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Transplantation-Oncology Infectious Diseases

Translational Research

Walsh, Small, Satlin, Petraitiene, Petraitis, Kodiyanplakkal, Plate, Drelick, Soave, Helfgott

Infectious diseases are important causes of morbidity and mortality in immunocompromised patients with cancer, and those undergoing transplantation. The research mission of the Transplantation-Oncology Infectious Diseases Program is to develop new strategies for diagnosis, treatment, and prevention of life-threatening infections in immunocompromised patients with transplantation and neoplastic diseases through multidisciplinary translational research. The tools of this research include epidemiology, pathogenesis, host defenses, antimicrobial pharmacology, immunopharmacology, and molecular diagnostic microbiology, and clinical trials.

Following the observations at the bedside, we work systematically through in vitro systems, laboratory animal models, phase I-II clinical trials, and, where applicable, to multicenter phase III clinical trials. Our clinical trials are conducted with consortia composed of seasoned clinical investigators with expertise in immunocompromised patients. Among the patient populations studied within the Program are those with hematological malignancies, aplastic anemia, myelodysplasia, hematopoietic stem cell transplantation, and solid organ transplantation, including kidney, liver, and pancreas.

Our strategy for translational research is predicated on an iterative process of bedside to bench to bedside with an emphasis on the critical role of the physician-scientist in this process. These studies are conducted in collaboration with our colleagues in Oncology, Hematology, Nephrology, Hepatobiliary Transplantation Surgery, Pediatrics, Clinical Microbiology, Pharmacology, Microbiology & Immunology, Critical Care Medicine, and Ophthalmology. We have a long and successful tradition of mentoring the future leaders in the field of infections in immunocompromised patients. We also are developing a Weill Cornell-Columbia University NYPH-wide Transplantation-Oncology Infectious Diseases Fellowship.

Invasive fungal infections

Recognizing the severe morbidity and mortality caused by invasive mycoses, the study of invasive fungal infections with specific emphasis on Candida spp., Aspergillus spp., the Mucorales, and emerging pathogens such as Candida auris, Fusarium spp., and Scedosporium spp., is a critical element of our mission. We conduct translational research in three major areas of medical mycology: antifungal pharmacology, molecular diagnosis, innate host defenses, and biofilms.

Among our recent advances:

  • identification of the development and validation of the first multispecies PCR system for Aspergillus spp. and Mucorales to be made available in a U.S. reference laboratory
  • rapid molecular diagnosis of invasive candidiasis with T2 technology
  • plasma pharmacokinetics of posaconazole in pediatric patients
  • in vitro and in vivo interspecies analysis of virulence in experimental pulmonary mucormycosis: correlation with circulating molecular biomarkers
  • sporangiospore germination and hyphal metabolism
  • in vitro and in vivo antifungal combination studies against medically important fungi
  • epidemiology and treatment of osteoarticular mycoses (collaboration with Hospital for Special Surgery)
  • pathogenesis and treatment of fungal biofilms

Ongoing clinical trials include ibrexafungerp (SCY 078) for treatment of infections caused by Candida auris and other resistant Candida spp., treatment of resistant invasive mould infections with pharmacokinetic studies of novel triazoles (Dr. Helfgott and Dr. Walsh), and diagnostic biomarkers in immunocompromised children and adults (Dr. Petraitiene).

Petraitiene R, Petraitis V, Maung BW, Naing E, Kavaliauskas P, Walsh TJ. Posaconazole Alone and in Combination with Caspofungin for Treatment of Experimental Exserohilum rostratum Meningoencephalitis: Developing New Strategies for Treatment of Phaeohyphomycosis of the Central Nervous System. J Fungi (Basel). 2020 Mar 5;6(1):33.

Petraitis V, Petraitiene R, Valdez JM, Pyrgos V, Lizak MJ, Klaunberg BA, Kalasauskas D, Basevicius A, Bacher JD, Benjamin DK Jr, Hope WW, Walsh TJ. Amphotericin B Penetrates into the Central Nervous System Through Focal Disruption of the Blood Brain Barrier in Experimental Hematogenous Candida Meningoencephalitis. Antimicrob Agents Chemother. 2019 Oct 7;63(12):e01626-19.

Petraitis V, Petraitiene R, McCarthy MW, Kovanda LL, Zaw MH, Hussain K, Shaikh N, Maung BBW, Sekhon NK, Hope WW, Walsh TJ. Combination Therapy with Isavuconazole and Micafungin for Treatment of Experimental Invasive Pulmonary Aspergillosis. Antimicrob Agents Chemother. 2017 Aug 24;61(9):e00305-17.

Sfeir MM, Jiménez-Ortigosa C, Gamaletsou MN, Schuetz AN, Soave R, Van Besien K, Small CB, Perlin DS, Walsh TJ. Breakthrough Bloodstream Infections Caused by Echinocandin-Resistant Candida tropicalis: An Emerging Threat to Immunocompromised Patients with Hematological Malignancies. J Fungi (Basel). 2020 Jan 31;6(1):20.

Walsh TJ, Hospenthal DR, Petraitis V, Kontoyiannis DP. Necrotizing Mucormycosis of Wounds Following Combat Injuries, Natural Disasters, Burns, and Other Trauma. J Fungi (Basel). 2019 Jul 4;5(3):57.

Multidrug resistant bacterial infections

The Translational Research Laboratory is developing new strategies for pharmacodynamically rational methods for administration of existing antibacterial agents, development of new antimicrobial compounds against multidrug resistant bacterial pathogens, particularly Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, Stenotrophomonas maltophilia, and MRSA. Dr. Satlin is currently characterizing the molecular epidemiology of carbapenem-resistant Enterobacteriaceae in patients with hematological malignancies, as well as investigating molecular diagnostic approaches to rapid identification of resistant bacteria as a guide to empirical antibacterial therapy of febrile neutropenic patients. Drs. Petraitis and Petraitiene are conducting laboratory studies of the pharmacokinetics and pharmacodynamics of ceftazidime/avibactam and polymyxin B in the treatment of experimental pneumonia caused by carbapenemase-producing Klebsiella pneumoniae in immunocompromised and immunocompetent rabbits. They are also exploring the pharmacokinetics and pharmacodynamics of ceftolozane/tazobactam in treatment of experimental Pseudomonas aeruginosa pneumonia. We are harnessing bacteriophage technology for treatment and prevention of experimental sepsis caused by KPC. As a logical extension of these preclinical studies, we also are opening clinical trials in Pseudomonas aeruginosa pneumonia and multidrug resistant Gram-negative bacteremia.

Petraitiene R, Petraitis V, Kavaliauskas P, Maung BBW, Khan F, Naing E, Aung T, Zigmantaite V, Grigaleviciute R, Kucinskas A, Stakauskas R, Georgiades BN, Mazur CA, Hayden JA, Satlin MJ, Walsh TJ. Pharmacokinetics and efficacy of ceftazidime/avibactam in the treatment of experimental pneumonia caused by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) in persistently neutropenic rabbits. Antimicrob Agents Chemother. 2020 Feb 3. pii: AAC.02157-19.

Petraitis V, Petraitiene R, Naing E, Aung T, Wai Phyo T, Kavaliauskas P, DeRyke CA, Culshaw DL, Nicolau D, Satlin MG, Walsh TJ. Ceftolozane/tazobactam in the treatment of experimental Pseudomonas aeruginosa pneumonia in persistently neutropenic rabbits: impact on strains with genetically defined mechanisms of resistance. Antimicrob Agents Chemother. 2019 Jun 24. pii: AAC.00344-19.

Prakapaite R, Saab F, Planciuniene R, Petraitis V, Walsh TJ, Petraitiene R, Semoskaite R, Baneviciene R, Kalediene L, Kavaliauskas P. Molecular Characterization of Uropathogenic Escherichia coli Reveals Emergence of Drug Resistant O15, O22 and O25 Serogroups. Medicina (Kaunas). 2019 Nov 11;55(11):733.

Satlin MJ, Chen L, Patel G, Gomez-Simmonds A, Weston G, Kim AC, Seo SK, Rosenthal ME, Sperber SJ, Jenkins SG, Hamula CL, Uhlemann AC, Levi MH, Fries BC, Tang YW, Juretschko S, Rojtman AD, Hong T, Mathema B, Jacobs MR, Walsh TJ, Bonomo RA, Kreiswirth BN. Multicenter Clinical and Molecular Epidemiological Analysis of Bacteremia Due to Carbapenem-Resistant Enterobacteriaceae (CRE) in the CRE Epicenter of the United States. Antimicrob Agents Chemother. 2017 Mar 24;61(4):e02349-16.

Satlin MJ, Chavda KD, Baker TM, Chen L, Shashkina E, Soave R, Small CB, Jacobs SE, Shore TB, van Besien K, Westblade LF, Schuetz AN, Fowler VG Jr, Jenkins SG, Walsh TJ, Kreiswirth BN. Colonization With Levofloxacin-resistant Extended-spectrum β-Lactamase-producing Enterobacteriaceae and Risk of Bacteremia in Hematopoietic Stem Cell Transplant Recipients. Clin Infect Dis. 2018 Nov 13;67(11):1720-1728.

Viral infections

In an effort to better understand the epidemiology of community associated respiratory viruses, Dr. Small is characterizing the epidemiology and risk factors for development of human rhinovirus (HRV) respiratory tract infections in HSCT recipients. Dr. Small is conducting clinical trials with novel antiviral agents against viral respiratory tract infections. These studies, including respiratory syncytial virus (RSV), influenza, parainfluenza, CMV, and COVID-19 infections will provide our patients with new agents that may improve outcome from these serious infections in our immunocompromised population. The epidemiology of respiratory viral infections in these patients continues to evolve and will be the subject of further study. Immunization is an important adjunct to the management of viral infections in immunocompromised patients.

Salvatore M, Satlin MJ, Jacobs SE, Jenkins SG, Schuetz AN, Moss RB, Van Besien K, Shore T, Soave R. DAS181 for Treatment of Parainfluenza Virus Infections in Hematopoietic Stem Cell Transplant Recipients at a Single Center. Biol Blood Marrow Transplant. 2016 May;22(5):965-70.

Linder K, Kovacs C, Mullane K, Wolfe C, Clark N, Small C, et al. Letermovir Treatment for Established Cytomegalovirus Infection in Transplant Recipients. [abstract]. Am J Transplant 20 (suppl 3, 2020).

Kodiyanplakkal RP, Brown M, Guarneri D, Soave R, Drelick A, Shore T, Gergis U, Mayer S, Phillips A, Hsu J, Walsh T, Small C, van Besien K. Efficacy of Letermovir Prophylaxis in Cytomegalovirus Seropositive Allogeneic Hematopoietic Stem Cell Transplant Recipients Receiving in-Vitro-T-Cell Depletion. Presented at EBMT, Frankfurt Germany, March 2019.

Chemaly RF, Dadwal SS, Bergeron A, Ljungman P, Kim YJ, Cheng GS, Pipavath SN, Limaye AP, Blanchard E, Winston DJ, Stiff PJ, Zuckerman T, Lachance S, Rahav G, Small CB, Mullane KM, Patron RL, Lee DG, Hirsch HH, Waghmare A, McKevitt M, Jordan R, Guo Y, German P, Porter DP, Gossage DL, Watkins TR, Marty FM, Chien JW, Boeckh M. A phase 2, randomized, double-blind, placebo-controlled trial of presatovir for the treatment of respiratory syncytial virus upper respiratory tract infection in hematopoietic-cell transplant recipients. Clin Infect Dis. 2019 Dec 3:ciz1166.

Marty FM, Chemaly RF, Mullane KM, Lee DG, Hirsch HH, Small CB, Bergeron A, Shoham S, Ljungman P, Waghmare A, Blanchard E, Kim YJ, McKevitt M, Porter DP, Jordan R, Guo Y, German P, Boeckh M, Watkins TR, Chien JW, Dadwal SS. A Phase 2b, Randomized, Double-blind, Placebo-Controlled Multicenter Study Evaluating Antiviral Effects, Pharmacokinetics, Safety, and Tolerability of Presatovir in Hematopoietic Cell Transplant Recipients with Respiratory Syncytial Virus (RSV) Infection of the Lower Respiratory Tract. Clin Infect Dis. 2019 Dec 3:ciz1167.

HIV

Dr. Small is leading an innovative research effort for development of novel approaches to the management of HIV infection in patients with neoplastic diseases and in those undergoing HSCT, as well as in solid organ transplantation.

Dr. Small developed the HIV Transplantation Program and is the PI on two Hope in Action U01s (HIV to HIV transplantation) in solid organ transplantation (kidney, liver). She has participated in 21 clinical research trials evaluating antiretroviral agents for the treatment of HIV infection, and has been the PI/co-investigator on eight HIV-related investigator-initiated trials. She is currently the PI on an investigator-initiated study in HIV+ renal transplant recipients investigating the ideal ARV regimen to use in this population, and the interaction with immunosuppressive agents.

Durand, C, Malinas, M, Gilbert A, Elias N, Hand JM, Pruett T, Small CB, et al. Letter to the Editor: Clarifying the HOPE Act Landscape: The Challenge of Donors with False-Positive HIV Results. Am J of Transplant, 20: 617-619, 2020.

Durand CM, Zhang W, Brown DM, Yu S, Desai N, Redd AD, Bagnasco SM, Naqvi FF, Seaman S, Doby BL, Ostrander D, Bowring MG, Eby Y, Fernandez RE, Friedman-Moraco R, Turgeon N, Stock P, Chin-Hong P, Mehta S, Stosor V, Small CB, Gupta G, Mehta SA, Wolfe CR, Husson J, Gilbert A, Cooper M, Adebiyi O, Agarwal A, Muller E, Quinn TC, Odim J, Huprikar S, Florman S, Massie AB, Tobian AAR, Segev DL; HOPE in Action Investigators. A prospective multicenter pilot study of HIV-positive deceased donor to HIV-positive recipient kidney transplantation: HOPE in action. Am J Transplant. 2020 Jul 23.

Small CB, Margolis DA, Shaefer MS, Ross LL. HLA-B*57:01 allele prevalence in HIV-infected North American subjects and the impact of allele testing on the incidence of abacavir-associated hypersensitivity reaction in HLA-B*57:01-negative subjects. BMC Infect Dis. 2017 Apr 11;17(1):256.

Wohl DA, Bhatti L, Small CB, Edelstein H, Zhao HH, Margolis DA, DeJesus E, Weinberg WG, Ross LL, Shaefer MS. The ASSURE study: HIV-1 suppression is maintained with bone and renal biomarker improvement 48 weeks after ritonavir discontinuation and randomized switch to abacavir/lamivudine + atazanavir. HIV Med. 2016 Feb;17(2):106-17.

COVID-19 infections

We have been studying the clinical course and outcomes as well as the inflammatory effects of COVID-19 infection, especially in immunocompromised hosts. Drs. Small and Walsh are currently co-PIs on a COVID-19 treatment grant which they helped to design, and they are co-investigators on three other major COVID-19 treatment trials. They are collaborating on the development of three clinical research trials on COVID-19 infection in the solid organ transplant population and in patients with hematologic malignancies.

Pereira MR, Mohan S, Cohen DJ, Husain SA, Dube GK, Ratner LE, Arcasoy S, Aversa MM, Benvenuto LJ, Dadhania DM, Kapur S, Dove LM, Brown RS Jr, Rosenblatt RE, Samstein B, Uriel N, Farr MA, Satlin M, Small CB, Walsh TJ, Kodiyanplakkal RP, Miko BA, Aaron JG, Tsapepas DS, Emond JC, Verna EC. COVID-19 in solid organ transplant recipients: Initial report from the US epicenter. Am J Transplant. 2020 Jul;20(7):1800-1808.

Goyal P, Choi JJ, Pinheiro LC, Schenck EJ, Chen R, Jabri A, Satlin MJ, Campion TR Jr, Nahid M, Ringel JB, Hoffman KL, Alshak MN, Li HA, Wehmeyer GT, Rajan M, Reshetnyak E, Hupert N, Horn EM, Martinez FJ, Gulick RM, Safford MM. Clinical Characteristics of Covid-19 in New York City. N Engl J Med. 2020 Jun 11;382(24):2372-2374.

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