Agencies expand programs on resistant staph

VISA cases prompt action as MRSA, VRE increase

Responding to the threat of emerging vancomycin resistance in Staphylococcus aureus, government infectious disease experts are increasing research, expanding national surveillance, and establishing an international network of investigators.

The National Institute of Allergy and Infectious Diseases (NIAID) is forming a network of scientists and clinicians in order to link investigators conducting basic research on resistance and virulence factors with those studying the clinical microbiology of resistant strains of S. aureus. The Centers for Disease Control and Prevention is exploring options to expand surveillance for the emerging pathogen and advising clinical labs of appropriate testing methods to identify vancomycin-resistant staph strains. The agencies are collaborating on various aspects of the projects, which were spurred by the emergence of vancomycin intermediate-resistant S. aureus (VISA) in Japan and the United States.^1-3 (See Hospital Infection Control, October 1997, pp. 145-152.)

"Those reports clearly prompted us to move," says Stephen Heyse, MD, MPH, program officer in the NIAID medical bacteriology and antibacterial resistance branch.

To address the problem, the National Institutes of Health assembled a panel of expert advisors last September and began mapping out priorities for action.

"We brought together some of our investigators working on staph, the CDC, and the FDA and spent a day trying to figure out what we need to do to get ready for this emerging problem," Heyse says. "One of the issues was the lack of communication among the investigators and the need for access to the strains as they become available. [Advisors] also strongly recommended that the genome be sequenced."

As a result, the NIAID network investigators will conduct genetic sequencing of MRSA strains and non-resistant strains to complement the ongoing research on the VISA strains recovered from patients in Japan and the United States. A better understanding of the pathogenesis of staph strains could open up possibilities for new antibiotics and vaccine development, Heyse notes. While no additional VISA cases have been confirmed in the United States, the work is also being done in preparedness for the anticipated eventual emergence of fully vancomycin-resistant staph strains.

"We think that ultimately it will spring up," he says.

The network will acquire isolates from VISA cases and grow additional quantities for study after confirming the identity, purity, and resistance properties of the isolates. In addition to strains from the first two U.S. cases, the NIH network will attempt to include those that appear globally as well, Heyse says, adding that another VISA isolate was recently reported in the United Kingdom.⁴

"We would want to collect those isolates, particularly since they are so rare at this point," Heyse says. "The intention is to support our U.S.-based investigators, but we will try to identify the international strains too."

Likewise, the CDC is also discussing a collaborative effort with officials in Japan, including the clinician who documented the first case there, Keiichi Hiramatsu, MD, PhD, professor of bacteriology at Juntendo University in Tokyo and chairman of the Japanese Symposium on Staphylococci Infections.

"We are trying to work with Dr. Hiramatsu and the Japanese Ministry of Health to see if we can collaborate in doing some further studies," says William Jarvis, MD, acting director of the CDC hospital infections program. "Those discussions are ongoing."

In addition, the CDC is discussing plans to expand surveillance for the pathogen beyond the member hospitals of its National Nosocomial Infections Surveillance (NNIS) system.

"[NNIS] catches approximately 265 hospitals, but we would like to have the net wider than that," he says. "We are talking to a number of different groups about trying to have a more comprehensive surveillance system out there for these strains."

'A different beast'

An immediate research question is whether the first VISA strains sacrificed some measure of virulence in reportedly developing thicker cell walls to thwart vancomycin.

"If anything, these strains that are of intermediate susceptibility seem perhaps less virulent then strains that are fully sensitive to vancomycin," Heyse says. "There is some expenditure that the organism has to make to develop this resistance apparently, and it is probably sacrificing other attributes in terms of virulence. They seem to be very slow-growing. In fact, one of our reasons for forming this network is to try to figure out whether these have been around for some time and people just haven't noticed them. They made their determination of susceptibility before that particular strain did any growing."

In that regard, Fred Tenover, PhD, chief of the CDC nosocomial pathogens laboratory branch, recently noted the slow metabolic rate of VISA strains in alerting clinical laboratorians that disk diffusion tests will not detect such strains.

"This just a different beast in the laboratory and a different beast in the patient," he said recently in Atlanta at the first International Conference on Emerging Infectious Diseases. ". . . The BHI agar screen plate we currently use for vancomycin detection in enterococci works very well for finding these strains with MICs of eight in staphylococci. So a test that is already in many of your laboratories can be used to find these new strains."

Even though the VISA strains occurred only after prolonged exposure to vancomycin in the first cases and appear to be rare, Tenover underscored the severity of the situation in urging heightened scrutiny in clinical labs.

"These strains right now are rare, but they have the propensity to develop and spread quickly," Tenover said. ". . . We feel very strongly at the CDC that these are clinically important strains."

Vancomycin-resistant enterococci provide an example of how such pathogens can emerge rapidly after the first clinical isolates appear, Jarvis added at the same conference session on antibiotic resistance.

"First recovered from a patient in the United States in 1989, it has dramatically increased both in ICU patients and non-ICU patients, where now 16% of the enterococci causing infections are resistant to vancomycin," Jarvis said.

According to CDC NNIS system data, other antibiotic resistant pathogens like ceftazidime-resistant Klebsiella pneumoniae have made similar, steady climbs from minuscule origins. (See chart, p. 71.)

"These are pathogens recovered from patients with infections - not colonization," Jarvis said. "We see all of these major pathogens have all significantly increased in predominance during this time period."

References

1. Centers for Disease Control and Prevention. Reduced susceptibility of Staphylococcus aureus to vancomycin - Japan, 1996. MMWR 1997; 46:624-626.

2. Centers for Disease Control and Prevention. Staphylococcus aureus with reduced susceptibility to vancomycin - United States, 1997. MMWR 1997; 46:765-766.

3. Centers for Disease Control and Prevention. Update: Staphylococcus aureus with reduced susceptibility to vancomycin - United States, 1997. MMWR 1997; 46:813-814.

4. Howe RA, Bowker KE, Walsh TR, et al. Vancomycin-resistant Staphylococcus aureus (correspondence). Lancet 1998; 351:602.