Publications by authors named "Maurizio Sanguinetti"

386 Publications

Targeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models.

Cancers (Basel) 2021 Nov 7;13(21). Epub 2021 Nov 7.

Department of Biotechnology, Chemistry & Pharmacy, University of Siena, I-53100 Siena, Italy.

DDX3X is an ATP-dependent RNA helicase that has recently attracted interest for its involvement in viral replication and oncogenic progression. Starting from hit compounds previously identified by our group, we have designed and synthesized a new series of DDX3X inhibitors that effectively blocked its helicase activity. These new compounds were able to inhibit the proliferation of cell lines from different cancer types, also in DDX3X low-expressing cancer cell lines. According to the absorption, distribution, metabolism, elimination properties, and antitumoral activity, compound BA103 was chosen to be further investigated in glioblastoma models. BA103 determined a significant reduction in the proliferation and migration of U87 and U251 cells, downregulating the oncogenic protein β-catenin. An in vivo evaluation demonstrated that BA103 was able to reach the brain and reduce the tumor growth in xenograft and orthotopic models without evident side effects. This study represents the first demonstration that DDX3X-targeted small molecules are feasible and promising drugs also in glioblastoma.
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http://dx.doi.org/10.3390/cancers13215569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8582824PMC
November 2021

Diagnosis and Treatment of Bacterial Pneumonia in Critically Ill Patients with COVID-19 Using a Multiplex PCR Assay: A Large Italian Hospital's Five-Month Experience.

Microbiol Spectr 2021 Nov 10:e0069521. Epub 2021 Nov 10.

Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy.

Bacterial pneumonia is a challenging coronavirus disease 2019 (COVID-19) complication for intensive care unit (ICU) clinicians. Upon its implementation, the FilmArray pneumonia plus (FA-PP) panel's practicability for both the diagnosis and antimicrobial therapy management of bacterial pneumonia was assessed in ICU patients with COVID-19. Respiratory samples were collected from patients who were mechanically ventilated at the time bacterial etiology and antimicrobial resistance were determined using both standard-of-care (culture and antimicrobial susceptibility testing [AST]) and FA-PP panel testing methods. Changes to targeted and/or appropriate antimicrobial therapy were reviewed. We tested 212 samples from 150 patients suspected of bacterial pneumonia. Etiologically, 120 samples were positive by both methods, two samples were culture positive but FA-PP negative (i.e., negative for on-panel organisms), and 90 were negative by both methods. FA-PP detected no culture-growing organisms (mostly Staphylococcus aureus or Pseudomonas aeruginosa) in 19 of 120 samples or antimicrobial resistance genes in two culture-negative samples for S. aureus organisms. Fifty-nine (27.8%) of 212 samples were from empirically treated patients. Antibiotics were discontinued in 5 (33.3%) of 15 patients with FA-PP-negative samples and were escalated/deescalated in 39 (88.6%) of 44 patients with FA-PP-positive samples. Overall, antibiotics were initiated in 87 (72.5%) of 120 pneumonia episodes and were not administered in 80 (87.0%) of 92 nonpneumonia episodes. Antimicrobial-resistant organisms caused 78 (60.0%) of 120 episodes. Excluding 19 colistin-resistant Acinetobacter baumannii episodes, AST confirmed appropriate antibiotic receipt in 101 (84.2%) of 120 episodes for one or more FA-PP-detected organisms. Compared to standard-of-care testing, the FA-PP panel may be of great value in the management of COVID-19 patients at risk of developing bacterial pneumonia in the ICU. Since bacterial pneumonia is relatively frequent, suspicion of it in COVID-19 patients may prompt ICU clinicians to overuse (broad-spectrum) antibiotics, particularly when empirical antibiotics do not cover the suspected pathogen. We showed that a PCR-based, culture-independent laboratory assay allows not only accurate diagnosis but also streamlining of antimicrobial therapy for bacterial pneumonia episodes. We report on the actual implementation of rapid diagnostics and its real-life impact on patient treatment, which is a gain over previously published studies on the topic. A better understanding of the role of that or similar PCR assays in routine ICU practice may lead us to appreciate the effectiveness of their implementation during the COVID-19 pandemic.
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http://dx.doi.org/10.1128/Spectrum.00695-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579927PMC
November 2021

Fecal microbiota transplantation for recurrent C. difficile infection in patients with inflammatory bowel disease: experience of a large-volume European FMT center.

Gut Microbes 2021 Jan-Dec;13(1):1994834

Digestive Disease Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica Del Sacro Cuore, Rome, Italy.

Inflammatory bowel disease (IBD) is a risk factor for infection (CDI), which, in turn, complicates the clinical course of IBD. Fecal microbiota transplantation (FMT) is safe and effective in patients with IBD and recurrent CDI (rCDI). In our study, patients with IBD and rCDI received FMT by colonoscopy and were followed-up for 8 weeks. The primary outcome was negative toxin 8 weeks after FMT. Eighteen patients with IBD were enrolled. Eight patients received sequential FMT either for pseudomembranous colitis or failure of single fecal infusion. At 8-week follow-up the toxin was negative in 17 patients, and most (83%) experienced also improvement of IBD disease activity. Overall, we did not observe any serious adverse event.FMT appears to be highly effective and safe in patients with IBD and rCDI and is likely not only to eradicate CDI but also to improve disease activity of IBD.
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http://dx.doi.org/10.1080/19490976.2021.1994834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555518PMC
October 2021

A machine-learning parsimonious multivariable predictive model of mortality risk in patients with Covid-19.

Sci Rep 2021 10 27;11(1):21136. Epub 2021 Oct 27.

Sezione di Malattie Infettive, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.

The COVID-19 pandemic is impressively challenging the healthcare system. Several prognostic models have been validated but few of them are implemented in daily practice. The objective of the study was to validate a machine-learning risk prediction model using easy-to-obtain parameters to help to identify patients with COVID-19 who are at higher risk of death. The training cohort included all patients admitted to Fondazione Policlinico Gemelli with COVID-19 from March 5, 2020, to November 5, 2020. Afterward, the model was tested on all patients admitted to the same hospital with COVID-19 from November 6, 2020, to February 5, 2021. The primary outcome was in-hospital case-fatality risk. The out-of-sample performance of the model was estimated from the training set in terms of Area under the Receiving Operator Curve (AUROC) and classification matrix statistics by averaging the results of fivefold cross validation repeated 3-times and comparing the results with those obtained on the test set. An explanation analysis of the model, based on the SHapley Additive exPlanations (SHAP), is also presented. To assess the subsequent time evolution, the change in paO2/FiO2 (P/F) at 48 h after the baseline measurement was plotted against its baseline value. Among the 921 patients included in the training cohort, 120 died (13%). Variables selected for the model were age, platelet count, SpO2, blood urea nitrogen (BUN), hemoglobin, C-reactive protein, neutrophil count, and sodium. The results of the fivefold cross-validation repeated 3-times gave AUROC of 0.87, and statistics of the classification matrix to the Youden index as follows: sensitivity 0.840, specificity 0.774, negative predictive value 0.971. Then, the model was tested on a new population (n = 1463) in which the case-fatality rate was 22.6%. The test model showed AUROC 0.818, sensitivity 0.813, specificity 0.650, negative predictive value 0.922. Considering the first quartile of the predicted risk score (low-risk score group), the case-fatality rate was 1.6%, 17.8% in the second and third quartile (high-risk score group) and 53.5% in the fourth quartile (very high-risk score group). The three risk score groups showed good discrimination for the P/F value at admission, and a positive correlation was found for the low-risk class to P/F at 48 h after admission (adjusted R-squared = 0.48). We developed a predictive model of death for people with SARS-CoV-2 infection by including only easy-to-obtain variables (abnormal blood count, BUN, C-reactive protein, sodium and lower SpO2). It demonstrated good accuracy and high power of discrimination. The simplicity of the model makes the risk prediction applicable for patients in the Emergency Department, or during hospitalization. Although it is reasonable to assume that the model is also applicable in not-hospitalized persons, only appropriate studies can assess the accuracy of the model also for persons at home.
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http://dx.doi.org/10.1038/s41598-021-99905-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551240PMC
October 2021

Improved gut microbiota features after the resolution of SARS‑CoV‑2 infection.

Gut Pathog 2021 Oct 16;13(1):62. Epub 2021 Oct 16.

Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) has a tropism for the gastrointestinal tract and several studies have shown an alteration of the gut microbiota in hospitalized infected patients. However, long-term data on microbiota changes after recovery are lacking.

Methods: We enrolled 30 patients hospitalized for SARS‑CoV‑2-related pneumonia. Their gut microbiota was analyzed within 48 h from the admission and compared with (1) that of other patients admitted for suspected bacterial pneumonia (control group) (2) that obtained from the same subject 6 months after nasopharyngeal swab negativization.

Results: Gut microbiota alpha-diversity increased 6 months after the resolution of SARS-CoV-2 infection. Bacteroidetes relative abundance was higher (≈ 36.8%) in patients with SARS-CoV-2, and declined to 18.7% when SARS-CoV-2 infection resolved (p  =  0.004). Conversely, Firmicutes were prevalent (≈ 75%) in controls and in samples collected after SARS-CoV-2 infection resolution (p  =  0.001). Ruminococcaceae, Lachnospiraceae and Blautia increased after SARS-CoV-2 infection resolution, rebalancing the gut microbiota composition.

Conclusion: SARS-CoV-2 infection is associated with changes in the gut microbiome, which tend to be reversed in long-term period.
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http://dx.doi.org/10.1186/s13099-021-00459-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520333PMC
October 2021

Characterization of gut microbiota in patients with metabolic syndrome candidates for bariatric/metabolic surgery: Preliminary findings of a multi-center prospective study.

Diabetes Res Clin Pract 2021 Oct 29;180:109079. Epub 2021 Sep 29.

Division of General Surgery and Bariatric Center of Excellence IFSO-EC, Department of Medico-Surgical Sciences and Biotechnologies, University "La Sapienza" of Rome, Italy. Electronic address:

Introduction: gut microbiota (GM) seems to be involved in the pathophysiology and progression of both metabolic syndrome (MS) and obesity. The aim was to investigate GM's composition in patients with severe obesity, candidates for bariatric/metabolic surgery BMS.

Materials And Methods: Multicentre, prospective, cohort study, enrolling 84 patients with BMI 40-55 kg/m, divided bymetabolic status (MS) inhealthy(group A), pre-MS (B), or MS (C).

Results: No differences were foundregarding anthropometric,nutritional parameters, except for vitamin D.As a whole the alpha and beta diversity examinations showed no statistical differences in GM profile. A total of 5/7 phyla with relative frequencies were identified above 0.1% (Actinobacteria,Bacteroidetes,Firmicutes,Proteobacteria,Verrucomicrobia).FusobacteriaandPatescibacteriarepresented the less abundant. There were no significant differences in the top ten genera.Data onBacteroidetes(inversely related to triglycerides and LDL and directly related to HDL levels) and onFirmicutes(opposite trend) relative abundances suggest no differences among the three conditions.No correlation between the relative abundance of themain phylaand plasmatic glucose levels was observed.

Conclusions: In a selected cohort of patients with obesity, MS did not affect the preoperative GM's profile. Severe obesity, per se, seems to be an independent condition affecting GM.
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http://dx.doi.org/10.1016/j.diabres.2021.109079DOI Listing
October 2021

A New PCR-Based Assay for Testing Bronchoalveolar Lavage Fluid Samples from Patients with Suspected Pneumonia.

J Fungi (Basel) 2021 Aug 24;7(9). Epub 2021 Aug 24.

Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Roma, Italy.

To support the clinical laboratory diagnosis of () pneumonia (PCP), an invasive fungal infection mainly occurring in HIV-negative patients, in-house or commercial -specific real-time quantitative PCR (qPCR) assays are todays' reliable options. The performance of these assays depends on the type of gene (multi-copy mitochondrial versus single-copy nuclear) targeted by the assay. We described the development of a -PCR assay targeting the dihydrofolate reductase (DHFR)-encoding gene. After delineating its analytical performance, the -PCR assay was used to test bronchoalveolar lavage (BAL) fluid samples from 200 patients (only seven were HIV positive) with suspected PCP. Of 211 BAL fluid samples, 18 (8.5%) were positive and 193 (91.5%) were negative by -PCR. Of 18 -PCR-positive samples, 11 (61.1%) tested positive and seven (38.9%) tested negative with the immunofluorescence assay (IFA). All (100%) of the 193 -PCR-negative samples were IFA negative. Based on IFA/PCR results, patients were, respectively, classified as having ( = 18) and not having ( = 182) proven (-PCR+/IFA+) or probable (-PCR+/IFA-) PCP. For 182 patients without PCP, alternative infectious or non-infectious etiologies were identified. Our -PCR assay was at least equivalent to IFA, fostering studies aimed at defining a qPCR-based standard for PCP diagnosis in the future.
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http://dx.doi.org/10.3390/jof7090681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466016PMC
August 2021

The Italian National Faecal Microbiota Transplantation Program: a coordinated effort against Clostridioides difficile infection.

Ann Ist Super Sanita 2021 Jul-Sep;57(3):239-243

Centro Nazionale Trapianti, Istituto Superiore di Sanità, Rome, Italy.

Clostridioides (previously Clostridium) difficile infection (CDI) is a common cause of antibiotic-associated diarrhea, whose symptoms range from mild diarrhea to life-threatening pseudomembranous colitis. CDI is characterized by significant recurrence rate following initial resolution and recurrent C. difficile infection (rCDI) represents an onerous burden for the healthcare systems. Conventional antibiotic-based approaches are generally used for the treatment of rCDI but the effective therapy remains elusive. Recently, the faecal microbiota transplantation (FMT) has emerged as an alternative therapeutic strategy against rCDI, with high treatment success rate. In 2018, the Italian National FMT Program was launched, with the aim to provide high quality standards in FMT application to adults with rCDI not responding to antibiotic therapy. Here, we sketch out the key characteristics and the progress of the Italian National FMT Program during the COVID-19 pandemic.
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http://dx.doi.org/10.4415/ANN_21_03_07DOI Listing
October 2021

Direct Testing for KPC-Mediated Carbapenem Resistance from Blood Samples Using a T2 Magnetic Resonance Based Assay.

Antibiotics (Basel) 2021 Aug 6;10(8). Epub 2021 Aug 6.

Microbiologia Medica, Dipartimento di Medicina, Università degli Studi di Perugia, 06129 Perugia, Italy.

Molecular-based carbapenem resistance testing in Gram-negative bacterial bloodstream infections (BSIs) is currently limited because of the reliance on positive blood culture (BC) samples. The T2Resistance™ panel may now allow the detection of carbapenemase- and other β-lactamase encoding genes directly from blood samples. We detected carbapenem resistance genes in 11 (84.6%) of 13 samples from patients with BC-documented BSIs (10 caused by KPC-producing and 1 caused by VIM/CMY-producing ). Two samples that tested negative for carbapenem resistance genes were from patients with BC-documented BSIs caused by KPC-producing who were receiving effective antibiotic therapy. In conclusion, our findings suggest that the T2Resistance™ panel can be a reliable tool for diagnosing carbapenem-resistant Gram-negative bacterial BSIs.
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http://dx.doi.org/10.3390/antibiotics10080950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388919PMC
August 2021

Disentangling the Possible Drivers of Microbiome: A Threatened Lemur Species of Madagascar.

Front Microbiol 2021 6;12:668274. Epub 2021 Aug 6.

Department of Agricultural and Food Sciences, University of Bologna, Bologna, Italy.

Research on the gut microbiome may help with increasing our understanding of primate health with species' ecology, evolution, and behavior. In particular, microbiome-related information has the potential to clarify ecology issues, providing knowledge in support of wild primates conservation and their associated habitats. Indri () is the largest extant living lemur of Madagascar. This species is classified as "critically endangered" by the IUCN Red List of Threatened Species, representing one of the world's 25 most endangered primates. Indris diet is mainly folivorous, but these primates frequently and voluntarily engage in geophagy. Indris have never been successfully bred under human care, suggesting that some behavioral and/or ecological factors are still not considered from the conservation protocols. Here, we explored gut microbiome composition of 18 indris belonging to 5 different family groups. The most represented phyla were Proteobacteria 40.1 ± 9.5%, Bacteroidetes 28.7 ± 2.8%, Synergistetes 16.7 ± 4.5%, and Firmicutes 11.1 ± 1.9%. Further, our results revealed that bacterial alpha and beta diversity were influenced by indri family group and sex. In addition, we investigated the chemical composition of geophagic soil to explore the possible ecological value of soil as a nutrient supply. The quite acidic pH and high levels of secondary oxide-hydroxides of the soils could play a role in the folivorous diet's gut detoxification activity. In addition, the high contents of iron and manganese found the soils could act as micronutrients in the indris' diet. Nevertheless, the concentration of a few elements (i.e., calcium, sulfur, boron, nickel, sodium, and chromium) was higher in non-geophagic than in geophagic soils. In conclusion, the data presented herein provide a baseline for outlining some possible drivers responsible for the gut microbiome diversity in indris, thus laying the foundations for developing further strategies involved in indris' conservation.
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http://dx.doi.org/10.3389/fmicb.2021.668274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378179PMC
August 2021

SARS-CoV-2 Antigen Detection to Expand Testing Capacity for COVID-19: Results from a Hospital Emergency Department Testing Site.

Diagnostics (Basel) 2021 Jul 5;11(7). Epub 2021 Jul 5.

Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.

Background: SARS-CoV-2 antigen detection has currently expanded the testing capacity for COVID-19, which yet relies on the SARS-CoV-2 RNA RT-PCR amplification.

Objectives: To report on a COVID-19 testing algorithm from a tertiary care hospital emergency department (ED) that combines both antigen (performed on the ED) and RT-PCR (performed outside the ED) testing.

Methods: Between December 2020 and January 2021, in a priori designated, spatially separated COVID-19 or non-COVID-19 ED areas, respectively, symptomatic or asymptomatic patients received SARS-CoV-2 antigen testing on nasopharyngeal swab samples. Antigen results were promptly accessible to guide subsequent, outside performed confirmatory (RT-PCR) testing.

Results: Overall, 1083 (100%) of 1083 samples in the COVID-19 area and 1815 (49.4%) of 3670 samples in the non-COVID-19 area had antigen results that required confirmation by RT-PCR. Antigen positivity rates were 12.4% (134/1083) and 3.7% (66/1815), respectively. Compared to RT-PCR testing results, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of antigen testing were, respectively, 68.0%, 98.3%, 88.8%, and 94.1% in the COVID-19 area, and 41.9%, 97.3%, 27.3%, and 98.6% in non-COVID-19 area. Practically, RT-PCR tests were avoided in 50.6% (1855/3670) of non-COVID-19 area samples (all antigen negative) from patients who, otherwise, would have needed antigen result confirmation.

Conclusions: Our algorithm had value to preserve RT-PCR from avoidable usage and, importantly, to save time, which translated into a timely RT-PCR result availability in the COVID-19 area.
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http://dx.doi.org/10.3390/diagnostics11071211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304665PMC
July 2021

Vaccine-induced thrombotic thrombocytopenia, a rare but severe case of friendly fire in the battle against COVID-19 pandemic: What pathogenesis?

Eur J Intern Med 2021 09 29;91:88-89. Epub 2021 Jun 29.

Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy.

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http://dx.doi.org/10.1016/j.ejim.2021.06.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238658PMC
September 2021

Graphene nanoplatelet and graphene oxide functionalization of face mask materials inhibits infectivity of trapped SARS-CoV-2.

iScience 2021 Jul 25;24(7):102788. Epub 2021 Jun 25.

Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, Rome 00168, Italy.

Recent advancements in bidimensional nanoparticles production such as graphene (G) and graphene oxide (GO) have the potential to meet the need for highly functional personal protective equipment (PPE) against SARS-CoV-2 infection. The ability of G and GO to interact with microorganisms provides an opportunity to develop engineered textiles for use in PPE and limit the spread of COVID-19. PPE in current use in high-risk settings for COVID transmission provides only a physical barrier that decreases infection likelihood and does not inactivate the virus. Here, we show that virus pre-incubation with soluble GO inhibits SARS-CoV-2 infection of VERO cells. Furthermore, when G/GO-functionalized polyurethane or cotton was in contact SARS-CoV-2, the infectivity of the fabric was nearly completely inhibited. The findings presented here constitute an important innovative nanomaterial-based strategy to significantly increase PPE efficacy in protection against the SARS-CoV-2 virus that may implement water filtration, air purification, and diagnostics methods.
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http://dx.doi.org/10.1016/j.isci.2021.102788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233064PMC
July 2021

Post-Prescription Audit Plus Beta-D-Glucan Assessment Decrease Echinocandin Use in People with Suspected Invasive Candidiasis.

Medicina (Kaunas) 2021 Jun 26;57(7). Epub 2021 Jun 26.

Department of Laboratory and Infectious Diseases Sciences, A. Gemelli University Hospital Foundation IRCCS, 00168 Rome, Italy.

Overtreatment with antifungal drugs is often observed. Antifungal stewardship (AFS) focuses on optimizing the treatment for invasive fungal diseases. The objective of the present study was to evaluate the utility of a post-prescription audit plus beta-D-glucan (BDG) assessment on reducing echinocandin use in persons with suspected invasive candidiasis. This is a prospective, pre-post quasi-experimental study of people starting echinocandins for suspected invasive candidiasis. The intervention of the study included review of each echinocandin prescription and discontinuation of treatment if a very low probability of fungal disease or a negative BDG value were found. Pre-intervention data were compared with the intervention phase. The primary outcome of the study was the duration of echinocandin therapy. Secondary outcomes were length of hospital stay and mortality. Ninety-two echinocandin prescriptions were reviewed, 49 (53.3%) in the pre-intervention phase and 43 (46.7%) in the intervention phase. Discontinuation of antifungal therapy was possible in 21 of the 43 patients in the intervention phase (48.8%). The duration of echinocandin therapy was 7.4 (SD 4.7) in the pre-intervention phase, 4.1 days (SD 2.9) in persons undergoing the intervention, and 8.6 (SD 7.3) in persons in whom the intervention was not feasible ( at ANOVA = 0.016). Length of stay and mortality did not differ between pre-intervention and intervention phases. An intervention based on pre-prescription restriction and post-prescription audit when combined with BDG measurement is effective in optimizing antifungal therapy by significantly reducing excessive treatment duration.
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http://dx.doi.org/10.3390/medicina57070656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306264PMC
June 2021

Seroprevalence of SARS-CoV-2 Antibodies in HIV-Infected Patients in Rome, Italy during the COVID-19 Outbreak.

Diagnostics (Basel) 2021 Jun 24;11(7). Epub 2021 Jun 24.

UOC Malattie Infettive, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.

Background: this study aimed to determine the proportion of people living with HIV (PLWH) with anti-SARS-CoV-2 IgG antibodies in a large sample from a single HIV referral center in Rome, Italy; the time-frame included both the first and the second wave of the Italian COVID-19 pandemic; Methods: we conducted a cross-sectional study on stored cryopreserved samples from 1 March 2020 to 30 November 2020. Total antibodies against SARS-CoV-2 were preliminarily tested using a chemiluminescent immunoassay. Positive results were re-tested with an ELISA assay as an IgG confirmatory test; Results: overall, 1389 samples were analyzed from 1106 PLWH: 69% males, median age 53 years, 94% on antiretroviral treatment, 93% with HIV-RNA < 50 copies/mL, median CD4 cell count 610 cell/µL. Our analysis revealed a total of n = 8 patients who tested IgG positive during the study period. Seroprevalence was equal to 0% in the first months (March-June); this started to increase in July and reached a maximum rate of 1.59% in October 2020. The overall seroprevalence was 0.72% (8/1106, 95% CI 0.37-1.42).

Conclusion: our findings from this setting show a low IgG SARS-CoV-2 prevalence among PLWH as compared to data available from the general population.
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http://dx.doi.org/10.3390/diagnostics11071154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303907PMC
June 2021

Role of lung ultrasound for the etiological diagnosis of acute lower respiratory tract infection (ALRTI) in children: a prospective study.

J Ultrasound 2021 Jun 19. Epub 2021 Jun 19.

Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, Largo A. Gemelli 8, 00168, Rome, Italy.

Objective And Design: Our prospective study assesses the role of detailed lung ultrasound (LUS) features to discriminate the etiological diagnosis of acute lower respiratory tract infection (ALRTI) in children.

Methodology: We analyzed patients aged from 1 month to 17 years admitted between March 2018 and April 2020 who were hospitalized for ALRTI. For all patients, history, clinical parameters, microbiological data, and lung ultrasound data were collected. Patients were stratified into three main groups ("bacterial", "viral", "atypical") according to the presumed microbial etiology and LUS findings evaluated according to the etiological group. Nasopharyngeal swabs were obtained from all patients. A qualitative diagnostic test developed by Nurex S.r.l. was used for identification of bacterial and fungal DNA in respiratory samples. The Seegene Allplex™ Respiratory assays were used for the molecular diagnosis of viral respiratory pathogens. In addition, bacterial culture of blood and respiratory samples were performed, when indicated.

Results: A total of 186 children with suspected ALRTI (44% female) with an average age of 6 were enrolled in the study. We found that some ultrasound findings as size, number and distribution of consolidations, the position and motion of air bronchograms, pleural effusions and distribution of vertical artifacts significantly differ (p < 0.05) in children with bacterial, viral and atypical ALRTI.

Conclusion: Our study provides a detailed analysis of LUS features able to predict the ALRTI ethology in children. These findings may help the physicians to better manage a child with ALRTI and to offer personalized approach, from diagnosis to treatment and follow-up.
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http://dx.doi.org/10.1007/s40477-021-00600-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213536PMC
June 2021

COVID-19 and RA share an SPP1 myeloid pathway that drives PD-L1+ neutrophils and CD14+ monocytes.

JCI Insight 2021 06 18;6(13). Epub 2021 Jun 18.

Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), University of Glasgow, United Kingdom.

We explored the potential link between chronic inflammatory arthritis and COVID-19 pathogenic and resolving macrophage pathways and their role in COVID-19 pathogenesis. We found that bronchoalveolar lavage fluid (BALF) macrophage clusters FCN1+ and FCN1+SPP1+ predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48hiS100A12+ and CD48+SPP1+ that drive rheumatoid arthritis (RA) synovitis. BALF macrophage cluster FABP4+ predominant in healthy lung was transcriptionally related to STM cluster TREM2+ that governs resolution of synovitis in RA remission. Plasma concentrations of SPP1 and S100A12 (key products of macrophage clusters shared with active RA) were high in severe COVID-19 and predicted the need for Intensive Care Unit transfer, and they remained high in the post-COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared with other causes of severe pneumonia, and IHC localized SPP1+ macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives proinflammatory activation of CD14+ monocytes and development of PD-L1+ neutrophils, both hallmarks of severe COVID-19. In summary, COVID-19 pneumonitis appears driven by similar pathogenic myeloid cell pathways as those in RA, and their mediators such as SPP1 might be an upstream activator of the aberrant innate response in severe COVID-19 and predictive of disease trajectory including post-COVID-19 pathology.
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http://dx.doi.org/10.1172/jci.insight.147413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328085PMC
June 2021

Staphylococcus aureus ventilator-associated pneumonia in patients with COVID-19: clinical features and potential inference with lung dysbiosis.

Crit Care 2021 06 7;25(1):197. Epub 2021 Jun 7.

Dipartimento Di Scienze Biotecnologiche Di Base, Cliniche Intensivologiche E Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy.

Background: Hospitalized patients with COVID-19 admitted to the intensive care unit (ICU) and requiring mechanical ventilation are at risk of ventilator-associated bacterial infections secondary to SARS-CoV-2 infection. Our study aimed to investigate clinical features of Staphylococcus aureus ventilator-associated pneumonia (SA-VAP) and, if bronchoalveolar lavage samples were available, lung bacterial community features in ICU patients with or without COVID-19.

Methods: We prospectively included hospitalized patients with COVID-19 across two medical ICUs of the Fondazione Policlinico Universitario A. Gemelli IRCCS (Rome, Italy), who developed SA-VAP between 20 March 2020 and 30 October 2020 (thereafter referred to as cases). After 1:2 matching based on the simplified acute physiology score II (SAPS II) and the sequential organ failure assessment (SOFA) score, cases were compared with SA-VAP patients without COVID-19 (controls). Clinical, microbiological, and lung microbiota data were analyzed.

Results: We studied two groups of patients (40 COVID-19 and 80 non-COVID-19). COVID-19 patients had a higher rate of late-onset (87.5% versus 63.8%; p = 0.01), methicillin-resistant (65.0% vs 27.5%; p < 0.01) or bacteremic (47.5% vs 6.3%; p < 0.01) infections compared with non-COVID-19 patients. No statistically significant differences between the patient groups were observed in ICU mortality (p = 0.12), clinical cure (p = 0.20) and microbiological eradication (p = 0.31). On multivariable logistic regression analysis, SAPS II and initial inappropriate antimicrobial therapy were independently associated with ICU mortality. Then, lung microbiota characterization in 10 COVID-19 and 16 non-COVID-19 patients revealed that the overall microbial community composition was significantly different between the patient groups (unweighted UniFrac distance, R 0.15349; p < 0.01). Species diversity was lower in COVID-19 than in non COVID-19 patients (94.4 ± 44.9 vs 152.5 ± 41.8; p < 0.01). Interestingly, we found that S. aureus (log fold change, 29.5), Streptococcus anginosus subspecies anginosus (log fold change, 24.9), and Olsenella (log fold change, 25.7) were significantly enriched in the COVID-19 group compared to the non-COVID-19 group of SA-VAP patients.

Conclusions: In our study population, COVID-19 seemed to significantly affect microbiological and clinical features of SA-VAP as well as to be associated with a peculiar lung microbiota composition.
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http://dx.doi.org/10.1186/s13054-021-03623-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182737PMC
June 2021

Metal-Free Antibacterial Additives Based on Graphene Materials and Salicylic Acid: From the Bench to Fabric Applications.

ACS Appl Mater Interfaces 2021 Jun 26;13(22):26288-26298. Epub 2021 May 26.

Department of Chemistry "Ugo Schiff", Università di Firenze, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy.

The custom functionalization of a graphene surface allows access to engineered nanomaterials with improved colloidal stability and tailored specific properties, which are available to be employed in a wide range of applications ranging from materials to life science. The high surface area and their intrinsic physical and biological properties make reduced graphene oxide and graphene oxide unique materials for the custom functionalization with bioactive molecules by exploiting different surface chemistries. In this work, preparation (on the gram scale) of reduced graphene oxide and graphene oxide derivatives functionalized with the well-known antibacterial agent salicylic acid is reported. The salicylic acid functionalities offered a stable colloidal dispersion and, in addition, homogeneous absorption on a sample of textile manufacture (i.e., cotton fabrics), as shown by a Raman spectroscopy study, thus providing nanoengineered materials with significant antibacterial activity toward different strains of microorganisms. Surprisingly, graphene surface functionalization also ensured resistance to detergent washing treatments as verified on a model system using the quartz crystal microbalance technique. Therefore, our findings paved the way for the development of antibacterial additives for cotton fabrics in the absence of metal components, thus limiting undesirable side effects.
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http://dx.doi.org/10.1021/acsami.1c02330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289172PMC
June 2021

Donor program for fecal microbiota transplantation: A 3-year experience of a large-volume Italian stool bank.

Dig Liver Dis 2021 11 21;53(11):1428-1432. Epub 2021 May 21.

Digestive Disease Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo "A. Gemelli", 8, 00168, Rome, Italy. Electronic address:

Background: Due to the increasing rise of C. difficile infection, stool banks and donor programs have been launched to grant access to fecal microbiota transplantation (FMT). Our aim is to describe characteristics and outcomes of the donor program at our stool bank.

Methods: Donor candidates underwent a four-step selection process, including a clinical interview, blood and stool testing, a further questionnaire and a direct stool testing the day of each donation. From March 2020, specific changes to this process were introduced to avoid the potential transmission of COVID-19. We evaluated the rate of excluded candidates at each step of the screening, as well as the number of total fecal aliquots provided by qualified donors.

Results: Overall, 114 donor candidates were evaluated. Seventy-five candidates declined to join the program for logistic or personal issues, three were excluded after the questionnaire and seven for positive stool exams. Finally, 29 (25%) subjects qualified as stool donors, and provided 70 stool samples. Fifteen samples were excluded after direct molecular stool testing. A total of 127 aliquots was finally obtained.

Conclusions: Donor recruitment for FMT is a challenging process, and only a small rate of candidates are eligible as donors.
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http://dx.doi.org/10.1016/j.dld.2021.04.009DOI Listing
November 2021

Characteristic of IgA and IgG antibody response to SARS-CoV-2 infection in an Italian referral COVID-19 Hospital.

Intern Emerg Med 2021 May 10. Epub 2021 May 10.

Department of Laboratory Sciences and Infectious Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Introduction: Antibody response plays a fundamental role in the natural history of infectious disease. A better understanding of the immune response in patients with SARS-CoV-2 infection could be important for identifying patients at greater risk of developing a more severe form of disease and with a worse prognosis.

Methods: We performed a cross-sectional analysis to determine the presence and the levels of both anti-SARS-CoV-2 IgG and IgA in a cohort of hospitalized patients with confirmed infection at different times in the natural history of the disease. Patients enrolled when admitted at the emergency department were prospectively followed up during hospital stay.

Results: Overall, 131 patients were considered with a total of 237 samples processed. Cross-sectional analysis showed that seroconversion for IgA seems to occur between days 6 and 15, while IgG response seems to occur slightly later, peaking at day 20 after symptoms onset. Both IgA and IgG were maintained beyond 2 months. Severe patients showed a higher IgA response compared with mild patients when analyzing optical density (8.3 versus 5.6, p < 0.001). Prospective analysis conducted on 55 patients confirmed that IgA appear slightly earlier than IgG. After stratifying for the severity of disease, both the IgA and IgG responses were more vigorous in severe cases. Moreover, while IgG tended to stabilize, there was a relevant decline after the first month of IgA levels in mild cases.

Conclusion: IgA and IgG antibody response is closely related, although seroconversion for IgA occurs earlier. Both IgA and IgG are maintained beyond 2 months. Severe patients showed a more vigorous IgA and IgG response. IgA levels seem to decline after 1 month since the onset of symptoms in mild cases. Our results should be interpreted with cautions due to several limitations in our study, mainly the small number of cases, lack of data on viral load and clinical setting.
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http://dx.doi.org/10.1007/s11739-021-02750-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107418PMC
May 2021

COVID-19 influences lung microbiota dynamics and favors the emergence of rare infectious diseases: A case report of Hafnia Alvei pneumonia.

J Crit Care 2021 08 18;64:173-175. Epub 2021 Apr 18.

Dipartimento di Scienze dell' Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Facoltà di medicina e chirurgia "A. Gemelli", Università Cattolica del Sacro Cuore, Rome, Italy.

The coronavirus disease 2019 causes a wide degree of organ dysfunction and is associated with bacterial secondary infections. We reported lung microbiota dynamics in a critically ill patient with coronavirus disease 2019, who developed severe Hafnia alvei ventilator-associated pneumonia and required extracorporeal membrane oxygenation support.
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http://dx.doi.org/10.1016/j.jcrc.2021.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053226PMC
August 2021

Risk Factors for Mortality in Adult COVID-19 Patients Who Develop Bloodstream Infections Mostly Caused by Antimicrobial-Resistant Organisms: Analysis at a Large Teaching Hospital in Italy.

J Clin Med 2021 Apr 17;10(8). Epub 2021 Apr 17.

Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, 00168 Roma, Italy.

The aim of this study was to characterize COVID-19 (SARS-CoV-2-infected) patients who develop bloodstream infection (BSI) and to assess risk factors associated with in-hospital mortality. We conducted a retrospective observational study of adult patients admitted for ≥48 h to a large Central Italy hospital for COVID-19 (1 March to 31 May 2020) who had or had not survived at discharge. We included only patients having blood cultures drawn or other inclusion criteria satisfied. Kaplan-Meier survival or Cox regression analyses were performed of 293 COVID-19 patients studied, 46 patients (15.7%) had a hospital-acquired clinically relevant BSI secondary to SARS-CoV-2 infection, accounting for 58 episodes (49 monomicrobial and 9 polymicrobial) in total. Twelve episodes (20.7%) occurred at day 3 of hospital admission. Sixty-nine species were isolated, including (32.8%), Enterobacterales (20.7%), (17.2%), (13.8%) and (10.3%). Of 69 isolates, 27 (39.1%) were multidrug-resistant organisms. Twelve (54.5%) of 22 patients for whom empirical antimicrobial therapy was inappropriate were infected by a multidrug-resistant organism. Of 46 patients, 26 (56.5%) survived and 20 (43.5%) died. Exploring variables for association with in-hospital mortality identified > 75-year age (HR 2.97, 95% CI 1.15-7.68, = 0.02), septic shock (HR 6.55, 95% CI 2.36-18.23, < 0.001) and BSI onset ≤ 3 days (HR 4.68, 95% CI 1.40-15.63, = 0.01) as risk factors independently associated with death. In our hospital, mortality among COVID-19 patients with BSI was high. While continued vigilance against these infections is essential, identification of risk factors for mortality may help to reduce fatal outcomes in patients with COVID-19.
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http://dx.doi.org/10.3390/jcm10081752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073579PMC
April 2021

Saliva Is a Valid Alternative to Nasopharyngeal Swab in Chemiluminescence-Based Assay for Detection of SARS-CoV-2 Antigen.

J Clin Med 2021 Apr 2;10(7). Epub 2021 Apr 2.

Laboratorio di Virologia, Istituto Nazionale per le Malattie Infettive (INMI) Lazzaro Spallanzani IRCCS, 00149 Rome, Italy.

Diagnostic methods based on SARS-CoV-2 antigens detection are a promising alternative to SARS-CoV-2 RNA amplification. We evaluated the automated chemiluminescence-based Lumipulse G SARS-CoV-2 Ag assay on saliva samples, using Simplexa™ COVID-19 Direct assay as a reference test. Analytical performance was established on a pool of healthy donors' saliva samples spiked with the 2019-nCoV/Italy-INMI1 isolate, whereas clinical performance was assessed on fresh saliva specimens collected from hospitalized patients with suspect or confirmed COVID-19 diagnosis. The limit of detection (LOD) was 0.65 Log TCID50/mL, corresponding to 18,197 copies/mL of SARS-CoV-2 RNA. Antigen concentrations and SARS-CoV-2 RNA were highly correlated (r = 0.99; < 0.0001). Substantial agreement (80.3%) and significant correlation (r = -0.675; = 0.0006) were observed between Lumipulse G assay results and Ct values on clinical samples, with 52.4% sensitivity and specificity 94.1%. Sensitivity exceeded 90.0% when calculated on samples with Ct < 25, and specificity was 100% when excluding samples from recovered patients with previous COVID-19 diagnosis. Overall, chemiluminescence-based antigen assay may be reliably applied to saliva samples to identify individuals with high viral loads, more likely to transmit the virus. However, the low positive predictive value in a context of low SARS-CoV-2 prevalence underscores the need for confirmatory testing in SARS-CoV-2 antigen-positive cases.
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http://dx.doi.org/10.3390/jcm10071471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038133PMC
April 2021

First description of the katG gene deletion in a Mycobacterium tuberculosis clinical isolate and its impact on the mycobacterial fitness.

Int J Med Microbiol 2021 May 19;311(4):151506. Epub 2021 Apr 19.

Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Rome, Italy; Dipartimento di Scienze biotecnologiche di base, cliniche intensivologiche e perioperatorie - Sezione di Microbiologia, Università Cattolica del Sacro Cuore, Rome, Italy.

Isoniazid (INH) is the cornerstone of the anti-tuberculosis regimens and emergence of Mycobacterium tuberculosis (Mtb) resistant strains is a major threat to our ability to control tuberculosis (TB) at global level. Mutations in the gene coding the catalase KatG confer resistance to high level of INH. In this paper, we describe for the first time a complete deletion of the genomic region containing the katG gene in an Mtb clinical strain isolated in Italy in a patient with HIV infection that previously completed INH preventive therapy. We genotypically characterized the Mtb strain and showed that katG deletion confers high-level resistance to INH (MIC > 25.6 μg/mL). The katG deletion did not impact significantly on Mtb fitness as we did not detect enhanced susceptibility to HO compared to the wild type Mtb strains nor impaired growth in in vitro infection models. These findings highlight the ability of Mtb to acquire resistance to INH while maintaining fitness and pathogenic potential.
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http://dx.doi.org/10.1016/j.ijmm.2021.151506DOI Listing
May 2021

Hand hygiene and facemask use to prevent droplet-transmitted viral diseases during air travel: a systematic literature review.

BMC Public Health 2021 04 20;21(1):760. Epub 2021 Apr 20.

Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy.

Background: Transmission of viral diseases (e.g., influenza A H1N1) via respiratory droplets takes place mainly in confined spaces, including in aircraft during commercial air travel. The adoption of hygiene measures may help to prevent disease spread aboard aircraft. This review summarizes the evidence on hand hygiene and the use of facemasks as viral disease prevention measures in aircraft.

Methods: A literature search was performed in the PubMed, Scopus, and Web of Science databases up to 10 June 2020, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. A population, intervention, comparison, outcomes, and study design (PICOS) approach was used to define the review question.

Results: We included four studies published between 2007 and 2020, all targeting influenza virus disease, in the qualitative synthesis. Three studies used mathematical models to simulate single- or multiple-direction flights, and two of them showed that facemask (e.g., N95 respirator) use considerably reduced infection probability. In the third study, hand cleaning by 20 to 60% of people at any time in all airports (including on aircraft) reduced the measure of airports' power to spread the disease across the globe by ~ 24 to 69%. The fourth study was a case-control study designed to trace an influenza outbreak in two flights during the 2009 influenza A H1N1 pandemic. The study showed that none (0%) of nine infected passengers compared to 15 (47%) of 32 healthy control passengers in the aircraft cabin during one of these flights wore a facemask (odds ratio, 0.0; 95% confidence interval, 0.0-0.7). In contrast, both case and control passengers appeared to be equally compliant in self-assessed hand hygiene.

Conclusions: Facemask use combined with hand hygiene may minimize the chance of droplet-transmitted virus spread by air travelers. Thus, it is necessary that hygiene measures become an integral part of standard procedures in commercial air travel.
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http://dx.doi.org/10.1186/s12889-021-10814-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056366PMC
April 2021

Simulated Pediatric Blood Cultures to Assess the Inactivation of Clinically Relevant Antimicrobial Drug Concentrations in Resin-Containing Bottles.

Front Cell Infect Microbiol 2021 19;11:649769. Epub 2021 Mar 19.

Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy.

The bacteremia level as well as the administration of antibiotics before blood collection may significantly affect the recovery of bacterial pathogens from pediatric blood cultures in BacT/Alert Virtuo or Bactec FX BC systems, which remain the common techniques to diagnose bacteremia in pediatric patients. We simulated pediatric blood cultures with low or intermediate bacteremia level to evaluate BacT/Alert PF Plus and Bactec Peds Plus blood culture bottles for resin-based inactivation of 16 antibiotic-bacterium combinations. Overall, 105/192 (54.7%) of BacT/Alert PF Plus bottles and 69/192 (36.0%) of Bactec Peds Plus bottles allowed organisms to grow when exposed to antibiotics. In particular, both BacT/Alert PF Plus and Bactec Peds Plus bottles proved to be effective with piperacillin/tazobactam and or with oxacillin and methicillin-susceptible (100% growth), whereas no effectiveness was apparent with ceftriaxone and , , or or with cefepime and (0% growth). In some relevant instances (, with vancomycin and methicillin-resistant or ), BacT/Alert PF Plus bottles were superior to Bactec Peds Plus bottles. Together, these findings underscore the potentiality of resin-containing bottles to enhance diagnosis of bacteremia in pediatric patients on antimicrobial therapy. This is particularly true with one of the evaluated BC systems and with simulated intermediate bacteremia level only.
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http://dx.doi.org/10.3389/fcimb.2021.649769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044943PMC
July 2021

Systematic review and meta-analysis of in vitro efficacy of antibiotic combination therapy against carbapenem-resistant Gram-negative bacilli.

Int J Antimicrob Agents 2021 May 20;57(5):106344. Epub 2021 Apr 20.

Division of Infectious Diseases, Department of Diagnostic and Public Health, University of Verona, P.Le L.A. Scuro 10, 37134 Verona, Italy; Division of Infectious Diseases, Department of Internal Medicine I, German Center for Infection Research, University of Tübingen, Otfried Müller Straße 12, 72074 Tübingen, Germany; German Centre for Infection Research (DZIF), Clinical Research Unit for Healthcare Associated Infections, Tübingen, Germany. Electronic address:

The superiority of combination therapy for carbapenem-resistant Gram-negative bacilli (CR-GNB) infections remains controversial. In vitro models may predict the efficacy of antibiotic regimens against CR-GNB. A systematic review and meta-analysis was performed including pharmacokinetic/pharmacodynamic (PK/PD) and time-kill (TK) studies examining the in vitro efficacy of antibiotic combinations against CR-GNB [PROSPERO registration no. CRD42019128104]. The primary outcome was in vitro synergy based on the effect size (ES): high, ES ≥ 0.75, moderate, 0.35 < ES < 0.75; low, ES ≤ 0.35; and absent, ES = 0). A network meta-analysis assessed the bactericidal effect and re-growth rate (secondary outcomes). An adapted version of the ToxRTool was used for risk-of-bias assessment. Over 180 combination regimens from 136 studies were included. The most frequently analysed classes were polymyxins and carbapenems. Limited data were available for ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. High or moderate synergism was shown for polymyxin/rifampicin against Acinetobacter baumannii [ES = 0.91, 95% confidence interval (CI) 0.44-1.00], polymyxin/fosfomycin against Klebsiella pneumoniae (ES = 1.00, 95% CI 0.66-1.00) and imipenem/amikacin against Pseudomonas aeruginosa (ES = 1.00, 95% CI 0.21-1.00). Compared with monotherapy, increased bactericidal activity and lower re-growth rates were reported for colistin/fosfomycin and polymyxin/rifampicin in K. pneumoniae and for imipenem/amikacin or imipenem/tobramycin against P. aeruginosa. High quality was documented for 65% and 53% of PK/PD and TK studies, respectively. Well-designed in vitro studies should be encouraged to guide the selection of combination therapies in clinical trials and to improve the armamentarium against carbapenem-resistant bacteria.
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http://dx.doi.org/10.1016/j.ijantimicag.2021.106344DOI Listing
May 2021
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