Key Point:

The development of a vancomycin-resistant Staphylococcus aureus strain appears to have resulted from the transfer of a vancomycin resistance gene called vanA from enterococci to staphylococci.

ATLANTA—In June 2002, news quickly broke about the emergence of a strain of Staphylococcus aureus with high-level resistance to vancomycin, one of the few antibiotics left that reliably kills this bacterium. A new study helps explain how this resistance developed.

“Vancomycin has long been the standard fail-safe therapy for S aureus and is the drug most clinicians will turn to for a patient who has a serious infection due to methicillin-resistant S aureus,” said Linda M. Weigel, PhD, of the Centers for Disease Control and Prevention. “Thus, the finding of vancomycin-resistant S aureus was enormously troubling as it further limited the treatment options for these infections to a few antibiotics that are very expensive.”

In an effort to control the problem of emerging antibiotic resistance, Dr. Weigel and her colleagues have been studying the new isolate and recently published a report highlighting the molecular mechanism by which it acquired its vancomycin resistance.[1]

According to Dr. Weigel, one of the study’s lead investigators, the event conferring vancomycin resistance was an interspecies transfer of a vancomycin resistance gene called vanA, which is carried on the transposon Tn1546. The path to uncovering this mechanism began with the identification of three different bacterial strains from the affected patient, a woman who, at the time, was being treated at a Detroit dialysis center:
• A methicillin-resistant but vancomycin-sensitive strain of S aureus (MRSA).
• The new S aureus with both methicillin and vancomycin resistance (VRSA); this strain had been isolated from a foot ulcer.
• A co-isolate from the same foot ulcer, a vancomycin-resistant strain of Enterococcus faecalis (VRE).

Dr. Weigel and her team showed that plasmids isolated from the two S aureus strains were very similar, although the VRSA bacterium was larger than the MRSA organism (57.9 kb vs about 47 kb). They also found that the plasmids from the E faecalis strains (of which there were two distinct types) were constituted quite differently.

Given that Tn1546 is 10.8 kb in size, the math was starting to add up, said Dr. Weigel; she and her team localized Tn1546-associated vanA within plasmid fragments from both the E faecalis and VRSA strains, but not within fragments from the MRSA isolate. Dr. Weigel suggested that within the woman’s ulcer, an enterococcus likely “sidled up” to a staphylococcus and transferred its plasmid, enabling Tn1546 (and with it vanA) to jump from the VRE plasmid to the MRSA plasmid, thus creating the long-dreaded VRSA.

Because no trace of VRE plasmid was evident in the VRSA isolate, it is likely that enzymes within the staphylococci destroyed what remained of the foreign plasmid’s genome. The probability of a cross-species exchange is further supported by additional analyses, which identified both the VRE plasmid and the VRSA plasmid as conjugative plasmids.

“Conjugation is the direct transfer of a plasmid from one bacterial cell to another via cell-cell interaction. In gram-positive organisms such as S aureus, cell surface elements and, in some cases, extracellular peptide signals known as pheromones mediate transfer of DNA. This type of transfer often involves plasmids carrying antimicrobial resistance genes and may occur between organisms of very diverse genera,” Dr. Weigel said.

An alternative, but less likely hypothesis, is that the transposon could have been transferred by transduction. “Transduction, on the other hand, is the transfer of DNA from one bacterial cell to another by bacteriophage.”

Three features of the VRSA strain they studied led Dr. Weigel’s team to describe it as a “triple-threat” microbe. Not only was the organism resistant to vancomycin, its degree of resistance was quite robust. Most S aureus strains with decreased susceptibility to vancomycin have a relatively low minimal inhibitory concentration—somewhere near or below 16 mg/mL. The new strain had a minimal inhibitory concentration of 1,024 mg/mL. “The vanA element encodes enzymes that alter cell wall components that are targets for vancomycin,” thereby making them unrecognizable, Dr. Weigel noted. “This cellular change is a much more efficient mechanism of resistance than the previously reported phenotype, in which a thickened cell wall leads to reduced susceptibility to vancomycin but not to high-level resistance.”

A second concern is that the new strain also exhibited resistance to several other common antibiotics, including members of the aminoglycoside, ß-lactam, and macrolide families. The only antibiotics to which the new strain remains susceptible are linezolid, quinupristin/dalfopristin, and trimethoprim–sulfamethoxazole.

Lastly, the new VRSA bacterium was shown to be capable of sharing its resistance with other S aureus strains.

—Verna L. Schwartz, MS

Reference
1. Weigel LM, Clewell DB, Gill SR, et al. Genetic analysis of a high-level vancomycin-resistant isolate of Staphylococcus aureus. Science. 2003;302:1569-1571.

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