Ceftazidime-Avibactam (C/A) Resistant, Meropenem Sensitive KPC-Producing Klebsiella pneumoniae in ICU Setting: We Are What We Are Treated with?

The continuous spread of carbapenem-resistant Klebsiella pneumoniae (CP-Kp) strains presents a severe challenge to the healthcare system due to limited therapeutic options and high mortality. Since its availability, ceftazidime/avibactam (C/A) has become a first-line option against KPC-Kp, but C/A-resistant strains have been reported increasingly, especially with pneumonia or prior suboptimal blood exposure to C/A treatment. A retrospective, observational study was conducted with all patients admitted to the Intensive Care Unit (ICU) dedicated to COVID-19 patients at the City of Health & Sciences in Turin, between 1 May 2021 and 31 January 2022, with the primary endpoint to study strains with resistance to C/A, and secondly to describe the characteristics of this population, with or without previous exposure to C/A. Seventeen patients with colonization or invasive infection due to Klebsiella pneumoniae, C/A resistance, and susceptibility to meropenem (MIC = 2 µg/L) were included;the blaKPC genotype was detected in all isolates revealing D179Y mutation in the blaKPC-2 (blaKPC-33) gene. Cluster analysis showed that 16 out of the 17 C/A-resistant KPC-Kp isolates belonged to a single clone. Thirteen strains (76.5%) were isolated in a 60-day period. Only some patients had a previous infection with non-mutant KPC at other sites (5;29.4%). Eight patients (47.1%) underwent previous large-spectrum antibiotic treatment, and four patients (23.5%) had prior treatment with C/A. The secondary spread of the D179Y mutation in the blaKPC-2 during the COVID-19 pandemic needs to be addressed constantly by an interdisciplinary interaction between microbiologists, infection control personnel, clinicians, and infectious diseases consultants to properly diagnose and treat patients.

Burden of primary influenza and respiratory syncytial virus pneumonia in hospitalised adults: insights from a 2-year multi-centre cohort study (2017-2018).

BACKGROUND: Viral community-acquired pneumonia (CAP) is a potentially serious illness, particularly in adult patients with underlying chronic conditions. In addition to the most recent SARS-CoV-2, influenza, and respiratory syncytial virus (RSV) are considered the most relevant causes of viral CAP. AIMS: To describe the clinical features of hospitalised adults admitted for influenza-A/B and RSV pneumonia and analyse, according to aetiology, factors associated with non-invasive ventilation (NIV) failure and in-hospital death (IHD). METHODS: This was a retrospective and multi-centre study of all adults who were admitted for laboratory-confirmed influenza-A/B or RSV pneumonia, during two consecutive winter seasons (October-April 2017-2018 and 2018-2019) in three tertiary hospitals in Portugal, Italy and Cyprus. RESULTS: A total of 356 adults were included in the study. Influenza-A, influenza-B and RSV were deemed to cause pneumonia in 197 (55.3%), 85 (23.9%) and 74 (20.8%) patients, respectively. Patients with both obstructive sleep apnoea or obesity hypoventilation syndrome and influenza-A virus pneumonia showed a higher risk for NIV failure (odds ratio (OR) 4.66; 95% confidence interval (CI) 1.42-15.30). Patients submitted to NIV showed a higher risk for IHD, regardless of comorbidities (influenza-A OR 3.00; 95% CI 1.35-6.65, influenza-B OR 4.52; 95% CI 1.13-18.01, RSV OR 5.61; 95% CI 1.26-24.93). CONCLUSION: The increased knowledge of influenza-A/B and RSV pneumonia burden may contribute to a better management of patients with viral CAP.

Ceftazidime-Avibactam (C/A) Resistant, Meropenem Sensitive KPC-Producing Klebsiella pneumoniae in ICU Setting: We Are What We Are Treated with?

The continuous spread of carbapenem-resistant Klebsiella pneumoniae (CP-Kp) strains presents a severe challenge to the healthcare system due to limited therapeutic options and high mortality. Since its availability, ceftazidime/avibactam (C/A) has become a first-line option against KPC-Kp, but C/A-resistant strains have been reported increasingly, especially with pneumonia or prior suboptimal blood exposure to C/A treatment. A retrospective, observational study was conducted with all patients admitted to the Intensive Care Unit (ICU) dedicated to COVID-19 patients at the City of Health & Sciences in Turin, between 1 May 2021 and 31 January 2022, with the primary endpoint to study strains with resistance to C/A, and secondly to describe the characteristics of this population, with or without previous exposure to C/A. Seventeen patients with colonization or invasive infection due to Klebsiella pneumoniae, C/A resistance, and susceptibility to meropenem (MIC = 2 µg/L) were included; the blaKPC genotype was detected in all isolates revealing D179Y mutation in the blaKPC-2 (blaKPC-33) gene. Cluster analysis showed that 16 out of the 17 C/A-resistant KPC-Kp isolates belonged to a single clone. Thirteen strains (76.5%) were isolated in a 60-day period. Only some patients had a previous infection with non-mutant KPC at other sites (5; 29.4%). Eight patients (47.1%) underwent previous large-spectrum antibiotic treatment, and four patients (23.5%) had prior treatment with C/A. The secondary spread of the D179Y mutation in the blaKPC-2 during the COVID-19 pandemic needs to be addressed constantly by an interdisciplinary interaction between microbiologists, infection control personnel, clinicians, and infectious diseases consultants to properly diagnose and treat patients.

Multicentre Surveillance of Candida Species from Blood Cultures during the SARS-CoV-2 Pandemic in Southern Europe (CANCoVEU Project).

Introduction: Surveillance of Candida species isolates from blood cultures (BCs) in Europe is considered fragmented, unable to allow the definition of targets of antifungal stewardship recommendations especially during the SARS-CoV-2 pandemic. Methods: We performed a multicentric retrospective study including all consecutive BC Candida isolates from six Southern European tertiary hospitals (1st January 2020 to 31st December 2021). Etiology, antifungal susceptibility patterns, and clinical setting were analyzed and compared. Results: C. albicans was the dominant species (45.1%), while C. auris was undetected. Candida species positive BC events increased significantly in COVID-19 ICUs in 2021 but decreased in other ICUs. Resistance to azole increased significantly and remained very high in C. albicans (fluconazole from 0.7% to 4.5%, p = 0.03) and C. parapsilosis complex (fluconazole up to 24.5% and voriconazole up to 8.9%), respectively. Resistance to caspofungin was remarkable in C. tropicalis (10%) and C. krusei (20%), while resistance to at least one echinocandin increased in 2021, especially in C. parapsilosis complex (from 0.8% to 5.1%, p = 0.05). Although no significant differences were observed over the study period, fluconazole and echinocandin resistance increased in COVID-19 ICUs by up to 14% and 5.8%, respectively, but remained undetected in non-intensive COVID-19 wards. Conclusions: Antifungal stewardship activities aimed at monitoring resistance to echinocandin in C. tropicalis and C. krusei, and against the spread of fluconazole resistant C. parapsilosis complex isolates are highly desirable. In COVID-19 patients, antifungal resistance was mostly present when the illness had a critical course.

The humoral and cellular response to mRNA SARS-CoV-2 vaccine is influenced by HLA polymorphisms.

Host genetic variability contributes to susceptibility to SARS-CoV-2 infection and COVID-19 evolution and the role of HLA system has not clearly emerged, suggesting the involvement of other factors. Studying response to vaccination with Spyke protein mRNA represents an ideal model to highlight whether the humoral or cellular responses are influenced by HLA. Four hundred and sixteen workers, vaccinated with Comirnaty beginning 2021, were selected within the Azienda Ospedaliera Universitaria "Città della Salute e della Scienza di Torino." The humoral response was determined with the LIAISON® kit, while the analysis of the cellular response was performed with the Quantiferon SARS-CoV-2 assay, for the S1 (receptor-binding domain; Ag1) and S1 and S2 (Ag2) subunits of the Spyke protein. Six HLA loci were typed by next-generation sequencing. Associations between HLA and vaccine response were performed with univariate and multivariate analyses. An association was found between A*03:01, B*40:02 and DPB1*06:01 and high antibody concentration and between A*24:02, B*08:01 and C*07:01 and low humoral responses. The haplotype HLA-A*01:01 ~ B1*08:01 ~ C*07:01 ~ DRB1*03:01 ~ DQB1*02:01 conferred an increased risk of low humoral response. Considering cellular responses, 50% of the vaccinated subjects responded against Ag1 and 59% against Ag2. Carriers of DRB1*15:01 displayed a higher cellular response both to Ag1 and Ag2 compared to the rest of the cohort. Similarly, DRB1*13:02 predisposed to a robust cellular response to Ag1 and Ag2, while DRB1*11:04 showed an opposite trend. Cellular and humoral responses to Comirnaty are influenced by HLA. Humoral response is mainly associated to class I alleles, with A*03:01, previously associated to protection against severe COVID-19, and response to vaccination, standing out. Cellular response predominantly involves class II alleles, with DRB1*15:01 and DPB1*13:01 prevailing. Affinity analysis for Spyke peptides is generally in line with the association results.

Extraction Bottleneck in the Diagnosis of SARS-CoV-2: Evaluation of an Alternative Protocol Derived from Veterinary Use.

The COVID-19 pandemic represented a challenge for health-care systems, and a major bottleneck in SARS-CoV-2 diagnosis was the unavailability of extraction reagents. To overcome this limitation, we performed a comparative analysis to evaluate the performance of an alternative extraction protocol derived from veterinary use adapted to an open robotic platform (Testing method). A total of 73 nasopharyngeal swabs collected for diagnosis of SARS-CoV-2 infection were simultaneously extracted with the Testing protocol and the laboratory Standard of Care in order to assess the performance of the first one. The Cohen's coefficient between both procedures was excellent (K Value = 0.955). Analysis of cycle threshold and linear regression showed a significant correlation between the two methods for each tested genetic target. Although validated for veterinary applications, the Testing method showed excellent performances in RNA extraction, with several advantages: lower sample input volume, the possibility to overcome the lack of deep-well plates and adaptability to robotic liquid handlers.

Convalescent or standard plasma versus standard of care in the treatment of COVID-19 patients with respiratory impairment: short and long-term effects. A three-arm randomized controlled clinical trial.

BACKGROUND: The efficacy of early treatment with convalescent plasma in patients with COVID-19 is debated. Nothing is known about the potential effect of other plasma components other than anti-SARS-CoV-2 antibodies. METHODS: To determine whether convalescent or standard plasma would improve outcomes for adults in early phase of Covid19 respiratory impairment we designed this randomized, three-arms, clinical trial (PLACO COVID) blinded on interventional arms that was conducted from June 2020 to August 2021. It was a multicentric trial at 19 Italian hospitals. We enrolled 180 hospitalized adult patients with COVID-19 pneumonia within 5 days from the onset of respiratory distress. Patients were randomly assigned in a 1:1:1 ratio to standard of care (n = 60) or standard of care + three units of standard plasma (n = 60) or standard of care + three units of high-titre convalescent plasma (n = 60) administered on days 1, 3, 5 after randomization. Primary outcome was 30-days mortality. Secondary outcomes were: incidence of mechanical ventilation or death at day 30, 6-month mortality, proportion of days with mechanical ventilation on total length of hospital stay, IgG anti-SARS-CoV-2 seroconversion, viral clearance from plasma and respiratory tract samples, and variations in Sequential Organ Failure Assessment score. The trial was analysed according to the intention-to-treat principle. RESULTS: 180 patients (133/180 [73.9%] males, mean age 66.6 years [IQR 57-73]) were enrolled a median of 8 days from onset of symptoms. At enrollment, 88.9% of patients showed moderate/severe respiratory failure. 30-days mortality was 20% in Control arm, 23% in Convalescent (risk ratio [RR] 1.13; 95% confidence interval [CI], 0.61-2.13, P = 0.694) and 25% in Standard plasma (RR 1.23; 95%CI, 0.63-2.37, P = 0.544). Time to viral clearance from respiratory tract was 21 days for Convalescent, 28 for Standard plasma and 23 in Control arm but differences were not statistically significant. No differences for other secondary endpoints were seen in the three arms. Serious adverse events were reported in 1.7%, 3.3% and 5% of patients in Control, Standard and Convalescent plasma arms respectively. CONCLUSIONS: Neither high-titer Convalescent nor Standard plasma improve outcomes of COVID-19 patients with acute respiratory failure. Trial Registration Clinicaltrials.gov Identifier: NCT04428021. First posted: 11/06/2020.

Implementation of Chromatic Super CAZ/AVI® medium for active surveillance of ceftazidime-avibactam resistance: preventing the loop from becoming a spiral.

Acquired resistance towards ceftazidime-avibactam (CAZ-AVI) is increasingly reported. Several mechanisms can be involved, but mutations in the Ω-loop region of ß-lactamases are the most described. Herein, we assessed the implementation of Chromatic Super CAZ/AVI® medium in rectal swab surveillance cultures in a geographic area with endemic distribution of KPC-producing Klebsiella pneumoniae. Routine rectal swabs collected from the intensive care unit (ICU) and non-ICU patients were screened for carbapenemase-producing Enterobacterales (CPE), carbapenem-resistant Gram-negative organisms (CR-GN) and CAZ-AVI-resistant organisms by Chromatic CRE and Super CAZ/AVI® media. Among the 1839 patients screened, 146 (7.9%) were found to be colonized by one or more CPE and/or CR-GN isolates during hospitalization. Overall, among colonized patients the most common bacteria encountered were KPC-producing Enterobacterales (n = 60; 41.1%), carbapenem-resistant Pseudomonas aeruginosa (n = 41; 28.1%) and carbapenem-resistant A. baumannii (n = 34; 23.3%). Among patients colonized by KPC-producing Enterobacterales, thirty-five (58.3%) had CAZ-AVI-resistant strains. A 30.5% rate of faecal carriage of CAZ-AVI-resistant KPC-producing K. pneumoniae, substantially higher than that of susceptible isolates (2.8%), was observed in the COVID-19 ICU. Prevalence of faecal carriage of metallo-ß-lactamase-producing organisms was low (0.5% and 0.2% for Enterobacterales and P. aeruginosa, respectively). Chromatic Super CAZ/AVI® medium showed 100% sensitivity in detecting CPE or CR-GN isolates resistant to CAZ-AVI regardless of both MIC values and carbapenemase content. Specificity was 86.8%. The Chromatic Super CAZ/AVI® medium might be implemented in rectal swab surveillance cultures for identification of patients carrying CAZ-AVI-resistant organisms to contain the spread of these difficult-to-treat pathogens.

Immune Response of a Heterologous mRNA-1273 Second-Dose Immunization after a First Dose of ChadOx1 against SARS-CoV-2: A Cross-Sectional Study.

Heterologous vaccination regimens could contribute to broadening vaccination coverage. To date, there is little evidence on the effectiveness of a combination of adenoviral COVID-19 vaccines with a second dose of mRNA vaccines. This study aims to evaluate the antibody response to the SARS-CoV-2 spike protein 25 weeks after vaccination with mRNA-1273 after a first dose of ChAdOx1. A cross-sectional study was conducted collecting sociodemographic data, clinical characteristics, and serological data from among the general population. Antibody levels were expressed as binding antibody units (BAU) per mL (cutoff = 33.8 BAU/mL). Linear regression models were used to assess the relationship between the subjects' characteristics and anti-SARS-CoV-2 antibody levels. A total of 229 participants were followed up after a median time of 173 days. The overall anti-SARS-CoV-2 IgG antibody titer was 729.0 BAU/mL. The multivariable analysis showed that the only factor associated with anti-SARS-CoV-2 IgG levels was the BMI (p = 0.007), with decreases within the healthy range weight and increases in under- or overweight people. Our results support the use of heterologous COVID-19 vaccination regimens, as they can guarantee a sustained immune antibody response. More studies are needed to understand the link between BMI and body composition and the immune response to COVID-19 vaccinations.

First Cases of Candida auris in a Referral Intensive Care Unit in Piedmont Region, Italy.

Candida auris is an emerging healthcare-associated infection that can easily cause dissemination in hospitals through colonizing the skin and contaminating environmental surfaces, especially in Intensive Care Units (ICU). Difficulties with identification of this organism, uncertainty about routes of transmission and antifungals resistance have impacted significantly outbreak detection and management. Here, we describe our experience with colonization/infection of C. auris among critically ill patients, admitted to a referral ICU of a University Hospital, in a transitional period (July 2021-March 2022) between management of non-COVID-19 and COVID-19 patients due to the reconversion of the ICU between two waves. A total of 8 patients presented colonization from C. auris, and two of them developed invasive infection from C. auris. The fungal pathogen was cultured from different sites: the skin (7 isolates), urine (2), respiratory tract (1), blood (1). The median time from admission to first detection is 24 days with 100% of patients requiring mechanical ventilation. All 8 patients received broad-spectrum antibiotic therapy for bacterial infections before identification of C. auris; 62.5% of the patients had prior antifungal exposure; 87.5% received steroids; 37.5% patients used immunomodulatory; and 75% had severe COVID-19 illness prior to C. auris identification. Only two cases (25%) were treated with antifungals as C. auris infections (1 patient for suspected UTI; 1 patient with candidemia). Infection control measures, including rapid microbiological identification, contact isolation, screening of contacts, antisepsis of colonized patients, dedicated equipment, cleaning and disinfection of the environment and subsequent follow-up sampling, remain essential in critically ill patients. Our experience highlights the importance of establishing a multidisciplinary model and bundling of practices for preventing C. auris' spread.

An Observational Study of MDR Hospital-Acquired Infections and Antibiotic Use during COVID-19 Pandemic: A Call for Antimicrobial Stewardship Programs.

The pandemic caused by the COVID-19 virus has required major adjustments to healthcare systems, especially to infection control and antimicrobial stewardship. The objective of this study was to describe the incidence of multidrug-resistant (MDR) hospital-acquired infections (HAIs) and antibiotic consumption during the three waves of COVID-19 and to compare it to the period before the outbreak at Molinette Hospital, located in the City of Health and Sciences, a 1200-bed teaching hospital with surgical, medical, and intensive care units. We demonstrated an increase in MDR infections: particularly in K. pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp), A. baumannii, and MRSA. Fluoroquinolone use showed a significant increasing trend in the pre-COVID period but saw a significant reduction in the COVID period. The use of fourth- and fifth-generation cephalosporins and piperacillin-tazobactam increased at the beginning of the COVID period. Our findings support the need for restoring stewardship and infection control practices, specifically source control, hygiene, and management of invasive devices. In addition, our data reveal the need for improved microbiological diagnosis to guide appropriate treatment and prompt infection control during pandemics. Despite the infection control practices in place during the COVID-19 pandemic, invasive procedures in critically ill patients and poor source control still increase the risk of HAIs caused by MDR organisms.

Cellular Immune Response to BNT162b2 mRNA COVID-19 Vaccine in a Large Cohort of Healthcare Workers in a Tertiary Care University Hospital.

We describe the results of a T-cell immunity evaluation performed after a median elapsed time of 7 months from second-dose BNT162b2 vaccine administration, in a representative sample of 419 subjects from a large cohort of hospital workers. Overall, the Quantiferon SARS-CoV-2 assay detected a responsive pattern in 49.9%, 59.2% and 68.3% of subjects to three different antigenic stimuli from SARS-CoV-2, respectively, with 72.3% of positivity to at least one antigenic stimulus. Potential predictors of cellular response were explored by multivariable analyses; factors associated with positivity to cellular response (to Ag1 antigenic stimulus) were a previous SARS-CoV-2 infection (OR = 4.24, 95% CI 2.34-7.67, p < 0.001), increasing age (per year: OR = 1.03 95% CI 1.01-1.06, p = 0.019 and currently smoking (compared to never smoking) (OR = 1.93, 95% CI 1.11-3.36, p = 0.010). Increasing time interval between vaccine administration and T-cell test was associated with decreasing cellular response (per week of time: OR = 0.94, 95% CI 0.91-0.98, p = 0.003). A blood group A/AB/B (compared to group O) was associated with higher levels of cellular immunity, especially when measured as Ag2 antigenic stimulus. Levels of cellular immunity tended to be lower among subjects that self-reported an autoimmune disorder or an immunodeficiency and among males. Further studies to assess the protective significance of different serological and cellular responses to the vaccine toward the risk of reinfection and the severity of COVID-19 are needed to better understand these findings.

Factors Influencing Level and Persistence of Anti SARS-CoV-2 IgG after BNT162b2 Vaccine: Evidence from a Large Cohort of Healthcare Workers.

We aimed at evaluating quantitative IgG response to BNT162b2 COVID-19 vaccine among health care workers (HCW), and exploring the role of demographic, clinical, and occupational factors as predictors of IgG levels. On May 2021, among 6687 HCW at the largest tertiary care University-Hospital of Northwestern Italy, at a median of 15 weeks (Interquartile range-IQR 13.6-16.0) after second-dose, serological response was present in 99.8%. Seropositivity was >97% in all the subgroups, except those self-reporting immunodeficiency (94.9%). Overall, the median serological IgG value was 990 BAU/mL (IQR 551-1870), with most of subjects with previous SARS-CoV-2 infection or with shorter time lapse (2-8 weeks) between vaccination and serology with values in the highest quintile (>2080). At multivariable analysis, significant predictors of lower values were increasing age, male, current smoking, immunodeficiency, recent occupational contacts, and increasing time lapse from vaccination; conversely, previous infection and recent household contacts were significantly associated with higher IgG levels. Subjects with previous infection kept a very high level (around 2000 BAU/mL) up to 120 days. These results, besides supporting a high serological response up to 4-5 months, suggest predictive factors of faster decay of IgG levels that could be useful in tailoring vaccination strategies.

SARS-CoV-2 infection: use and effectiveness of antigenic swab for the health surveillance of healthcare workers.

BACKGROUND:  The gold standard to identify SARS-CoV-2 infections is the Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) on rhino-pharyngeal swabs, but faster and cheaper methods such as antigenic swabs have been developed. A retrospective observational study on antigenic swabs included in the extraordinary health surveillance protocol of a large Hospital in Turin was aimed to assess their performance validity. Methods: From 30 October 2020 to 4 May 2021, 4000 antigenic swabs were carried out in three groups of healthcare workers (HCWs), respectively (i) asymptomatic, (ii) cohabiting with a positive case, and (iii) not recently exposed to the virus.  Results: Overall sensitivity and specificity associated with a prevalence of 1.30% were 26.9%, 97.2%, respectively, the corresponding positive (PPV) and negative predictive value (NPV) being 11.29% and 99.02% [95% IC (99.00 - 99.04)] respectively; a prevalence of 0.29% was observed in the asymptomatic group, among whom sensitivity and specificity were 25.0% and 98.9%, respectively, the corresponding PPV and NPV being 6.25% and 99.78% [95% IC (99.76 - 99.81)], respectively; the cohabitant group showed a prevalence of 21.11%, sensitivity and specificity were 47.4%, 81.7%, respectively, giving rise to a PPV of 40.91% and NPV of 85.29% [95% IC (85.18 - 85.41)] respectively. The prevalence in the not exposed group was 0.77%, sensitivity and specificity were 29.2%, 97.4%, respectively, and PPV and NPV 8.05% and 99.44% [95% IC (99.42 - 99.46)] respectively. Conclusions: Antigenic swabs reduced costs and provided reliable diagnostic results. In the cohabitant group, the higher-prevalence groups showed poor test performances, likely because of the high prevalence of pre-symptomatic illness in this group. Owing to the relatively low NPV, a negative result would still require confirmation with a molecular test to be acceptable for a surveillance program that effectively reduces the virus's intra-hospital spread.

Occurrence of multi-carbapenemases producers among carbapenemase-producing Enterobacterales and in vitro activity of combinations including cefiderocol, ceftazidime-avibactam, meropenem-vaborbactam, and aztreonam in the COVID-19 era.

PURPOSE: To evaluate the prevalence of multi-carbapenemase-producing Enterobacterales (EB) and the activity of cefiderocol (CFDC), meropenem-vaborbactam (MEV), ceftazidime-avibactam (CZA), and combinations of CZA plus aztreonam (ATM), MEV plus ATM and CFDC plus CZA against them. METHODS: A collection of carbapenemase-producing EB clinical isolates (n = 1242) was investigated by lateral flow immunoassay NG-Test CARBA-5 and molecular testing. Cefiderocol MICs were determined using broth microdilution SensititreTM panel. MICs of CZA and MEV were determined by the gradient diffusion method. Antimicrobial synergy testing was performed using gradient diffusion strip crossing. RESULTS: KPC were the most frequent carbapenemases (83.2%), followed by VIM (9.2 %), OXA-48-like (4.3 %) and NDM enzymes (4.1%). Multi-carbapenemase producers were found in 10 (0.8%) isolates. Three combinations of two different carbapenemases were observed: KPC+VIM (n = 4), NDM+OXA-48-like (n = 4), and VIM+OXA-48-like (n = 2). CFDC showed potent activity against eight out of ten dual-carbapenemases producers, while resistance or reduced susceptibility was shown towards CZA and MEV. CFDC in combination with CZA showed no synergistic effects and only two additive effects on seven (87.5%) of the CFDC-susceptible strains. Conversely, CZA plus ATM and MEV plus ATM combinations were synergistic against all ATM-resistant strains regardless of dual-carbapenemases phenotype. CONCLUSIONS: The occurrence of multi-carbapenemase producers is not uncommon in Northern Italy area. MEV in combination with ATM might be considered as a potential therapeutic option, alternative to CZA plus ATM. CFDC susceptibility testing and synergy evaluation of ATM-based combinations should be performed in the lab routine to evaluate the most in vitro active antimicrobial regimen.

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

Seroconversion After Coronavirus Disease 2019 Vaccination in Patients Awaiting Liver Transplantation: Fact or Fancy?

Chronic liver disease increased the risk of severe coronavirus disease 2019 (COVID-19). Trials to assess efficacy/safety of COVID-19 vaccines in liver disease are underway. We evaluated the humoral immune response and safety of anti-COVID-19 vaccination among patients waiting liver transplantation (LT). We enrolled all pre-LT adults who completed anti-COVID-19 vaccination between January 2021-August 2021 as study group. Patients with histories of COVID-19 received 1 vaccine dose, and all others received 2 doses. Patients were tested for COVID-19 immunoglobulin G (IgG) within 1 and 2 months after vaccination. Safety was evaluated with telephone interviews/outpatient visits. A control group of 30 healthcare workers who underwent vaccination in January 2021 and tested for IgG after 4 months was included. In the 89 pre-LT patients, at T1 (23 days after vaccination), seroconversion rate was 94.4%, and median IgG value was 1980 binding antibody units/mL (interquartile range 646-2080), and at T2 (68 days after vaccination) was 92.0%, with IgG value of 1450 (577-2080); (T1 versus T2, P = 0.38). In the 10/89 patients who received 1 vaccine dose, the median IgG value was 274 (68-548) before vaccine (T0), 2080 (1165-2080) at T1, and 2030 (964-2080) at T2 (T0 versus T1, P = 0.03; T1 versus T2, P = 0.99). All controls tested positive at 4 months after vaccination, with a median value of 847 (509-1165; P < 0.001 versus T1 and P = 0.04 versus T2 in the study group). No serious adverse event was reported in both groups. Our data from 89 pre-LT patients suggest a high rate of immunization (94.4%) after a median time of 23 days from safe COVID-19 vaccine. None of the patients developed COVID-19.