CDC pulling out all stops to contain first U.S. cases of resistant staph

Japanese discoverer of resistant staph says strain probably exists in U.S.

In a dramatic response that underscores the severity of the situation, the Centers for Disease Control and Prevention has issued strikingly stringent measures to prevent emerging vancomycin-resistant Staphylococcus aureus from gaining a foothold in the United States.

In the first official guidance issued in response to the emergence of low-level and intermediate-resistant strains in Japan, the CDC outlined some of the strictest infection control measures it has issued for a bacterial pathogen.1,2 Measures include advising health care workers to don masks — though airborne spread is considered unlikely — and have baseline cultures taken before treating patients infected with S. aureus that have less susceptibility to vancomycin. Infection control professionals should routinely assess the designated health care workers treating the infected patient, who in turn should not be transferred within or between facilities before the CDC is contacted. (See recommendations, p. 115.)

The recommendations — which also include re-emphasizing careful use of vancomycin — were issued because the recent confirmation of an intermediate-resistant staph isolate in Japan increases the likelihood that fully resistant strains of the most common cause of nosocomial infections may now emerge, the CDC reports.3 (See Hospital Infection Control, June 1997, pp. 81-85; July 1997, pp. 97-102.)

"This is not theoretical now. The facilities need to make sure they have the appropriate procedures in place, and the responsible personnel know about them and how to implement them," says David Bell, MD, assistant director for antimicrobial resistance at the CDC national center for infectious diseases. "The dissemination of a staphylococcal strain that’s either partially or completely resistant to vancomycin in a hospital would be such a disaster that we want to take every possible precaution to be sure that doesn’t happen."

A similar draconian approach, including a recommendation for use of masks, was put forth by clinicians in an article published last year.4 They noted that "although few data support the idea that airborne transmission of staphylococci is possible," such conservative initial measures with the first cases of vancomycin-resistant staph are warranted for procedures like suctioning and bronchoscopy that may create an aerosol. The CDC went even further in recommending routine mask wear for care of infected patients, but the agency decided to err on the side of caution with the first cases that appear in the United States, Bell notes.

"We are doing other things that are quite extra ordinary in terms of formal recommendations, including assigning specific health care workers to care for only these infected patients and avoiding transferring patients," he says. "These are measures that have been used to contain particular outbreaks of infections, but to recommend them across the board when one case develops is a very strong response. The recommendation to wear masks is in the same vein. We are basically pulling out all the stops to contain this infection."

Endemic strains tough to eradicate

It will be critical to prevent the strains — which were initially called "intermediate-resistant" and are now described as having "reduced susceptibility" — from establishing an endemic presence in a health care setting in the United States, according to the CDC. Experience with methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE) has shown that infection control measures work with a small number of cases, but resistant strains can be quite difficult to eradicate once they become endemically established in a hospital.

"We don’t want hospitals trying to contain this on their own and then calling us once it is endemic," Bell says. "We want to hear about the first case so we can be there immediately. And it is not just the laboratory detection and infection control aspects. There is the patient treatment aspect, so we are working with the FDA to set up a procedure whereby a physician could obtain an investigational drug. This also requires immediate notification in order to get the drug."

The effect of reduced vancomycin susceptibility on clinical outcomes is difficult to assess because even fully susceptible S. aureus strains cause serious infections that often require a combination of surgery and aggressive antimicrobial therapy, the CDC warns. Several antimicrobial agents in clinical development (i.e., Synercid) may be effective in treating infections with S. aureus strains that have reduced susceptibility to vancomycin, the CDC notes. Physicians treating infections caused by staphylococci with reduced vancomycin susceptibility can get information about investigational drug therapies from the Food and Drug Admini stration’s division of anti-infective drug products [telephone: (301) 827-2120]. Clinicians will be asked to send the isolate to the CDC for microbiologic and epidemiologic evaluation.

Is resistant MRSA strain already here?

The urgency apparent in the CDC’s pre-emptive strike approach may be well-founded. The first cases may soon be detected in the United States because the country likely shares similar MRSA strains with Japan, says the discoverer of the resistant strain, Keiichi Hiramatsu, MD, PhD, professor of bacteriology at Juntendo University in Tokyo and chairman of the Japanese Symposium on Staphylococci Infections. From his Tokyo office, Hiramatsu tells Hospital Infection Control that the same clonal type of MRSA that is developing vancomycin resistance in Japan is very likely already in the United States.

"I think you will have trouble too," he says. "If the CDC surveys the MRSA strains in your country, I am sure they will find one or two."

Hiramatsu bases his supposition in part on historic patterns of MRSA dissemination among countries with cultural and business ties, noting, for example, that the same strains of MRSA can be found in widely separated countries throughout the world that were once part of the former British Empire.

"If you look at the clonal types all over the world, you can see that where there is a lot of travel of people, then the MRSA is shared," he says. "Japan and the United States share a lot of social and cultural links, so I think we are sharing the same strains [of MRSA]."

Asked if he thought that meant MRSA in the United States would begin showing the emergence of vancomycin resistance as seen in Japan, Hiramatsu tells HIC, "Yes, I am definitely convinced."

While that may prove to be the case, there are no data to support the contention that the same MRSA strain is in the United States, says Fred Tenover, MD, chief of the nosocomial pathogens laboratory branch in the CDC hospital infections program, who ran the tests that confirmed intermediate resistance in Hiramatsu’s isolate from Japan.

"To the best of my knowledge, he has not collected MRSA from the U.S. and shown that same pulse field pattern is actually present in the U.S," he says. "We are collecting isolates from a large number of hospitals to look at this, but there are no data that say these strains are currently in the U.S."

Regardless, questions of whether similar strains will arise under similar conditions or be imported on the skin flora of travelers may ultimately be little more than academic. Infectious diseases have increasingly gone global, and control efforts should be geared to that expectation, Bell says.

"I don’t know if the same MRSA is over here. I know we have a lot of MRSA," he says. "Since the mechanism of reduced vancomycin susceptibility is not entirely worked out, I don’t know if it requires that same MRSA strain. So it almost doesn’t matter. We have learned that if a bacteria like this shows up anywhere in the world, we are going to see it here sooner or later. Whether it is already here, all I can say is we have no reports of it. But I think it can be taken as a matter of near certainty that we are going to see it here."

Cell walls thicker in resistant strain

To facilitate the search, the CDC is collecting MRSA nosocomial isolates from sentinel hospitals in its National Nosocomial Infections Surveillance System. The MRSA isolates will be studied to determine vancomycin susceptibility and other factors, Tenover says, noting that if reduced susceptibility to vancomycin is found in any isolate, electron microscopy may then be used to determine if the organism shows signs of developing thicker cell walls — the mechanism of resistance Hiramatsu found in the strain in Japan. A strain there called Mu50 has developed cell walls with twice the normal thickness of S. aureus, Hiramatsu discovered.

"There is an enhanced supply of cell wall material produced in the cell," Hiramatsu says. "Vancomycin works by attaching to the cell wall, so you have to use more vancomycin to suppress the growth of the cell."

As previously reported in HIC, Hiramatsu says the first case in Japan occurred in a four-month-old male baby who developed an MRSA surgical site infection after heart surgery. The patient was treated with vancomycin for 29 days without cure, and Hiramatsu subsequently isolated the Mu50 MRSA strain with intermediate resistance to vancomycin based on a minimum inhibitory concentration (MIC) of 8. The patient eventually recovered after being treated with a drug combination that included arbekacin (an aminoglycoside approved for MRSA infection in Japan but not in the United States) and ampicillin/ sulbactam.

While Hiramatsu has not found any other clinical isolates of Mu50 in Japan, he has detected a much more prevalent clonal strain there called Mu3, which has an MIC to vancomycin in the 2 to 4 range. The CDC advises U.S. clinicians that any isolate of S. aureus with an MIC of 4 or above should be considered a "candidate strain" for reduced vancomycin susceptibility. Though technically vancomycin-susceptible by laboratory definitions, Mu3 may be a precursor of more resistant strains because it shows the ability to develop an MIC of 8 — essentially becoming Mu50 — when exposed to large doses of vancomycin in lab experiments, Hiramatsu says.

"Mu3 and Mu50 have exactly the same pulse field gel electrophoresis pattern," he explains. "That means they are closely related, a clone of the same strain. After selecting Mu3 in vitro with various concentrations of vancomycin, we could raise exactly the same level of vancomycin resistance to that of Mu50 in vitro. So Mu3, a heterogenous strain, is considered to be a precursor of vancomycin-resistant MRSA: Mu50."

The finding is troubling because while Mu50 is still rare in Japan, a survey of MRSA isolates from seven Japanese university hospitals found that 8.8% of the isolates were Mu3. The emerging pathogen accounted for 1.3% of MRSA strains isolated from 195 non-university hospitals in Japan, Hiramatsu reports. While posing the threat of possibly mutating into the Mu50 strain, the less resistant Mu3 still causes therapeutic failure in infected patients and necessitates prolonged use of vancomycin or other drugs, he says. That said, Hiramatsu is doubtful Mu50 will emerge from Mu3 in clinical settings in any broad way if vancomycin use is controlled. Only infections requiring large volumes of vancomycin for a very prolonged period will likely select out Mu50 strains from Mu3, he says.

Hiramatsu gives peritonitis infections as an example. "In that case you could make Mu50-type strains out of Mu3," he says. "But if you discourage situations where MRSA is exposed to very high concentrations of vancomycin, then Mu50-like strains will not multiply and increase. But the heterogenous strains will increase anyway, and that in itself is causing therapeutic failure."

While noting that he is aware of some 10 immunocompromised Japanese patients who have died after Mu3 MRSA infections, Hiramatsu said it would take much more detailed investigation and case-control studies to try to establish a mortality rate for the pathogen. In most cases, combination therapy with arbekacin is clearing the infections, he says.

The CDC guidelines will be used to push for improved infection control and for antibiotic restrictions in Japan, as unmitigated use of vancomycin and a broad spectrum of other drugs likely gave rise to the current situation, Hiramatsu says.

"After the MMWR comes out, the government is going to move and they are going to reinforce those kinds of general precautions for nosocomial infection prevention," he says. "We are going to more strict precaution measures, and the more important measure in Japan is the use of antibiotics. There are no policies for antibiotic use in hospitals in Japan."

Indeed, with no equivalent to the CDC, and cultural barriers to infection control — nurses have said they were reluctant to wear gloves for fear of hurting patients’ feelings — the primary hope of containing the emerging pathogen in Japan is that a version of the CDC guidelines will be adopted there, says an American nurse who frequently travels to Japan to lecture about infection control and nursing care.

"Historically, Japan only changes due to pressure from the outside," says Ann Hardee, RN, president of Rann Med International in San Antonio, TX. "So with the CDC writing these guidelines, I think they [the Japanese] are going to write a guideline."

Just back from a recent trip to Japan, Hardee reports that the clinicians she spoke to there were largely unaware of the situation until she shared the first reports from HIC with them.

"They said that was the only time they had ever heard about it, and I talked to at least five different hospitals and a pharmaceutical company," she says. "Except for Dr. Hiramatsu, everyone is really trying to downplay it — the people who know about it, that is. Most don’t even know about it yet."

If emerging resistant staph continues to spread in Japanese health care settings, it is possible the country could essentially become the global equivalent of the endemically infected hospital, giving the strain a foothold from which it could gradually spread to other countries. The CDC remains involved with the situation there, but appears to be devoting its primary efforts to detecting and preventing subsequent transmission of the first U.S. cases.

"Our information about the situation in Japan is really pretty limited," Bell says. "CDC has not officially sent anybody to Japan to assist in their investigation. We are in frequent communication with Japanese health officials, and we have discussed the case with them. As they continue their investigation, we will continue to be in contact with them and provide whatever assistance seems appropriate. Whether that will involve telephone conversations or visits, we don’t know."

Regardless, Hiramatsu is optimistic that even diminished effectiveness of vancomycin will not herald a post-antibiotic era for Japan or the United States if clinicians are resourceful and fight each infection with enthusiasm.

"From now on, clinicians must be alert enough to find the weak points of individual MRSA strains to cure the individual patient," he says. "They have to be ingenious in finding combinations of drugs. Up until now, clinicians have been blindly dependent on the pharmaceutical companies providing very potent wonder drugs. This is the end of wonder drugs. But we still have a lot of antibiotics — they are the treasure of this century — and we have to make the best use of them."

References

1. Centers for Disease Control and Prevention. Interim guidelines for prevention and control of staphylococcal infection associated with reduced susceptibility to vancomycin. MMWR 1997; 46:626-628.

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

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

4. Centers for Disease Control and Prevention. Recommendations for preventing the spread of vancomycin resistance. Recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC). MMWR 1995; 44:(RR-12)1-13.