Gene transfer makes staph vancomycin-resistant
In a sci-fi scenario researchers have long feared, vancomycin-resistant genetic material from a co-infecting enterococci strain apparently has transferred to Staphylococcus aureus within a patient, creating the first clinical strain of a much-anticipated superbug: vancomycin-resistant S. aureus (VRSA).
Infection control just got a lot more important.
"There are major implications," says Denise Cardo, MD, chief of the prevention and evaluation branch at the Centers for Disease Control and Prevention’s (CDC) division of healthcare quality promotion. "It highlights the importance of prevention of transmission of multidrug-resistant microorganisms in health care settings. Antibiotic resistance in health care settings is a very important problem."
The case occurred in June 2002, when VRSA was isolated from a swab obtained from a catheter exit site of a 40-year-old Michigan resident with diabetes, peripheral vascular disease, and chronic renal failure.1 The patient — who is recovering after successful treatment of the VRSA infection — had been intermittently co-infected with both vancomycin-resistant enterococci (VRE) and methicillin-resistant S. aureus (MRSA).
"If you were to predict what patient population would get vancomycin-resistant Staph aureus, this is exactly the one," says Gary Noskin, MD, hospital epidemiologist and medical director of infection control at Northwestern University Hospital in Chicago. "[Dialysis patients] are frequently at risk for staph and MRSA. They have both colonization and infection with this organism, and they are frequently exposed to vancomycin. One of the dilemmas that face clinicians taking care of dialysis patients is that vancomycin is very convenient to administer. You only need to give it once a week."
From VISA to full-blown VRSA
Indeed, most of the cases of vancomycin-intermediate S. aureus (VISA), which began occurring in the mid-1990s, have been in dialysis patients. As of June 2002, eight patients with clinical infections caused by VISA, which is partially resistant to vancomycin, have been confirmed in the United States. The mechanism of resistance in the VISA strains was the development of thickened cell walls after repeated exposure to vancomycin.
In contrast, all indications are that the Michigan case involved a genetic transfer from VRE to MRSA. The vancomycin-resistance determinant vanA, typically found in VRE but never in a clinical staph strain, was found in the VRSA isolate. Researchers in England proved such a genetic transfer could occur a decade ago in controversial laboratory studies that produced a fully resistant strain in vitro.2
"Initially, it was speculation," Cardo says. "Now we see that it is possible. We need to prevent the spread of these organisms in health care settings. Because if they can transfer genetic materials, it means we really need to be serious about this."
While vancomycin resistance is defined as an isolate having a minimum inhibitory concentration (MIC) of at least 32 µg/mL, the infecting strain from Michigan had a MIC of 128. "That was very high, and we thought initially since the culture was mixed with VRE that this was probably because of the VRE," Cardo says. "We haven’t seen something like that with Staph aureus."
In addition to the vanA vancomycin resistance gene from enterococci, the isolate contained the oxacillin-resistance gene mecA. Essentially, it was an MRSA strain that developed vancomycin resistance, but the result was not an untreatable pathogen. The isolate was susceptible to the relatively new drugs linezolid and quinupristin/ dalfopristin, as well as tetracycline, and trimethoprim/sulfamethoxazole. The patient was successfully treated with trimethoprim/ sulfamethoxazole. Though the organism is still susceptible to several drugs, the appearance of complete resistance to vancomycin in a staph strain has long been one of the dreaded milestones toward a "post-antibiotic era."
"It is clearly a significant event; you have the first staph aureus that is vancomycin-resistant," Noskin says. "But it is a little bit different now then when we first started talking about this five or 10 years ago, mainly because we do have antibiotics that have activity against this organism. While it is a serious concern, this is not the multidrug-resistant organism that is resistant to every known antibiotic that I think many of us feared."
An aggressive search for transmission
Nevertheless, the CDC was extremely aggressive about obtaining "hundreds" of cultures from any possible contacts, including dialysis workers, hospital staff, family members, and even a nail parlor the patient visited. All known results thus far are negative. The CDC is well aware what can happen if a drug-resistant strain starts getting transmitted around until it finds a niche and establishes a reservoir. VRE, for example, started in a few East Coast hospitals and then rapidly expanded nationwide.
"I think we have learned," Cardo says. "That’s the reason we are being very radical in terms of testing more people than we would have in the past. We are trying to contain any potential transmission. People [wonder] why are we testing patients [who] are hospitalized now since they did not have any contact with the index patient? Because we want to detect any potential transmission and stop it right now. We are being aggressive."
Infection control practices in the dialysis center included standard precautions consistent with CDC guidelines. After the identification of VRSA, dialysis center staff went to special precautions that included gloves, gowns, and masks for all contacts with the patient. They also performed dialysis on the patient using a dedicated machine during the last shift of the day in an area separate from other patients.
A dialysis technician was dedicated to provide care only for the patient, using dedicated, noncritical patient-care items. Assessment of infection control practices in other health care settings in which the patient was treated is ongoing.
The CDC was already in the process of revising its patient isolation guidelines, but Cardo could not say whether special measures would be added, for example, for dialysis patients co-infected with VRE and MRSA. There is no obvious indication in the clinical course of the patient that would suggest a similar genetic transfer could not occur again under similar circumstances.
"I don’t know that this patient’s clinical course was significantly different from others with complicated diabetes and chronic ulcerations," says Matthew Boulton, MD, MPH, state epidemiologist at the Michigan Department of Community Health in Lansing. "It’s not at all uncommon to have seen multiple courses of vancomycin used in individuals like this," Boulton says. "I don’t think that the clinical history and the pattern of antibiotic use were particularly unique. The question now is: Are we going to see this arise elsewhere through gene transfer, now that we have seen this first one?"
Anomaly or harbinger?
Is the long-awaited arrival of VRSA some kind of an anomaly or a harbinger of widespread emergence? "Perhaps neither of those," says William Schaffner, MD, chairman of the department of preventive medicine at Vanderbilt University Hospital in Nashville. "Once the vancomycin intermediate strains appeared, everyone anticipated that at some point, a totally resistant Staph aureus would occur. I would not anticipate a rash of new observations, but from time to time, I think we will see other institutions reporting such organisms. Unless great attention is given to containment, we may see gradual spread," he says.
MRSA has been endemically entrenched for decades in some hospitals and is increasingly found in the community. Could a similar path be carved out by VRSA? "It is an important question that is hard to answer," Noskin says. "Vancomycin has been out since 1958, so it had been out for 40-plus years before we saw this. Why is it that it took so long for staphylococci to become resistant to vancomycin? For other classes of antibiotics resistance can develop within months and years. It is impossible to predict. [But] there is clearly well-documented person-to-person transmission of Staph aureus and MRSA, so you would think that just because this organism had acquired resistance determinants it shouldn’t prevent it from person-to-person transmission."
After the initial success of penicillin in treating S. aureus infection, penicillin-resistant S. aureus became a major threat in hospitals and nurseries in the 1950s, requiring the use of methicillin and related drugs for treatment of S. aureus infections. In the 1980s, methicillin-resistant S. aureus emerged and became endemic in many hospitals, leading to increasing use of vancomycin. Now we have the next chapter.
"Anybody with any kind of contact with hospital infection control is acutely aware of the inexorable and undeterable march of these resistant organisms," Boulton says. "They seem to have the capacity to develop resistance to just about everything that we develop. That’s very disconcerting."
Though it remains susceptible to other drugs, the fact that the VRSA strain is impervious to both vancomycin and methicillin-class drugs limits treatment options. "It is potentially treatable; that would be fair to say," Noskin says. "It is very complex for the clinicians out there because, on the one hand, on a national level, 40% to 50% of staph are MRSA, which means your initial therapy for the most part has been vancomycin. So when you understand the epidemiology of Staph aureus and the need to use vancomycin, then you can see it is a vicious cycle to select out for these resistant strains."
Prevention of transmission remains a critical issue should subsequent cases arise, Boulton emphasizes. "We have gone to an extraordinary extent to make sure there is not transmission from this [patient] to others," he says. "That, of course, is very resource- and personnel-intensive. Is that practical in the hospital setting? Now that we actually have VRSA, it is really changing the complexion of the discussion about this."
Much in the way the anthrax attacks transformed the bioterrorism discussions from theory to reality, the arrival of VRSA may galvanize the longstanding struggle for judicious antibiotic use and stringent infection control. "The approach is the same that we have been preaching for a long time," Cardo says. "The difference is now this shows that we really need to be serious. Health care settings should have this as one of their first priorities."
(Editor’s note: Will the first case of VRSA lead to full emergence and endemic spread like we have seen with VRE and MRSA? Answer our poll question on this important subject on your subscriber web site at www.HIConline.com.)
1. Centers for Disease Control and Prevention. Staphylococcus aureus resistant to vancomycin, United States, 2002. MMWR 2002; 51:565-567.
2. 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; 93:195-198.