Resisting Super Bugs A longterm collaboration between academia, government, and others is tackling the serious problem of antibiotic resistance in hospitals. An alarming trend in antibiotic resistance showed up in 1998. Bacteria that previously had shown only one mechanism to fight off an antibiotic were demonstrating multiple means of resistance. The bugs were getting smarter still, developing enzymes to deactivate an antibiotic, pumps to quickly push the antibiotic out before it could be effective, and cell wall alterations to make antibiotic penetration impossible.

The trend was identified by Project ICARE (Intensive Care Antimicrobial Resistance Epidemiology), a joint project between the Division of Health Quality Promotion at the CDC and the Rollins School of Public Health (RSPH). For nine years, Project ICARE has pursued a large mandate: to reduce the emergence and spread of resistant superbugs that are threatening to diminish the medical advances of the last century.

Antibiotic resistance is a serious problem globally and in the United States. The CDC, for example, estimates that more than one-third of the 150 million prescriptions written for antibiotics each year are unnecessary. In hospitals, antibiotic resistance is of particular concern. Each year nearly 2 million patients in the United States get an infection while in a hospital, and 90,000 of those die as a result. More than 70% of bacteria that cause hospital-acquired infections are resistant to at least one of the drugs commonly used to treat them.

Project ICARE links epidemiology with laboratory study, collecting and investigating emerging resistant bacteria from clinical laboratories. To date, more than 60 laboratories have participated in the study by forwarding samples.

The laboratory component is critical for Project ICARE because new patterns of resistance develop quickly, especially in hospital intensive care units. Investigators need to know quickly the specifics of these occurrences to develop strategies and drugs for control and treatment.

ICARE represents a strong collaboration between the CDC and Emory. The laboratory techniques for molecular typing, some of which were developed at CDC, form the basis of ICARE investigation. Nine RSPH students have trained in the ICARE labs, and six of those have gone on to work at CDC in full-time or contractor positions. The ICARE staff work closely with CDC colleagues and co-author research papers. Close to 100 publications and abstracts for national and international meetings have resulted from ICARE data.

Current RSPH staff includes John McGowan (principal investigator and professor of epidemiology), a doctoral student, a medical technologist, two MPH students, a part-time researcher, and arriving this fall, the project’s first postdoctoral student.

“We want to simplify the testing process so that it is useful to the ordinary clinical lab.” –John McGowan Because antibiotic resistance requires a bigger solution than any one group can provide, Project ICARE has reached out to partners beyond academia and government. Through successful proposals to private pharmaceutical and health care companies, RSPH has augmented CDC’s efforts to slow antibiotic resistance. Seven private pharmaceutical companies currently support the effort, with prior support coming from research foundations and professional societies.

One of the most important outcomes of Project ICARE so far is CDC’s launching of the Antibiotic Use and Resistance (AUR) Surveillance System. Based on the ICARE model, AUR monitors antibiotic resistance in hospitals throughout the United States.

Squashing emerging superbugs
In earlier phases of Project ICARE, the research was relatively straightforward, says McGowan, who has a joint appointment with RSPH and the Emory School of Medicine. The investigators identified and characterized resistance patterns, determined whether laboratories in the field could detect the organisms, and in cases where the tests were too complicated or expensive, developed simpler and cheaper screening tools.

However, with the emergence of superbugs with multiple resistance, ICARE investigators have honed in on two main questions: Are bacterial organisms changing in a way that presents a clinical and public health problem of antibiotic resistance? If so, are the newly emerging resistant bacteria a potential problem for public health and clinical laboratories to recognize?

For example, while vancomycin-resistant staphylococci present a major clinical problem, these bugs are relatively simple for hospital laboratories to detect. However, gram-negative bacteria resistant to classes of drugs such as cephalosporins, fluoroquinolones, and carbapenems, do present a problem for identification by the hospital or public health laboratory. For that reason, ICARE’s focus is now on these and similar organisms. “We want to simplify the testing process so that it is useful to the ordinary clinical lab,” says McGowan. Currently, Project ICARE collects organisms that have shown resistance in hospital laboratories. They are then retested for susceptibility to antibiotics in the ICARE research laboratory, and those results are reported back to the laboratories that submitted the specimens.

Like her predecessors, current MPH student Leigh Ann Clark hopes to use ICARE data as the basis of her epidemiology master’s thesis.

The system still has bugs of its own, and McGowan expresses a concern that problem areas of testing identified as long as five years ago continue to persist. Laboratories have not received the resources to produce accurate results when testing these problem organisms. “This is a critical problem,” says McGowan, “because accurate information is crucial not only for patient care but also to inform public health policies on antibiotic resistance.”

The latest phase of the study expands testing to include an international component. Eight laboratories in Brazil are now participating in ICARE, providing more unusual and resistant bugs to study. “There is so much information to be gleaned from these fresh samples that we almost have data overload,” McGowan says. Although still a rare occurrence, several drug resistant bacteria similar to those identified in Brazil have appeared in North American hospitals—a trend that is likely to increase, McGowan predicts.

Creating the gold standard

Christine Steward has designed an educational outreach program on antibiotic resistance for hospital laboratory staff and the public.

Christine Steward, MPH96, has witnessed ICARE’s developments from its beginning. As a student in epidemiology, she worked on the pilot study, preparing the original isolates collected from hospitals, and later helping to stock and organize the ICARE research laboratory at RSPH. Under the direction of CDC’s Fred Tenover, adjunct professor of epidemiolgy and co-director of the laboratory project, she learned a technique called pulsed-field gel electrophoresis, which separates DNA fragments to reveal a genetic fingerprint. Using this technique, ICARE scientists can distinguish different strains of organisms and glean specific information about clustering of resistant isolates. After graduation, Steward joined Tenover at CDC to work full-time on resistance testing.

She recently returned to RSPH to teach in the ICARE laboratories and to design an educational outreach program for participating hospitals and the public. In July, she and one of the MPH students she mentored were among the authors of a paper on how to optimize computer software to get the best analysis of pulsed-field gel electrophoresis, a topic that illustrates one important lesson that Steward learned at the CDC. We are the ones in the forefront, she says. We are the ones who are creating the gold standard.

By Rhonda Mullen