Molnupiravir compared to nirmatrelvir/ritonavir for COVID-19 in high-risk patients with haematological malignancy in Europe. A matched-paired analysis from the EPICOVIDEHA registry.

INTRODUCTION: Molnupiravir and nirmatrelvir/ritonavir are antivirals used to prevent progression to severe SARS-CoV-2 infections and decrease hospitalisation and mortality rates. Nirmatrelvir/ritonavir was authorised in Europe in December 2021, whereas molnupiravir is not yet licensed in Europe as of February 2022. Molnupiravir may be an alternative to nirmatrelvir/ritonavir because it is associated with fewer drug-drug interactions and contraindications. A caveat for molnupiravir is the mode of action induces viral mutations. Mortality rate reduction with molnupiravir was less pronounced than that with nirmatrelvir/ritonavir in patients without haematological malignancy. Little is known about the comparative efficacy of the two drugs in patients with haematological malignancy at high-risk of severe COVID-19. Thus, molnupiravir and nirmatrelvir/ritonavir were compared in a cohort of patients with haematological malignancies. METHODS: Clinical data from patients treated with molnupiravir or nirmatrelvir/ritonavir monotherapy for COVID-19 were retrieved from the EPICOVIDEHA registry. Patients treated with molnupiravir were matched by sex, age (±10 years), and severity of baseline haematological malignancy to controls treated with nirmatrelvir/ritonavir. RESULTS: A total of 116 patients receiving molnupiravir for the clinical management of COVID-19 were matched to an equal number of controls receiving nirmatrelvir/ritonavir. In each of the groups, 68 (59%) patients were male; with a median age of 64 years (interquartile range [IQR] 53-74) for molnupiravir recipients and 64 years (IQR 54-73) for nirmatrelvir/ritonavir recipients; 56.9% (n=66) of the patients had controlled baseline haematological malignancy, 12.9% (n=15) had stable disease, and 30.2% (n=35) had active disease at COVID-19 onset in each group. During COVID-19 infection, one third of patients from each group were admitted to hospital. Although a similar proportion of patients in the two groups were vaccinated (molnupiravir n=77, 66% vs. nirmatrelvir/ritonavir n=87, 75%), more of those treated with nirmatrelvir/ritonavir had received four vaccine doses (n=27, 23%) compared with those treated with molnupiravir (n=5, 4%) (P<0.001). No differences were detected in COVID-19 severity (P=0.39) or hospitalisation (P=1.0). No statistically significant differences were identified in overall mortality rate (P=0.78) or survival probability (d30 P=0.19, d60 P=0.67, d90 P=0.68, last day of follow up P=0.68). Deaths were either attributed to COVID-19, or the infection was judged by the treating physician to have contributed to death. CONCLUSIONS: Hospitalisation and mortality rates with molnupiravir were comparable to those with nirmatrelvir/ritonavir in high-risk patients with haematological malignancies and COVID-19. Molnupiravir is a plausible alternative to nirmatrelvir/ritonavir for COVID-19 treatment in patients with haematological malignancy.

Septic Arthritis of the Atlanto-Occipital Joint Caused By S. Intermedius in a 5-Year-Old Girl: A Case Report.

Septic arthritis of the atlanto-occipital joint caused by Streptococcus intermedius is extremely rare. We present the first case report of this entity in a fully immunocompetent 5-year-old girl. The magnetic resonance imaging and blood tests were consistent with septic arthritis, so she started empirical antibiotic therapy. Septic arthritis should be excluded in children with torticollis, fever and neck pain.

Risk Factors for Intra-Abdominal Candidiasis in Intensive Care Units: Results from EUCANDICU Study.

INTRODUCTION: Intra-abdominal infections represent the second most frequently acquired infection in the intensive care unit (ICU), with mortality rates ranging from 20% to 50%. Candida spp. may be responsible for up to 10-30% of cases. This study assesses risk factors for development of intra-abdominal candidiasis (IAC) among patients admitted to ICU. METHODS: We performed a case-control study in 26 European ICUs during the period January 2015-December 2016. Patients at least 18 years old who developed an episode of microbiologically documented IAC during their stay in the ICU (at least 48 h after admission) served as the case cohort. The control group consisted of adult patients who did not develop episodes of IAC during ICU admission. Matching was performed at a ratio of 1:1 according to time at risk (i.e. controls had to have at least the same length of ICU stay as their matched cases prior to IAC onset), ICU ward and period of study. RESULTS: During the study period, 101 case patients with a diagnosis of IAC were included in the study. On univariate analysis, severe hepatic failure, prior receipt of antibiotics, prior receipt of parenteral nutrition, abdominal drain, prior bacterial infection, anastomotic leakage, recurrent gastrointestinal perforation, prior receipt of antifungal drugs and higher median number of abdominal surgical interventions were associated with IAC development. On multivariate analysis, recurrent gastrointestinal perforation (OR 13.90; 95% CI 2.65-72.82, p = 0.002), anastomotic leakage (OR 6.61; 95% CI 1.98-21.99, p = 0.002), abdominal drain (OR 6.58; 95% CI 1.73-25.06, p = 0.006), prior receipt of antifungal drugs (OR 4.26; 95% CI 1.04-17.46, p = 0.04) or antibiotics (OR 3.78; 95% CI 1.32-10.52, p = 0.01) were independently associated with IAC. CONCLUSIONS: Gastrointestinal perforation, anastomotic leakage, abdominal drain and prior receipt of antifungals or antibiotics may help to identify critically ill patients with higher probability of developing IAC. Prospective studies are needed to identify which patients will benefit from early antifungal treatment.

MR-proADM as prognostic factor of outcome in COVID-19 patients.

Mid Regional pro-ADM (MR-proADM) is a promising novel biomarker in the evaluation of deteriorating patients and an emergent prognosis factor in patients with sepsis, septic shock and organ failure. It can be induced by bacteria, fungi or viruses. We hypothesized that the assessment of MR-proADM, with or without other inflammatory cytokines, as part of a clinical assessment of COVID-19 patients at hospital admission, may assist in identifying those likely to develop severe disease. A pragmatic retrospective analysis was performed on a complete data set from 111 patients admitted to Udine University Hospital, in northern Italy, from 25th March to 15th May 2020, affected by SARS-CoV-2 pneumonia. Clinical scoring systems (SOFA score, WHO disease severity class, SIMEU clinical phenotype), cytokines (IL-6, IL-1b, IL-8, TNF-α), and MR-proADM were measured. Demographic, clinical and outcome data were collected for analysis. At multivariate analysis, high MR-proADM levels were significantly associated with negative outcome (death or orotracheal intubation, IOT), with an odds ratio of 4.284 [1.893-11.413], together with increased neutrophil count (OR = 1.029 [1.011-1.049]) and WHO disease severity class (OR = 7.632 [5.871-19.496]). AUROC analysis showed a good discriminative performance of MR-proADM (AUROC: 0.849 [95% Cl 0.771-0.730]; p < 0.0001). The optimal value of MR-proADM to discriminate combined event of death or IOT is 0.895 nmol/l, with a sensitivity of 0.857 [95% Cl 0.728-0.987] and a specificity of 0.687 [95% Cl 0.587-0.787]. This study shows an association between MR-proADM levels and the severity of COVID-19. The assessment of MR-proADM combined with clinical scoring systems could be of great value in triaging, evaluating possible escalation of therapies, and admission avoidance or inclusion into trials. Larger prospective and controlled studies are needed to confirm these findings.

Lung Ultrasound Signs and Their Correlation With Clinical Symptoms in COVID-19 Pregnant Women: The "PINK-CO" Observational Study.

OBJECTIVE: To analyze the application of lung ultrasound (LUS) diagnostic approach in obstetric patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and compare LUS score and symptoms of the patients. DESIGN: A single-center observational retrospective study from October 31, 2020 to March 31, 2021. SETTING: Department of Ob/Gyn at the University-Hospital of Udine, Italy. PARTICIPANTS: Pregnant women with SARS-CoV-2 diagnosed with reverse transcription-PCR (RT-PCR) swab test were subdivided as symptomatic and asymptomatic patients with COVID-19. EXPOSURE: Lung ultrasound evaluation both through initial evaluation upon admission and through serial evaluations. MAIN OUTCOME: Reporting LUS findings and LUS score characteristics. RESULTS: Symptomatic patients with COVID-19 showed a higher LUS (median 3.5 vs. 0, p < 0.001). LUS was significantly correlated with COVID-19 biomarkers as C-reactive protein (CPR; p = 0.011), interleukin-6 (p = 0.013), and pro-adrenomedullin (p = 0.02), and inversely related to arterial oxygen saturation (p = 0.004). The most frequent ultrasound findings were focal B lines (14 vs. 2) and the light beam (9 vs. 0). CONCLUSION: Lung ultrasound can help to manage pregnant women with SARS-CoV-2 infection during a pandemic surge. STUDY REGISTRATION: ClinicalTrials.gov, NCT04823234. Registered on March 29, 2021.

Blood ozonization in patients with mild to moderate COVID-19 pneumonia: a single centre experience.

The emerging outbreak of the coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide. We prescribed some promising medication to our patients with mild to moderate pneumonia due to SARS-CoV-2, however such drugs as chloroquine, hydrossichloroquine, azithromycin, antivirals (lopinavir/ritonavir, darunavir/cobicistat) and immunomodulating agents (steroids, tocilizumab) were not confirmed as effective against SARS-CoV2. We, therefore, started to use auto-hemotherapy treated with an oxygen/ozone (O2/O3) gaseous mixture as adjuvant therapy. In Udine University Hospital (Italy) we performed a case-control study involving hospitalized adult patients with confirmed COVID-19 with mild to moderate pneumonia. Clinical presentations are based upon clinical phenotypes identified by the Italian Society of Emergency and Urgency Medicine (SIMEU-Società Italiana di Medicina di Emergenza-Urgenza) and patients that met criteria of phenotypes 2 to 4 were treated with best available therapy (BAT), with or without O3-autohemotherapy. 60 patients were enrolled in the study: 30 patients treated with BAT and O2/O3 mixture, as adjuvant therapy and 30 controls treated with BAT only. In the group treated with O3-autohemotherapy plus BAT, patients were younger but with more severe clinical phenotypes. A decrease of SIMEU clinical phenotypes was observed (2.70 ± 0.67 vs. 2.35 ± 0.88, p = 0.002) in all patients during hospitalization but this clinical improvement was statistically significant only in O3-treated patients (2.87 ± 0.78 vs. 2.27 ± 0.83, p < 0.001), differently to the control group (2.53 ± 0.51 vs. 2.43 ± 0.93, p = 0.522). No adverse events were observed associated with the application of O2/O3 gaseous mixture. O2/O3 therapy as adjuvant therapy could be useful in mild to moderate pneumonia due to SARS-CoV-2. Randomized prospective study is ongoing [Clinical Trials.gov ID: Z7C2CA5837].

Clinical Features and Mortality of Nosocomial Candidemia in Very Old Patients: A Multicentre Italian Study.

INTRODUCTION: Being elderly is a well-known risk factor for candidemia, but few data are available on the prognostic impact of candidemia in the very old (VO) subjects, as defined as people aged ≥75 years. OBJECTIVE: The aim of this study was to assess risk factors for nosocomial candidemia in two groups of candidemia patients, consisting of VO patients (≥75 years) and adult and old (AO) patients (18-74 years). In addition, risk factors for death (30-day mortality) were analysed separately in the two groups. METHODS: We included all consecutive candidemia episodes from January 2011 to December 2013 occurring in six referral hospitals in north-eastern Italy. RESULTS: A total of 683 nosocomial candidemia episodes occurred. Of those, 293 (42.9%) episodes were in VO and 390 (57.1%) in AO patients. Hospitalization in medical wards, chronic renal failure, urinary catheter, and peripheral parenteral nutrition (PPN) were more common in VO than in AO patients. In the former patient group, adequate antifungal therapy (73.2%) and central venous catheter (CVC) removal (67.6%) occurred less frequently than in AO patients (82.5 and 80%, p < 0.002 and p < 0.004, respectively). Thirty-day mortality was higher in VO compared to AO patients (47.8 vs. 23.6%, p < 0.0001). In AO patients, independent risk factors for death were age (OR 1.04, 95% CI 1.00-1.09, p = 0.038), recent history of chemotherapy (OR 22.01, 95% CI 3.12-155.20, p = 0.002), and severity of sepsis (OR 40.68, 95% CI 7.42-223.10, p < 0.001); CVC removal was associated with higher probability of survival (OR 0.10, 95% CI 0.03-0.33, p < 0.001). In VO patients, independent risk factors for death were PPN (OR 3.5, 95% CI 1.17-10.47, p = 0.025) and hospitalization in medical wards (OR 2.58, 95% CI 1.02-6.53, p = 0.046), while CVC removal was associated with improved survival (OR 0.40, 95% CI 0.16-1.00, p = 0.050). CONCLUSION: Thirty-day mortality was high among VO patients and was associated with inadequate management of candidemia, especially in medical wards.

Comparison of the Safety and Tolerance Profile of Micafungin with that of Other Echinocandins and Azoles in Patients with Pre-existing Child-Pugh B or C Liver Disease: A Case-Control Retrospective Study.

INTRODUCTION: To assess the association between exposure to micafungin, other echinocandins, or azoles and the development of short-term liver injury (STLI) or long-term liver injury (LTLI) in patients with Child-Pugh B or C liver disease. METHODS: Multicenter case-control study of patients with Child-Pugh B or C liver disease who received antifungals (AF) for ≥ 72 h (May 2009-May 2015) in six Spanish and Italian hospitals. All micafungin patients were randomly matched with one patient who received another echinocandin and with one patient who received azole treatment. Primary outcome was development of STLI or LTLI (development of any type of liver tumor during the follow-up period). RESULTS: Of 2335 patients with chronic liver disease admitted to the six centers, 20 (0.85%) were found to have Child-Pugh B or C liver disease and received micafungin for ≥ 72 h. During AF treatment, the frequency of STLI was 10% in each group. Most cases of STLI were asymptomatic, and AFs had to be switched to another class of AF in only two patients (one micafungin and one azole). No patients developed acute liver insufficiency, were admitted to the ICU, or had to undergo transplantation. Follow-up data (median of 1.3 years) were available for 30 patients. LTLI was observed in only one patient, who had previously received treatment with azoles. CONCLUSIONS: Our study suggests that the administration of micafungin to patients with end-stage liver disease does not imply a higher risk of developing STLI or LTLI.

Incremental value of FDG-PET/CT to monitor treatment response in infectious spondylodiscitis.

OBJECTIVE: To assess the added value of serial 2-deoxy-2-[18F]fluoro-D-glucose (FDG) uptake analysis in predicting clinical response to treatment in infectious spondylodiscitis (IS). We sought to analyze changes in quantitative FDG-PET/CT parameters among patients with clinical response or treatment failure and to compare the sensitivity and specificity of serial FDG-PET/CT and MRI in predicting treatment response in IS. MATERIALS AND METHODS: This retrospective study consisted of 68 FDG-PET/CT examinations in 34 patients performed before and after at least 2 weeks of antibiotic treatment. Serial MRI scans were available in 32 (94%) patients before and after treatment. FDG-avid lesions were quantified as maximum standardized uptake value (SUVmax), partial-volume corrected lesion metabolic volume (LMV), and partial-volume corrected lesion metabolic activity (LMA). RESULTS: All FDG-PET/CT parameters significantly decreased in patients with clinical improvement (31/34, 91%, P < 0.001), while patients with disease progression did not show FDG-PET/CT improvement. FDG uptake decrease was similar between patients undergoing early assessment (< 6 weeks) compared with those performing FDG-PET/CT after 6 weeks of treatment. SUVmax, LMV, and LMA decrease over time was 39.0%, 97.4%, and 97.1%, respectively. In predicting clinical responses, SUVmax reduction > 15% and > 25% showed 94% and 89% sensitivity and 67% and 100% specificity compared with 37% and 50% of MRI, respectively. Low degree of agreement with clinical response was shown for MRI compared with FDG-PET/CT parameters using the Cohen kappa coefficient. CONCLUSIONS: FDG-PET/CT monitoring is a valuable tool to predict clinical response to treatment in IS and has greater sensitivity and specificity compared with MRI.

Role of procalcitonin in predicting etiology in bacteremic patients: Report from a large single-center experience.

BACKGROUND: Procalcitonin (PCT) is routinely used for an early recognition of severe infections and for promoting appropriate use of antibiotics. However, limited data correlating values of PCT with etiology of infection has been reported. METHODS: During 2016, all positive blood cultures (BC) were retrospectively extracted in a 1100-beds Italian tertiary-care hospital. PCT and C-reactive protein (CRP) values were recorded within 24h from BC collection. Primary endpoint of the study was to investigate the correlation between PCT and CRP values and the occurrence of bloodstream infections (BSI) caused by bacteria or fungi. RESULTS: During the study period, 1296 positive BC were included: 712 (54.9%) due to Gram-positive (GP), 525 (40.5%) due to Gram-negative (GN) strains, and 59 (4.6%) caused by fungi. Among GN isolates, enterobacteriaceae were reported in 453 (86.3%) cases. PCT values were higher in patients with GN etiology (26.1±14.2ng/mL) compared to GP (6.9±4.5) and fungi (3.3±2.4). Mean values for CRP in GN, GP, and fungi were not different. Receiver Operating Characteristic (ROC) curves showed an area under curve (AUC) of 0.71 for PCT and 0.51 for CRP among GN isolates; an AUC of 0.7 for PCT and 0.52 for CRP among enterobacteriaceae. Lower AUC for PCT were reported for GP and fungi. CONCLUSIONS: PCT showed moderate performance in early detection (within 24h) of Gram-negative infections, especially those caused by enterobacteriaceae. Further prospective studies are mandatory to confirm these observations.

Proactive therapeutic drug monitoring (TDM) may be helpful in managing long-term treatment with linezolid safely: findings from a monocentric, prospective, open-label, interventional study.

BACKGROUND: Thrombocytopenia may be a dose-dependent adverse effect of linezolid therapy. OBJECTIVES: To assess whether proactive therapeutic drug monitoring (TDM) could be helpful in preventing and/or in recovering from the occurrence of linezolid-induced thrombocytopenia during long-term treatment. METHODS: This was a monocentric, prospective, open-label, interventional study conducted between June 2015 and December 2017 among adult patients receiving >10 days of linezolid therapy and undergoing proactive TDM (desired trough level 2-8 mg/L) and platelet count assessment at day 3-5 and then once weekly up to the end of treatment. RESULTS: Sixty-one patients were included. Twenty-eight (45.9%) always had desired trough level (group A) and 33 (54.1%) experienced linezolid overexposure (group B) [29/33 transiently (subgroup B1) and 4/33 persistently (subgroup B2)]. No patient experienced linezolid underexposure. Median duration of treatment for the different groups ranged between 19 and 54 days. Thrombocytopenia occurred overall in 14.8% of cases (9/61). The incidence rate of thrombocytopenia was significantly lower (P=0.012) in both group A (10.7%; 3/28) and subgroup B1 (10.3%; 3/29) than in subgroup B2 (75.0%; 3/4). Thrombocytopenic patients belonging to both group A and group B1 recovered from thrombocytopenia without the need for discontinuing therapy. Multivariate linear regression analysis revealed that thrombocytopenia was independently associated with baseline platelet count and with median linezolid trough concentrations. CONCLUSIONS: Proactive TDM of linezolid may be beneficial either in preventing or in recovering from dose-dependent thrombocytopenia, even when treatment lasts for more than 28 days. Larger prospective studies are warranted to confirm our findings.

Incidence and outcome of invasive candidiasis in intensive care units (ICUs) in Europe: results of the EUCANDICU project.

BACKGROUND: The objective of this study was to assess the cumulative incidence of invasive candidiasis (IC) in intensive care units (ICUs) in Europe. METHODS: A multinational, multicenter, retrospective study was conducted in 23 ICUs in 9 European countries, representing the first phase of the candidemia/intra-abdominal candidiasis in European ICU project (EUCANDICU). RESULTS: During the study period, 570 episodes of ICU-acquired IC were observed, with a cumulative incidence of 7.07 episodes per 1000 ICU admissions, with important between-center variability. Separated, non-mutually exclusive cumulative incidences of candidemia and IAC were 5.52 and 1.84 episodes per 1000 ICU admissions, respectively. Crude 30-day mortality was 42%. Age (odds ratio [OR] 1.04 per year, 95% CI 1.02-1.06, p < 0.001), severe hepatic failure (OR 3.25, 95% 1.31-8.08, p 0.011), SOFA score at the onset of IC (OR 1.11 per point, 95% CI 1.04-1.17, p 0.001), and septic shock (OR 2.12, 95% CI 1.24-3.63, p 0.006) were associated with increased 30-day mortality in a secondary, exploratory analysis. CONCLUSIONS: The cumulative incidence of IC in 23 European ICUs was 7.07 episodes per 1000 ICU admissions. Future in-depth analyses will allow explaining part of the observed between-center variability, with the ultimate aim of helping to improve local infection control and antifungal stewardship projects and interventions.

Successful and safe long-term treatment of cerebral aspergillosis with high-dose voriconazole guided by therapeutic drug monitoring.

We report the case of a patient who had cerebral aspergillosis after otorhinolaryngologic surgery and who was successfully and safely treated with high-dose voriconazole (200 mg q6h) for more than 1 year thanks to a TDM-guided approach coupled with pharmacological review and with genotyping of CYP2C19 polymorphisms. The findings support the idea that personalized medicine based on TDM coupled with the need of avoiding drug-drug interactions may be helpful for maximizing the net benefit (probability of efficacy vs. probability of adverse events) of voriconazole in the management of long-term treatment of cerebral aspergillosis.

Role of procalcitonin in bacteremic patients and its potential use in predicting infection etiology.

INTRODUCTION: Bloodstream infections (BSI) and their evolution to sepsis or septic shock are one of the most important causes of morbidity and mortality; for this reason, arapid recognition and diagnosis of these infections are crucial to improve patients' outcome. Area covered: Procalcitonin (PCT) is considered an important biomarker for diagnosis of infection, routinely used to identify patients developing severe bacterial infections. In this scenario, management of BSI is complicated by the increasing rate of multidrug-resistantstrains, and an early recognition of severe infections is mandatory. Moreover, an appropriate use and prescription of antibiotics is important to reduce the risk of development of further antibiotic resistances. Expert opinion: we reviewed recent literature about the use of PCT in bacteremic patients to determine its role to predict infections, severity of clinical condition and antibiotic therapy duration; its role was defined in many studies to reduce duration of antibiotic treatment, especially in critically ill patients and for lower respiratory tract infections. Moreover, we reported recent studies in which PCT showed ahigh performance to detect precociously infections due to Gram-negativestrains. Data from the literature confirm that PCT should not be used as astand-alonetest in the absence of clinical judgment.

Epidemiological and clinical features of imported malaria at the three main hospitals of the Friuli-Venezia Giulia Region, Italy.

BACKGROUND: Imported malaria cases continue to occur in non-endemic regions among travellers returning from tropical and subtropical countries. At particular risk of acquiring malaria is the group of travellers identified as immigrants who return to their home country with the specific intent of visiting friends or relatives (VFRs) and who commonly believe they are immune to malaria and fail to seek pre-travel advice. Our aim was to review the current trends of imported malaria in the three main hospitals of the Friuli-Venezia Giulia region (FVG), North Eastern Italy, focusing in particular on patient characteristics and laboratory findings. METHODS: In this retrospective study, we examined all malaria cases among patients admitted from January 2010 through December 2014 to the emergency department of the three main hospitals located in FVG. RESULTS: During the 5-year study period from 2010 to 2014, there were a total of 140 patients with a diagnosis of suspected malaria and who received microscopic confirmation of malaria. The most common species identified was P. falciparum, in 96 of 140 cases (69%), followed by P. vivax (13%), P. ovale (4%), P. malariae (4%), and mixed infection (4%). The most common reason for travel was VFRs (54%), followed by work (17%), and recent immigration (15%). Moreover, 78% of all patients took no chemoprophylaxis, 80 (79%) of whom were foreigners. Notably, the percentage of Italian travellers who took chemoprophylaxis was only 20% (8 of 39 Italian cases), and the regimen was appropriate in only four cases. Parasitaemia greater than 5% was observed in 11 cases (10%), all due to P. falciparum infection. CONCLUSIONS: We highlight that VFRs have the highest proportion of malaria morbidity and the importance of improving patient management in this category. These data are useful for establishing appropriate malaria prevention measures and recommendations for international travellers.