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1. Clinical safety and efficacy of novel antifungal, fosmanogepix, for the treatment of candidaemia: results from a Phase 2 trial.

Author

Pappas, Peter, Vazquez, Jose, Oren, Ilana, Rahav, Galia, Aoun, Mickael, Bulpa, Pierre, Ben-Ami, Ronen, Ferrer, Ricard, Mccarty, Todd, Schlamm, Haran, Bien, Paul, Barbat, Sara, Wedel, Pamela, Oborska, Iwona, Tawadrous, Margaret, Hodges, Michael, and Thompson, George

Subjects
Adult, Humans, Antifungal Agents, Candidemia, Fungi, Candida, Treatment Outcome
Abstract

BACKGROUND: Fosmanogepix is a first-in-class antifungal targeting the fungal enzyme Gwt1, with broad-spectrum activity against yeasts and moulds, including multidrug-resistant fungi, formulated for intravenous (IV) and oral administration. METHODS: This global, multicenter, non-comparative study evaluated the safety and efficacy of fosmanogepix for first-line treatment of candidaemia in non-neutropenic adults. Participants with candidaemia, defined as a positive blood culture for Candida spp. within 96 h prior to study entry, with ≤2 days of prior systemic antifungals, were eligible. Participants received fosmanogepix for 14 days: 1000 mg IV twice daily on Day 1, followed by maintenance 600 mg IV once daily, and optional switch to 700 mg orally once daily from Day 4. Eligible participants who received at least one dose of fosmanogepix and had confirmed diagnosis of candidaemia (

Published
2023

2. The ancestral stringent response potentiator, DksA has been adapted throughout Salmonella evolution to orchestrate the expression of metabolic, motility, and virulence pathways

Author

Cohen, Helit, Adani, Boaz, Cohen, Emiliano, Piscon, Bar, Azriel, Shalhevet, Desai, Prerak, Bähre, Heike, McClelland, Michael, Rahav, Galia, and Gal-Mor, Ohad

Subjects
Microbiology, Biological Sciences, Bioinformatics and Computational Biology, Emerging Infectious Diseases, Infectious Diseases, Digestive Diseases, Genetics, Biodefense, Foodborne Illness, Prevention, Vaccine Related, 2.2 Factors relating to the physical environment, Aetiology, Infection, Bacterial Proteins, Citric Acid Cycle, Escherichia coli, Escherichia coli Proteins, Evolution, Molecular, Gene Expression Regulation, Bacterial, Gene Transfer, Horizontal, Glycolysis, Humans, Pyrimidines, Regulon, Salmonella, Salmonella Infections, Salmonella typhimurium, Virulence, Virulence Factors, DksA, virulence, pathogenicity, regulation, SPIs, HGT, RNA-Seq, enteric pathogens
Abstract

DksA is a conserved RNA polymerase-binding protein known to play a key role in the stringent response of proteobacteria species, including many gastrointestinal pathogens. Here, we used RNA-sequencing of Escherichia coli, Salmonella bongori and Salmonella enterica serovar Typhimurium, together with phenotypic comparison to study changes in the DksA regulon, during Salmonella evolution. Comparative RNA-sequencing showed that under non-starved conditions, DksA controls the expression of 25%, 15%, and 20% of the E. coli, S. bongori, and S. enterica genes, respectively, indicating that DksA is a pleiotropic regulator, expanding its role beyond the canonical stringent response. We demonstrate that DksA is required for the growth of these three enteric bacteria species in minimal medium and controls the expression of the TCA cycle, glycolysis, pyrimidine biosynthesis, and quorum sensing. Interestingly, at multiple steps during Salmonella evolution, the type I fimbriae and various virulence genes encoded within SPIs 1, 2, 4, 5, and 11 have been transcriptionally integrated under the ancestral DksA regulon. Consequently, we show that DksA is necessary for host cells invasion by S. Typhimurium and S. bongori and for intracellular survival of S. Typhimurium in bone marrow-derived macrophages (BMDM). Moreover, we demonstrate regulatory inversion of the conserved motility-chemotaxis regulon by DksA, which acts as a negative regulator in E. coli, but activates this pathway in S. bongori and S. enterica. Overall, this study demonstrates the regulatory assimilation of multiple horizontally acquired virulence genes under the DksA regulon and provides new insights into the evolution of virulence genes regulation in Salmonella spp.

Published
2022

5. Nationwide Outbreak of Candida auris Infections Driven by COVID-19 Hospitalizations, Israel, 2021-2022

Author

Biran, Roni, Cohen, Regev, Finn, Talya, Brosh-Nissimov, Tal, Rahav, Galia, Yahav, Dafna, Amit, Sharon, Shachor-Meyouhas, Yael, Atamna, Alaa, Bishara, Jihad, Ashkenazi-Hoffnung, Liat, Zvi, Haim Ben, Hershman-Sarafov, Mirit, Maayan, Shlomo, Maor, Yasmin, Schwartz, Orna, Zimhony, Oren, Lellouche, Jonathan, Elbaz, Meital, Burdelova, Ela, Mizrahi, Naama, Novikov, Anna, Henig, Oryan, and Ben-Ami, Ronen

Subjects
Epidemics -- Statistics -- Risk factors -- Israel, Hospital care -- Statistics, Candidiasis -- Statistics -- Risk factors, Health
Abstract

Candida auris is a drug-resistant fungal pathogen that has emerged over the past decade as a cause of nosocomial outbreaks with substantial mortality rates (1-3). Widespread resistance to triazole antifungals, [...]

Published
2023
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7. Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial

Author

Akova, Murat, AlAgha, Rawan, Alangaden, George, Albrecht, Svenja J, Alexander, Barbara, Al-Obaidi, Mohanad, Ambasch, German, Armestar Rodriguez, Fernando, Azap, Alpay, Baffoe-Bonnie, Anthony, Belkhir, Leila, Ben-Ami, Ronen, Boutoille, David, Cascio, Antonio, Chai, Louis YA, Chaiwarith, Romanee, Chayakulkeeree, Methee, Chen, Sharon, Chen, Yee-Chun, Chen, Yen-Hsu, Choi, Jun Yong, Choi, Young Hwa, Chotiprasitsakul, Darunee, Chung, Jin Won, Danion, François, Denis, Blandine, Diaz Santos, Emilio, Dictar, Miguel O, Diltoer, Marc, Dupont, Herve, Feng, Sizhou, Ferre Colomer, Maria Angeles, Ferrer, Ricard, Forel, Jean-Marie Fernand Roger, Fortún-Abete, Jesús, Garcia-Diaz, Julia, Girardis, Massimo, He, Fang, Hites, Maya, Ho, Mao-Wang, Honore, Patrick, Horcajada Gallego, Juan Pablo, Huang, Haihui, Huang, Po-Yen, Huang, Yong, Hussein, Osamah, Intalapaporn, Poj, Jaruratanasirikul, Sutep, Jauregui-Peredo, Luis, Johnson, Misty, Jung, Dong Sik, Jutivorakool, Kamonwan, Kern, Winfried V, Kett, Daniel H, Khawcharoenporn, Thana, Kim, Young Keun, Koehler, Philipp, Kotanidou, Anastasia, Lachiewicz, Anne, Lin, Qinhan, Lopez Cortes, Luis Eduardo, Luo, Hong, Luzzati, Roberto, Maor, Yasmin, McCarty, Todd, Merelli, Maria, Merino Amador, Paloma, Midturi, John, Migliorino, Guglielmo Marco, Mira, Jean-Paul, Mootsikapun, Piroon, Morrissey, Orla, Munoz Garcia de Paredes, Patricia, Mussini, Cristina, Mylonakis, Eleftherios, Nseir, Saadalla, Nseir, William, Odabasi, Zekaver, Papastamopoulos, Vasileios, Paterson, David, Patterson, Thomas F, Peck, Kyong Ran, Peng, Zhiyong, Permpalung, Nitipong, Plantefeve, Gaetan J, Poromanski, Ivan G, Powell, Debra, Psichogiou, Mina, Puah, Ser Hon, Pullman, John, Rahav, Galia, Martinez, Antonio Ramos, Ramos Ramos, Juan Carlos, Raz-Pasteur, Ayelet, Restrepo Castro, Carlos A, Riera, Fernando, Roblot, France, Rodriguez Alvarez, Regino Jose, Rogers, Benjamin, Roilides, Emmanuel, Sanchez Vallejo, Gregorio, Sganga, Gabriele, Sipsas, Nikolaos, Slavin, Monica, Soriano, Alex, Spec, Andrej, Strahilevitz, Jacob, Tancheva, Dora M, Tao, Zhen, Teschner, Daniel, Thompson, George R, Van Wijngaerden, Eric, Vazquez, Jose, Vergidis, Paschalis, Viale, Pierluigi, Wang, Fu-Der, Wang, Shifu, Weber, Gabriel, Weng, Jianyu, Xu, Jinfu, Yao, Li, Yavuz, Serap, Yilmaz, Mesut, Young, Jo-Anne, Zarate, Abel H, Zeng, Jun, Zhang, Yong, Thompson, George R, III, Cornely, Oliver A, Kullberg, Bart Jan, Kollef, Marin, Honore, Patrick M, Bassetti, Matteo, Poromanski, Ivan, Dignani, Cecilia, Das, Anita F, Sandison, Taylor, and Pappas, Peter G

Published
2023
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10. Safety, efficacy, and pharmacokinetics of gremubamab (MEDI3902), an anti-Pseudomonas aeruginosa bispecific human monoclonal antibody, in P. aeruginosa-colonised, mechanically ventilated intensive care unit patients: a randomised controlled trial

Author

Chastre, Jean, François, Bruno, Bourgeois, Marc, Komnos, Apostolos, Ferrer, Ricard, Rahav, Galia, De Schryver, Nicolas, Lepape, Alain, Koksal, Iftihar, Luyt, Charles-Edouard, Sánchez-García, Miguel, Torres, Antoni, Eggimann, Philippe, Koulenti, Despoina, Holland, Thomas L., Ali, Omar, Shoemaker, Kathryn, Ren, Pin, Sauser, Julien, Ruzin, Alexey, Tabor, David E., Akhgar, Ahmad, Wu, Yuling, Jiang, Yu, DiGiandomenico, Antonio, Colbert, Susan, Vandamme, Drieke, Coenjaerts, Frank, Malhotra-Kumar, Surbhi, Timbermont, Leen, Oliver, Antonio, Barraud, Olivier, Bellamy, Terramika, Bonten, Marc, Goossens, Herman, Reisner, Colin, Esser, Mark T., and Jafri, Hasan S.

Published
2022
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13. Analysis of HSV1/2 Infection Reveals an Association between HSV-2 Reactivation and Pregnancy.

Author

Dovrat, Sara, Shabat, Adar, Yahav-Dovrat, Anat, Soufiev, Zvia, Mendelson, Ella, Kashi-Zagdoun, Ela, and Rahav, Galia

Subjects
HUMAN herpesvirus 2, INFECTION, MEDICAL centers, DATA analysis, PROGESTERONE
Abstract

The herpes simplex viruses consist of the strains, HSV-1 and HSV-2, which are prevalent worldwide and lack a definitive cure. We aimed to explore the specific characteristics of HSV 1 and 2 infections, such as differences between gender assigned at birth, age at infection, site of infection, comorbidities, and effect of pregnancy, through a data analysis. Between 2011 and 2018, the Israeli Central Virology Laboratory diagnosed 9189 samples using multiplexed real-time PCR. In addition, we extracted all of the medical data for 287 females hospitalized at the Sheba Medical Center with HSV-1 (161) or HSV-2 (126) genital infections. HSV-2 was almost absent in the orofacial samples from both genders, while in other lesion sites, HSV-2 was significantly more abundant in females than in males (p < 0.05,). HSV-2 was initially detected at puberty. In the hospitalized females' malignancies, both HSV-1 and HSV-2 were found with a non-significant difference. Simultaneously, pregnancies were more common in females who were HSV-2-positive compared with those who were HSV-1-positive (27.8% vs. 12.4%, respectively, p < 0.01). Primary infections occur more with HSV-1 than with HSV-2 (15.6% vs. 3.2%, respectively). Our findings demonstrate that genital HSV-2 infection episodes are more frequent during pregnancy, suggesting that pregnancy may serve as a risk factor for HSV-2 reactivation or infection. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Efficacy of Preexposure Prophylaxis with Monoclonal Antibody Tixagevimab-Cilgavimab against Emerging SARS-CoV-2 Resistant Variants in Patients with Chronic Lymphocytic Leukemia

Author

Benjamini, Ohad, primary, Tadmor, Tamar, additional, Avigdor, Abraham, additional, Gershon, Rotem, additional, Kliker, Limor, additional, Fares, Florin, additional, Atari, Nofar, additional, Laevsky, Ilana, additional, Abdelkader, Bayan, additional, Hod, Tammy, additional, Golan-Shany, Orit, additional, Mandelboim, Michal, additional, and Rahav, Galia, additional

Published
2024
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21. Global guideline for the diagnosis and management of rare mould infections: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology and the American Society for Microbiology

Author

Hoenigl, Martin, Salmanton-García, Jon, Walsh, Thomas J, Nucci, Marcio, Neoh, Chin Fen, Jenks, Jeffrey D, Lackner, Michaela, Sprute, Rosanne, Al-Hatmi, Abdullah M S, Bassetti, Matteo, Carlesse, Fabianne, Freiberger, Tomas, Koehler, Philipp, Lehrnbecher, Thomas, Kumar, Anil, Prattes, Juergen, Richardson, Malcolm, Revankar, Sanjay, Slavin, Monica A, Stemler, Jannik, Spiess, Birgit, Taj-Aldeen, Saad J, Warris, Adilia, Woo, Patrick C Y, Young, Jo-Anne H, Albus, Kerstin, Arenz, Dorothee, Arsic-Arsenijevic, Valentina, Bouchara, Jean-Philippe, Chinniah, Terrence Rohan, Chowdhary, Anuradha, de Hoog, G Sybren, Dimopoulos, George, Duarte, Rafael F, Hamal, Petr, Meis, Jacques F, Mfinanga, Sayoki, Queiroz-Telles, Flavio, Patterson, Thomas F, Rahav, Galia, Rogers, Thomas R, Rotstein, Coleman, Wahyuningsih, Retno, Seidel, Danila, and Cornely, Oliver A

Published
2021
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22. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Author

Bazzalo, Ignacio J., Casas, Marcelo M., Nuñez, Sebastián A., Pere, Yael, Ibarrola, Carlos M., Solis Aramayo, Marco A., Cuesta, Maria C., Duarte, Andrea E., Gutierrez Fernandez, Pablo M., Iannantuono, Maria A., Miyazaki, Erica A., Silvio, Javier P., Scublinsky, Dario G., Bales, Alessandra, Catarino, Daniela, Fiss, Elie, Mohrbacher, Sara, Sato, Victor, Baylao, Antonio, Cavalcante, Adilson, Correa, Francini, de Andrade, Celso A., Furtado, Juvencio, Ribeiro Filho, Nelson, Telles, Valéria, Trevelin, Leopoldo T., Vipich, Ricardo, Boldo, Rodrigo, Borges, Paula, Lobo, Suzana, Luckemeyer, Graziela, Machado, Luana, Alves, Maysa B., Iglessias, Ana C., Lago, Marianna M., Santos, Daniel W., Chapdelaine, Hugo, Falcone, Emilia L., Jamal, Rahima, Luong, Me-Linh, Durand, Madeleine, Doucet, Stephane, Carrier, François-Martin, Coburn, Bryan A., Del Sorbo, Lorenzo, Walmsley, Sharon L., Belga, Sara, Chen, Luke Y., Mah, Allison D., Steiner, Theodore, Wright, Alissa J., Hajek, J., Adhikari, Neill, Fowler, Robert A., Daneman, Nick, Khwaja, Kosar A., Shahin, Jason, Gonzalez, Carolina, Silva, Rafael, Lindh, Marcelo, Maluenda, Gabriel, Fernandez, Patricia, Oyonarte, Maite, Lasso, Martin, Boyer, Alexandre, Bronnimann, Didier, Bui, Hoang-Nam, Cazanave, Charles, Chaussade, Helene, Desclaux, Arnaud, Ducours, Mailys, Duvignaud, Alexandre, Malvy, Denis, Martin, Lisa, Neau, Didier, Nguyen, Duc, Pistone, Thierry, Soubrane-Wirth, Gaetane, Leitao, Julie, Allavena, Clotilde, Biron, Charlotte, Bouchez, Sabelline, Gaborit, Benjamin, Gregoire, Antoine, Le Turnier, Paul, Lecompte, Anne-Sophie, Lecomte, Raphael, Lefebvre, Maeva, Raffi, Francois, Boutoille, David, Morineau, Pascale H., Guéry, Romain, Chatelus, Emmanuel, Dumoussaud, Nathalie, Felten, Renaud, Luca, Florina, Goichot, Bernard, Schneider, Francis, Taquet, Marie-Caroline, Groh, Matthieu, Roumier, Mathilde, Neuville, Mathilde, Bachelard, Antoine, Isernia, Valentina, Lescure, F-Xavier, Phung, Bao-Chau, Rachline, Anne, Sautereau, Aurelie, Vallois, Dorothee, Bleher, Yves, Boucher, Delphine, Coudon, Clémentine, Esnault, Jean, Guimard, Thomas, Leautez-Nainville, Sophie, Merrien, Dominique, Morrier, Marine, Motte-Vincent, Pauline, Gabeff, Romain, Leclerc, Hélène, Cozic, Céline, Decours, Romain, Février, Ronan, Colin, Gwenhael, Abgrall, Sophie, Vignes, Dorothee, Sterpu, Raluca, Kuellmar, Mira, Meersch-Dini, Melanie, Weiss, Raphael, Zarbock, Alexander, Antony, Christiane, Berger, Marc, Brenner, Thorsten, Taube, Christian, Herbstreit, Frank, Dolff, Sebastian, Konik, Margarethe, Schmidt, Karsten, Zettler, Markus, Witzke, Oliver, Boell, Boris, Garcia Borrega, Jorge, Koehler, Philipp, Zander, Thomas, Dusse, Fabian, Al-Sawaf, Othman, Köhler, Philipp, Eichenauer, Dennis, Kochanek, Matthias, Shimabukuro-Vornhagen, Alexander, Mellinghoff, Sibylle, Claßen, Annika, Heger, Jan-Michel, Meyer-Schwickerath, Charlotte, Liedgens, Paul, Heindel, Katrin, Belkin, Ana, Biber, Asaf, Gilboa, Mayan, Levy, Itzchak, Litachevsky, Vladislav, Rahav, Galia, Finesod Wiedner, Anat, Zilberman-Daniels, Tal, Oster, Yonatan, Strahilevitz, Jacob, Sviri, Sigal, Baldissera, Elena M., Campochiaro, Corrado, Cavalli, Giulio, Dagna, Lorenzo, De Luca, Giacomo, Della Torre, Emanuel, Tomelleri, Alessandro, Bernasconi De Luca, Davide, Capetti, Amedeo F., Coen, Massimo, Cossu, Maria V., Galli, Massimo, Giacomelli, Andrea, Gubertini, Guido A., Rusconi, Stefano, Burastero, Giulia J., Digaetano, Margherita, Guaraldi, Giovanni, Meschiari, Marianna, Mussini, Cristina, Puzzolante, Cinzia, Volpi, Sara, Aiello, Marina, Ariani, Alarico, Chetta, Alfredo A., Frizzelli, Annalisa, Ticinesi, Andrea, Tuttolomondo, Domenico, Aliberti, Stefano, Blasi, Francesco B., Di Pasquale, Marta F., Misuraca, Sofia, Pilocane, Tommaso, Simonetta, Edoardo, Aghelmo, Alessio M., Angelini, Claudio, Brunetta, Enrico, Canonica, Giorgio W., Ciccarelli, Michele, Dal Farra, Sara, De Santis, Maria, Ferri, Sebastian, Folci, Marco, Guidelli, Giacomo M., Heffler, Enrico M., Loiacono, Ferdinando, Malipiero, Giacomo, Paoletti, Giovanni, Pedale, Rosa, Puggioni, Francesca A., Racca, Francesca, Zumbo, Aurora, Satou, Morihiko, Honda, Hitoshi, Lisun, Tatyana, Protsenko, Denis, Rubtsov, Nikolay, Beloglazova, Irina, Fomina, Daria, Lysenko, Mariana, Serdotetskova, Sofia, Firstov, Vitali, Gordeev, Ivan, Kokorin, Ilia, Komissarova, Ksenia, Lapochkina, Nina, Luchinkina, Elena, Malimon, Valentin, Mamedguseyinova, Sevinch, Polubatonova, Ksenia, Suvorova, Natalia, Arribas, Jose, Borobia Perez, Alberto M., de la Calle Prieto, Fernando, Figueira, Juan Carlos, Motejano Sanchez, Rocio, Mora-Rillo, Marta, Prados Sanchez, Concepcion, Queiruga Parada, Javier, Fernandez Arnalich, Francisco, Guerro Barrientos, Maria, Bendala Estrada, Alejandro, Caballero Marcos, Aranzazu, Garcia Leoni, Maria E., García-Martínez, Rita, Collado, Ana María, Munoz Garcia, Patricia, Torres do Rego, Ana, Villalba García, María V., Burrillo, Almudena, Valerio Minero, Maricela, Gijon Vidaurreta, Paloma, Infante Herrero, Sonsoles, Velilla, Elena, Machado, Marina, Olmedo, Maria, Pinilla, Blanca, Almirante Gragera, Benito, Cañas Ruano, Maria de la Esperanza, Contreras Medina, Sofia, Cortés Herrera, Alejandro, Falcó Ferrer, Vicenç, Ferrer Roca, Ricard, Nuvials Casals, Xavier, Ribera Pascuet, Esteve, Suanzes Diez, Paula, Rebollo Castro, Pedro, Garcia Alcaide, Felipe, Soriano, Alejandro, Oliver Caldes, Aina, González Cordón, Ana, Cardozo, Celia, De la Mora Cañizo, Lorena, Pena López, Romina, Chamorro, Sandra, Crespillo-Andujar, Clara, Escudero Sanchez, Rosa, Fortún-Abete, Jesús, Monge-Maillo, Begoña, Moreno Zamora, Ana, Norman, Francesca, Sanchez Conde, Matilde, Serrano Villar, Sergio, Vizcarra, Pilar, Lescure, François-Xavier, Fowler, Robert A, Lazar, Jennifer Sloane, Shi, Genming, Wung, Peter, Patel, Naimish, and Hagino, Owen

Published
2021
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23. The Impact of Carbapenem Resistance on Mortality in Patients With Klebsiella Pneumoniae Bloodstream Infection: An Individual Patient Data Meta-Analysis of 1952 Patients

Author

Maraolo, Alberto E., Corcione, Silvia, Grossi, Adriano, Signori, Alessio, Alicino, Cristiano, Hussein, Khetam, Trecarichi, Enrico M., Viale, Pierluigi, Timsit, Jean-François, Veeraraghavan, Balaji, Villegas, Maria V., Rahav, Galia, Daikos, George L., Vardakas, Konstantinos Z., Roilides, Emmanuel, Uhlemann, Anne-Catrin, Ghafur, Abdul K., Mornese Pinna, Simone, Bassetti, Matteo, Kohler, Philipp P., and Giacobbe, Daniele R.

Published
2021
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24. Compassionate use of convalescent plasma for treatment of moderate and severe pneumonia in COVID-19 patients and association with IgG antibody levels in donated plasma

Author

Maor, Yasmin, Cohen, Daniel, Paran, Nir, Israely, Tomer, Ezra, Vered, Axelrod, Ofra, Shinar, Eilat, Izak, Marina, Rahav, Galia, Rahimi-Levene, Naomi, Bazofin, Baruch M, Gelman, Ram, Dicker, Dror, Brosh-Nissimov, Tal, Megged, Orli, Dahan, David, Benov, Avi, Paz, Alona, Edward, Kaykov, Moran, Amit, Rogowski, Ori, Sorkine, Patrick, Mayo, Ami, Zimhony, Oren, and Chen, Jacob

Published
2020
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25. Environmental shedding of toxigenic Clostridioides difficile by asymptomatic carriers: A prospective observational study

Author

Amital, Howard, Beni, Sharon, Ben-Zvi, Ilan, Blausov, Natasha, Brom, Adi, Cohen, Carmit, Feld-Simon, Olga, Fluss, Ronen, Gilboa, Mayan, Eden-Friedman, Yehudit, Halevy, Shiraz, Houri-Levi, Esther, Hupert, Amit, Jbarien, Amnah, Keller, Naty, Leibowitz, Avshalom, Mayan, Haim, Maizels, Leonid, Meltzer, Eyal, Pinas-Zade, Nani, Rahav, Galia, Raibman-Spector, Shir, Regev-Yochay (PI), Gili, Romiantsev, Marina, Shachar, Dalit, Sharif, Kassem, Segal, Gadi, Segal, Shoshi, Segev, Amitai, Smollan, Gill, Stienlauf, Shmuel, Tal, Ilana, Yonath, Hagit, Zilberman-Daniels, Tal, Zimlichman, Eyal, Gilboa, M., Houri-Levi, E., Cohen, C., Tal, I., Rubin, C., Feld-Simon, O., Brom, A., Eden-Friedman, Y., Segal, S., Rahav, G., and Regev-Yochay, G.

Published
2020
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26. Persistent Infections by Nontyphoidal Salmonella in Humans: Epidemiology and Genetics

Author

Marzel, Alex, Desai, Prerak T, Goren, Alina, Schorr, Yosef Ilan, Nissan, Israel, Porwollik, Steffen, Valinsky, Lea, McClelland, Michael, Rahav, Galia, and Gal-Mor, Ohad

Subjects
Human Genome, Biodefense, Genetics, Infectious Diseases, Digestive Diseases, Prevention, Foodborne Illness, Vaccine Related, Emerging Infectious Diseases, Aetiology, 2.2 Factors relating to the physical environment, 2.1 Biological and endogenous factors, Infection, Adolescent, Adult, Aged, Animals, Child, Child, Preschool, Chronic Disease, DNA, Bacterial, Disease Models, Animal, Female, Genome, Bacterial, Humans, Infant, Israel, Male, Mice, Retrospective Studies, Salmonella Infections, Salmonella enterica, Sequence Analysis, DNA, Young Adult, salmonellosis, persistent infection, WGS, epidemiology, Biological Sciences, Medical and Health Sciences, Microbiology
Abstract

BackgroundAlthough chronic infections by typhoidal Salmonella are well-known, prolonged human infections by nontyphoidal Salmonella (NTS) are poorly characterized.MethodsWe retrospectively analyzed 48 345 culture-confirmed NTS infections that occurred in Israel 1995-2012. A case-control study was performed to identify risk factors associated with persistent infections. Whole-genome-sequencing, pulsed-field gel electrophoresis (PFGE), and a mouse infection model were used to study genetic and phenotypic differences between same-patient persistent, recurring isolates.ResultsIn total, 1047 cases of persistent NTS infections, comprising 2.2% of all reported cases of salmonellosis, were identified. The persistence periods ranged between 30 days to 8.3 years. The majority (93%) of the persistently infected patients were immunocompetent, and 65% were symptomatic with relapsing diarrhea, indicating a distinct clinical manifestation from the asymptomatic carriage of typhoidal Salmonella. Four NTS serovars (Mbandaka, Bredeney, Infantis and Virchow) were found to be significantly more frequently associated with persistence than others. Comparative genomics between early and later isolates obtained from the same patients confirmed clonal infection and showed 0 to 10 SNPs between persistent isolates. A different composition of mobile genetic elements (plasmids and phages) or amino acid substitutions in global regulators was identified in multiple cases. These changes resulted in differences in phenotype and virulence between early and later same-patient isolates.ConclusionsThese results illuminate the overlooked clinical manifestation of persistent salmonellosis that can serve as a human reservoir for NTS infections. Additionally, we demonstrate mechanisms of in-host microevolution and exhibit their potential to shape Salmonella pathogenicity, antimicrobial resistance and host-pathogen interactions.

Published
2016

27. Differences in Host Cell Invasion and Salmonella Pathogenicity Island 1 Expression between Salmonella enterica Serovar Paratyphi A and Nontyphoidal S. Typhimurium

Author

Elhadad, Dana, Desai, Prerak, Grassl, Guntram A, McClelland, Michael, Rahav, Galia, and Gal-Mor, Ohad

Subjects
Microbiology, Medical Microbiology, Biomedical and Clinical Sciences, Biological Sciences, Vaccine Related, Biodefense, Emerging Infectious Diseases, Biotechnology, Foodborne Illness, Digestive Diseases, Genetics, Prevention, Infectious Diseases, Aetiology, 2.1 Biological and endogenous factors, Animals, Bacterial Proteins, Cloning, Molecular, Cytokines, Female, Gene Expression Regulation, Bacterial, Mice, Mice, Inbred C57BL, Salmonella paratyphi A, Salmonella typhimurium, Trans-Activators, Agricultural and Veterinary Sciences, Medical and Health Sciences, Immunology, Medical microbiology
Abstract

Active invasion into nonphagocytic host cells is central to Salmonella enterica pathogenicity and dependent on multiple genes within Salmonella pathogenicity island 1 (SPI-1). Here, we explored the invasion phenotype and the expression of SPI-1 in the typhoidal serovarS Paratyphi A compared to that of the nontyphoidal serovarS Typhimurium. We demonstrate that while S. Typhimurium is equally invasive under both aerobic and microaerobic conditions, S. Paratyphi A invades only following growth under microaerobic conditions. Transcriptome sequencing (RNA-Seq), reverse transcription-PCR (RT-PCR), Western blot, and secretome analyses established that S. Paratyphi A expresses much lower levels of SPI-1 genes and secretes lesser amounts of SPI-1 effector proteins than S. Typhimurium, especially under aerobic growth. Bypassing the native SPI-1 regulation by inducible expression of the SPI-1 activator, HilA, considerably elevated SPI-1 gene expression, host cell invasion, disruption of epithelial integrity, and induction of proinflammatory cytokine secretion by S. Paratyphi A but not by S. Typhimurium, suggesting that SPI-1 expression is naturally downregulated inS Paratyphi A. Using streptomycin-treated mice, we were able to establish substantial intestinal colonization byS Paratyphi A and showed moderately higher pathology and intestinal inflammation in mice infected with S. Paratyphi A overexpressing hilA Collectively, our results reveal unexpected differences in SPI-1 expression between S. Paratyphi A andS Typhimurium, indicate that S. Paratyphi A host cell invasion is suppressed under aerobic conditions, and suggest that lower invasion in aerobic sites and suppressed expression of immunogenic SPI-1 components contributes to the restrained inflammatory infection elicited by S. Paratyphi A.

Published
2016

28. Genetic and Phenotypic Characterization of a Salmonella enterica serovar Enteritidis Emerging Strain with Superior Intra-macrophage Replication Phenotype.

Author

Shomer, Inna, Avisar, Alon, Desai, Prerak, Azriel, Shalhevet, Smollan, Gill, Belausov, Natasha, Keller, Nathan, Glikman, Daniel, Maor, Yasmin, Peretz, Avi, McClelland, Michael, Rahav, Galia, and Gal-Mor, Ohad

Subjects
Enteritidis, Salmonella enterica, food born infection, gastroenteritis, intracellular replication, outbreak, pathogenicity, virulence, Microbiology, Environmental Science and Management, Soil Sciences
Abstract

Salmonella enterica serovar Enteritidis (S. Enteritidis) is one of the ubiquitous Salmonella serovars worldwide and a major cause of food-born outbreaks, which are often associated with poultry and poultry derivatives. Here we report a nation-wide S. Enteritidis clonal outbreak that occurred in Israel during the last third of 2015. Pulsed field gel electrophoresis and whole genome sequencing identified genetically related strains that were circulating in Israel as early as 2008. Global comparison linked this outbreak strain to several clinical and marine environmental isolates that were previously isolated in California and Canada, indicating that similar strains are prevalent outside of Israel. Phenotypic comparison between the 2015 outbreak strain and other clinical and reference S. Enteritidis strains showed only limited intra-serovar phenotypic variation in growth in rich medium, invasion into Caco-2 cells, uptake by J774.1A macrophages, and host cell cytotoxicity. In contrast, significant phenotypic variation was shown among different S. Enteritidis isolates when biofilm-formation, motility, invasion into HeLa cells and uptake by THP-1 human macrophages were studied. Interestingly, the 2015 outbreak clone was found to possess superior intra-macrophage replication ability within both murine and human macrophages in comparison to the other S. Enteritidis strains studied. This phenotype is likely to play a role in the virulence and host-pathogen interactions of this emerging clone.

Published
2016

29. Sink-traps are a major source for carbapenemase-producing Enterobacteriaceae transmission

Author

Regev-Yochay, Gili, primary, Margalit, Ili, additional, Smollan, Gillian, additional, Rapaport, Rotem, additional, Tal, Ilana, additional, Hanage, William P., additional, Pinas Zade, Nani, additional, Jaber, Hanaa, additional, Taylor, Bradford P., additional, Che, You, additional, Rahav, Galia, additional, Zimlichman, Eyal, additional, and Keller, Nati, additional

Published
2023
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30. Automated processing of thermal imaging to detect COVID-19

Author

Brzezinski, Rafael Y., Rabin, Neta, Lewis, Nir, Peled, Racheli, Kerpel, Ariel, Tsur, Avishai M., Gendelman, Omer, Naftali-Shani, Nili, Gringauz, Irina, Amital, Howard, Leibowitz, Avshalom, Mayan, Haim, Ben-Zvi, Ilan, Heller, Eyal, Shechtman, Liran, Rogowski, Ori, Shenhar-Tsarfaty, Shani, Konen, Eli, Marom, Edith M., Ironi, Avinoah, Rahav, Galia, Zimmer, Yair, Grossman, Ehud, Ovadia-Blechman, Zehava, Leor, Jonathan, and Hoffer, Oshrit

Published
2021
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33. Flagellin Is Required for Host Cell Invasion and Normal Salmonella Pathogenicity Island 1 Expression by Salmonella enterica Serovar Paratyphi A

Author

Elhadad, Dana, Desai, Prerak, Rahav, Galia, McClelland, Michael, and Gal-Mor, Ohad

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Microbiology, Clinical Sciences, Medical Microbiology, Biodefense, Foodborne Illness, Vaccine Related, Digestive Diseases, Infectious Diseases, Emerging Infectious Diseases, Rare Diseases, Genetics, Prevention, 2.2 Factors relating to the physical environment, Aetiology, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Bacterial Proteins, Blotting, Western, Caco-2 Cells, Flagellin, Humans, Mass Spectrometry, Paratyphoid Fever, Reverse Transcriptase Polymerase Chain Reaction, Salmonella paratyphi A, Agricultural and Veterinary Sciences, Medical and Health Sciences, Immunology, Medical microbiology
Abstract

Salmonella enterica serovar Paratyphi A is a human-specific serovar that, together with Salmonella enterica serovar Typhi and Salmonella enterica serovar Sendai, causes enteric fever. Unlike the nontyphoidal Salmonella enterica serovar Typhimurium, the genomes of S. Typhi and S. Paratyphi A are characterized by inactivation of multiple genes, including in the flagellum-chemotaxis pathway. Here, we explored the motility phenotype of S. Paratyphi A and the role of flagellin in key virulence-associated phenotypes. Motility studies established that the human-adapted typhoidal S. Typhi, S. Paratyphi A, and S. Sendai are all noticeably less motile than S. Typhimurium, and comparative transcriptome sequencing (RNA-Seq) showed that in S. Paratyphi A, the entire motility-chemotaxis regulon is expressed at significantly lowers levels than in S. Typhimurium. Nevertheless, S. Paratyphi A, like S. Typhimurium, requires a functional flagellum for epithelial cell invasion and macrophage uptake, probably in a motility-independent mechanism. In contrast, flagella were found to be dispensable for host cell adhesion. Moreover, we demonstrate that in S. Paratyphi A, but not in S. Typhimurium, the lack of flagellin results in increased transcription of the flagellar and the Salmonella pathogenicity island 1 (SPI-1) regulons in a FliZ-dependent manner and in oversecretion of SPI-1 effectors via type three secretion system 1. Collectively, these results suggest a novel regulatory linkage between flagellin and SPI-1 in S. Paratyphi A that does not occur in S. Typhimurium and demonstrate curious distinctions in motility and the expression of the flagellum-chemotaxis regulon between these clinically relevant pathogens.

Published
2015

34. Feverlike Temperature is a Virulence Regulatory Cue Controlling the Motility and Host Cell Entry of Typhoidal Salmonella

Author

Elhadad, Dana, McClelland, Michael, Rahav, Galia, and Gal-Mor, Ohad

Subjects
Prevention, Vaccine Related, Biodefense, Digestive Diseases, Foodborne Illness, Emerging Infectious Diseases, Genetics, Infectious Diseases, Rare Diseases, Aetiology, 2.2 Factors relating to the physical environment, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Cell Line, Endocytosis, Epithelial Cells, Fever, Gene Expression Regulation, Bacterial, Humans, Locomotion, Macrophages, Salmonella enterica, Temperature, Virulence, Virulence Factors, enteric fever, pyrexia, paratyphoid, Salmonella, pathogenicity, motility, flagella, invasion, Biological Sciences, Medical and Health Sciences, Microbiology
Abstract

Human infection with typhoidal Salmonella serovars causes a febrile systemic disease, termed enteric fever. Here we establish that in response to a temperature equivalent to fever (39 °C-42 °C) Salmonella enterica serovars Typhi, Paratyphi A, and Sendai significantly attenuate their motility, epithelial cell invasion, and uptake by macrophages. Under these feverlike conditions, the residual epithelial cell invasion of S. Paratyphi A occurs in a type III secretion system (T3SS) 1-independent manner and results in restrained disruption of epithelium integrity. The impaired motility and invasion are associated with down-regulation of T3SS-1 genes and class II and III (but not I) of the flagella-chemotaxis regulon. In contrast, we demonstrate up-regulation of particular Salmonella pathogenicity island 2 genes (especially spiC) and increased intraepithelial growth in a T3SS-2-dependent manner. These results indicate that elevated physiological temperature is a novel cue controlling virulence phenotypes in typhoidal serovars, which is likely to play a role in the distinct clinical manifestations elicited by typhoidal and nontyphoidal salmonellae.

Published
2015

36. Hospital-onset adult invasive pneumococcal disease in Israel: Sicker patients, different pathogens

Author

Dagan, Ron, Assous, Marc, Ben-Zvi, Haim, Bishara, Jihad, Bardenstein, Rita, Brik, Larissa, Chazan, Bibiana, Chowers, Michal, Cohen-Poradosu, Ronit, Finn, Talia, Embon, Alicia, Freimann, Sarit, Geffen, Yuval, Glikman, Danny, Hershman, Mirit, Istomin, Valery, Katzir, Michal, Kennes, Yoram, Khakshoor, Shirley, Khoury-Assi, Camellia, Sari, Mandelbaum, Maor, Yasmin, Miron, Danny, Oren, Ilana, Paitan, Yosi, Paran, Yael, Peled, Nehama, Peretz, Avi, Porat, Nurit, Potasman, Israel, Rahav, Galia, Rechnitzer, Hagai, Reisenberg, Klaris, Sela, Shifra, Schwartz, David, Schwartz, Orna, Shaked-Mishan, Pninit, Sheindler, Yehudit, Smollan, Gill, Srugo, Itzhak, Stein, Michal, Strahilevitz, Jacob, Sverdlob, Olga, Temper, Violetta, Tsyba, Evgenia, Wiener-Well, Yonit, Weber, Gabriel, Weinberger, Miriam, Zimhony, Oren, Kenig, Ariel, Regev-Yochay, Gili, Glikman, Daniel, and Hershman-Sarafov, Mirit

Published
2019
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38. Integrative Analysis of Salmonellosis in Israel Reveals Association of Salmonella enterica Serovar 9,12:l,v:− with Extraintestinal Infections, Dissemination of Endemic S. enterica Serovar Typhimurium DT104 Biotypes, and Severe Underreporting of Outbreaks

Author

Marzel, Alex, Desai, Prerak T, Nissan, Israel, Schorr, Yosef Ilan, Suez, Jotham, Valinsky, Lea, Reisfeld, Abraham, Agmon, Vered, Guard, Jean, McClelland, Michael, Rahav, Galia, and Gal-Mor, Ohad

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Biodefense, Foodborne Illness, Biotechnology, Vaccine Related, Digestive Diseases, Infectious Diseases, Emerging Infectious Diseases, Rare Diseases, Genetics, Prevention, 2.1 Biological and endogenous factors, Aetiology, Infection, Good Health and Well Being, DNA, Bacterial, Electrophoresis, Gel, Pulsed-Field, Genotype, Humans, Israel, Molecular Sequence Data, Molecular Typing, Salmonella Infections, Salmonella enterica, Sequence Analysis, DNA, Serogroup, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Microbiology, Clinical sciences, Medical microbiology
Abstract

Salmonella enterica is the leading etiologic agent of bacterial food-borne outbreaks worldwide. This ubiquitous species contains more than 2,600 serovars that may differ in their host specificity, clinical manifestations, and epidemiology. To characterize salmonellosis epidemiology in Israel and to study the association of nontyphoidal Salmonella (NTS) serovars with invasive infections, 48,345 Salmonella cases reported and serotyped at the National Salmonella Reference Center between 1995 and 2012 were analyzed. A quasi-Poisson regression was used to identify irregular clusters of illness, and pulsed-field gel electrophoresis in conjunction with whole-genome sequencing was applied to molecularly characterize strains of interest. Three hundred twenty-nine human salmonellosis clusters were identified, representing an annual average of 23 (95% confidence interval [CI], 20 to 26) potential outbreaks. We show that the previously unsequenced S. enterica serovar 9,12:l,v:- belongs to the B clade of Salmonella enterica subspecies enterica, and we show its frequent association with extraintestinal infections, compared to other NTS serovars. Furthermore, we identified the dissemination of two prevalent Salmonella enterica serovar Typhimurium DT104 clones in Israel, which are genetically distinct from other global DT104 isolates. Accumulatively, these findings indicate a severe underreporting of Salmonella outbreaks in Israel and provide insights into the epidemiology and genomics of prevalent serovars, responsible for recurring illness.

Published
2014

40. Persistent SARS CoV2 Pneumonia in Patients Treated with Anti-CD20 Monoclonal Antibodies

Author

Furie, Nadav, primary, Mandelboim, Michal, additional, Zuckerman, Neta, additional, Belkin, Ana, additional, Seluk, Lior, additional, Shafran, Inbal, additional, Mass, Ronen, additional, Levy, Liran, additional, Chatterji, Sumit, additional, Baltaxe, Erik, additional, Peled, Michael, additional, Shulimzon, Tiberiu, additional, Avigdor, Abraham, additional, Amit, Sharon, additional, Onn, Amir, additional, Marom, Edith M, additional, Rahav, Galia, additional, and Segel, Michael J, additional

Published
2023
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41. Exported Case of Sin Nombre Hantavirus Pulmonary Syndrome — Israel, 2017

Author

Kofman, Aaron, Rahav, Galia, Yazzie, Del, Shorty, Herman, Yaglom, Hayley D., Peterson, Dallin, Peek-Bullock, Melissa, Choi, Mary J., Wieder-Finesod, Anat, D. Klena, John, Venkat, Heather, Chiang, Cheng-Feng, Knust, Barbara, Gaither, Marlene, Maurer, Matthew, Hoeschele, Donald R., and Nichol, Stuart T.

Published
2018

46. Virulence Gene Profiling and Pathogenicity Characterization of Non-Typhoidal Salmonella Accounted for Invasive Disease in Humans

Author

Suez, Jotham, Porwollik, Steffen, Dagan, Amir, Marzel, Alex, Schorr, Yosef Ilan, Desai, Prerak T, Agmon, Vered, McClelland, Michael, Rahav, Galia, Gal-Mor, Ohad, and Chabalgoity, Jose Alejandro

Subjects
Enterica Serovar Typhi, Host Adaptation, Bacterial Virulence, Epithelial-Cells, Genomic Island, Typhimurium, Evolution, Mice, Identification, Infectionfe-ga alloys, magnetoelasticity, galfenol
Published
2013

47. Effect and Safety of Meropenem–Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial

Author

Wunderink, Richard G., Giamarellos-Bourboulis, Evangelos J., Rahav, Galia, Mathers, Amy J., Bassetti, Matteo, Vazquez, Jose, Cornely, Oliver A., Solomkin, Joseph, Bhowmick, Tanaya, Bishara, Jihad, Daikos, George L., Felton, Tim, Furst, Maria Jose Lopez, Kwak, Eun Jeong, Menichetti, Francesco, Oren, Ilana, Alexander, Elizabeth L., Griffith, David, Lomovskaya, Olga, Loutit, Jeffery, Zhang, Shu, Dudley, Michael N., and Kaye, Keith S.

Published
2018
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50. Sink-traps are a major source for carbapenemase-producing Enterobacteriaceaetransmission

Author

Regev-Yochay, Gili, Margalit, Ili, Smollan, Gillian, Rapaport, Rotem, Tal, Ilana, Hanage, William P., Pinas Zade, Nani, Jaber, Hanaa, Taylor, Bradford P., Che, You, Rahav, Galia, Zimlichman, Eyal, and Keller, Nati

Abstract

AbstractObjective:We studied the extent of carbapenemase-producing Enterobacteriaceae (CPE) sink contamination and transmission to patients in a nonoutbreak setting.Methods:During 2017–2019, 592 patient-room sinks were sampled in 34 departments. Patient weekly rectal swab CPE surveillance was universally performed. Repeated sink sampling was conducted in 9 departments. Isolates from patients and sinks were characterized using pulsed-field gel electrophoresis (PFGE), and pairs of high resemblance were sequenced by Oxford Nanopore and Illumina. Hybrid assembly was used to fully assemble plasmids, which are shared between paired isolates.Results:In total, 144 (24%) of 592 CPE-contaminated sinks were detected in 25 of 34 departments. Repeated sampling (n = 7,123) revealed that 52%–100% were contaminated at least once during the sampling period. Persistent contamination for >1 year by a dominant strain was common. During the study period, 318 patients acquired CPE. The most common species were Klebsiella pneumoniae, Escherichia coli, and Enterobacterspp. In 127 (40%) patients, a contaminated sink was the suspected source of CPE acquisition. For 20 cases with an identical sink-patient strain, temporal relation suggested sink-to-patient transmission. Hybrid assembly of specific sink-patient isolates revealed that shared plasmids were structurally identical, and SNP differences between shared pairs, along with signatures for potential recombination events, suggests recent sharing of the plasmids.Conclusions:CPE-contaminated sinks are an important source of transmission to patients. Although traditionally person-to-person transmission has been considered the main route of CPE transmission, these data suggest a change in paradigm that may influence strategies of preventing CPE dissemination.

Published
2024
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