatment weighting (IPTW) was also performed. A total of 124 patients were included: 47 (37.9%) received cefiderocol, while 77 (62.1%) colistin-containing regimens. Overall, 79 (63.7%) patients had a bloodstream infection (BSI), 35 (28.5%) a ventilator-associated pneumonia (VAP) and 10 (8.1%) other infections. Thirty-day mortality was higher in patients receiving colistin- compared to those who received cefiderocol-containing regimens (55.8% versus 34%, P = 0.018). This difference was confirmed in patients with BSI, but not in those with VAP. On multivariable analysis, septic shock, SOFA score, and age were independently associated with 30-day mortality, while cefiderocol therapy was protective in an IPTW analysis (Hazard ratio 0.44, 95% confidence interval 0.22-0.66, P < 0.001). Nephrotoxicity was more common in the colistin group. Microbiological failure occurred in 17.4% of patients receiving cefiderocol versus 6.8% of those receiving colistin (P = 0.079). Among 8 cases in the cefiderocol group who experienced microbiological failure, 4 (50%) developed resistance to cefiderocol. Cefiderocol represents a promising therapeutic option in patients with severe CRAB infections. Randomized clinical trial in this specific patient population should confirm our findings.

Early Use of Remdesivir and Risk of Disease Progression in Hospitalized Patients With Mild to Moderate COVID-19.

PURPOSE: Preliminary data suggest that remdesivir may influence the course of COVID-19 according to the duration of pre-admission symptoms. We aim to evaluate whether early use of remdesivir is associated with a reduced COVID-19 progression in a homogeneous cohort of patients with mild to moderate COVID-19. METHODS: This prospective, observational study included patients with COVID-19 pneumonia treated with remdesivir at the University Hospital of Pisa (Italy) from September 2020 to January 2021. According to national recommendations, remdesivir was prescribed in patients with pneumonia who required oxygen supplementation by nasal cannula or mask but without the need for high-flow nasal cannula, non-invasive or invasive mechanical ventilation and had symptoms from no more than 10 days. Patients who received early (≤5 days from onset of symptoms) versus late (>5 days from onset of symptoms) remdesivir were compared. The primary outcome was a composite of high-flow nasal cannula, non-invasive or invasive mechanical ventilation, or death. A multivariate logistic regression analysis was performed to identify factors independently associated with the composite endpoint. FINDINGS: Among 312 consecutive patients with COVID-19 pneumonia who received remdesivir, 90 (28.8%) received early remdesivir, whereas 222 (71.2%) received late remdesivir. Twenty-nine patients (32.2%) in the early-remdesivir group versus 104 patients (46.8%) in the late-remdesivir group met the primary end point (P = 0.018). On multivariate analysis, a history of dyspnea at home (odds ratio = 2.53; 95% CI, 1.55-4.12; P < 0.001) was the strongest factor independently associated with the progression to severe COVID-19, whereas early-remdesivir use was a protective factor (odds ratio = 0.49; 95% CI, 0.27-0.87; P = 0.015). The delayed admission to the hospital was associated with a delayed administration of remdesivir. IMPLICATIONS: The early use of remdesivir (<5 days from symptoms onset) may reduce COVID-19 progression. The identification of patients who need early hospitalization and early remdesivir may provide clinical benefit in patients with COVID-19.