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.

Description, Organization, and Individual Postgraduate Perspectives of One Italian School of Anesthesia and Intensive Care.

INTRODUCTION: The study aims to describe the organization of one accredited school of Anesthesia and Intensive Care of University of Modena and Reggio Emilia, Italy. The analysis of the post-graduation period aims to measure the time-to-first job, the perceived challenges, what postgraduate residents choose as first employ, and the overall satisfaction rating of a cohort of residents completing their training until 2017 with the usual and standard training program. METHODS: We collected organization and administrative records of the five-year program of the A-IC School of 4 cohorts of residents who joined from 2009 to 2012 and we performed a survey. We also analyzed the differences among school cohorts during the medical training. In the end, it was investigated as a reason to choose hub hospitals or not. RESULTS: The focus of the training activities revolved around the operating room with a mean of 30.41 ± 6.6 (sd), months followed by Intensive care with 17.29 ± 4.49 (sd) months. Although 7.5% of the respondents were not fully satisfied of the school's program, 89.7% of residents rated their training as adequate. In fact, 97.2% respondents reported they could overcome the professional challenges they faced after graduation. The multiple variables logistic regression showed a correlation among working in hub hospitals and training performed in university hospitals with a p value of 0.015. CONCLUSION: This paper describes the postgraduation period. This point should be examined as an integral part of the accreditation procedure. Knowing the satisfaction rate, perception autonomy, and which type of hospitals are preferred can measure the education training capacity of a postgraduation school.

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.

Cytokine mass balance levels in donation after circulatory death donors using hemoadsorption: Case series report.

The use of hemadsorption has been purposed to reduce cytokine levels during the reperfusion phase during donation after circulatory death (DCD) programs. This paper aims to describe a cases series of the inflammatory cytokine levels before and after hemadsorption during normothermic reperfusion in DCD donors of liver and kidneys. In this observational pilot paper, we describe 8 DCD donors of liver or kidneys in our center from the year 2018 to 2019. All DCD donor subjects had similar age, were younger than 60 years, without evident critical conditions, no liver or kidney dysfunction known, and they presented with poor neurological outcomes instrumentally and clinically documented. We observed in our patients an interesting reduction of IL-10 and TNF-α levels during the normothermic reperfusion with hemadsorption. We transplanted all livers and kidneys from DCD donors without significant compliances.

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.

Endobronchial valve positioning for alveolar-pleural fistula following ICU management complicating COVID-19 pneumonia.

BACKGROUND: The main clinical consequences of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection are pneumonia and respiratory failure even requiring mechanical ventilation. In this context, the lung parenchyma is highly prone to ventilator-related injury, with pneumothorax and persistent air leak as the most serious adverse events. So far, endobronchial valve (EBV) positioning has proved efficacious in treating air leaks with a high success rate. CASE PRESENTATION: We report, for the first time, two cases of patients affected by SARS-CoV-2-related pneumonia complicated with bacterial super-infection, experiencing pneumothorax and persistent air leaks after invasive mechanical ventilation. Despite the severity of respiratory failure both patients underwent rigid interventional bronchoscopy and were successfully treated through EBV positioning. CONCLUSIONS: Persistent air leaks may result from lung tissue damage due to a complex interaction between inflammation and ventilator-related injury (VILI), especially in the advanced stages of ARDS. EBV positioning seems to be a feasible and effective minimally invasive therapeutic option for treating this subset of patients.

Quality of life of COVID-19 critically ill survivors after ICU discharge: 90 days follow-up.

PURPOSE: The onset of the coronavirus disease 19 (COVID-19) pandemic in Italy induced a dramatic increase in the need for intensive care unit (ICU) beds for a large proportion of patients affected by COVID-19-related acute respiratory distress syndrome (ARDS). The aim of the present study was to describe the health-related quality of life (HRQoL) at 90 days after ICU discharge in a cohort of COVID-19 patients undergoing invasive mechanical ventilation and to compare it with an age and sex-matched sample from the general Italian and Finnish populations. Moreover, the possible associations between clinical, demographic, social factors, and HRQoL were investigated. METHODS: COVID-19 ARDS survivors from 16 participating ICUs were followed up until 90 days after ICU discharge and the HRQoL was evaluated with the 15D instrument. A parallel cohort of age and sex-matched Italian population from the same geographic areas was interviewed and a third group of matched Finnish population was extracted from the Finnish 2011 National Health survey. A linear regression analysis was performed to evaluate potential associations between the evaluated factors and HRQoL. RESULTS: 205 patients answered to the questionnaire. HRQoL of the COVID-19 ARDS patients was significantly lower than the matched populations in both physical and mental dimensions. Age, sex, number of comorbidities, ARDS class, duration of invasive mechanical ventilation, and occupational status were found to be significant determinants of the 90 days HRQoL. Clinical severity at ICU admission was poorly correlated to HRQoL. CONCLUSION: COVID-19-related ARDS survivors at 90 days after ICU discharge present a significant reduction both on physical and psychological dimensions of HRQoL measured with the 15D instrument. TRIAL REGISTRATION: NCT04411459.

Sustained oxygenation improvement after first prone positioning is associated with liberation from mechanical ventilation and mortality in critically ill COVID-19 patients: a cohort study.

BACKGROUND: Prone positioning (PP) has been used to improve oxygenation in patients affected by the SARS-CoV-2 disease (COVID-19). Several mechanisms, including lung recruitment and better lung ventilation/perfusion matching, make a relevant rational for using PP. However, not all patients maintain the oxygenation improvement after returning to supine position. Nevertheless, no evidence exists that a sustained oxygenation response after PP is associated to outcome in mechanically ventilated COVID-19 patients. We analyzed data from 191 patients affected by COVID-19-related acute respiratory distress syndrome undergoing PP for clinical reasons. Clinical history, severity scores and respiratory mechanics were analyzed. Patients were classified as responders (≥ median PaO2/FiO2 variation) or non-responders (< median PaO2/FiO2 variation) based on the PaO2/FiO2 percentage change between pre-proning and 1 to 3 h after re-supination in the first prone positioning session. Differences among the groups in physiological variables, complication rates and outcome were evaluated. A competing risk regression analysis was conducted to evaluate if PaO2/FiO2 response after the first pronation cycle was associated to liberation from mechanical ventilation. RESULTS: The median PaO2/FiO2 variation after the first PP cycle was 49 [19-100%] and no differences were found in demographics, comorbidities, ventilatory treatment and PaO2/FiO2 before PP between responders (96/191) and non-responders (95/191). Despite no differences in ICU length of stay, non-responders had a higher rate of tracheostomy (70.5% vs 47.9, P = 0.008) and mortality (53.7% vs 33.3%, P = 0.006), as compared to responders. Moreover, oxygenation response after the first PP was independently associated to liberation from mechanical ventilation at 28 days and was increasingly higher being higher the oxygenation response to PP. CONCLUSIONS: Sustained oxygenation improvement after first PP session is independently associated to improved survival and reduced duration of mechanical ventilation in critically ill COVID-19 patients.

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.

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.

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.

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.