Giusy Tiseo
@unipi.it
Department of Clinical and Experimental Medicine
University of Pisa
RESEARCH INTERESTS
Infectious disease, multidrug resistance and antimicrobial therapy
Scopus Publications
Scopus Publications
Giusy Tiseo, Dafna Yahav, Alaa Atamna, Tomer Avni, Manuel Causse, Elena Pérez-Nadales, Alessandra Mularoni, Elena Reigadas, María Olmedo-Samperio, Mario Fernández-Ruiz,et al.
Elsevier BV
Gabriele Marchetti, Lorenzo Roberto Suardi, Giusy Tiseo, Valentina Francesca Del Ricco, Niccolò Riccardi, Laura Rindi, and Marco Falcone
Elsevier BV
Marco Falcone, Valentina Galfo, and Giusy Tiseo
Ovid Technologies (Wolters Kluwer Health)
Purpose of review To correlate the resistance mechanisms and the susceptibility to new antibiotics in Pseudomonas aeruginosa. Recent findings Definition of antibiotic resistance in Pseudomonas aeruginosa is still debated. Carbapenem-resistant Pseudomonas aeruginosa (CRPA) and difficult-to-treat resistant Pseudomonas aeruginosa (DTR-PA) are used but which of them better correlate with the risk of mortality remains debated. Mechanisms underlying resistance in Pseudomonas aeruginosa are complex and may be combined, resulting in unpredictable phenotype and cross-resistance. Thus, not all CRPA are alike and tailoring antibiotic therapy on resistance mechanisms is challenging. Summary Current guidelines recommend the use of new antipseudomonal agents for CRPA or DTR-PA infections but they don’t provide specific information on how tailoring antibiotic therapy on underlying resistance mechanisms. This review may be useful to understand which mechanisms are involved in CRPA and may have practical implications helping clinicians to select an appropriate antibiotic regimen. Several antibiotics are now available for Pseudomonas aeruginosa but their rational use is important to avoid development of future resistance. The knowledge of local epidemiology and most common resistance mechanisms may guide empirical therapy, but targeted antibiotic therapy should be re-evaluated as soon as susceptibility testing profile is available and selected according to Pseudomonas aeruginosa phenotype.
Francesca Minnai, Filippo Biscarini, Martina Esposito, Tommaso A. Dragani, Luis Bujanda, Souad Rahmouni, Marta E. Alarcón-Riquelme, David Bernardo, Elena Carnero-Montoro, Maria Buti,et al.
Springer Science and Business Media LLC
AbstractThe clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10−8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10−8). A total of 113 variants were associated with survival at P-value < 1.0 × 10−5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways.
Ryan K Shields, Ava J Dorazio, Giusy Tiseo, Kevin M Squires, Alessandro Leonildi, Cesira Giordano, Ellen G Kline, Simona Barnini, Alina Iovleva, Marissa P Griffith,et al.
Oxford University Press (OUP)
Abstract Background Cefiderocol exhibits potent in vitro activity against carbapenem-resistant Acinetobacter baumannii (CRAb), but this activity has not consistently translated to improved outcomes among patients. Cefiderocol heteroresistance, or the presence of a resistant subpopulation, has been proposed as one possible explanation. The objective of this study was to explore associations between heteroresistance and outcomes of patients with CRAb infections. Methods Baseline CRAb isolates were collected from 27 consecutive patients in the USA and Italy. Cefiderocol susceptibility was tested by broth microdilutions in triplicate. Heteroresistance was defined by population analysis profiling in duplicate. Resistance mechanisms and strain relatedness were evaluated through comparative genomic analysis. Results Overall, 59% of infecting CRAb isolates were identified as cefiderocol-heteroresistant; rates were higher among isolates from Italy (79%) than the USA (38%). The median Charlson Comorbidity and SOFA scores were 4 and 5, respectively; 44% of patients had pneumonia, which was the most common infection type. Rates of 28-day clinical success and survival were 30% and 73%, respectively. By broth microdilution, cefiderocol MICs ≥1 mg/L were associated with higher failure rates than MICs ≤0.5 mg/L (81% versus 55%). Rates of clinical failure were numerically higher among patients infected by cefiderocol-heteroresistant compared with susceptible CRAb (81% versus 55%). Whole-genome sequencing identified a premature stop codon in the TonB-dependent receptor gene piuA in six isolates, all of which were heteroresistant. Conclusions This pilot study supports the hypothesis that cefiderocol treatment failure may be associated with higher MICs and/or the presence of heteroresistance. Further studies are needed to confirm these findings.
Marianna Meschiari, Antoine Asquier-Khati, Giusy Tiseo, David Luque-Paz, Rita Murri, David Boutoille, Marco Falcone, Cristina Mussini, and Pierre Tattevin
Elsevier BV
Gabriele Martelloni, Alessio Turchi, Chiara Fallerini, Andrea Degl’Innocenti, Margherita Baldassarri, Simona Olmi, Simone Furini, Alessandra Renieri, and
Frontiers Media SA
The impact of common and rare variants in COVID-19 host genetics has been widely studied. In particular, in Fallerini et al. (Human genetics, 2022, 141, 147–173), common and rare variants were used to define an interpretable machine learning model for predicting COVID-19 severity. First, variants were converted into sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. After that, the Boolean features, selected by these logistic models, were combined into an Integrated PolyGenic Score (IPGS), which offers a very simple description of the contribution of host genetics in COVID-19 severity.. IPGS leads to an accuracy of 55%–60% on different cohorts, and, after a logistic regression with both IPGS and age as inputs, it leads to an accuracy of 75%. The goal of this paper is to improve the previous results, using not only the most informative Boolean features with respect to the genetic bases of severity but also the information on host organs involved in the disease. In this study, we generalize the IPGS adding a statistical weight for each organ, through the transformation of Boolean features into “Boolean quantum features,” inspired by quantum mechanics. The organ coefficients were set via the application of the genetic algorithm PyGAD, and, after that, we defined two new integrated polygenic scores (IPGSph1 and IPGSph2). By applying a logistic regression with both IPGS, (IPGSph2 (or indifferently IPGSph1) and age as inputs, we reached an accuracy of 84%–86%, thus improving the results previously shown in Fallerini et al. (Human genetics, 2022, 141, 147–173) by a factor of 10%.
Marco Falcone, Cesira Giordano, Alessandro Leonildi, Valentina Galfo, Aurelio Lepore, Lorenzo Roberto Suardi, Niccolò Riccardi, Simona Barnini, and Giusy Tiseo
Oxford University Press (OUP)
Abstract Background Metallo-β-lactamase (MBL)–producing Enterobacterales are increasing worldwide. Our aim was to describe clinical features, treatments, and outcomes of infections by MBL-Enterobacterales. Methods A prospective observational study conducted in the Pisa University Hospital (January 2019 to October 2022) included patients with MBL-producing Enterobacterales infections. The primary outcome measure was the 30-day mortality rate. Multivariable Cox regression analysis was performed to identify factors associated with that mortality rate, and adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated. Results The study’s 343 patients included 15 with Verona integron-encoded MBL (VIM)- and 328 with New Delhi MBL (NDM)–producing Enterobacterales infections; there were 199 patients (58%) with bloodstream infections, 60 (17.5%) with hospital-acquired or ventilator-associated pneumonia, 60 (17.5%) with complicated urinary tract infections, 13 (3.8%) with intra-abdominal infections, and 11 (3.2%) with skin and soft-tissue infections. The 30-day mortality rate was 29.7%. Of 343 patients, 32 did not receive in vitro active antibiotic therapy, 215 (62.7%) received ceftazidime-avibactam plus aztreonam, 33 (9.6%) received cefiderocol-containing regimens, 26 (7.6%) received colistin-containing regimens, and 37 (10.8%) received other active antibiotics. On multivariable analysis, septic shock (aHR, 3.57 [95% CI, 2.05–6.23]; P &lt; .001) and age (1.05 [1.03–1.08]; P &lt; .001) were independently associated with the 30-day mortality rate, while in vitro active antibiotic therapy within 48 hours after infection (0.48 [.26–.8]; P = .007) and source control (0.43 [.26–.72]; P = .001) were protective factors. Sensitivity analysis showed that ceftazidime-avibactam plus aztreonam, compared with colistin, was independently associated with a reduced 30-day mortality rate (aHR, 0.39 [95% CI, .18–.86]; P = .02). Propensity score analyses confirmed these findings. Conclusions MBL-producing carbapenem-resistant Enterobacterales infections are associated with high 30-day mortality rates. Patients with MBL-producing Enterobacterales infections should receive early active antibiotic therapy.
Kamilia Abdelraouf, Christian M Gill, Matthew Gethers, Giusy Tiseo, Simona Barnini, Marco Falcone, Francesco Menichetti, and David P Nicolau
Oxford University Press (OUP)
Abstract Background In vitro–in vivo discordance in β-lactams’ activities against metallo-ß-lactamase (MBL)-producing Enterobacterales has been described. We aimed to assess whether this discordance is attributed to the supra-physiologic zinc concentration in in vitro testing media. Methods A clinical and microbiological observational study of patients with bloodstream infections due to New Delhi metallo-ß-lactamase-producing Klebsiella pneumoniae was performed. Outcomes of patients treated empirically with non-MBL-active β-lactam therapy (carbapenems and ceftazidime/avibactam) and MBL-active β-lactam therapy (ceftazidime/avibactam + aztreonam) were documented. The patients’ isolates were used to induce septicemia in mice, and survival upon meropenem treatment was recorded. Meropenem minimum inhibitory concentrations (MICs) were determined in standard media and in the presence of physiological zinc concentrations. Results Twenty-nine patients receiving empiric non-MBL-active β-lactams (median duration, 4 days) were compared with 29 receiving MBL-active β-lactams. The 14-day mortality rates were 21% and 14%, respectively. In the murine septicemia model, meropenem treatment resulted in protection from mortality (P &lt; .0001). Meropenem MICs in the physiologic zinc concentration broth were 1- to &gt;16-fold lower vs MICs in zinc-unadjusted broth (≥64 mg/L). Conclusions Our data provide foundational support to establish pharmacokinetic/pharmacodynamic relationships using MICs derived in physiologic zinc concentration, which may better predict β-lactam therapy outcome.
Giusy Tiseo, Valentina Galfo, Sergio Carbonara, Andrea Marino, Giovanni Di Caprio, Anna Carretta, Alessandra Mularoni, Michele Fabiano Mariani, Alberto Enrico Maraolo, Riccardo Scotto,et al.
Springer Science and Business Media LLC
Valentina Galfo, Giusy Tiseo, Niccolò Riccardi, and Marco Falcone
Elsevier BV
Marco Falcone, Giusy Tiseo, Gabriele Marchetti, Jona Kalo, Valentina Galfo, Sara Occhineri, Francesco Almerigogna, Tommaso Matucci, Niccolò Riccardi, Lorenzo Roberto Suardi,et al.
Informa UK Limited
We emulated a hypothetical target trial in which hematological subjects cared at the University Hospital of Pisa (Italy) received or not SARS-CoV-2 prophylaxis with tixagevimab/cilgavimab. Subjects who received prophylaxis (cases) were compared to those who did not (controls). The main outcome was SARS-CoV-2 infection in the subsequent 6 months. Inverse probability weighting (IPW) was used to adjust for confounders. A multivariable analysis was performed to identify variables associated with SARS-CoV-2 infection. We recruited 462 patients: 228 received prophylaxis, 234 were controls. COVID-19 was lower in cases compared to controls (16.7% vs 24.8%, p = 0.03, after IPW 14.3% vs 24.6%, p = 0.01). On multivariable analysis, B-cell depleting therapies (HR 2.09, 95%CI 1.05-4.18, p = 0.037) were associated with increased risk of COVID-19, while tixagevimab/cilgavimab prophylaxis (HR 0.45, 95%CI 0.27-0.73, p = 0.001) and previous SARS-CoV-2 infection (HR 0.27, 95%CI 0.14-0.51, p < 0.001) were protective. In conclusion, prophylaxis with monoclonal antibodies may reduce the risk of COVID-19 in hematological patients.
Veronica Strazza, Marco Rossi, Andrea Avati, Giusy Tiseo, Marco Falcone, Maria Grazia Cusi, Francesco Menichetti, Paola Ricciardi-Castagnoli, Cristina Tinti, and Piero Pileri
Frontiers Media SA
Monoclonal antibodies (mAbs) are one of the most important classes of biologics with high therapeutic and diagnostic value, but traditional methods for mAbs generation, such as hybridoma screening and phage display, have limitations, including low efficiency and loss of natural chain pairing. To overcome these challenges, novel single B cell antibody technologies have emerged, but they also have limitations such as in vitro differentiation of memory B cells and expensive cell sorters. In this study, we present a rapid and efficient workflow for obtaining human recombinant monoclonal antibodies directly from single antigen-specific antibody secreting cells (ASCs) in the peripheral blood of convalescent COVID-19 patients using ferrofluid technology. This process allows the identification and expression of recombinant antigen-specific mAbs in less than 10 days, using RT-PCR to generate linear Ig heavy and light chain gene expression cassettes, called “minigenes”, for rapid expression of recombinant antibodies without cloning procedures. This approach has several advantages. First, it saves time and resources by eliminating the need for in vitro differentiation. It also allows individual antigen-specific ASCs to be screened for effector function prior to recombinant antibody cloning, enabling the selection of mAbs with desired characteristics and functional activity. In addition, the method allows comprehensive analysis of variable region repertoires in combination with functional assays to evaluate the specificity and function of the generated antigen-specific antibodies. Our approach, which rapidly generates recombinant monoclonal antibodies from single antigen-specific ASCs, could help to identify functional antibodies and deepen our understanding of antibody dynamics in the immune response through combined antibody repertoire sequence analysis and functional reactivity testing.
Giusy Tiseo, Valentina Galfo, Niccolò Riccardi, Lorenzo Roberto Suardi, Manuela Pogliaghi, Cesira Giordano, Alessandro Leonildi, Simona Barnini, and Marco Falcone
Springer Science and Business Media LLC
Abstract Purpose Real-world experience with meropenem/vaborbactam (M/V) is limited. Our aim is to report a clinical experience of M/V in the treatment of resistant Gram-negative bacilli. Methods This is a prospective observational study including patients hospitalized in the University Hospital of Pisa (March 2021–Jan 2023) with infections by both extended-spectrum β-lactamases (ESBL)-producing Enterobacterales and carbapenem-resistant Klebsiella pneumoniae (Kp) treated with M/V. The primary outcome measure was clinical success, defined as a composite of survival, resolution of signs and symptoms and absence of microbiological failure at day 30 from infection onset. A multivariable regression analysis was performed to identify factors associated with clinical failure. Odds ratio (OR) with 95% confidence intervals (CI) was calculated. Results A total of 104 patients who received M/V were included: 24/104 (23.1%) infections were caused by ESBL non-hypervirulent Enterobacterales, 17/104 (16.3%) by ESBL-producing hypervirulent Klebsiella pneumoniae (hvKp) and 63/104 (60.6%) by CRE. The most common infections were bloodstream infections, followed by urinary tract infections, hospital-acquired pneumonia, intra-abdominal infections and others. Septic shock occurred in 16/104 (15.4%) patients. Clinical success was achieved in 77% of patients, and 30-day mortality rate was 15.4%. In patients with KPC-producing Kp infections, clinical success and 30-day mortality rates were 82% and 11.5%, respectively. On multivariable analysis, SOFA score (OR 1.32, 95% CI 1.02–1.7, p=0.032) was independently associated with clinical failure, while source control (OR 0.16, 95% CI 0.03–0.89, p=0.036) was protective. Conclusions M/V is a promising therapeutic option against infections caused by difficult-to-treat ESBL-producing Enterobacterales and CR-Kp.
Su Young Lee, Christian M Gill, David P Nicolau, Elif Aktas, Wadha Alfouzan, Lori Bourassa, Adrian Brink, Carey-Ann D Burnham, Rafael Canton, Yehuda Carmeli,et al.
Oxford University Press (OUP)
Abstract Background Antimicrobial resistance in Pseudomonas aeruginosa is complex and multifaceted. While the novel β-lactamase inhibitors (BLIs) avibactam, relebactam and vaborbactam inhibit serine-based β-lactamases, the comparative potency of the novel β-lactam (BL)/BLI combinations against serine carbapenemase-producing P. aeruginosa is unknown. Objectives To compare the in vitro activity of ceftazidime/avibactam, ceftazidime, imipenem/relebactam, imipenem, meropenem/vaborbactam and meropenem against serine β-lactamase-producing P. aeruginosa. Methods Carbapenem-resistant P. aeruginosa were collated through the Enhancing Rational Antimicrobials against Carbapenem-resistant P. aeruginosa (ERACE-PA) Global Surveillance. Isolates positive for serine-based carbapenemases were assessed. MICs were determined by broth microdilution to each novel BL/BLI and BL alone. Results GES was the most common carbapenemase identified (n = 59) followed by KPC (n = 8). Ceftazidime/avibactam had MIC50/MIC90 values of 4/8 mg/L and 91% of isolates were susceptible. Conversely, ceftazidime alone was active against only 3% of isolates. The MIC50/MIC90 of imipenem/relebactam were 16/&gt;16 mg/L and 13% of all isolates were defined as susceptible. Of the KPC-producing isolates, 38% were susceptible to imipenem/relebactam, compared with 0% to imipenem. The meropenem/vaborbactam MIC50/MIC90 were &gt;16/&gt;16 mg/L, and 6% of isolates were susceptible, which was similar to meropenem alone (MIC50/90, &gt;8/&gt;8 mg/L; 3% susceptible) suggesting the addition of vaborbactam cannot overcome co-expressed, non-enzymatic resistance mechanisms. Conclusions Among the novel BL/BLIs, ceftazidime/avibactam displayed better in vitro activity and thus is a rational treatment option for serine carbapenemase-harbouring P. aeruginosa. While imipenem/relebactam displayed some activity, particularly against isolates with blaKPC, meropenem/vaborbactam exhibited poor activity, with MICs similar to meropenem alone.
Giusy Tiseo, Valentina Galfo, and Marco Falcone
Ovid Technologies (Wolters Kluwer Health)
Purpose of review The aim of this study was to discuss the potential clinical significance of heteroresistance in nonfermenting Gram-negative bacilli (GNB). Recent findings Recently, heteroresistance has been considered potentially responsible for clinical failure in Acinetobacter baumannii infections. This raised a scientific debate, still open, about the potential clinical significance of heteroresistance in nonfermenting GNB. Summary We reviewed the literature of last 20 years and found a limited number of studies evaluating the relationship between heteroresistance and clinical outcome in nonfermenting GNB. Unlike Gram-positive bacteria, heteroresistance is reported in a significant proportion of nonfermenting GNB with some studies describing it in all tested strains and for several antibiotics (including tigecycline, carbapenems, levofloxacin, cefiderocol, colistin). One important issue is the need for validated detection method since the population analysis profile test, that is considered the gold standard, requires high costs and time. Studies evaluating the correlation between heteroresistance and clinical outcome are contrasting and have several limitations. Although in-vitro detection of heteroresistance in nonfermenting GNB has not been associated with in-vivo treatment failure, its presence may suggest to prefer combination regimens instead monotherapy when treating infections by nonfermenters. Further studies are needed to clarify the clinical significance of heteroresistance.
Laura Bergantini, Margherita Baldassarri, Miriana d’Alessandro, Giulia Brunelli, Gaia Fabbri, Kristina Zguro, Andrea Degl’Innocenti, Francesca Mari, Sergio Daga, Ilaria Meloni,et al.
Springer Science and Business Media LLC
Abstract Background Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel coronavirus that caused an ongoing pandemic of a pathology termed Coronavirus Disease 19 (COVID-19). Several studies reported that both COVID-19 and RTEL1 variants are associated with shorter telomere length, but a direct association between the two is not generally acknowledged. Here we demonstrate that up to 8.6% of severe COVID-19 patients bear RTEL1 ultra-rare variants, and show how this subgroup can be recognized. Methods A cohort of 2246 SARS-CoV-2-positive subjects, collected within the GEN-COVID Multicenter study, was used in this work. Whole exome sequencing analysis was performed using the NovaSeq6000 System, and machine learning methods were used for candidate gene selection of severity. A nested study, comparing severely affected patients bearing or not variants in the selected gene, was used for the characterisation of specific clinical features connected to variants in both acute and post-acute phases. Results Our GEN-COVID cohort revealed a total of 151 patients carrying at least one RTEL1 ultra-rare variant, which was selected as a specific acute severity feature. From a clinical point of view, these patients showed higher liver function indices, as well as increased CRP and inflammatory markers, such as IL-6. Moreover, compared to control subjects, they present autoimmune disorders more frequently. Finally, their decreased diffusion lung capacity for carbon monoxide after six months of COVID-19 suggests that RTEL1 variants can contribute to the development of SARS-CoV-2-elicited lung fibrosis. Conclusion RTEL1 ultra-rare variants can be considered as a predictive marker of COVID-19 severity, as well as a marker of pathological evolution in pulmonary fibrosis in the post-COVID phase. This notion can be used for a rapid screening in hospitalized infected people, for vaccine prioritization, and appropriate follow-up assessment for subjects at risk. Trial Registration NCT04549831 (www.clinicaltrial.org)
Giusy Tiseo, Lorenzo Roberto Suardi, Alessandro Leonildi, Cesira Giordano, Simona Barnini, and Marco Falcone
Oxford University Press (OUP)
N. Riccardi, S. Occhineri, T. Matucci, G. Marchetti, L. Rindi, G. Tiseo, D. M. Cirillo, and M. Falcone
International Union Against Tuberculosis and Lung Disease
Riccardo Taddei, Niccolò Riccardi, Giusy Tiseo, Valentina Galfo, and Giandomenico Biancofiore
MDPI AG
Despite recent advances in the transplant field, infectious complications after orthotopic liver transplantation (OLT) are major causes of morbidity and mortality. Bacterial intra-abdominal infections (IAIs) are predominant during the first month post-transplantation and affect patient and graft survival. Recently, the emergence of multidrug resistant bacteria has generated great concern in OLT patients. We performed this narrative review of the literature in order to propose a “ready-to-use” flowchart for reasoned empirical antibiotic therapy in the case of suspected post-OLT IAIs. The review was ultimately organized into four sections: “Epidemiology and predisposing factors for IAI”; “Surgical-site infections and perioperative prophylaxis”; “MDRO colonization and infections”; and “Reasoned-empirical antibiotic therapy in early intra-abdominal infections post OLT and source control”. Multidisciplinary teamwork is warranted to individualize strategies for the prevention and treatment of IAIs in OLT recipients, taking into account each patient’s risk factors, the surgical characteristics, and the local bacterial epidemiology.
Ivan Gentile, Antonio Riccardo Buonomo, Silvia Corcione, Laurenza Paradiso, Daniele Roberto Giacobbe, Davide Fiore Bavaro, Giusy Tiseo, Francesca Sordella, Michele Bartoletti, Giulia Palmiero,et al.
Elsevier BV
Elena Pérez-Nadales, Mario Fernández-Ruiz, Alejandra M. Natera, Belén Gutiérrez-Gutiérrez, Alessandra Mularoni, Giovanna Russelli, Ligia Camera Pierrotti, Maristela Pinheiro Freire, Marco Falcone, Giusy Tiseo,et al.
Elsevier BV
Marco Falcone, Giusy Tiseo, Sergio Carbonara, Andrea Marino, Giovanni Di Caprio, Anna Carretta, Alessandra Mularoni, Michele Fabiano Mariani, Alberto Enrico Maraolo, Riccardo Scotto,et al.
Oxford University Press (OUP)
Abstract Background Our aim was to analyze mortality attributable to carbapenem-resistant (CR) gram-negative bacilli (GNB) in patients with bloodstream infections (BSIs). Methods Prospective multicentric study including patients with GNB-BSI from 19 Italian hospitals (June 2018–January 2020). Patients were followed-up to 30 days. Primary outcomes were 30-day mortality and attributable mortality. Attributable mortality was calculated in the following groups: Klebsiella pneumoniae carbapenemase (KPC)–producing Enterobacterales, metallo-β-lactamases (MBL)–producing Enterobacterales, CR-Pseudomonas aeruginosa (CRPA), CR-Acinetobacter baumannii (CRAB). A multivariable analysis with hospital fixed-effect was built to identify factors associated with 30-day mortality. Adjusted OR (aORs) were reported. Attributable mortality was calculated according to the DRIVE-AB Consortium. Results Overall, 1276 patients with monomicrobial GNB BSI were included: 723/1276 (56.7%) carbapenem-susceptible (CS)-GNB, 304/1276 (23.8%) KPC-, 77/1276 (6%) MBL-producing CRE, 61/1276 (4.8%) CRPA, and 111/1276 (8.7%) CRAB BSI. Thirty-day mortality in patients with CS-GNB BSI was 13.7% compared to 26.6%, 36.4%, 32.8% and 43.2% in patients with BSI by KPC-CRE, MBL-CRE, CRPA and CRAB, respectively (P &lt; .001). On multivariable analysis, age, ward of hospitalization, SOFA score, and Charlson Index were factors associated with 30-day mortality, while urinary source of infection and early appropriate therapy resulted protective factors. Compared to CS-GNB, MBL-producing CRE (aOR 5.86, 95% CI 2.72–12.76), CRPA (aOR 1.99, 95% CI 1.48–5.95) and CRAB (aOR 2.65, 95% CI 1.52–4.61) were significantly associated with 30-day mortality. Attributable mortality rates were 5% for KPC-, 35% for MBL, 19% for CRPA, and 16% for CRAB. Conclusions In patients with BSIs, carbapenem-resistance is associated with an excess of mortality, with MBL-producing CRE carrying the highest risk of death.
Giusy Tiseo, Cesira Giordano, Alessandro Leonildi, Niccolò Riccardi, Valentina Galfo, Federica Limongi, Manuela Nicastro, Simona Barnini, and Marco Falcone
Oxford University Press (OUP)
Abstract Background Carbapenem-resistant Acinetobacter baumannii (CRAB) infections are associated with high mortality rates. The optimal treatment regimen for CRAB has not been defined. Cefiderocol has been recently introduced in the armamentarium against CRAB but there is concern about treatment-emergent resistance. Since mortality rates in CRAB infections remain high, further antibiotic options are needed. Methods We report a case of severe infection by CRAB resistant to both colistin and cefiderocol treated with sulbactam/durlobactam and describe the molecular features of the strain. Susceptibility to cefiderocol was detected by disc diffusion according to EUCAST breakpoints. Susceptibility to sulbactam/durlobactam was determined by Etest according to preliminary breakpoints provided by Entasis Therapeutics. Whole Genome Sequencing (WGS) of the CRAB isolate was performed. Results A burn patient with ventilator-associated pneumonia by CRAB resistant to colistin and cefiderocol received sulbactam/durlobactam as compassionate use. She was alive after 30 days from the end of therapy. Complete microbiological eradication of CRAB was achieved. The isolate harboured blaADC-30, blaOXA-23 and blaOXA-66. A missense mutation in PBP3 was detected. The isolate harboured a mutation in the TonB-dependent siderophore receptor gene piuA that showed a frameshift mutation causing a premature stop codon (K384fs). Moreover, the fepA gene, which is orthologous to pirA, was interrupted by a transposon insertion P635-ISAba125 (IS30 family). Conclusions Further treatment options for severe infections by CRAB resistant to all available antibiotics are urgently needed. Sulbactam/durlobactam may be a future option against MDR A. baumannii.
Ili Margalit, Giusy Tiseo, Marco Ripa, Vanni Borghi, Hefziba Green, Virginie Prendki, Niccolò Riccardi, Giovanni Battista Perego, Alessandro Grembiale, Laura Galli,et al.
Oxford University Press (OUP)
Abstract Introduction The effect of remdesivir on COVID-19 mortality remains conflicting. Elderly individuals are at risk for poor COVID-19 outcomes. We aimed to assess the effect of remdesivir on COVID-19 mortality among elderly individuals, using real-world data. Methods Retrospective multinational cohort of individuals aged ≥65 years, hospitalized with COVID-19 in six medical centres between January 2020 and May 2021. Associations with in-hospital mortality were evaluated using a multivariable logistic regression model with propensity score adjustment for remdesivir therapy and while implementing generalized estimating equations to control for centre effect. Sensitivity analysis was performed by stratification according to the degree of respiratory support. Results Of 3010 individuals included, 2788 individuals required either oxygen supplementation or non-invasive/invasive mechanical ventilation, 489 (16%) were treated with remdesivir, and 836 (28%) died. Median age was 77 (IQR 70–84) years and 42% were women. Remdesivir was the only therapeutic intervention associated with decreased mortality [adjusted OR (aOR) 0.49, 95% CI 0.37–0.66, P &lt; 0.001]. This protective effect was shown for individuals requiring oxygen support and non-invasive mechanical ventilation, while no association was found among individuals necessitating invasive mechanical ventilation. Risk factors for mortality included invasive ventilation (aOR 5.18, 95% CI 2.46–10.91, P &lt; 0.001), higher serum creatinine (aOR 1.25, 95% CI 1.09–1.43, P = 0.001) and dyspnoea (aOR 1.40, 95% CI 1.07–1.84, P = 0.015) on presentation, and other non-modifiable factors, such as comorbidities. Conclusions Among elderly individuals hospitalized with COVID-19, remdesivir carries survival benefit for those with moderate to severe disease. Its role among individuals with critical illness should be further assessed.