Rust never sleeps: Staph eats away at vanc efficacy
Rust never sleeps: Staph eats away at vanc efficacy
FDA lowers vancomycin breakpoints
The much-feared widespread emergence of vancomycin-resistant Staphylococcus aureus has not occurred, with true VRSA still a rare phenomenon. But perhaps the path to this milestone toward a post-antibiotic era will occur in more incremental steps.
Researchers are finding that vancomycin is "losing potency" against methicillin-resistant S. aureus (MRSA) infections, meaning the time honored antimicrobial may yield to drug resistance in a very different way than originally imagined.1
Vancomycin use has increased dramatically worldwide since the mid-1980s, largely as a result of empirical and directed therapy against burgeoning MRSA infections. With limited choices, clinicians have traditionally relied on vancomycin alone in the management of serious MRSA infections and have enjoyed a significant period free of vancomycin resistance in S. aureus. Even now, five decades after its introduction, vancomycin resistance among S. aureus strains, as currently defined microbiologically, remains rare. "Yet it is becoming clear that vancomycin is losing potency against S. aureus, including MRSA," the authors conclude. "Serious infections due to MRSA defined as susceptible in the laboratory are not responding well to vancomycin. This is demonstrated by increased mortality seen in patients with MRSA infection and markedly attenuated vancomycin efficacy caused by vancomycin heteroresistance in S. aureus. Therefore, it appears that our definition of vancomycin susceptibility requires further scrutiny as applied to serious MRSA infections, such as bacteremia and pneumonia."
As a result of such findings, the Food and Drug Administration recently lowered the vancomycin "breakpoints" for staph infections. The Infectious Disease Society of America reported on its web site that FDA made the move in an updated package insert for a vancomycin injection product; the first of what will apparently be new cut-point labeling for all vancomycin meds. The minimum inhibitory concentration (MIC) (µg/mL) has been lowered from ≤ 4 to ≤ 2 for susceptible; from 8-16 to 4-8 for intermediate; and ≥ 32 to ≥ 16 for resistant. The change follows mounting evidence that patients infected with S. aureus strains with MIC of 4 µg/mL were failing therapy. Robert C. Moellering Jr., MD, FIDSA, past president of IDSA and lead author of the aforementioned paper, explained the situation to Hospital Infection Control.
"The old breakpoints were set at a time when there was no resistance [to vancomycin] and there were no failures," said Moellering, physician-in-chief and chairman of the department of medicine at the Beth Israel Deaconess Medical Center in Boston. "People began noticing a lot of things that were occurring. [For example], the old breakpoints had 8 and 16 MIC as being intermediate, when it was clear that organisms were essentially resistant and then [patients] failed therapy."
Cases of vancomycin-intermediate S. aureus (VISA) began occurring in the United States in the mid-1990s after first being reported in Japan. In 2002, a sci-fi scenario researchers had long feared occurred when vancomycin-resistant genetic material from a coinfecting enterococci strain to S. aureus within a patient, creating the first clinical strain of a much-anticipated superbug: VRSA. These strains continue to be reported sporadically, but did not emerge and flourish as feared — all the while though vancomycin was losing efficacy at the lower end of the scale.
"There were a bunch of strains they began calling hetero-VISA strains, which MICs that were susceptible but when you tested them in the laboratory they had numerous small colonies, subpopulations for which the MIC was a lot higher," Moellering says. "They also were beginning to fail therapy. There has also been what is called 'vancomycin creep,' that is that the minimal inhibitory concentration of vancomycin as far as the strains in the susceptible range have been going up imperceptibly. As those MICs go up, more and more of those become heteroresistant as well."
The upshot of the revised breakpoints is "that vancomycin should no longer be used to treat organisms that have a MIC of 4," he adds. "Now it turns out there are not a huge amount of MRSA strains floating around that that have vancomycin MICs of 4. So changing the breakpoints doesn't have a gigantic impact, but people are re-looking at it now because there is even a question of whether they ought to drop it one more set of dilutions, i.e., down to 2. When you start getting strains with MICs as high as 2, there are a lot of them that are heteroresistant that don't show it by standard testing in the clinical lab, but for which vancomycin is clinically less effective."
There are other drug alternatives, but gradually losing the old mainstay against MRSA is none the less discomforting. "Right now because testing for heteroresistance in particular is so difficult, many clinicians haven't really caught on to the fact vancomycin is losing its efficacy up front," Moellering says.
The incremental resistance is occurring through a number of genetic changes in staph strains. "It is not one simple mutation," he says. "Some of them lead to cell wall thickening, some may allow the organism to become tolerant to vancomycin, so it inhibits but doesn't kill it. Some of these changes actually lead to decreased virulence in these organisms, which is why you see patients who have prolonged vancomycin-resistant staph or MRSA and don't die."
Reference
- Sakoulas G, Moellering RC. Increasing antibiotic resistance among methicillin-resistant Staphylococcus aureus strains. Clin Infect Dis 2008; 46: S360-S367.
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