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Vancomycin resistance appears in epidemic CA-MRSA strain

First VISA case reported in a USA300 clone

In an ominous finding, an epidemic strain of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has developed intermediate resistance to vancomycin, the classic antibiotic weapon against resistant staph infections, Hospital Infection Control has learned.

The finding is significant because the strain in question is USA300, the hardy and easily transmitted, predominant U.S. strain that has been detected in some 40 states. Though other drug options remain available, the appearance of vancomycin resistance in staph strains has long been one of the dreaded warning signs of a "post-antibiotic" era. Emerging resistance in a CA-MRSA strain that is causing serious infections in the community and has been displacing traditional nosocomial strains in some hospitals is particularly troubling.

"That's one of the infectious disease doctor's nightmares," reacted William Schaffner, MD, chairman of the department of preventive medicine at Vanderbilt University School of Medicine in Nashville. "It's [concerning] to have vancomycin resistance — whether it be intermediate or complete — in any staphylococcal strain; but to have it occur in a community-associated strain that has a great capacity to spread is very, very disturbing. I hope they have that patient in a bubble."

The details of the case were not available pending publication of the research, but the finding was mentioned by one of the investigators recently in San Francisco at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). In response to questions by Hospital Infection Control, Francoise Perdreau-Remington, PhD, a leading MRSA researcher at the University of California in San Francisco and San Francisco General Hospital, confirmed that vancomycin-intermediate S. aureus (VISA) had been detected in an isolate of the predominant community strain of CA-MRSA in the United States.

"The mechanism of resistance is a thickening of the cell wall," she said. "The VISA strains that have been [previously] described were nosocomial strains that originated in the hospital. What we described is a USA300 developing intermediate vancomycin resistance after a six-week treatment with vancomycin."

Gene transfer could create USA300 VRSA

With the findings slated for publication, Perdreau-Remington declined to answer questions about the patient involved, infection control measures, antibiotic susceptibility profile, and other critical aspects of the case. The first documented VISA case occurred in Japan in 1996, and then other cases were detected in the United States and elsewhere.¹ Prolonged courses of therapy with vancomycin are a common prelude to VISA cases. As opposed to the thickened cell walls found in VISA isolates, the mechanism of resistance in all of the U.S. cases of vancomycin-resistant S. aureus (VRSA), since it appeared in 2002, has been a genetic transfer from vancomycin-resistant enterococci (VRE) to MRSA.² The vancomycin-resistance determinant vanA, typically found in VRE but never in clinical staph strains, has been found in the VRSA isolates in all of the six U.S. cases.

Indeed, while the emergence of intermediate resistance is concerning, Perdreau-Remington cited a potentially bigger problem: The USA300 clone appears to have the necessary plasmids to be receptive to a genetic transfer of vancomycin resistance from VRE. That finding was published earlier this year when she and colleagues detailed the complete genome sequence of USA300.³ That means that not only could future USA300 VISA cases arise through prolonged treatment with vancomycin, but the USA300 strain could acquire full resistance via genetic transfer from VRE.

"We did the whole genome sequence, and I am concerned that the USA300 strain carries two of the three plasmids that are resistance markers," Perdreau-Remington said. "One of the plasmids carries clindamycin resistance and also carries mupiricin resistance. It's a conjugated plasmid that carries the transfer region which was described in a strain of VRSA. So we have this plasmid that doesn't carry the vanAgene but it has the biological [ability] to take it."

With reports increasing that CA-MRSA USA300 strains are displacing traditional nosocomial strains and becoming predominant in some hospitals, it appears the pathogen will have increasing opportunities to be exposed to VRE in a patient coinfected or colonized with both bugs. "We don't know whether these [USA300] strains are more or less likely to pick up the resistance genes from VRE than conventional strains," Schaffner says. "Conventional MRSA has had ample exposure to VRE in hospitals and [genetic transfer] is a rare event, thank goodness."

Indeed, much-feared VRSA has not emerged beyond sporadic cases, but the convergence of MRSA and VRE globally will continue to present opportunities for genetic transfer. "It's pretty unpredictable when that gene is going to jump from VRE to MRSA, but obviously as we have larger and larger numbers of patients who are co-colonized with both of those organisms, the opportunity for that happening worldwide continues to increase," says infection control consultant William Jarvis, MD, a former epidemiologist at the Centers for Disease Control and Prevention. "Recognition is part of the problem. North America and Western Europe have very good microbiology laboratories that will detect them. But for a large proportion of the world where MRSA is highly endemic and VRE is starting to emerge, the likelihood of detection of it may be much less."

Emerging resistance across the board

Again, the antibiotic susceptibility profile of the USA300 VISA isolate was not reported, but many community-acquired MRSA strains tend to be susceptible to tetracycline, clindamycin, and trimethoprim/sulfamethoxazole (TMP/SMX). However, resistance patterns in CA-MRSA strains in general are changing and becoming a matter of increasing concern.

"What is worrisome is that some of the [CA-MRSA] strains now carry up to four different classes of resistance," said Perdreau-Remington. "The idea that community MRSA is multisusceptible is losing [ground], at least in San Francisco in this population."

It was suggested in ICAAC discussions that emerging resistance is possibly a reflection of the wide variety of treatment strategies — some of them no doubt inappropriate — being tried in the community for CA-MRSA. "We are looking into this issue in the patients with high resistance strains, but the data are not there yet," Perdreau-Remington said. There are calls for a consistent antibiotic management strategy for CA-MRSA, but she added, "You need to know the situation in your institution and your patient population."

Other drugs are available, but staph resistance is appearing even in some of the most recently developed antimicrobials. Regardless, if resistance to a time-honored weapon such as vancomycin emerges in a community staph strain, changing physician prescribing practices will be no small feat. "It takes time for doctors to get the new information and change their prescribing practices," Schaffner says. "If vancomycin resistance emerges, we are going to see a period of transition where there is a lot inappropriate transcribing; and as a consequence, patients won't do as well."

Another critical question in the evolving situation is what kind of infections CA-MRSA is going to cause if it displaces nosocomial strains and becomes a hospital-acquired pathogen. "They are typically seen in skin and soft-tissue infections in the community; whereas, hospital staph causes line infection and pulmonary infections," Schaffner says. "If we have these CA-MRSA [strains] — which like to cause these necrotic kinds of pneumonias — coming into hospitals, that is going to be very serious. If you add on top on that the potential that they may not respond to vancomycin, that is not an attractive prospect."

It appears in general that CA-MRSA may cause more severe infections than typical hospital strains, as data presented at ICAAC indicated there have been 40 reports worldwide of necrotizing pneumonia. CA-MRSA infection also has caused other severe outcomes such as necrotizing fasciitis and toxic shock syndrome.⁴

"It's a very serious problem, although the number of serious infections is still relatively low percentagewise," said Perdreau-Remington. "The problem is that some of the virulence factors that we see in CA-MRSA have not been found or found only in very low rates in nosocomial strains. How does the physician detect and find out — how fast does he understand that the patient may have a community strain and go on to develop a necrotizing pneumonia? That is the question that for now cannot be answered quickly. It's really the physician's ability to think of CA-MRSA, to realize what kind of serious disease can happen and switch antibiotics. Switching to the right antibiotic will probably not be the only answer because these toxins act very fast."

SF at 'point of spear' on CA-MRSA

Amid all the uncertainty there is one clear trend: CA-MRSA USA300 is rapidly emerging in San Francisco and other areas of the United States. Seven out of nine San Francisco hospitals recently reported MRSA rates that are higher than 50%, meaning that between 50% and 75% of all staph infections are caused by resistant strains.

"We found that in five of these hospitals USA300 was responsible for an average of 68% of all infections," Perdreau-Remington said. "The number of cases of MRSA in our institution went from under 200 cases in 1996 to over 1,200 in 2004. We are now in 2006 at 1,800 total cases. However, the increase only happened in the community. The nosocomial strains did not increase."

Similarly, methicillin-susceptible staph strains have remained stable, while CA-MRSA — primarily the USA300 clone — has exploded into hospital and clinic populations at San Francisco General. With emergency departments becoming crowded with these patients, the hospital established a skin and soft-tissue infection clinic to deal with the deluge.

"We looked at the different wards and clinics associated with increasing MRSA; and when we compared data from 2000 to 2004, we found that the pediatric clinics had a 20-fold increase of infections due to MRSA," Perdreau-Remington reported. "The HIV ward had a 14-fold increase, primary care 11-fold, jails ninefold, urgent care fourfold. However, again, medical ICUs were [not seeing increased prevalence]. I think this really [reflects] what we are seeing in the community. The increasing admission in children is really where the major problem is."

That conclusion was underscored by data presented at ICAAC from 10 North Carolina hospitals in the Duke Infection Control Outreach network.⁵ The researchers found that pediatric patients were at nearly six times greater risk of CA-MRSA infections than adult patients. "They showed an age-related variability in the prevalence of community MRSA infections," said Perdreau-Remington. "They [found that] 74% of cases in children under 18 were due to community MRSA."

Though beset by the tide of CA-MRSA, San Francisco General has not adopted the "active surveillance" approach to detect colonization in incoming patients. "So far, we are not doing regular active surveillance," she said. "We did active surveillance in 2005; and among those patients, we had 8.6% MRSA colonized patients admitted to the hospital, and of those 86% were USA300. . . . Is there a need to test everybody? I don't think so. What do we do with the data? Are you going to treat everybody? I think if a person is admitted to a hospital for elective surgery — maybe depending on the rate of infection in the hospital — active surveillance may be a way."

Regarding colonization, the pediatric connection holds true for CA-MRSA. A study published last year found a 10-fold increase in nasal colonization of healthy children since 2001.⁶ "As colonization typically precedes infection, this increase may be a major factor in the emergence of community-associated MRSA as a pathogen of healthy children," the authors concluded.

Nasal carriage appears to be increasing in some adult populations as well. "In 1996 when I came to San Francisco, we did a study in the HIV population looking at nasal carriage in more than 250 individuals," Perdreau-Remington said. "We had zero MRSA. Zero. An increase has happened over the last six years and it is spreading like fire."

References

Centers for Disease Control and Prevention. Reduced susceptibility of Staphylococcus aureus to vancomycin — Japan, 1996. MMWR 1997; 46:624-626.
Centers for Disease Control and Prevention. Staphylococcus aureus resistant to vancomycin, United States, 2002. MMWR2002; 51:565-567.
Diep BA, Gill SR, Chang RF, et al. Complete genome sequence of USA300, an epidemic clone of community-acquired methicillin-resistant Staphylococcus aureus. Lancet 2006; 367:731-739.
Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Eng J Med 2005; 352:1,445-1,453.
Collins D, Anderson DA, Sexton DJ, et al. Age-related variability in the prevalence of community-acquired methicillin-resistant Staphylococcus aureus infections, 2000-2005. Abstract K-802. Presented at the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco; Sept. 27-30, 2006.
Creech CB, Kernodle D, Alsentzer A, et al. Increasing rates of nasal carriage of methicillin-resistant Staphylococcus aureus in healthy children. Ped Infect Dis J 2005; 24:617-621.