From the Deputy Director for Intramural Research

Response to a Public Health Dilemma

MIchael Gottesman

The problem of hospital-acquired (nosocomial) infections has been with us for many years. These organisms tend to be resistant to most antibiotics in common use, since hospital patients are exposed routinely to potent, broad-spectrum antibiotics. These organisms cause significant, and sometimes fatal, infections in patients whose immune systems are compromised.

The recent cluster of carbapenem-resistant Klebsiella pneumoniae (KPC) at the NIH Clinical Center, fatal to seven of 19 infected or colonized patients with compromised immune systems, represents the tip of an iceberg illustrating the increasing intransigence of microbes to treatment with antibiotics. It also demonstrates how the NIH intramural research program is able to apply cutting-edge technology to identify an important public health problem and develop a strategy to deal with it.

The story began in 2011 when a cluster of KPC cases in the Clinical Center resulted from the transfer of a patient from a hospital in New York City. In a paper that appeared in Science Translational Medicine, Evan Snitkin and numerous colleagues at the NIH including David Henderson and Tara Palmore, our hospital infection officers, and Julie Segre, a senior investigator in NHGRI who studies the human microbiome, described the cluster of patients and how whole KPC genome sequencing was used to identify the course of transmission to 17 patients who were infected after the index case. (The transmission to the 18th patient was discovered after the paper was published; Sci Transl Med 4:148ra116, 2012.)

This sophisticated approach showed unequivocally that most of the patients had not been in direct contact with each other, and that transmission from silently colonized patients was largely responsible for the cluster.

Rigorous infection-containment approaches targeting the typical modes of transmission of nosocomial infections—such as grouping the clinicians treating KPC-colonized or KPC-infected patients into cohorts, isolating infected individuals and carriers, using direct observation to ensure scrupulous attention to hand washing, and paying attention to the details of disinfection of the environment and sterilization of equipment—enabled containment of the outbreak.

KPC is not the only organism that can become intractable to antibiotic therapy. Acinetobacter species, methicillin-resistant Staphylococcal aureus (MRSA), Clostridium difficile, Mycobacterium tuberculosis, and other organisms can be responsible for infections that prove fatal because they no longer respond to antibiotics. This, of course, is not a new problem. When I was a medical intern from 1970 to 1971, Klebsiella pneumoniae infections were often fatal because of the limited armamentarium of antibiotics then available. For awhile, the pharmaceutical industry kept pace with the development of antibiotic resistance, but we are now seeing, at an accelerating pace, antibiotic resistance spreading faster than the production of new antibiotics.

Many internal and public discussions of the implications of the KPC cluster have occurred. The intramural program has contributed in a meaningful way to this discussion by providing important data that define the extent and nature of the problem and by offering several ways forward.

The Snitkin et al. paper sets a new standard for hospital epidemiologic investigations. In addition, clinical and scientific leadership at the NIH has recognized the importance of launching a trans-NIH research program focusing on the development of treatments for multidrug-resistant bacteria. NIAID has taken the lead in this effort, with its scientific director, Kathryn Zoon, developing a program to enhance our research expertise in nosocomial infections and antibiotic-resistant organisms, joining our considerable investment in studying MRSA and M. tuberculosis.

The Clinical Center, NHGRI, NCATS, and other NIH microbial physiology experts will participate in a trans-NIH effort to turn the challenges posed by the KPC cluster into learning experiences to improve public health. They plan to identify new targets for antimicrobials and develop antimicrobial compounds. This activity is in the best tradition of NIH efforts to deal with public health risks whenever they arise. If the past is any indication of the future, we are likely to make considerable contributions to international research on this ubiquitous problem.