Use of nebulized liposomal amphotericin B and posaconazole as antifungal prophylaxis in patients with severe SARS-CoV2 infection in intensive care unit.

PURPOSE: COVID-19 associated pulmonary aspergillosis (CAPA) is common and linked with high fatality rates. To assess the impact on the incidence and outcome of CAPA of an antifungal prophylaxis (AFP) we compared two cohorts of COVID-19 patients admitted to intensive care units (ICU) in Brescia, Italy, from January to August 2021. METHODS: The study cohort included all mechanically ventilated patients observed between April 2021 and August 2021 with SARS-CoV-2-pneumonia, who received AFP with oral posaconazole (200 mg every 6 h) and nebulized liposomal amphotericin B (50 mg every 2 weeks) from ICU admission to 7 days after discharge or, if applicable, until tracheostomy removal. The control cohort included COVID-19 patients admitted to the same ICU between January and March 2021 who did not receive any AFP. Subjects with CAPA at ICU admission were excluded. RESULTS: We included 270 patients, of whom 64 (23.7%) received AFP. In patients in the study group, CAPA-related mortality was significantly reduced (29% vs. 48% p = 0.04), as well as the incidence of CAPA (3.1% vs 12.1%, p = 0.03). Patients who developed CAPA were older (mean of 70-y-old vs 63-y-old, p < 0.001). One subject discontinued posaconazole due to an adverse reaction. Among the 46 patients who received it, only one patient reached an effective plasma concentration of posaconazole. CONCLUSION: AFP was associated with reduced incidence and mortality from CAPA and was well tolerated in patients with severe COVID-19. Posaconazole concentrations below the efficacy threshold in almost all patients may be attributable to drug interactions and prompt further studies to define its clinical significance.

Time is running out. No excuses to delay implementation of antimicrobial stewardship programmes: impact, sustainability, resilience and efficiency through an interrupted time series analysis (2017-2022).

Introduction: The WHO declared antimicrobial resistance (AMR) a significant concern in 2014, sparking initiatives to ensure responsible antibiotic use. In human medicine, Antimicrobial Stewardship Programmes (ASPs) in hospitals play a pivotal role in combating AMR. Although evidence supports the effectiveness of ASPs in optimizing antimicrobial use, often the lack of resources becomes an excuse to limit their dissemination and use. This paper provides a comprehensive report on a 6-year analysis of an ASP implemented in a healthcare region in north-east Italy. Methods: A retrospective data collection was conducted to assess the programme's impact on antibiotic consumption expressed as DDDs/100 patient-days, its sustainability over time, resilience during the COVID-19 pandemic and the efficiency of the ASP (relationship between workload and human resources). Results: A substantial overall reduction in antibiotic consumption (-14%), particularly in fluoroquinolones (-64%) and carbapenems (-68%), was demonstrated, showcasing the programme's impact. Sustainability was confirmed through enduring trends in antibiotic consumption and ecological analysis over time. The ASP demonstrates resilience by maintaining positive trends even amid the challenging COVID-19 pandemic. Efficiency was underscored by an increase in on-site consultations despite consistent human resources until 2021. Conclusions: This study offers insights into the prolonged success of a resource-efficient ASP, emphasizing the crucial role of long-term commitment in fostering responsible antibiotic use in the context of global health challenges such as AMR.

Two cases of drug induced hypersensitivity to dolutegravir-rilpivirine fixed-dose combination: A case report.

BACKGROUND: Two-drug regimens antiretroviral therapies are increasingly prescribed to HIV patients, as they are recommended by international guidelines, and they show an excellent efficacy, safety, and tolerability profile. Regimens administered as single tablets (STRs) are usually preferred by patients and they are associated with higher adherence. CASE REPORT: We report two cases of drug-induced hypersensitivity (DIH) that occurred after switching from dolutegravir (DTG) plus rilpivirine (RPV) in separate pills to a fixed dose combination containing the same molecules (DTG/RPV; Juluca®). Following the DIH event, DTG/RPV coformulation was discontinued. At symptomatic resolution, they continued to receive DTG plus RPV in separate pills uneventfully. The component present only in the DTG/RPV coformulation was iron oxide red (E172), contained in the film-coating. Iron oxide red is an approved colorant, used as drug excipient. Patch test with DTG/RV coformulation performed several months after the DIH event was negative. Drug allergy to excipients remains underappreciated and underreported and frequently leads to inappropriate medication discontinuation. CONCLUSION: Our case underscores the role of meticulous medication allergy history in differentiating true medication allergy from excipient allergy. This observation may be useful in the era of antiretroviral simplification to two-drug regimens.

Actinomyces spp. Prosthetic Vascular Graft Infection (PVGI): A Multicenter Case-Series and Narrative Review of the Literature.

BACKGROUND: Actinomycosis represents a challenging and under-reported complication of vascular surgery. Optimal management of Actinomyces spp. prosthetic vascular graft infection (PVGI) is highly uncertain because of the paucity of reports on this disease. METHODS: We conducted a retrospective case-series of Actinomyces-PVGI that occurred in the last five years in two major university hospitals in northern Italy. We searched for previously published cases in the scientific literature. RESULTS: We report five original cases of Actinomyces spp. prosthetic vascular graft infection following aortic aneurysm repair. Our literature review retrieved eight similar cases. Most patients were immunocompetent males. Most infections were polymicrobial (11/13 cases), with a prevalence of A. odontolyticus involvement (3/13 cases were associated with. Salmonella spp. infection). All cases had a late presentation (≥4 months from graft placement), with 61% associated with an aorto-enteric fistula. All patients received antibiotic therapy, but the duration was highly heterogeneous (from two weeks to life-long antibiotics). The patients without surgical revision experienced septic recurrences (2/13), permanent dysfunction (1/13), or a fatal outcome (2/13), while of the remainder who underwent vascular graft explant, six recovered completely and one developed a periprosthetic abscess. In two cases follow-up was not available. CONCLUSIONS: This case-series aims to raise the diagnostic suspicion and to describe the current management of Actinomyces-PVGIs. We highlight a high heterogeneity in antibiotic duration, choice of the antibiotic regimen, and surgical management. Higher reporting rate is advisable to produce better evidence and optimize management of this rare complication of vascular surgery.

The Management of Recurrent Urinary Tract Infection: Non-Antibiotic Bundle Treatment.

Recurrent urinary tract infections (rUTIs) are a common condition with high morbidity and negatively impact the quality of life. They account for approximately 25% of all antibiotic prescriptions and are a public health concern in an era of increasing multidrug-resistant organisms (MDROs). Several non-antibiotic treatment strategies have been tried to curb antimicrobial use, and many are effective to some degree, but no experience testing multimodal interventions. We created a "care bundle" consisting of behavioral interventions, vaginal and oral probiotics, D-mannose, and cranberry to be followed for six months. We enrolled women with rUTIs over three years. Changes in urinary tract infections, antibiotic use, chronic symptoms, and quality of life were compared in the six months before and after participation in the study. Forty-seven women were enrolled in the study, six of whom were excluded from the final analysis. We observed a 76% reduction in urinary tract infections (p < 0.001) and a reduction in total antibiotic exposure of more than 90% (p < 0.001); all chronic symptoms showed a trend toward reduction. Adherence to the bundle was high (87.2%). Overall, 80.5% of women experienced an improvement in their quality of life. In our experience, a bundle protocol is effective in reducing recurrences and antimicrobial use in a cohort of women with rUTIs and results in a subjective improvement in chronic symptoms and quality of life. Further research with larger sample size is needed to confirm these findings.

Dalbavancin in catheter-related bloodstream infections: a pilot study.

Background: Catheter-related bloodstream infections (CRBSI) represent a frequent complication of vascular catheterization, with high morbidity, mortality, and associated costs. Most infections are caused by Gram-positive bacteria; thus dalbavancin, a new long-acting lipoglicopeptide, may have a role in early patient discharge strategies optimizing treatment and reducing overall costs. Methods: In this small pilot feasibility study, we assessed the efficacy and safety of a "single step" treatment strategy combining dalbavancin administration (1500 mg IV single dose), catheter removal, and early discharge in adult patients admitted to medical wards in a three-year period. Results: We enrolled sixteen patients with confirmed Gram-positive CRBSI, with a mean age of 68 years and relevant comorbidities (median Charlson Comorbidity index=7). The most frequent causative agents were staphylococci, with 25% of methicillin-resistant strains, and the majority of infected devices were short term central venous catheter (CVC) and peripherally inserted central catheter (PICC). Ten out of sixteen patients had been treated empirically before dalbavancin administration. The mean time from dalbavancin administration to discharge was 2 days; none of the patients had adverse drug-related reactions; at 30- and 90-day follow-up, no patients have been readmitted to the hospital due to bacteraemia recurrence. Conclusions: Our results indicate that single-dose dalbavancin is highly effective, well-tolerated, and cost-saving for Gram-positive CRBSI.

Mortality predictors in hospitalised COVID-19 patients and the role of anti-SARS-CoV-2 IgG antibodies and remdesivir.

Background: In a pre-vaccination era serologic tests may be used to evaluate the seroprevalence and efficacy of containment strategies applied to the community. Subsequently, SARS-CoV-2 vaccination has successfully reduced hospitalization and admission to intensive care. The role of antiviral treatment for COVID-19 remains debated. Objective: We investigated the effect of SARS-CoV-2 IgG Spike (S) antibody responses in hospitalized patients on 30-day mortality. Finally, we assessed whether other predictive factors affected mortality after 30 days. Methods: Observational study on COVID-19 patients admitted from October 1, 2021, to January 30, 2022. Results: 520 patients were studied; 108 died at the 30-day follow-up (21%). A borderline significance for mortality was observed in favour of the high antibody titer group (24% vs 17%, p=0.05). From the univariate Cox regression analysis, a high IgG-S titer was significantly correlated to lower 30-day mortality (p=0.04, HR: 0.7; 95%CI: 0.44-0.98). The administration of remdesivir (p=0.01) and the age <65 years (p=2.3e-05) were found to be protective for the considered outcome (respectively, HR: 0.5, 95%CI: 0.34-0.86, and HR: 0.1, 95%CI: 0.04-0.30). Conclusions: S-antibodies and remdesivir could play a protecting role in increasing the survival of hospitalized COVID-19 patients who are not suffering from a critical disease. Advanced age is a risk factor for poor outcomes among infected people.

Home management of COVID-19 symptomatic patients: a safety study on COVID committed home medical teams.

To reduce the overburden in the hospital, during the COVID-19 pandemic, some "COVID Committed Home Medical Teams" (CCHTs) were created in Italy. These units consist of a small pool of general practitioners who aim to evaluate all patients with COVID-19 who require a medical examination directly at home. After the first visit (which can end with patient hospitalisation or home management), CCHTs periodically monitor the patients' clinical conditions and vital signs (usually a revaluation every 24-48 hours, except for a sudden worsening). However, this strategy - which reduces the pressure on hospitals - has never been evaluated for patient safety. Our study aims to determine whether a home-based monitoring and treatment strategy for non-severe COVID-19 patients was safe as direct hospital admission by the emergency department. We conducted a retrospective observational study about 1,182 patients admitted to the hospital for COVID-19 between September 2020 and April 2021, confronting in-hospital and 30-day mortality in both CCHT-referred (n=275) and directly admitted by emergency department (n=907). Patients assessed by the CCHT had lower in-hospital and 30-day mortality (18% vs 28%, p=0.001; and 20% vs 30%, p=0.002); but, in the propensity score matching comparison, there was no characteristic between the two groups turned out significantly different. CCHT did not correlate with in-hospital or 30-day mortality. CCHT is a safe strategy to reduce hospital overburden for COVID-19 during pandemic surges.

Results of an Innovative Program for Surveillance, Prophylaxis, and Treatment of Infectious Complications Following Allogeneic Stem Cell Transplantation in Hematological Malignancies (BATMO Protocol).

Background: Infectious complications are a significant cause of morbidity and mortality in patients undergoing allogeneic haematopoietic stem cell transplantation (Allo-SCT). The BATMO (Best-Antimicrobial-Therapy-TMO) is an innovative program for infection prevention and management and has been used in our centre since 2019. The specific features of the BATMO protocol regard both prophylaxis during neutropenia (abandonment of fluoroquinolone, posaconazole use in high-risk patients, aerosolized liposomal amphotericin B use until engraftment or a need for antifungal treatment, and letermovir use in CMV-positive recipients from day 0 to day +100) and therapy (empirical antibiotics based on patient clinical history and colonization, new antibiotics used in second-line according to antibiogram with the exception of carbapenemase-producing K pneumoniae for which the use in first-line therapy is chosen). Methods: Data on the infectious complications of 116 transplant patients before BATMO protocol (Cohort A; 2016 - 2018) were compared to those of 84 transplant patients following the introduction of the BATMO protocol (Cohort B; 2019 - 2021). The clinical and transplant characteristics of the 2 Cohorts were comparable, even though patients in Cohort B were at a higher risk of developing bacterial, fungal, and CMV infections, due to a significantly higher proportion of myeloablative regimens and haploidentical donors. Results: No change in the incidence of infections with organ localization was observed between the two Cohorts. A significant reduction in Clostridioides difficile infections by day +100 was observed in Cohort B (47% vs. 15%; p=0.04). At day +30, a higher incidence of Gram-negative bloodstream infections (BSIs) was observed in Cohort B (12% vs. 23%; p=0.05). By day +100 and between days +100 and +180, the incidence of BSIs and of the various etiological agents, the mortality from Gram-negative bacteria, and the incidence of invasive fungal infections were not different in the two Cohorts. The incidence of CMV reactivations by day +100 dropped drastically in patients of Cohort B, following letermovir registration (51% vs. 15%; p=0.00001). Discussion: The results of this study suggest that the BATMO program is safe. In particular, the choice to avoid prophylaxis with fluoroquinolone was associated with an increase in Gram-negative BSIs by day +30, but this did not translate into higher levels of mortality. Moreover, this strategy was associated with a significant reduction of Clostridiodes difficile infections. The efficacy of anti-CMV prophylaxis with letermovir was confirmed by a significant reduction in CMV reactivations. Even though patients in Cohort B were at higher risk of developing fungal infections (more haploidentical transplants with more myeloablative regimens), the extensive use of posaconazole for prophylaxis balanced this risk, and no increase in the incidence of fungal-associated complications was observed.

Epidemiological and Clinical Characterization of Superinfections in Critically Ill Coronavirus Disease 2019 Patients.

To describe the epidemiology of superinfections (occurring > 48 hr after hospital admission) and their impact on the ICU and 28-day mortality in patients with coronavirus disease 2019 with acute respiratory distress syndrome, requiring mechanical ventilation. DESIGN: Retrospective analysis of prospectively collected observational data. SETTING: University-affiliated adult ICU. PATIENTS: Ninety-two coronavirus disease 2019 patients admitted to the ICU from February 21, 2020, to May 6, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The prevalence of superinfection at ICU admission was 21.7%, and 53 patients (57.6%) had at least one superinfection during ICU stay, with a total of 75 (82%) ventilator-associated pneumonia and 57 (62%) systemic infections. The most common pathogens responsible for ventilator-associated pneumonia were Pseudomonas aeruginosa (n = 26, 34.7%) and Stenotrophomonas maltophilia (n = 14, 18.7%). Bloodstream infection occurred in 16 cases, including methicillin-resistant Staphylococcus epidermidis (n = 8, 14.0%), Enterococcus species (n = 6, 10.5%), and Streptococcus species (n = 2, 3.5%). Fungal infections occurred in 41 cases, including 36 probable (30 by Candida albicans, six by C. nonalbicans) and five proven invasive candidiasis (three C. albicans, two C. nonalbicans). Presence of bacterial infections (odds ratio, 10.53; 95% CI, 2.31-63.42; p = 0.005), age (odds ratio, 1.17; 95% CI, 1.07-1.31; p = 0.001), and the highest Sequential Organ Failure Assessment score (odds ratio, 1.27; 95% CI, 1.06-1.63; p = 0.032) were independently associated with ICU or 28-day mortality. CONCLUSIONS: Prevalence of superinfections in coronavirus disease 2019 patients requiring mechanical ventilation was high in this series, and bacterial superinfections were independently associated with ICU or 28-day mortality (whichever comes first).

Real-life experience with compassionate use of cefiderocol for difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections.

OBJECTIVES: To describe our real-life experience with cefiderocol in XDR and difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections without any other available treatment options. METHODS: We included patients with a proven infection due to an XDR/DTR-P, who had failed on previous regimens, and were treated with cefiderocol, following them prospectively to day 90 or until hospital discharge or death. RESULTS: Seventeen patients treated for >72 h with cefiderocol were included: 14 receiving combination regimens (82.4%) and 3 receiving monotherapy (17.6%). Fourteen patients were males (82%) with a median age of 64 years (IQR 58-73). Fifteen patients (88.2%) were admitted to the ICU and five had septic shock (29%). Seven cases (41.2%) were ventilator-associated pneumonia, of which 71% (5/7) occurred in COVID-19 patients. Four were complicated intrabdominal infections, one ecthyma gangrenosum, one nosocomial pneumonia and one empyema, one osteomyelitis, one primary bacteraemia, and one nosocomial external ventricular drainage meningitis. Clinical cure and microbiological cure rates were 70.6% and 76.5%, respectively. There were six deaths (35.3%) after a median of 8 days (IQR 3-10) from the end of treatment, but only two of them (11.7%) were associated with P. aeruginosa infection progression. CONCLUSIONS: Our experience collecting this large case series of DTR-P treated with cefiderocol may help clinicians consider this new option in this hard-to-manage setting. Our results are even more relevant in the current scenario of ceftolozane/tazobactam shortage. Importantly, this is the first study providing real-life data indicating adequate cefiderocol concentrations in CSF.