Vancomycin resistance emerging in Staph aureus

Fourth case in U.S. follows familiar pattern

The fourth case of vancomycin intermediate-resistant Staphylococcus aureus (VISA) has been confirmed in the United States, suggesting that cases may continue to appear in patients undergoing prolonged treatment with the last-line antibiotic for infections with methicillin-resistant S. aureus (MRSA). Infection control professionals should be particularly wary of vancomycin resistance appearing in dialysis patients under treatment for MRSA, as three of the four U.S. cases have been found in that group.

"We remain very concerned that populations of patients that are likely to carry methicillin-resistant Staph aureus and have vancomycin exposure would be the most likely group to present with one of these [VISA] organisms. Certainly dialysis fits that bill on both counts," says Julie Gerberding, MD, director of the hospital infections program at the Centers for Disease Control and Prevention.

Possibility of full resistance increases

With VISA cases now identified in Europe, Asia, and the United States, the possibility appears to be increasing that some staph strains will become fully resistant to vancomycin, often the drug of last resort for MRSA infections. "The concern is if staph has learned this trick, it wouldn’t be unlikely that it would take it one step further," Gerberding tells Hospital Infection Control.

According to the CDC report of the case, in April 1999, a 63-year-old woman with MRSA bacteremia was transferred from a long-term-care facility to an Illinois hospital.1 The patient had a history of frequent hospitalizations for complications of hemodialysis-dependent, end-stage renal disease. The patient also had two failed arteriovenous grafts, multiple central venous catheter-associated infections, and intermittent receipt of vancomycin therapy through June 1998.

Thirteen days after hospital admission and 25 days after initiating vancomycin therapy, a culture from the patient’s blood raised clinical suspicions of a VISA infection. Confirmatory testing showed that the patient had a VISA strain with a minimum inhibitory concentration (MIC) of 8, the same level of intermediate resistance to vancomycin detected in the first documented case in Japan in 1996 and three subsequent U.S. cases in Michigan, New Jersey and New York.2-4 (See HIC, June 1998, pp. 80, 86-88; October 1997, pp. 145-152.)

In the Illinois case, an echocardiogram demonstrated a mitral valve vegetation, but the patient declined surgical intervention, the CDC reported. Despite treatment with intravenous vancomycin, rifampin, and tobramycin, the patient died 10 days after the first VISA blood specimen was drawn. The cause of death was endocarditis. The VISA isolates in the Illinois case were resistant to penicillin, oxacillin, clindamycin, erythromycin, ciprofloxacin, and rifampin. They were susceptible to trimethoprim-sulfamethoxazole, tetracycline, and gentamicin, and had intermediate susceptibility to chloramphenicol. No VISA strains were recovered from other body sites.

None of the U.S. cases appear to be epidemiologically linked, as all involve distinct VISA strains that arose independently after exposure to vancomycin for treatment of MRSA. The mechanism of resistance has generally been described as an apparent thickening of the cellular material in VISA isolates. In reporting the case, the CDC reiterated that the recovery of S. aureus with reduced susceptibility to vancomycin (e.g., MIC greater than or equal to 4 µg/mL) should be reported promptly to the agency and to local and state health departments. CDC-recommended infection-control precautions for VISA should be implemented, and an epidemiologic investigation should be conducted.5

The pathogen also has been described as "GISA" (glycopeptide intermediate S. aureus), but the CDC is trying to end the confusion by reverting to the VISA acronym. GISA is a technically more accurate description because all isolates have shown intermediate-level MICs for the glycopeptide drugs vancomycin and teicoplanin, the CDC noted. However, concerned that clinicians may not recognize the term "glycopeptide," the CDC reported the latest case as a VISA infection.

An encouraging note is that no secondary VISA transmission has occurred in any of the U.S. cases. In the Illinois case, the CDC reported that the infection control department at the unidentified hospital correctly implemented VISA isolation precautions and prevented any secondary transmission. None of 10 family members or 171 health care workers screened by nares culture was colonized with VISA. No other VISA isolates were identified in other hospitalized patients. "I think it is a reflection of the detection and response capabilities," Gerberding says. "Folks recognize that there is a risk here and implement the appropriate isolation precautions to prevent person-to-person spread, and also look aggressively to make sure that that hasn’t already happened."

Prevention of the strains arising is problematic, however, as vancomycin is often a last-line drug for MRSA, which continues to plague hospitals and is arising in community strains. "The [Illinois] patient had MRSA, so it is not surprising that they would have reasonable indications for vancomycin," she says. "That is the problem. Once you get the MRSA, then there is good reason to use vancomycin."

On the other hand, susceptibility testing of isolates can be used to determine whether to discontinue empiric use of vancomycin if the staph strain is methicillin-susceptible, she emphasizes. "I think we need to be absolutely sure we know what we are treating when a problem like this arises," Gerberding says. "If we are using the drug empirically, it is important that we get the appropriate culture information and stop that therapy if we have evidence that we don’t need it. Preventing MRSA infection is also a component of all of this, and that of course is a little harder to do."

In reporting the case, the CDC reminded that laboratorians may not be aware of proper methods for accurately identifying VISA. The hospital’s laboratory in the Illinois case properly identified the VISA-infected patient by using confirmatory testing. The CDC protocol calls for targeting "candidate" strains (i.e., vancomycin MIC greater than or equal to 4 µg/mL) for confirmatory testing.

However, in a related report, the CDC also cited a 1998 survey that found that 16% of the labs could be missing VISA strains due to inappropriate testing.6 "One could say, is the glass half empty or half full?" Gerberding notes. "The fact that 84% were using the appropriate methods to detect it — and that survey was fairly early, when [VISA] was just beginning to emerge — suggests that we will have the laboratory capacity to diagnose this. There are a few places that need to gear up. I don’t think there is a concern that we have missed a lot of cases at this point in time. But we need to make sure that everybody is geared up so nothing slips through the cracks."

The survey found that 278 (84%) of responding labs were using methods that allowed them to detect VISA isolates. However, 52 (16%) of responding labs — including labs in smaller hospitals and managed care-based labs — were using tests that would not identify the isolates, such as disk diffusion, with no additional method. Over all, approximately 40% of the laboratories were not performing confirmatory testing of S. aureus for reduced susceptibility to vancomycin. The testing of isolates of S. aureus for reduced susceptibility to vancomycin requires that laboratorians know the appropriate susceptibility testing methods and strategies for selecting candidate strains. (See article, p. 23.)

[Editor’s note: CDC Information on VISA confirmatory testing, investigation therapy, and infection control guidelines can be obtained at www.cdc.gov/ ncidod/hip/vanco/vanco.htm. The CDC is also seeking laboratory reports of confirmed cases of VISA infection for an ongoing nationwide epidemiologic study. Those wishing to report cases can contact CDC by phone at (404) 639-6413 or by e-mail at SEARCH@cdc.gov.]

References

1. Centers for Disease Control and Prevention. Staphylococcus aureus with reduced susceptibility to vancomycin — Illinois, 1999. MMWR 2000; 51:1,165-1,167.

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

5. 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.

6. Centers for Disease Control and Prevention. Laboratory capacity to detect antimicrobial resistance. MMWR 2000; 51:1,167-1,171.