Intravenous fosfomycin in combination regimens as a treatment option for difficult-to-treat infections due to multi-drug-resistant Gram-negative organisms: A real-life experience.

AIM: To investigate the efficacy of intravenous (IV) fosfomycin as combination therapy for treatment of difficult-to-treat (DTT) acute and subacute infections with multi-drug-resistant (MDR) Gram-negative bacteria (GNB), and risk factors associated with 90-day mortality. METHODS: A retrospective, observational, monocentric study enrolled patients treated with IV fosfomycin in combination regimens (≥72 h) for proven DTT-MDR-GNB infection. Multi-variate regression analysis identified independent risk factors for 90-day mortality. A propensity score for receiving fosfomycin was performed to control for confounding factors. RESULTS: In total, 70 patients were included in this study: 54.3% had carbapenem-resistant isolates, 31.4% had ceftazidime/avibactam-resistant isolates and 28.6% had ceftolozane/tazobactam-resistant isolates. The main pathogens were Pseudomonas aeruginosa (57.1%) and Klebsiella pneumoniae (22.9%). The most prevalent infections were nosocomial pneumonia (42.9%), osteomyelitis (17.1%) and intra-abdominal infections. All-cause 30- and 90-day mortality were 15.7% and 31.4%, respectively (18.9% and 50% considering acute DTT-MDR-GNB infections alone). Relapse at 30 days occurred in 22.9% of cases (29% with emergence of fosfomycin resistance). Mortality at 90 days was independently associated with septic shock and ceftolozane/tazobactam resistance. The relationship between resistance to ceftolozane/tazobactam and 90-day mortality was confirmed to be significant after adjustment by propensity score analysis (hazard ratio 5.84, 95% confidence interval 1.65-20.68; P=0.006). CONCLUSIONS: Fosfomycin seems to be a promising salvage, combination treatment in DTT-MDR-GNB infections. Resistance to ceftolozane/tazobactam seems to be independently associated with treatment failure. Randomized clinical trials focusing on pathogen and infection sites are needed urgently to demonstrate the superiority of fosfomycin in combination with other agents for the resolution of DTT-MDR-GNB infections.

Postoperative cognitive worsening in seniors with an age above life expectancy: a prospective longitudinal study.

BACKGROUND: The growing number of elderly patients in hospitals is a challenge for healthcare systems. The main objective is to measure the postoperative change in the cognitive status at hospital discharge and one year after discharge in elderly patients undergoing planned or deferrable surgery. METHODS: We planned a prospective longitudinal study, single-center study: secondary care level hospital, enrolment from September 2018 to May 2019. We enroll elderly patients, aged above life expectancy in Italy, who underwent planned or deferrable surgery (men over 80.5 years old, women over 85.0 years old). In six months, we enrolled 76 eligible patients. We collected the scores of the clinical impairment scales Charlson Index, Barthel Index, and Six-Item Cognitive Impairment Test (6CIT). The primary endpoint was the postoperative worsening of the cognitive status at one-year follow-up. Secondary endpoints aimed to describe postoperative disabilities and complications, to investigate possible risk factors for cognitive worsening, and to measure the role of anesthesia in cognitive changes. RESULTS: We recorded an increased rate of pathological 6CIT values during the hospitalization period, rising from 39.47% to 55.26% (McNemar test, P=0.007), and this rate was still increased at 55.56% (P=0.021) one year after discharge. Anesthesia did not show any significant harmful effect on cognitive status. The preoperative hemoglobin value seems to be a risk factor for cognitive status and one-year mortality. CONCLUSIONS: Elderly patients had a significantly worse 6CIT value after planned surgery, which may derive in part from age and in part from hospitalization. It is difficult to determine if general anesthesia alone has no harmful effects on cognitive performance in patients at discharge and one year later. Further data are necessary.

COVID-19 Biomarkers for Critically Ill Patients: A Compendium for the Physician.

BACKGROUND: SARS-CoV-2 clinical manifestation and progression are variable and unpredictable, hence the importance of considering biomarkers in clinical practice that can be useful for both diagnosis and prognostic evaluation. This review aims to summarize, for intensive care physicians, the most recent state of knowledge regarding known COVID-19 in critical patients. We searched PubMed® using the Boolean operators and identified all results on the PubMed® database of all studies regarding COVID-19 biomarkers. We selected studies regarding endothelium, cytokines, bacterial infection, coagulation, and cardiovascular biomarkers. METHODS: We divided the results into four essential paragraphs: "Cytokine storm", "Endothelium dysfunction and coagulation biomarkers in COVID-19", "Biomarker of sepsis", and Cardiovascular lung and new perspectives. RESULTS: The assessments of the severe COVID-19 prognosis should monitor, over time, IL-6, soluble Von Willebrand factor (VWF), P-selectin, sCD40L, thrombomodulin, VCAM-1, endothelin- Troponin, D-dimer, LDH, CRP, and procalcitonin. Metabolomic alterations and ACE2 receptors represent new perspectives. DISCUSSION AND CONCLUSIONS: Early identification of critically ill patients has been crucial in the first COVID-19 pandemic wave for the sustainability of the healthcare emergency system and clinical management. Only through the early identification of the most severe patients can they be provided with the most appropriate treatments.

Point-of-care pancreatic stone protein measurement in critically ill COVID-19 patients.

INTRODUCTION: Pancreatic stone protein (PSP) is a novel biomarker that is reported to be increased in pneumonia and acute conditions. The primary aim of this study was to prospectively study plasma levels of PSP in a COVID-19 intensive care unit (ICU) population to determine how well PSP performed as a marker of mortality in comparison to other plasma biomarkers, such as C reactive protein (CRP) and procalcitonin (PCT). METHODS: We collected clinical data and blood samples from COVID-19 ICU patients at the time of admission (T0), 72 h later (T1), five days later (T2), and finally, seven days later. The PSP plasma level was measured with a point-of-care system; PCT and CRP levels were measured simultaneously with laboratory tests. The inclusion criteria were being a critical COVID-19 ICU patient requiring ventilatory mechanical assistance. RESULTS: We enrolled 21 patients and evaluated 80 blood samples; we found an increase in PSP plasma levels according to mixed model analysis over time (p < 0.001), with higher levels found in the nonsurvivor population (p < 0.001). Plasma PSP levels achieved a statistically significant result in terms of the AUROC, with a value higher than 0.7 at T0, T1, T2, and T3. The overall AUROC of PSP was 0.8271 (CI (0.73-0.93), p < 0.001). These results were not observed for CRP and PCT. CONCLUSION: These first results suggest the potential advantages of monitoring PSP plasma levels through point-of-care technology, which could be useful in the absence of a specific COVID-19 biomarker. Additional data are needed to confirm these results.

COVID-19: Relative Risk of Non-Vaccinated to Vaccinated Individuals.

Following the outbreak of the COVID-19 pandemic, Italy has implemented an extensive vaccination campaign involving individuals above the age of 12, both sexes. The public opinion and the medical community alike questioned the usefulness and efficacy of the vaccines against SARS-CoV-2. The widespread opinion was that the vaccines protected individuals especially against serious conditions which could require intensive care and may lead to the death of the patient rather than against the possibility of infection. In order to quantify the effect of the vaccination campaign, we calculated the relative risks of non-vaccinated and vaccinated individuals for all possible outcomes of the disease: infection, hospitalization, admission to intensive care and death. Relative risk was assessed by means of likelihood ratios, the ratios of the probability of an outcome in non-vaccinated individuals to the probability of the same outcome in vaccinated individuals. Results support the hypothesis that vaccination has an extensive protective effect against both critical conditions and death. Nonetheless, the relative magnitude of the protection in vaccinated individuals compared to those non-vaccinated appears to be higher against the former outcome than the latter, for reasons which need to be investigated further.

Health Care Management during a Major Planned Event in Italy.

Events involving a high number of participants should be planned and implemented with the primary objective of guaranteeing the highest possible level of safety, which is ever more essential in the recent years due to the risk of terrorism, violence, and highly transmissible pathogens like coronavirus disease 2019 (COVID-19).The aim of this study was describing health care management of the Vasco Modena Park July 1, 2017 concert by the artist Vasco Rossi that involved 220,000 participants, more than doubling the population of Modena (Italy), the city hosting the event.Data were retrospectively collected from all health care registers used during the concert. Descriptive data regarding the event were recorded, as well as the medical records generated by the advanced medical posts.For analysis, patients were divided into two groups: the LOW-Severity (admission code green) and HIGH-Severity (admission codes yellow and red). The number of patients within the inclusion period was 1,088; there were 953 green discharge codes (97.74%), 16 yellow (1.64%), and six red (0.61%). Patients who needed a second-level assessment were 5.85% (57 events). HIGH-Severity patients needed to be further evaluated in 45.45% of the cases versus 4.93% of the LOW-Severity patient group (P value <.001).The health care management proved adequate to the number of participants and the severity of patients. Descriptive data reported add the mass-gathering database useful for further events.

Ceftazidime/Avibactam in Ventilator-Associated Pneumonia Due to Difficult-to-Treat Non-Fermenter Gram-Negative Bacteria in COVID-19 Patients: A Case Series and Review of the Literature.

Ventilator-associated pneumonia (VAP) in critically ill patients with COVID-19 represents a very huge global threat due to a higher incidence rate compared to non-COVID-19 patients and almost 50% of the 30-day mortality rate. Pseudomonas aeruginosa was the first pathogen involved but uncommon non-fermenter gram-negative organisms such as Burkholderia cepacea and Stenotrophomonas maltophilia have emerged as other potential etiological causes. Against carbapenem-resistant gram-negative microorganisms, Ceftazidime/avibactam (CZA) is considered a first-line option, even more so in case of a ceftolozane/tazobactam resistance or shortage. The aim of this report was to describe our experience with CZA in a case series of COVID-19 patients hospitalized in the ICU with VAP due to difficult-to-treat (DTT) P. aeruginosa, Burkholderia cepacea, and Stenotrophomonas maltophilia and to compare it with data published in the literature. A total of 23 patients were treated from February 2020 to March 2022: 19/23 (82%) VAPs were caused by Pseudomonas spp. (16/19 DTT), 2 by Burkholderia cepacea, and 6 by Stenotrophomonas maltophilia; 12/23 (52.1%) were polymicrobial. Septic shock was diagnosed in 65.2% of the patients and VAP occurred after a median of 29 days from ICU admission. CZA was prescribed as a combination regimen in 86% of the cases, with either fosfomycin or inhaled amikacin or cotrimoxazole. Microbiological eradication was achieved in 52.3% of the cases and the 30-day overall mortality rate was 14/23 (60.8%). Despite the high mortality of critically ill COVID-19 patients, CZA, especially in combination therapy, could represent a valid treatment option for VAP due to DTT non-fermenter gram-negative bacteria, including uncommon pathogens such as Burkholderia cepacea and Stenotrophomonas maltophilia.

Intensive Care Patients from the First COVID-19 Wave: One-Year Survival after Tocilizumab Treatment.

INTRODUCTION: An infection by COVID-19 triggers a dangerous cytokine storm, so tocilizumab has been introduced in Italy as an agent blocking the cytokine storm. This paper aims to describe the one-year survival of ICU patients treated with tocilizumab. METHODS: This observational study enrolled all patients confirmed to be infected by COVID-19 who were admitted to the ICU in our center. We offered tocilizumab to all non-septic patients if they did not present any contraindications. RESULTS: We enrolled 68 ICU patients in our center on 72 occasions during the enrollment period; we excluded four patients due to study criteria. The one-year mortality hazard ratio of treated patients was 0.64, with a confidence interval of 0.31 to 1.19, with p = 0.169. Among the survivors, 32 of 35 patients answered the phone interview (14 patients in the treated group and 18 in the untreated group); overall, the effect of COVID-19 on quality of life was 58.14%. These effects were lower in the tocilizumab group, with p = 0.016 *. CONCLUSIONS: Our observational data follow the most relevant largest trial. Patients treated with tocilizumab had lower rates of new-onset symptoms later COVID-19 ICU hospitalizations. As reported by recent medical literature, the presence of these symptoms suggests that a follow-up program for these types of patients could be useful.

Health-related quality of life profiles, trajectories, persistent symptoms and pulmonary function one year after ICU discharge in invasively ventilated COVID-19 patients, a prospective follow-up study.

BACKGROUND: Health-related quality of life (HRQoL) impairment is often reported among COVID-19 ICU survivors, and little is known about their long-term outcomes. We evaluated the HRQoL trajectories between 3 months and 1 year after ICU discharge, the factors influencing these trajectories and the presence of clusters of HRQoL profiles in a population of COVID-19 patients who underwent invasive mechanical ventilation (IMV). Moreover, pathophysiological correlations of residual dyspnea were tested. METHODS: We followed up 178 survivors from 16 Italian ICUs up to one year after ICU discharge. HRQoL was investigated through the 15D instrument. Available pulmonary function tests (PFTs) and chest CT scans at 1 year were also collected. A linear mixed-effects model was adopted to identify factors associated with different HRQoL trajectories and a two-step cluster analysis was performed to identify HRQoL clusters. RESULTS: We found that HRQoL increased during the study period, especially for the significant increase of the physical dimensions, while the mental dimensions and dyspnea remained substantially unchanged. Four main 15D profiles were identified: full recovery (47.2%), bad recovery (5.1%) and two partial recovery clusters with mostly physical (9.6%) or mental (38.2%) dimensions affected. Gender, duration of IMV and number of comorbidities significantly influenced HRQoL trajectories. Persistent dyspnea was reported in 58.4% of patients, and weakly, but significantly, correlated with both DLCO and length of IMV. CONCLUSIONS: HRQoL impairment is frequent 1 year after ICU discharge, and the lowest recovery is found in the mental dimensions. Persistent dyspnea is often reported and weakly correlated with PFTs alterations. TRIAL REGISTRATION: NCT04411459.

Mild to Severe Neurological Manifestations of COVID-19: Cases Reports.

The main focus of Coronavirus disease 2019 (COVID-19) infection is pulmonary complications through virus-related neurological manifestations, ranging from mild to severe, such as encephalitis, cerebral thrombosis, neurocognitive (dementia-like) syndrome, and delirium. The hospital screening procedures for quickly recognizing neurological manifestations of COVID-19 are often complicated by other coexisting symptoms and can be obscured by the deep sedation procedures required for critically ill patients. Here, we present two different case-reports of COVID-19 patients, describing neurological complications, diagnostic imaging such as olfactory bulb damage (a mild and unclear underestimated complication) and a severe and sudden thrombotic stroke complicated with hemorrhage with a low-level cytokine storm and respiratory symptom resolution. We discuss the possible mechanisms of virus entrance, together with the causes of COVID-19-related encephalitis, olfactory bulb damage, ischemic stroke, and intracranial hemorrhage.

pT3 N0 Laryngeal Squamous Cell Carcinoma: Oncologic Outcomes and Prognostic Factors of Surgically Treated Patients.

OBJECTIVES/HYPOTHESIS: To assess the disease control, survival rates, and prognostic factors of exclusive surgical treatment for patients with pT3 N0 laryngeal squamous cell carcinoma (LSCC). STUDY DESIGN: Multicentric retrospective cohort study. METHODS: Multicentric retrospective case series of previously untreated patients with pT3 R0N0 LSCC, who received exclusive surgery between 2011 and 2019. Tumor location; subsite involvement; grading; and lymphatic, vascular, and perineural invasion were reported. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were measured. RESULTS: Fifty-four patients (mean age 67.1; male sex 83.3%; mean follow-up period 37 months) underwent total laryngectomy (48.1%) or partial laryngectomy (51.9%). Ipsilateral or bilateral neck dissection was performed in 46 (85.2%) cases. Perineural invasion was more frequent in case of supraglottic involvement than glottic involvement (85.7% vs. 14.3%, P = .03). Five (9.3%) patients experienced recurrence (3 local recurrences, 1 nodal recurrence, 1 distant recurrence). Rate of recurrence differed between glottic (0%), supraglottic (80%), and transglottic (20%) tumors (P = .01), with a lower risk yielded by glottic involvement (odds ratio [OR], 0.05, 95% confidence interval [95% CI], 0.01-0.56, P = .01). A higher risk was recorded in case of perineural invasion (OR, 66.0, 95% CI, 1.41-3085.3, P = .03). The OS, DSS, and DFS were 79.6%, 96.3%, and 90.7%, without differences regarding the type of surgery. The DFS was lower in case of supraglottic involvement when compared to purely glottic LSCC (83.9% vs. 100%, P = 0.02). CONCLUSIONS: Exclusive surgery is a safe option for patients with pT3 R0N0 LSCC. Adjuvant treatments or closer follow-up monitoring might be considered in case of supraglottic involvement or perineural invasion. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2262-2268, 2021.

Dynamic angiopoietin-2 assessment predicts survival and chronic course in hospitalized patients with COVID-19.

This study examined the association between dynamic angiopoietin-2 assessment and COVID-19 short- and long-term clinical course. We included consecutive hospitalized patients from 1 February to 31 May 2020 with laboratory-confirmed COVID-19 from 2 Italian tertiary referral centers (derivation cohort, n = 187 patients; validation cohort, n = 62 patients). Serum biomarker levels were measured by sandwich enzyme-linked immunosorbent assay. Lung tissue from 9 patients was stained for angiopoietin-2, Tie2, CD68, and CD34. Cox model was used to identify risk factors for mortality and nonresolving pulmonary condition. Area under the receiver operating characteristic curve (AUROC) was used to assess the accuracy of 3- and 10-day angiopoietin-2 for in-hospital mortality and nonresolving pulmonary condition, respectively. Three-day angiopoietin-2 increase of at least twofold from baseline was significantly associated with in-hospital mortality by multivariate analysis (hazard ratio [HR], 6.69; 95% confidence interval [CI], 1.85-24.19; P = .004) with AUROC = 0.845 (95% CI, 0.725-0.940). Ten-day angiopoietin-2 of at least twofold from baseline was instead significantly associated with nonresolving pulmonary condition by multivariate analysis (HR, 5.33; 95% CI, 1.34-11.77; P ≤ .0001) with AUROC = 0.969 (95% CI, 0.919-1.000). Patients with persistent elevation of 10-day angiopoietin-2 levels showed severe reticular interstitial thickening and fibrous changes on follow-up computed tomography scans. Angiopoietin-2 and Tie2 were diffusely colocalized in small-vessel endothelia and alveolar new vessels and macrophages. Angiopoietin-2 course is strongly associated with COVID-19 in-hospital mortality and nonresolving pulmonary condition. Angiopoietin-2 may be an early and useful predictor of COVID-19 clinical course, and it could be a relevant part of disease pathogenesis. Angiopoietin-2 blockade may be a COVID-19 treatment option.

Why should you stay one night? Prospective observational study of enhanced recovery in elderly patients.

BACKGROUND: Delirium is a severe condition that can arise in many contexts during hospitalization. The aim of this research was to measure the incidence of postoperative delirium in patients aged 75 years or older, with the exclusion of those with preexisting neurocognitive disorders (NCD), who underwent fast-track, moderate surgery. METHODS: We conducted a prospective cohort study with patients ≥ 75 years of age who were eligible for fast-track, moderate surgery, without severe dementia, with a planned hospitalization of 24 h and with a physical status varying from very fit to vulnerable. The 4-item confusion assessment method (CAM4) was used to measure delirium. RESULTS: Of the 209 eligible patients, 195 subjects were enrolled in the study. The percentage of the population with a CAM4 score above 0 before surgery was 2.56%; after surgery, the percentage was 10.25%; and on the following day, the percentage was 4.61%. There was a statistically significant difference in the CAM4 scores between immediately after surgery and at 24 h after surgery (p = 0.0172). CONCLUSION: The data from this study support an enhanced recovery approach for elderly patients, in which after a minor surgical procedure with anaesthesia, a recovery period of one night in the hospital can contribute to normalizing the CAM4 score and reducing the incidence of delirium.

Keyboard Contamination in Intensive Care Unit: Is Cleaning Enough? Prospective Research of In Situ Effectiveness of a Tea Tree Oil (KTEO) Film.

After the SARS-CoV-2 pandemic, disinfection practices and microbial load reduction have become even more important and rigorous. To determine the contamination of keyboard surface and the relative risk to transfer healthcare-associated pathogens to susceptible patients, as it frequently happens in Intensive Care Unit (ICU), a standard keyboard (SK), a cleanable keyless keyboard (KK) with smooth surface and a standard keyboard coated with a 3 M Tegaderm® film added with active essential oil (tea tree oil) (KTEO) were tested. S. aureus, including MRSA strains, were detected in ICU, with values ranging from 15% to 57%. Gram negative strains belonging to the Enterobacteriaceae family were also found with values ranging from 14% to 71%. Similar Gram positive and Gram negative strains were found on all surfaces, but with low percentage, and only environmental bacteria were detected using the settling plates method. The Microbial Challenge Test performed on KTEO showed high rates of decrease for all the pathogens with statistical significance both at 24 and 48 h (p = 0.003* and p = 0.040*, respectively). Our results suggest that the use of KTEO may be a feasible strategy for reducing the transmission of pathogens in health care setting and may be complementary to surface cleaning protocols.

Hemoadsorption cartridge and coronavirus disease 2019 infections: A case report and brief literature review.

The cytokine storm has been frequently reported to occur in patients with severe coronavirus disease 2019 (COVID-19). Data from the literature suggest that elevated levels of inflammatory mediators, such as interleukin (IL)-6, IL-8, and tumor necrosis factor, indicate a severe course or the fatality of the disease. Several therapeutic options have been employed to treat critically ill patients, including hemoadsorption of inflammatory mediators. We here present a case of severe acute respiratory syndrome caused by COVID-19 and acute renal failure. The patient was admitted to our intensive care unit and treated with mechanical ventilation, renal replacement therapy, and hemoadsorption to reduce the cytokine release syndrome, which plays a fundamental role in the clinical presentation of COVID-19 patients. We also discuss the potential advantages of reducing cytokine plasma levels using a hemoadsorption cartridge.