Transplantation-Oncology Infectious Diseases

Translational Research

Walsh, Small, Soave, Helfgott, Satlin, Jacobs, Petraitiene, Petraitis, Katragkou

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 children and adults with transplantation and neoplastic diseases through multidisciplinary translational research. The tools of this research include epidemiology, pathogenesis, antimicrobial pharmacology, immunopharmacology, molecular diagnostic microbiology, and studies of innate host defenses.

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 pediatric and adult patient populations studied within the Program are those hematological malignancies, aplastic anemia, myelodysplasia, hematopoietic stem cell transplantation, and solid organ transplantation. 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 Pediatrics, Oncology, Hematology, Nephrology, Hepatobiliary Surgery, 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.

• Corzo-Leon D, Satlin, MJ, Soave R, Shore T, Schuetz A, Larone D, Walsh TJ: Epidemiology and outcomes of invasive fungal infections in 398 allogeneic hematopoietic stem cell transplant recipients. Mycoses. 58:325-336; 2015.
• Satlin MJ, Vardhana S, Soave R, Shore TB, Mark T, Jacobs SE, Walsh TJ, and Gergis U: Impact of prophylactic levofloxacin on rates of bloodstream infection and fever in neutropenic patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation. Biol Blood and Marrow Transplant 2015 (epub).
• Muthukumar T, Afaneh C, Ding R, Tsapepas D, Lubetzky M, Jacobs S, Lee J, Sharma V, Lee J, Dadhania D, Hartono C, McDermott J, Aull M, Leeser D, Kapur S, Serur D, Suthanthiran M. HIV-infected kidney graft recipients managed with an early corticosteroid withdrawal protol: clinical outcomes and messenger RNA profiles. Transplantation 2013;95:711-720.

Invasive Fungal Infections

Recognizing the severe morbidity and mortality cause of invasive mycoses, the study of invasive fungal infections with specific emphasis on Candida spp., Aspergillus spp. and the Mucorales (Zygomycetes), and emerging pathogens such as Fusarium spp. and Scedosporium spp., are critical elements of our mission. We conduct translational research in three major areas of medical mycology: antifungal pharmacology (Dr. Petraitis, Dr. Pantazotas), molecular diagnosis (Dr. Petraitiene), and innate host defenses (Dr. Katragkou).

Among our recent advances are the identification of the critical role of antifungal therapy in improving survival in patients with severe aplastic anemia, the combination antifungal therapy of Candida biofilms, transcriptional profiles and immunomodulatory activity of lipid formulations of amphotericin B on human monocytes, development and validation of the first multispecies PCR system for Aspergillus spp and Mucorales to be made available in a U.S. reference laboratory, plasma pharmacokinetics of posaconazole, 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, treatment of osteoarticular mycoses (collaboration with Hospital for Special Surgery), pathogenesis and treatment of fungal biofilms. Ongoing clinical trials include pharmacokinetic studies of novel triazoles (Dr. Helfgott and Dr. Walsh) and diagnostic biomarkers in immunocompromised children and adults (Dr. Petraitiene).

• Al Nakeeb Z, Petraitis V, Goodwin J, Petraitiene R, Walsh TJ, Hope WW: Pharmacodynamics of amphotericin B deoxycholate, amphotericin B lipid complex and liposomal amphotericin B against Aspergillus fumigatus. Antimicrob Agents Chemother. 59:2735-2745; 2015.
• Duarte RF, López-Jiménez J, Cornely OA, Laverdiere M, Helfgott D, Haider S, Chandrasekar P, Langston A, Perfect J, Ma L, van Iersel ML, Connelly N, Kartsonis N, Waskin H. Phase 1b study of new posaconazole tablet for prevention of invasive fungal infections in high-risk patients with neutropenia. Antimicrob Agents Chemother. 2014; 58:5758-65.
• Gamaletsou MN, Rammaert B, Bueno MA, Moriyama B, Sipsas NV, Kontoyiannis DP, Roilides E, Zeller V, Elie C, Prinapori R, Tajaldeen SJ, Brause B, Lortholary O, and Walsh TJ: Epidemiology, clinical manifestations, management and outcome of 179 cases of Aspergillus osteomyelitis. J Infect. 68:478-93; 2014.
• Katragkou A, McCarthy M, Alexander EL, Antachopoulos C, Meletiadis J, Jabra-Rizk MA, Petraitis V, Roilides E, and Walsh TJ: In vitro interactions between farnesol and fluconazole, amphotericin B or micafungin against Candida albicans biofilms. Antimicrob agents Chemother. 70:470-8; 2015.
• McCarthy M, Rosengart A, Kontoyiannis DP, and Walsh TJ: Mold infections of the central nervous system. N Engl J Med. 371:150-160; 2014.
• Petraitiene R, Petraitis V, Cotton MP, Greene L, Bacher JD, Roilides E, and Walsh TJ: Effects of host response and antifungal therapy on serum and BAL levels of galactomannan and (1®3)-β-D-glucan in experimental invasive pulmonary aspergillosis. Medical Mycol. 53:558-68; 2015.

Resistant Bacterial Infections

This program is developing new strategies for pharmacodynamically rational methods for administration of existing antibacterial agents, as well as development of new antimicrobial compounds against multidrug resistant bacterial pathogens, particularly Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, 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, study of the pharmacokinetics, and pharmacodynamics of ceftolozane/tazobactam in treatment of experimental Pseudomonas aeruginosa pneumonia, and telavancin in treatment of experimental MRSA osteomyelitis.

As a logical extension of these studies, we also are conducting clinical trials in Pseudomonas aeruginosa ventilator-associated pneumonia and multidrug resistant Gram-negative bacteremia.

• Chatzimoschou A, Simitsopoulou M, Antachopoulos C, Walsh TJ, and Roilides E: Antipseudomonal agents exhibit differential pharmacodynamic interactions with human polymorphonuclear leukocytes against established biofilms of Pseudomonas aeruginosa. Antimicrob Agents Chemother.59:2198-2205; 2015.
• Satlin MJ, Jenkins SG, Walsh TJ. The global challenge of carbapenem-resistant Enterobacteriaceae in transplant recipients and patients with hematologic malignancies. Clin Infect Dis. 2014;58(9):1274-83.
• Satlin MJ, Soave R, Racanelli AC, Shore TB, van Besien K, Jenkins SG, and Walsh TJ: The emergence of vancomycin-resistant enterococcal bacteremia in hematopoietic stem cell transplant recipients. Leukemia and Lymphoma. 55:2858-65; 2014.

Viral Infections

In an effort to better understand the epidemiology of community associated respiratory viruses; Dr. Jacobs is characterizing the epidemiology and risk factors for development of human rhinovirus (HRV) respiratory tract infections in HSCT recipients, as well as pursuing an ongoing prospective observational study characterizing the molecular epidemiology of these HRV infections. Dr. Soave is conducting clinical trials of the novel agent, Fludase for parainfluenza infections in immunocompromised hosts. Drs. Jacobs and Soave will be initiating clinical trials of a new oral agent for RSV infection in both immunocompetent and immunocompromised hosts. Studies of other parainfluenza compounds in collaboration with Dr. Moscona in Pediatrics 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. Dr. Soave is conducting an open label study of brincidofovir for adenovirus and other infections with DNA viruses in immunocompromised hosts.

Immunization is an important adjunct to the management of viral infections in immunocompromised patients. To that end, Dr. Satlin is conducting a study of anti-VZV vaccine in patients with myeloma. 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.

• Jacobs SE, Soave R, Shore TB, Satlin MJ, Schuetz AN, Magro C,Jenkins SG, Walsh TJ. Human rhinovirus infections of the lower respiratory tract in hematopoietic stem cell transplant recipients. Transpl Infect Dis 2013; 15:474-86.
• Jacobs SE, Lamson DM, St George K, Walsh TJ. Human rhinoviruses. Clin Microbiol Rev 2013; 26:135-62.
• Muthukumar T, Afaneh C, Ding R, Tsapepas D, Lubetzky M, Jacobs S, Lee J, Sharma V, Lee J, Dadhania D, Hartono C, McDermott J, Aull M, Leeser D, Kapur S, Serur D, Suthanthiran M. HIV-infected kidney graft recipients managed with an early corticosteroid withdrawal protocol: clinical outcomes and messenger RNA profiles. Transplantation 2013;95:711-20.