Has post-antibiotic era dawned in the Land of the Rising Sun?

CDC trying to confirm Japanese report of first clinical isolate of VRSA

Hospital Infection Control has learned that Japanese public health officials have asked the Centers for Disease Control and Pre ven tion to confirm what may be the first clinical isolate of vancomycin-resistant Staphylococcus aureus (VRSA), a much-anticipated pathogen that could cause infections untreatable by all current antibiotics.

Though reluctant to discuss the situation in detail, William Jarvis, MD, chief of the investigations and preventions branch of the CDC hospital infections program, confirmed that the agency is trying to verify a clinical isolate of reported VRSA from Japan. The CDC currently has the specimen and is conducting susceptibility tests to determine whether it is vancomycin-resistant, a condition that has only been found in S. aureus when induced in laboratory experiments.

"As we said before, this can emerge, if it is in fact [confirmed]," Jarvis told HIC recently in St. Louis at the annual conference of the Society for Healthcare Epidemiology of America (SHEA).

If the CDC confirms vancomycin resistance, Japanese public health officials are expected to announce the emergence of VRSA. Many epidemiologists have predicted that the appearance of VRSA in a clinical setting is probably inevitable because it has been created in both in vivo and in vitro lab experiments.1 Particularly worrisome is the possibility of resistance arising in strains of methicillin-resistant S. aureus (MRSA), which are already impervious to virtually all antimicrobials but vancomycin and have become endemic in many medical settings.

In 1995 the CDC encouraged hospital labs to routinely test all clinical isolates of S. aureus for vancomycin susceptibility, and to submit suspected VRSA for confirmation.2 No cases have been confirmed, and the CDC recommends careful testing and retesting on site before submission to the CDC. The agency advises laboratorians to restreak the colony when repeating testing to ensure the S. aureus culture is pure. If VRSA is confirmed, the CDC advises notifying the state health department and the CDC, and sending the isolate to the CDC via the state health department.

Some medical epidemiologists see the emergence of VRSA — which could cause both nosocomial and community-acquired infections — as a possible return to medical conditions akin to the pre-antibiotic era of untreatable infections. Underscoring the severity of the situation, Jarvis confirmed that the CDC still has contingency plans to go into the first U.S. hospital where VRSA appears and implement stringent infection control measures to try to prevent subsequent transmission. (See related story in HIC, September 1995, p. 113.)

A 60-year setback?

Though the CDC has not issued infection control guidelines specifically for VRSA, the kind of comprehensive approach that will be necessary was outlined last year in a forward-thinking article by Michael B. Edmond, MD, MPH, director of the internal medicine residency program at the Medical College of Virginia in Richmond, and colleagues.3 (See recommendations, p. 84.) Saying that the emergence of VRSA would represent the most important issue in antibiotic resistance since the beginning of the antibiotic era in the 1940s, Edmond and colleagues warned that such a "common, virulent bacterial agent with no known effective therapy would set infectious diseases back 60 years. The ability of S. aureus to acquire genes coding for the toxic shock syndrome only adds more concern." (See related story, p. 86.)

Word that the emergence of VRSA may be at hand was an undercurrent of concern in discussions outlining the formidable challenges of antibiotic resistance recently at the SHEA conference. (See related story, p. 85.) One of the principal speakers at the SHEA plenary session on antibiotic resistance, Edmond mentioned "rumors" that VRSA had been isolated and then discussed the implications afterward.

"This is something we have been worried about for several years," he tells HIC. "It was demonstrated in the laboratory setting several years ago. To this point, we had not been aware that it ever occurred in nature — at least we’d never isolated any S. aureus isolate that was resistant to vancomycin, and now we’re hearing that one has indeed happened. I think in some ways it heralds a new age because we have now a very virulent organism that may be resistant to all antibiotics. It means that we will have to use very, very strict infection control measures to try and limit that organism as much as possible."

It may be of little consolation to U.S. infection control professionals if the first clinical case of VRSA arises in Japan, as antibiotic resistance has increasingly become a global problem. The CDC has frequently emphasized the global nature of infection control in recent years, including the warning that exotic pathogens or drug-resistant organisms are only a plane ride away. For example, Canadian ICPs report that a persistent strain of MRSA — apparently brought in by a single patient who acquired it nosocomially in India — has become endemic in some areas. (See related story in HIC, November 1995, p. 143.) The emergence of vancomycin-resistant enterococci (VRE) in the Northeastern region of the U.S. — with virtually no initial cases reported on the West Coast — is another example, Edmond notes.

"Now there are even outbreaks occurring in some hospitals in California," he says. "What history would tell us is that these organisms are going to move from place to place until they eventually are seen globally."

Undetected barrier may exist

The aforementioned laboratory experiments showed that vancomycin resistance could be genetically transferred from Enterococcus faecalis to S. aureus. Some observers expect this transfer to inevitably occur between the two species in nature, particularly because there are now hospitals with overlapping nosocomial outbreaks and/or established endemic levels of both VRE and MRSA. Still, other clinicians suspect that there may be some undetected genetic or biochemical barrier that has prevented vancomycin resistance from arising in S. aureus. If the Japanese isolate is confirmed, the mechanism of resistance will be a telling factor in whether VRSA will pose major clinical problems, notes Louis Rice, MD, associate professor of medicine at Case Western Reserve School of Medicine in Cleveland and one of the principal speakers on antibiotic resistance at SHEA.

"If it turns out to be confirmed, I would like to know what the genetic mechanism of the resistance is," he tells HIC. "I am very surprised that VRSA hasn’t happened yet. I think now that it is 12 years past the first description of VRE, we have to wonder whether it is going to happen in a big way."

Usually only a few years pass before enterococci and staphylococci "trade resistance genes" for a given antibiotic, he says.

"The exception to that is the beta-lactamase gene in the enterococcus, which took 30 years to show up and in fact has never become a major clinical problem for reasons that we don’t know," he says.

Other experiments have shown that some level of vancomycin resistance can appear in S. aureus as a "second-step mutation" after the organism has developed resistance to another antibiotic, he explains. Such intrinsic resistance as a result of cellular mutation would not carry the clinical consequences of the appearance of a resistant gene, he notes.

"If it is that type of [mutation] resistance, it is probably not going to be a major problem," he says. "If it is an acquired gene, especially if it is a transferable gene, then I think we could be in a lot of trouble."

Search goes on in U.S.

But the fact that it has taken so long to occur — even if the first case is confirmed — may suggest that VRSA is not going to simply emerge and broadly proliferate.

"To say the sky is falling at this point is very wrong," Rice says. "Because the weight of evidence says those genes have never come out in staph, despite the huge number of VREs we have. That may mean there is something about their regulation system that staph will not tolerate and may not be likely to acquire."

New drug development will be an important adjunct to infection-control efforts, but one thing the past 50 years has shown is that resistance can develop to virtually any antimicrobial, Rice adds.

"I wouldn’t put anything past bugs under selective pressure to acquire resistance," he says. "It may be a resistance gene, it may be intrinsic resistance as a result of cellular mutations — there are all sorts of possibilities. But first of all we have to confirm it, because there have been other [VRSA] reports before that have turned out to not be true."

In the interim, clinical laboratories should continue routinely looking for vancomycin resistance in isolates of S. aureus, notes Edmond, one of the founders of an independent surveillance network of some 40 to 50 hospitals nationwide called SCOPE (Surveillance and Control of Pathogens of Epidemiologic Importance).

"We think labs should be looking at vancomycin susceptibility for S. aureus because the stage has been set for that organism to appear," he says. "We need to be vigilant. Over a year ago I sent a memo to all of the SCOPE hospitals [saying] if you see this organism call us immediately. We have no reports of any S. aureus resistance to vancomycin in all of our hospitals."

Edmond presented SCOPE data at SHEA based on 7,244 isolates for nosocomial bloodstream infections collected at the participating hospitals from April 1995 to March 1997. The major pathogens causing infections were coagulase-negative staphylococcus (32%); S. aureus (17%); enterococci (12%); and yeast (8%). About 25% of the S. aureus isolates in SCOPE data are resistant to methicillin, and 15% of the enterococci isolates are resistant to vancomycin, he noted.

In additional antibiotic resistance data presented at SHEA, the CDC reported the first case in the United States of a bloodstream infection due to a clinical isolate of Staphylococcus epidermidis with intermediate resistance to vancomycin.4 Though generally considered less of a public health threat, the finding of intermediate vancomycin resistance in S. epidermidis may be a harbinger of VRSA, the CDC reported. The case occurred last year, when a patient with a vancomycin-resistant coagulase-negative staphylococcus bloodstream infection died at a Virginia hospital. The CDC reviewed the hospital’s microbiology records, reviewed the patient’s medical and laboratory records, and obtained all available isolates. Nares cultures were obtained from exposed health care workers to identify possible colonization.

The patient, a 49-year-old woman with carcinoma, had been in contact isolation from admission because of her terminal condition. She had two blood cultures positive for coagulase-negative staph, and both isolates showed S. epidermidis with intermediate resistance to vancomycin. The patient died of her underlying disease and no health care workers were found to be colonized. Contact precautions likely played a major role in preventing nosocomial transmission, the CDC noted. In the SHEA poster ominously titled "The impending apocalypse," Denise O. Garrett, MD, a medical epidemiologist in the CDC hospital infections program, and colleagues concluded that the finding may be "the forewarning of VRSA in the near future."

References

1. Noble WC, Virani Z, Cree RG. Co-transfer of vancomycin and other resistance genes from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus. FEMS Microbiol Lett 1992; 72:195-198.

2. Centers for Disease Control and Prevention. Hospital Infection Control Practices Advisory Committee. Recom mend ations for preventing the spread of vancomycin resistance. Infect Control Hosp Epidemiol 1995; 16:105-113.

3. Edmond MB, Wenzel RP, Pasculle AW. Vancomycin-resistant Staphylococcus aureus: Perspectives on measures needed for control. Ann Intern Med 1996; 124:329-334.

4. Garrett DO, Jochimsen E, Murfitt K, et al. The impending apocalypse: The emergence of vancomycin resistance in Staphylococcus spp. (abstract). Seventh Annual Meeting of the Society for Healthcare Epidemiology of America. Infect Control Hosp Epidemiol 1997; 18:P32.