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
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.
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.
Tommaso Matucci, Niccolò Riccardi, Sara Occhineri, Agostina Pontarelli, Giusy Tiseo, Marco Falcone, Mariangela Puci, Laura Saderi, and Giovanni Sotgiu
Elsevier BV
Marco Falcone and Giusy Tiseo
Ovid Technologies (Wolters Kluwer Health)
Purpose of review To highlight the peculiarity of skin and soft tissue infections (SSTIs) in elderly patients and to provide useful elements for their optimal management. Recent findings In the COVID-19 era, early discharge from the hospital and implementation of outpatient management is of key importance. Summary Elderly patients are at high risk of SSTIs due to several factors, including presence of multiple comorbidities and skin factors predisposing to infections. Clinical presentation may be atypical and some signs of severity, such as fever and increase in C-reactive protein, may be absent or aspecific in this patients population. An appropriate diagnosis of SSTIs in the elderly is crucial to avoid antibiotic overtreatment. Further studies should explore factors associated with bacterial superinfections in patients with pressure ulcers or lower limb erythema. Since several risk factors for methicillin-resistant Staphylococcus aureus (MRSA) may coexist in elderly patients, these subjects should be carefully screened for MRSA risk factors and those with high risk of resistant etiology should receive early antibiotic therapy active against MRSA. Physicians should aim to several objectives, including clinical cure, patient safety, early discharge and return to community. SSTIs in the elderly may be managed using long-acting antibiotics, but clinical follow-up is needed.
Theodossis Papavramidis, Ivan Gentile, Anna Maria Cattelan, Laura Magnasco, Pierluigi Viale, Daniela Francisci, Diamantis P. Kofteridis, Giusy Tiseo, Evangelos J. Giamarellos-Bourboulis, Filippo Lagi,et al.
Elsevier BV
Giusy Tiseo, Ili Margalit, Marco Ripa, Vanni Borghi, Hefziba Green, Virginie Prendki, Niccolò Riccardi, Yael Dishon, Giovanni Battista Perego, Alessandro Grembiale,et al.
Elsevier BV
Francesca Ambrosini, Niccolò Riccardi, Sara Occhineri, Tommaso Matucci, Irene Paraboschi, Alessandro Calarco, Alfredo Berrettini, Giusy Tiseo, Diana Canetti, André Van Der Merwe,et al.
Informa UK Limited
Purpose Haemorrhagic cystitis may be due to different etiologies with infectious diseases representing an insidious cause to diagnose. The aim of this narrative review is to provide a comprehensive overview of less common but difficult-to-diagnose causes of infectious haemorrhagic cystitis of bacterial, mycobacterial, and parasitic origin, Moreover, we highlight possible diagnostic tools and currently available treatment options in order to give an updated tool for urologists to use in daily practice. Patients and Methods The search engine PubMed was used to select peer-reviewed articles published from 1/Jan/2010 to 31/Aug/2022. Results Bacteria, fungal, TB and schistosomiasis are uncommon causes of haemorrhagic cystitis burdened by high morbidity, especially if not promptly diagnosed. Conclusion Because haemorrhagic cystitis ranges in severity from mild dysuria associated with pelvic discomfort to severe life-threatening haemorrhage, punctual diagnosis, and immediate treatment are essential to avoid further complications.
G. Tiseo, Valentina Galfo, S. Occhineri, Arianna Forniti, C. Caroselli, M. Falcone and F. Menichetti
Edizioni Internazionali srl, Divisione EDIMES Edizioni Medico-Scientifiche
Background
Superinfections acquired during the hospital course represent common complications in COVID-19 patients. Several studies reported an increasing incidence of COVID-19 associated pulmonary aspergillosis (CAPA) and candidaemia. The aim of this study is to describe fungal superinfections in a large cohort of hospitalized patients with COVID-19 and identify factors independently associated with the risk of fungal superinfections.
Methods
Observational study including patients with COVID-19 admitted to the tertiary-care, University Hospital of Pisa, Italy from April 2020 to May 2021. Patients with pneumonia and laboratory confirmed SARS-CoV-2 infection with a RT-PCR test on a nasopharyngeal swab, were eligible for the study. Patients who died within 24 hours from admission and those with missing data were excluded. Data about fungal superinfections were collected. To identify factors independently associated with the development of fungal superinfections, a multivariate regression analysis was performed.
Results
Among 983 patients with COVID-19, 52 (5.3%) fungal superinfections were detected. Fungal superinfections included: 24/52 (46%) CAPA, 27/52 (51.9%) episodes of candidaemia and 1 case of pulmonary pneumocystosis in a haematological patient. All patients with CAPA were cared for in intensive care unit (ICU). The majority of patients received liposomal amphotericin B as antifungal treatment (83.3%). In-hospital mortality was 41.7%. Among 27 episodes of candidaemia, 16 (59.3%) occurred in ICU while 11 (40.7%) in medical wards. In-hospital mortality was 14.8%. Overall, patients with fungal superinfections had a median age of 73 (IQRs 59-77) years and a median length of ICU stay of 40 (17-50) days. In-hospital mortality among all patients with superinfections was 28.8%. On multivariable analysis, ICU stay (OR 17.63, 95% CI 8.3-37.41, p<0.001), high-dose steroids (OR 13.48, 95% CI 6.68-27.26, p<0.001), and diabetes mellitus (OR 2.14, 95% CI 1.09-4.17, p=0.026) were factors independently associated with the risk of developing a fungal superinfection.
Conclusions
Fungal superinfections may complicate the hospital course of COVID-19 patients, especially of those admitted to ICU. Surveillance with detection of galactomannan on bronchoalveolar lavage in patients with clinical deterioration should be performed. A rational use of steroids is essential to avoid the risk of developing a fungal superinfection.
A. De Vito, V. Fiore, A. Colpani, B. Zauli, C. Fanelli, G. Tiseo, S. Occhineri, S. Babudieri, M. Falcone and G. Madeddu
Dalbavancin is a novel long-acting semi-synthetic lipoglycopeptide. It is licensed for acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. Many studies on dalbavancin alternative use in clinical practice have been published recently, including osteomyelitis, prosthetic joint infections (PJIs), and infective endocarditis (IE). Thus, we conducted a narrative review on dalbavancin efficacy in difficult-to-treat infections, such as osteomyelitis, PJIs, and IE. We performed a comprehensive literature search through electronic databases (PubMed-MEDLINE) and search engines (Google Scholar). We included peer-reviewed publications (articles and reviews), and grey literature on dalbavancin use in osteomyelitis, PJIs, and IE. No time or language restrictions have been established. Despite the great interest in clinical practice, only observational studies and case series on the use of dalbavancin in infections other than ABSSSI are available. The reported success rate was extremely variable between studies, ranging from 44% to 100%. A low success rate has been reported for osteomyelitis and joint infections, while in endocarditis, the success rate was higher than 70% in all studies. However, there is no literature agreement about the correct regimen of dalbavancin for this type of infection heretofore. Dalbavancin showed great efficacy and a good safety profile, not only in patients with ABSSSI but also in those with osteomyelitis, PJIs, and endocarditis. Further randomized clinical trials are needed to assess the optimal dosing schedule depending on the site of infection. Implementing therapeutic drug monitoring for dalbavancin may represent the future step to achieving optimal pharmacokinetic/pharmacodynamic target attainment.
Christian M Gill, David P Nicolau, Elif Aktas, Wadha Alfouzan, Lori Bourassa, Adrian Brink, Carey-Ann D Burnham, Rafael Canton, Yehuda Carmeli, Marco Falcone,et al.
Oxford University Press (OUP)
Abstract Objectives To evaluate the genotypic and ceftazidime/avibactam-susceptibility profiles amongst ceftolozane/tazobactam-non-susceptible (NS), MBL-negative Pseudomonas aeruginosa in a global surveillance programme. Methods Isolates were collected as part of the ERACE-PA Global Surveillance programme. Carbapenem-resistant P. aeruginosa deemed clinically relevant by the submitting laboratories were included. Broth microdilution MICs were conducted per CLSI standards to ceftolozane/tazobactam, ceftazidime/avibactam, ceftazidime and cefepime. Genotypic carbapenemases were detected using CarbaR and CarbaR NxG (research use only). Isolates negative for carbapenemases by PCR were assessed via WGS. Isolates were included in the analysis if they were ceftolozane/tazobactam-NS and lacked detection of known MBLs. Results Of the 807 isolates collected in the ERACE-PA programme, 126 (16%) were ceftolozane/tazobactam-NS and lacked MBLs. Cross-resistance to ceftazidime and cefepime was common, with only 5% and 16% testing susceptible, respectively. Ceftazidime/avibactam retained in vitro activity, with 65% of isolates testing susceptible. GES was the most common enzymology, detected in 57 (45%) isolates, and 89% remained susceptible to ceftazidime/avibactam. Seven isolates harboured KPC and all tested susceptible to ceftazidime/avibactam. In the remaining 62 isolates, WGS revealed various ESBLs or OXA β-lactamases. While 39% remained susceptible to ceftazidime/avibactam, marked variability was observed among the diverse resistance mechanisms. Conclusions Ceftazidime/avibactam remained active in vitro against the majority of ceftolozane/tazobactam-NS, MBL-negative P. aeruginosa. Ceftazidime/avibactam was highly active against isolates harbouring GES and KPC β-lactamases. These data highlight the potential clinical utility of genotypic profiling as well as the need to test multiple novel agents when carbapenem-resistant P. aeruginosa are encountered.
Giusy Tiseo, Chiara Barbieri, Valentina Galfo, Sara Occhineri, Tommaso Matucci, Francesco Almerigogna, Jona Kalo, Pietro Sponga, Mario Cesaretti, Gabriele Marchetti,et al.
Springer Science and Business Media LLC
Vered Daitch, Dana Yelin, Muhammad Awwad, Giovanni Guaraldi, Jovana Milić, Cristina Mussini, Marco Falcone, Giusy Tiseo, Laura Carrozzi, Francesco Pistelli,et al.
Elsevier BV
Anthony Onoja, Nicola Picchiotti, Chiara Fallerini, Margherita Baldassarri, Francesca Fava, Francesca Mari, Sergio Daga, Elisa Benetti, Mirella Bruttini, Maria Palmieri,et al.
Springer Science and Business Media LLC
AbstractWe employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, supporting their link with COVID-19 severity outcome.