Factors involved in spread of CA-MRSA discussed

February 2005

A clinician and an epidemiologist shared their views on the emergence of methicillin-resistant Staphylococcus aureus (MRSA) at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington.

“Epidemiologic data about the scope and extent of staphylococcal infections are surprisingly few, and urgently needed,” said Robert S. Daum, MD, a professor of pediatrics at The University of Chicago.

Japanese researchers have identified three hospital MRSA isolates. “Types 2 and 3, in their sequence, had multiple resistance determinants to non-ß-lactam antibiotics. It is this very fact that explains why many of the hospital strains that were circulating in the 1990s were multiple resistant,” said Daum. “We approached these researchers about collaborating with us in sequencing the staphylococcal cassette chromosome [SCC] methicillin resistance determinant [mec] elements in our community-acquired strains. They did, and we discovered a novel SCC mec called type 4. Type 4, and now type 5, were both identified in community-acquired MRSA isolates.”

Interestingly, the type 4 and 5 elements are much smaller in size than types 1 through 3. “In fact, they are small enough to be mobilized onto a phage or a plasma; thus, they are more easily transmitted from strain to strain,” Daum said. “I think this is the basis, in part, for the current epidemic of community-acquired MRSA.”

The type 4 element has now been clearly recognized as being promiscuous. “It is found in multiple genetic backgrounds,” Daum said. “We also know that some of these so-called community-acquired strains have moved to the hospital setting and are circulating within the hospital.” Furthermore, some of the hospital strains that had been confined primarily to the institution are now moving into the community.

PVL

The Panton-Valentine leukocidin (PVL) gene is transmitted among S. aureus isolates known to be transmitted by more than one temperate bacteriophage. PVL is also lytic for a wide variety of cell lines. “This is a core-forming toxin that is highly toxic for certain biologic membranes, particularly macrophages and polys,” Daum said. “I believe this toxin is one of the most important hallmarks of why we are having an outbreak of community-acquired MRSA.”

The PVL gene inserts at a specific site in the genome. “But the segregation of the transmission of PVL genes does not occur anatomically near the insertion of SCC mec,” Daum said. “In fact, the most current view of transmission of PVL is that it is completely separate and not related to the transmission of SCC mec.”

PVL is believed to be very important in producing S. aureus necrotizing pneumonia, “which is a relatively new clinical syndrome, at least to me,” said Daum, also section chief of pediatric infectious diseases at the university. “Patients with PVL-positive S. aureus pneumonia are younger and more often have an antecedent flu-like illness. They may also have tachycardia syndrome, pleural effusion and leukopenia. A necrotic-looking picture appears on x-ray.” Death may occur.

“PVL is present in the vast majority of community-acquired MRSA strains,” Daum said. “Therefore, I propose that the PVL-containing strains, into which SCC mec type 4 inserts, probably have a biologic selective advantage. In other words, it is a more ‘fit’ pathogen.”

Disease manifestations

At The University of Chicago, the majority of disease from these strains is skin and soft-tissue infections of the foreknuckles, buttocks, legs and arms. “We are seeing a substantial proportion of patients with invasive disease caused by these strains,” Daum said. “And at the University of California, Los Angeles, there has been a growing number of reported cases of S. aureus necrotizing fasciitis; hitherto, a relatively unknown if known at all disease.”

The new “S. aureus sepsis syndrome” has been observed about 10 times at The University of Chicago in infants and young children. “This syndrome is associated with hypotension and shock, necrotizing pneumonia, coagulopathy and disseminated intravascular coagulopathy, Waterhouse-Friderichsen syndrome, thrombocytopenia and a high mortality rate,” Daum said. “Overall, 50% of our patients have died so far. We have seen this infection caused by MSSA strains and MRSA strains.”

The first two patients seen with S. aureus sepsis syndrome were siblings, who presented about the same time. One sibling died almost immediately. “Septic shock is only the tip of the iceberg,” Daum said. “The syndrome is caused by one of the community-acquired MRSA clonal types at our institution. We call it type G, which is MLST-1. It has a very striking pulsed-field gel electrophoretic pattern that matches the clones that caused the death of four children in Minnesota and North Dakota.”

Treatment choices

For treatment of community-acquired MRSA, “I think we now distinguish mild community-acquired MRSA syndromes from moderate and severe ones,” Daum said. For a mild condition, the incision and drainage of an abscess, for example, may be adequate. “Antibiotics might not even be needed,” Daum said.

The three antibiotic choices are clindamycin, trimethoprim-sulfamethoxazole and doxycycline. “However, we don’t have data supporting the efficacy of trimethoprim-sulfa, although many of us are using it now,” Daum said. Similarly, the data on doxycycline is sparse, and it is not recommended in young children because of potential toxicity.

“Many of the isolates are clindamycin-susceptible in pediatrics in particular, and probably in adults as well,” Daum said. “But in isolates that are erythromycin-resistant and clindamycin-susceptible, you may be dealing with the so-called Mlsd phenotype. The clinical failures with clindamycin in this setting have occurred uniformly in patients with the so-called inducible phenotype. Still, clindamycin is a major tool in our armamentarium for these strains. As a result, many patients, even with a positive disk diffusion induction test, or D test, can be successfully treated with clindamycin.”

Patients who are moderately or severely ill are admitted to the hospital. “Clindamycin is the choice we actually use in our institution because we have a pediatric population,” Daum said. “Other institutions use vancomycin or linezolid [Zyvox, Pharmacia] as initial therapy for more severely ill patients. But a 10-day course of linezolid retails for $2,000.”

As for combining vancomycin and clindamycin for syndromes involving hypotension and potential shock, “many of us are doing that sort of on speculation. There are very few data about using this combination,” Daum said.

Surveillance project

“Definitely, MRSA is an important public health problem and it continues to emerge,” said John A. Jernigan, MD, a medical epidemiologist in the division of Healthcare Quality Promotion at the CDC in Atlanta.

A population-based surveillance project conducted in Georgia, Maryland and Minnesota in 2001 and 2002 found that rates of community-acquired MRSA ranged from 8% to 20% among all MRSA isolated in the population. “Although these are very significant proportions, the lion’s share of MRSA still appears to be health care–associated, at least during the period of this surveillance,” Jernigan said.

Of those isolates deemed to be community-associated, about 78% were felt to be clinically relevant. “Most of it was skin and soft-tissue disease,” Jernigan said. “There was a low incidence of invasive disease.” However, 25% of patients who had community-acquired MRSA deemed clinically relevant were hospitalized for MRSA disease. “One might hypothesize the physicians’ decisions to admit these patients were influenced by knowledge that they were dealing with a resistant organism, but this is unlikely because 92% of the admissions occurred within two days or less after the specimen was actually collected, and in most cases MRSA reports would not have been available to the clinician within that time frame. This suggests that most of these patients were admitted based upon the clinical severity of the infection rather than on the basis of a culture report,” Jernigan said.

Community-associated MRSA isolates tended to be more susceptible to antimicrobials. “We observed a high level of susceptibility to many of the non-ß-lactam antibiotics,” Jernigan said. Of the isolates that were SCC mec typed, 76% of health care-associated isolates were found to have SCC mec type 2. “The community-associated MRSA strains were very different: 82% had SCC mec type 4,” Jernigan said. “Clearly, these community-acquired isolates seemed to have a very different origin than what was circulating in the hospitals at the time.”

As for toxin profiles, PVL was much more prevalent among the community-associated MRSA isolates. “Generally, there were fewer toxins identified among the health care–associated MRSA isolates,” Jernigan said.

Populations at risk

Recent outbreaks of community-associated MRSA have occurred in and among sports teams, prisons, men who have sex with men, military recruits, day care centers and Native Americans.

When an outbreak of MRSA infection occurs, CDC officials urge that an epidemiologic assessment should be initiated to identify risk factors for MRSA acquisition in the institution; and that physicians should save clinical isolates of MRSA and submit them for strain typing.

“Colonized or infected patients should be identified as quickly as possible, appropriate barrier precautions should be instituted, and handwashing by medical personnel before and after all patient contacts should be strictly adhered to,” CDC officials note on their Web site. All health care personnel should be reinstructed on appropriate precautions for patients colonized or infected with multiresistant microorganisms and on the importance of handwashing and barrier precautions in preventing contact transmission.

In an outbreak at a state prison in Mississippi in 2000, there were 59 cases of skin and soft-tissue infection. “These were significant infections,” Jernigan said. “But after being evaluated, only half of these patients had a recommendation to cover or dress their wounds. And among those patients, 90% were given no help or guidance in changing the dressings. They were expected to perform dressing changes themselves or with assistance from other inmates.” In addition, 89% of these patients admitted to sharing personal items that were potentially or known to be contaminated with pus (linens, pillows, tweezers). “It is not hard to imagine how MRSA might be transmitted very rapidly in a prison setting,” Jernigan said.

Similarly, an outbreak investigation among a professional football team found frequent towel sharing in the locker room (an average of three people per towel) as well as suboptimal hand hygiene, skin-abrasion management and environmental cleaning. “In this group, antimicrobial use was also very prevalent,” Jernigan said. The average number of antibiotic prescriptions per person per year for the team was 2.6. “This is statistically significantly higher than for the general population,” Jernigan said.

In the future, Jernigan believes that “the sort of clear distinction between the strain characteristics of health care- and community-associated MRSA may begin to blur. I think we will see more and more overlap in strain type between the different epidemiologic associations.” There are recent reports describing nosocomial transmission of community-associated strains among postpartum women in the neonatal ICU and surgical site infections following orthopedic surgery for prosthetic devices.

For more information:

• Daum RS, Jernigan JA. Methicillin-resistant Staphylococcus aureus in the community: infection control strategies. Presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. Oct. 30–Nov 2, 2004. Washington.