The Emergence of Carbapenem-Resistant Enterobacteriaceae

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The Emergence of Carbapenem-Resistant Enterobacteriaceae

Friday, February 17, 2012

The New York Academy of Sciences

The emergence of carbapenem resistant Enterobacteriaceae in the New York metropolitan area has foreshadowed the global spread of these highly resistant Gram negative pathogens. Carbapenem-resistant K. pneumoniae (KPC strains) are recovered routinely in many hospitals in New York City and New Jersey where they have caused high rates of morbidity and mortality, particularly among the critically ill. A similar story is emerging from the India, where resistant K. pneumoniae harboring NDM-1 resistance has been described in contaminated water in the community. The epidemiological and clinical dilemma is related to the fact that both KPC and NDM resistance is mediated on mobile plasmids that are able to spread among species with the Enterobacteriaceae family and that treatment is now limited to combinations with colistin, tigecycline, and rifampin, and resistance to all these agents has been reported. This symposium, organized in conjunction with the Public Health Research Institute, UMDNJ–NJMS, will discuss the issues surrounding the molecular epidemiology of carbapenem resistant Enterobacteriaceae, the complexity of their multidrug resistance, and the clinical challenges in both diagnosing resistance and treating immunocompromised patients.

Networking reception to follow.

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Agenda

* Presentation times are subject to change.


Friday, February 17, 2012

2:00 PM

Registration

2:30 PM

Welcome and Introductory Remarks
Jennifer Henry, PhD, The New York Academy of Sciences
David S. Perlin, PhD, Public Health Research Institute, UMDNJ–NJMS

2:45 PM

Molecular Epidemiology of Carbapenem Resistant Enterobacteriaceae
Barry N. Kreiswirth, PhD, Public Health Research Institute, UMDNJ–NJMS

3:30 PM

MDR Pa, Ab, and Kp: the Big Three
Robert Bonomo, MD, Case Western Reserve University

4:15 PM

Clinical Manifestations and Consequences of Carbapenem-Resistant Enterobacteriaciae: Therapeutic Implications of Emerging Multidrug Resistant Pathogens
Thomas J. Walsh, MD, NY Presbyterian Hospital/Weill

5:00 PM

Networking Reception

6:00 PM

Close

Speakers

Organizers

Barry N. Kreiswirth, PhD

Public Health Research Institute, UMDNJ–NJMS

Dr. Kreiswirth is the founding director of the PHRI TB Center, a Professor of Medicine at UMDNJ and Visiting Scientist at the Museum of Natural History. In 1992, in response to the New York City tuberculosis outbreaks, the PHRI TB Center was established under Dr. Kreiswirth's direction as a genotyping laboratory to study the molecular epidemiology of tuberculosis. The Center characterized the highly multidrug resistant strain W and beginning in 1992 it has genetically characterized over 27,000 M. tuberculosis isolates from global sources. Since its inception, the Center has worked closely with the CDC and Prevention and the NYC Department of Health to integrate the tools of molecular biology with tuberculosis control efforts. The Center has also focused on the molecular epidemiology of multidrug resistant pathogens including methicillin resistant S. aureus and carbapenem resistant Enterobacteriaceae and developed spa typing and other multiplex assays to track these resistant organisms.

David S. Perlin, PhD

Public Health Research Institute, UMDNJ–NJMS

Dr. David S. Perlin, PhD is Executive Director of the UMDNJ/New Jersey Medical School's Public Health Research Institute (PHRI), a 70 year old specialized center for global infectious diseases research. He is also Director of the new UMDNJ Regional Biocontainment Laboratory, one of thirteen national centers, and a Professor of Microbiology and Molecular Genetics. Dr. Perlin helped establish PHRI as a leading tuberculosis and opportunistic infections research organization. His primary expertise is in fungal infections, antifungal drug resistance and rapid diagnosis of opportunistic drug resistant pathogens in high-risk patients. His laboratory is supported by grants from the NIH, pharma and biotech sectors. He is on the editorial board of several scientific journals and serves on the Board of Directors of the Aaron Diamond AIDS Research Center and Scientific/Medical Advisory Boards for pharma and biotech companies, and PinnacleCare. He is also a member of the New York City Department of Health and Mental Hygiene Advisory Panel on Bioterrorism and Emerging Infections and the Executive Committee of the Northeast Biodefense Center.

Dr. Perlin earned an AB degree from Brandeis University in 1976 and a PhD from Cornell University in 1980. He pursued postdoctoral studies at the Yale University School of Medicine and the University of Rochester School of Medicine and Dentistry. Dr. Perlin joined PHRI in 1985; he was named Scientific Director in 1992, President in 2005, and Director of the new UMDNJ Center in 2006. He was appointed Professor of Microbiology and Molecular Genetics in 2003 and Executive Director of PHRI and the national Regional Biocontainment Laboratory in 2010. Dr. Perlin was named a Fellow of the New York Academy of Sciences in 2005 and a Visiting Professor at the University of Manchester, UK in 2009.

Issar Smith, PhD

Public Health Research Institute, UMDNJ–NJMS

Dr. Issar Smith is the Associate Director for Programs and Development at the PHRI Center, New Jersey Medical School–UMDNJ. He is involved in the development of new programs at the PHRI center (research, clinical and educational), the evaluation of existing programs, the recruitment of new faculty and the mentoring of young faculty in terms of the progress of research projects and critical evaluation of research grant applications, and the planning and organization of Institutional events such as the annual PHRI Symposium on Infectious Diseases. Dr. Smith is also a Professor at the PHRI Center and the Department of Medicine. His laboratory studies the genetics of Mycobacterium tuberculosis virulence to better understand the processes by which the bacterium causes tuberculosis. Some of his work has led to the development of M. tuberculosis mutant bacterial stains that are greatly attenuated and show promise as new vaccine candidates.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Robert Bonomo, MD

Case Western Reserve University

Dr. Robert A. Bonomo is Chief of the Medical Service at the Louis Stokes Cleveland VA Hospital. He also serves as Vice Chair for Veterans Affairs in the Department of Medicine at University Hospital Case Medical Center. Dr. Bonomo is also Professor of Medicine, Pharmacology, Molecular Biology and Microbiology at Case Western Reserve University. The research interests of Dr. Bonomo include the molecular basis of antibiotic resistance in Gram negative bacteria, the testing of novel antibacterial compounds, and the use of rapid molecular methods in the diagnosis of infectious diseases. Recent investigations in the Bonomo lab have centered upon the genetic and amino acid sequence requirements of carbapenemase enzymes.

Barry N. Kreiswirth, PhD

Public Health Research Institute, UMDNJ–NJMS

Dr. Kreiswirth is the founding director of the PHRI TB Center, a Professor of Medicine at UMDNJ and Visiting Scientist at the Museum of Natural History. In 1992, in response to the New York City tuberculosis outbreaks, the PHRI TB Center was established under Dr. Kreiswirth's direction as a genotyping laboratory to study the molecular epidemiology of tuberculosis. The Center characterized the highly multidrug resistant strain W and beginning in 1992 it has genetically characterized over 27,000 M. tuberculosis isolates from global sources. Since its inception, the Center has worked closely with the CDC and Prevention and the NYC Department of Health to integrate the tools of molecular biology with tuberculosis control efforts. The Center has also focused on the molecular epidemiology of multidrug resistant pathogens including methicillin resistant S. aureus and carbapenem resistant Enterobacteriaceae and developed spa typing and other multiplex assays to track these resistant organisms.

Thomas J. Walsh, MD

NY Presbyterian Hospital/Weill Cornell

Thomas J. Walsh, MD is Professor of Medicine and Director of the new Transplantation-Oncology Infectious Diseases Program. Following graduation from Johns Hopkins University School of Medicine, Dr. Walsh completed ten post-doctoral years of laboratory investigation, clinical research and patient care leading to boards in Medicine, Infectious Diseases and Oncology and laboratory expertise in antimicrobial pharmacology, innate host defenses, and molecular diagnostics. Following a distinguished career in the Pediatric Oncology Branch of the National Cancer Institute, Dr. Walsh was recruited to direct the new Transplantation-Oncology Infectious Diseases Program of Weill Medical College of Cornell University and the New York Presbyterian Hospital. The mission of the Program is to three-fold: [1] conduct leading edge translational research in diagnosis, treatment and prevention of life-threatening infections in immunocompromised patients; [2] provide outstanding patient care to patients with transplantation, cancer and other immunodeficiencies, and [3] to mentor and train the next generation of physician-scientists in understanding serious infections in immunocompromised patients. The Program's current laboratory and clinical investigations include antimicrobial pharmacology, immunopharmacology of innate host defense, biofilm cell biology, and molecular diagnosis of emerging fungal, bacterial and viral pathogens in immunocompromised patients.

Abstracts

Molecular Epidemiology of Carbapenem Resistant Enterobacteriaceae
Barry N. Kreiswirth, PhD, Public Health Research Institute, UMDNJ–NJMS

In 1969, Surgeon General William H. Stewart declared an end to the era of infectious diseases, as antibiotic pipelines were overflowing and the threat of drug resistant strains limited. What Stewart could not predict was the large increase in immunosuppressed patients, both the result of HIV disease and active suppression for transplantation surgery and other heroic medical efforts. As such, advancements in medicine enabled patients with otherwise life threatening diseases to live longer, commonly with the aid of anti-infectives. After 70 years of unabated use, the effectiveness of our most potent antimicrobials are being compromised evidenced in the remarkable and rapid evolution of drug resistance mechanisms, many on mobile genetic elements that are able to spread within and between species. The recent emergence of community acquired methicillin resistant S. aureus (MRSA), extensively drug resistant (XDR) M. tuberculosis and carbapenem-resistant Enterobacteriaceae are highly drug resistant strains that have limited treatment options. Compounding this problem is the hollow antibiotic pipeline, the absence of antibiotic discovery programs in most pharmaceutical companies, and the limited success in developing novel compounds. Advancements in diagnostics, including real-time nucleic amplification platforms at the bedside, can enhance prudent use of antibiotics however has yet to be integrated in our healthcare setting. The gravity of antibiotic resistance has consequently led to alternative strategies, including phage therapy, antibody treatment, inhibitory peptides, and immunomodulators; but similar to our dependence on oil, we remain hooked on antibiotics, even though they too may go the route of the dinosaur.
 

MDR Pa, Ab, and Kp: The Big Three
Robert Bonomo, MD, Case Western Reserve University

Multidrug resistant (MDR) Gram negative bacteria are a major threat to patients in the community and in the hospital. Among pathogens that exhibit resistance to all antibiotics, Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae are among the most notorious. Each of these MDR bacteria ("the big three") exhibit different mechanisms of resistance. A. baumannii has managed to collect a variety of genes from different origins and has assembled them in genetic constructs that defy comprehension. Interestingly, the virulence of A. baumannii has also seemed to increase in parallel with resistance phenotypes. This combination of "malicious" traits has made A. baumannii one of the most feared Gram negative bacteria on the planet. P. aeruginosa has also acquired a large variety of resistance genes that defy all antibiotics, but has assembled them in a different manner. For unknown reasons, we have become complacent with MDR P. aeruginosa. Lastly, K. pneumoniae, a pathogen that was among the minority of hospital acquired infections, has become a formidable hazard by its acquisition of resistance to all cephalosporins and carbapenems. This "perfect storm" has left us with few if any treatment options.
 

Clinical Manifestations and Consequences of Carbapenem-Resistant Enterobacteriaceae: Therapeutic Implications of Emerging Multidrug Resistant Pathogens
Thomas J. Walsh, MD, NY Presbyterian Hospital/Weill Cornell

Since the original descriptions of pneumonia caused Klebsiella pneumoniae in the nineteenth century, this organism has been recognized as a pathogen causing devastating infections that become increasingly lethal in more immunocompromised patients. With relentless emergence of resistance to the most potent of agents of the antimicrobial armamentarium, carbapenemase-producing K. pneumoniae (KPC) now have extended their host range into our profoundly immunocompromised patients. This expansion of host population also has been accompanied by the emergence of other members of the Enterobacteriaciae, including Escherichia coli and Enterboacter spp. Such patients present with critical illness, few therapeutic options, and consequently highly lethal infections.
 
Recent work in our Program by Dr. Michael Satlin in collaboration with Dr. Barry Kreiswirth of the Public Health Research Institute, International Center for Public Health, University of Medicine and Dentistry of New Jersey, Newark, NJ describes for the first time in the United States the emergence of carbapenem-resistant Enterobacteriaciae (CRE) as lethal causes of bloodstream infections (BSIs) in patients with hematologic malignancies [1]. CRE BSIs occurred in patients with newly diagnosed malignancies as well as in those with refractory or relapsed malignancies. Patients most frequently were exposed to numerous healthcare settings and received prior antibacterial therapy before developing CRE BSI. However, there were no consistent clinical manifestations among cases to indicate a CRE BSI. Although all patients received an antimicrobial regimen recommended for management of fever in immunocompromised hosts with cancer, these patients seldom received initial empirical therapy that was active in vitro against their bloodstream isolates, leading to significant delays in effective treatment. Mortality rates were high and all deaths were related to CRE BSI. The consequences of these infections are a clarion call for rapid diagnostic assays and new antimicrobial agents to provide life-saving interventions for our critically ill patients.
 

Reference
[1] Satlin MJ, Calfee DP, Fauntleroy KA, Jenkins SG, Kreiswirth BN, Walsh TJ: Carbapenem-resistant Enterobacteriaceae bloodstream infections in patients with hematologic malignancies. 49th Annual Meeting of the Infectious Diseases Society of America. 2011

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