Hospitalists try to figure out how to make the best of a flawed antibiotic by Deborah Gesensway
Published in the May 2007 issue of Today's Hospitalist.
In a packed room at a recent meeting of the Infectious Diseases Society of America (IDSA), a leading infectious diseases expert took a hard-line position on vancomycin during a debate on the drug.
"Current antibiotics have vanquished vancomycin," he told the audience. He went so far as to say that the 50-year-old antibiotic compound "is a weak stick for all of us."
The problem is that not only does vancomycin kill bacteria slowly and penetrate tissues poorly, but resistance to it is growing. That resistance can be widespread, as in the case of vancomycin-resistant
"Compared to 10 or even five years ago, I use vancomycin much more as first-line therapy."
–Lakshmi Halasyamani, MD St. Joseph Mercy Hospital
enterococci (VRE), or it can be rare, as in the new strains of methicillin-resistant Staphylococcus aureus (MRSA) that are either less sensitive or entirely resistant to the drug.
Despite those problems, however, reliance on the drug is clearly on the rise among front-line physicians. Far from being vanquished, vancomycin is more firmly entrenched in physicians' antibiotic arsenals than ever. In part, that's because many hospitalists find themselves turning to the drug more frequently when confronted with very sick patients whose skin and soft tissue infections, pneumonia, endocarditis, epidural abscesses or bacterimia may be caused by MRSA.
"No one now would fault you for starting vancomycin first-line for a sick enough patient," says Lakshmi Halasyamani, MD, a hospitalist and vice chair of the department of internal medicine at St. Joseph Mercy Hospital in Ann Arbor, Mich. "Compared to 10 or even five years ago, I use vancomycin much more as first-line therapy."
Although Dr. Halasyamani says she worries that making vancomycin her go-to drug could lead to "problems for the future," she is quick to add that she doesn't see any alternative. It's the classic dilemma: Is your responsibility to the patient in front of you, or to the community at large and a potential future patient for whom treatment may not work?
"We talk about that a lot," notes Scott Flanders, MD, associate professor of medicine at the University of Michigan in Ann Arbor and director of its hospitalist program. "Regardless of resistance, I have to treat the patient in front of me, so the pendulum seems to be shifting toward a lower threshold for using vancomycin."
Infectious diseases experts warn, however, that the way vancomycin is now being used may contribute to new resistance that could make MRSA even harder to treat. They also question whether doctors are using the drug against organisms without susceptibility and ordering it at dosage levels too low to work. Those problems could ensure the drug's legacy as a "weak stick" that prolongs patient suffering.
Although community-associated MRSA was nearly unheard of before the late 1990s, the organism is now widespread. Contrary to initial opinion, community-associated MRSA is now known to be a completely different strain of MRSA than the much older health care-acquired strain.
Although community-associated MRSA was first believed to infect only specific populations, including prisoners and others in close proximity, the organism is now found among all population groups, including healthy young people and children. A study in the Aug. 17, 2006, New England Journal of Medicine found that MRSA was a common, identifiable cause of skin and soft tissue infections among patients presenting to emergency departments in 11 U.S. cities, accounting for about 60% of all isolates.
So far, at least, data on the intersection between MRSA and vancomycin have been relatively good. According to the Centers for Disease Control and Prevention (CDC), only 16 cases of infection caused by vancomycin-intermediate S. aureus (VISA and heteroVISA) and six cases of vancomycin-resistant S. aureus (VRSA) had been reported in the U.S. as of April 2006.
But despite those data, the future is grim. "There is no question that vancomycin is losing its effectiveness because of the development of resistance among MRSA strains," says Robert C. Moellering Jr., MD, a Harvard Medical School professor and infectious diseases specialist at Beth Israel Deaconess Medical Center in Boston. The handful of lethal VRSA cases seen already could portend a future dominated by incurable deadly bacteria.
The comeback kid
For physicians who have been around, the growing concern over vancomycin may seem like a flashback of sorts. It wasn't all that long ago, after all, that the drug appeared to be headed toward the pharmaceutical dustbin.
When vancomycin was first approved, the drug's high expectations were quickly dashed because of concerns about potential toxicities.
"There was always the impression that this was the big gun," said Donald P. Levine, MD, professor of medicine and infectious diseases at Wayne State University in Detroit. The reality, however, was that vancomycin was physicians' only gun—and a "puny" one at that, he says.
That's because while vancomycin has long been considered the gold standard for treating many MRSA infections, it's far from perfect. In addition to low cure rates and many failures, it is burdensome to use because it is an IV-only drug.
Only a decade ago, in fact, few wanted to extend the drug's useful life. At that time, the CDC and others were promulgating guidelines aimed at reducing vancomycin use. Experts were rightly concerned that VRE had the potential to spread its resistance from enterococci to other pathogens, in particular to S. aureus.
Several CDC reports in the mid-1990s contained recommendations for controlling the spread of vancomycin resistance. But then came the rapid spread of community-associated MRSA.
"With that being such a moving target, many institutions that had been aggressive about restricting vancomycin use have had to relax a little bit," says James Pile, MD, a hospitalist and infectious diseases specialist at MetroHealth Medical Center in Cleveland.
Although several alternatives to vancomycin have emerged in the last decade, there's little proof that most work better against various MRSA-related illnesses.
The handful of head-to-head comparison studies of linezolid (Zyvox) and daptomycin (Cubicin) for several different MRSA infections have not shown clear superiority. Some suspect linezolid may penetrate lung tissues better than vancomycin and therefore should be used in MRSA pneumonia cases.
Meanwhile, daptomycin may be better for patients with bacterimia or endocarditis. Another New England Journal of Medicine study in the Aug. 17, 2006, issue concluded that daptomycin was "not inferior to standard therapy for S. aureus bacteremia and right-sided endocarditis."
However, each alternative has downsides, whether it's IV-only dosing (daptomycin) or toxicities and severe side effects such as low platelet counts and bone marrow suppression (linezolid). A third alternative—quinupristin/dalfopristin (Synercid)—is even more difficult to use because it is best infused through a central line and can cause debilitating myalgias and arthralgias.
"All these other drugs are quite expensive," adds Daniel Kaul, MD, assistant professor in the infectious diseases division at the University of Michigan. "They may turn out to be better than vancomycin, but at this point, for the average case, they have not been proven to be superior. And overuse of some of the newer drugs is already leading to significant rates of resistance."
With the absence of evidence showing a better alternative, "there is the argument that vancomycin doesn't work all that well, but at least it doesn't break the budget," adds Dr. Levine. "That's the reality." Several other drugs that, in testing, seem to work against vancomycin-resistant staph are in the development pipeline, says Harvard's Dr. Moellering, including other glycopeptides—such as televancin and oritavancin—and cephalosporins, including ceftobiprole and ceftaroline. They may be approved by the FDA for clinical use within the next two years, he says.
How to make do
Until a better alternative appears or the bacteria evolve further, clinicians need to make the best of the flawed antibiotic, and experts are now scrambling to figure out how to do just that.
A Jan. 1, 2006, supplement of the IDSA's journal Clinical Infectious Diseases was devoted to the topic of vancomycin, and several consensus panels are now working on papers to advise clinicians on how to use vancomycin and how to best treat community-associated MRSA.
But Dr. Levine, who sits on one of these panels, says experts still have a long way to go before they can offer clinicians concrete help. The only consensus so far, he claims, is that "we really need to stop using vancomycin the way we have been using it."
Cleveland's Dr. Pile suggests that "we compound the problem when we don't use the drug at the correct dosage." "In the past, we tended to underdose vancomycin, and we used a one-size-fits-all dose in patients with more or less normal renal function," he points out. Over the last several years, "we have gained a better sense that it needs to be dosed based on weight, and we need to be shooting for more aggressive levels."
Evidence for this is mixed, however, with at least one article in Chest in October 2006 concluding that "aggressive dosing strategies for vancomycin may not offer any advantage" for patients with MRSA health care-acquired pneumonia. And very little data exist to help physicians understand the relationship between vancomycin serum levels and treatment outcome.
"What to measure, when to measure and what is the relevance of those measurements?" Dr. Levine says are all areas that need investigation. "What predicts outcomes better: trough levels, peaks, under the curve?" The various consensus panels convening on this topic, he adds, "are trying to sort that out."
Testing for susceptibility
Another reason vancomycin may not help cure patients with MRSA infections as quickly or as effectively as needed, says Beth Israel's Dr. Moellering, is because clinicians may not understand that some of the organisms infecting the patient may be somewhat—or totally—resistant to vancomycin.
Although VRSA is extremely rare, heteroVISA and VISA are less so. The way most clinical laboratories test for susceptibility is not sensitive enough to show that type of resistance, many experts now believe, because tests do not regularly report minimum inhibitory concentrations (MICs). Nor do labs do the more sophisticated testing needed to demonstrate heteroresistance.
"Knowledge of the therapeutic concentration and MIC of the pathogen might overcome the intrinsic deficiencies of the drug and improve its utility," Dr. Levine wrote in an article in the 2006 Clinical Infectious Diseases supplement on vancomycin. "A return to monitoring serum levels, a practice almost abandoned long ago … might extend the useful life of this antibiotic."
Meanwhile, clinicians on the front lines are struggling with how to reduce use of a worrisome antibiotic, while still providing the best care for sick patients.
Michigan's Dr. Flanders says that hospitalists often find themselves treating patients who received oral levofloxacin or cephazolin from their doctor two days ago and are now in the ER because their skin infection is getting worse.
With cellulitis hard to culture, "we often are left wondering, 'Are they not getting better because they need an IV drug instead of an oral
drug? Do they need to have their foot elevated? Or is this community-associated MRSA and we have the wrong drug?' " Dr. Flanders explains. "Often we are stuck with giving them vancomycin, and we don't know if we are giving them unnecessarily broad and potent IV antibiotics."
Deborah Gesensway is a freelance writer who reports on U.S. health care from Toronto, Canada.
Getting the most mileage out of vancomycin
If vancomycin is here to stay—at least until the next chapter of its long history is written—then infectious disease experts recommend using it as judiciously as possible.
The biggest problem, they say, is that vancomycin is still used when it is not needed. While patients hospitalized for serious infections that may be caused by methicillin-resistant S. aureus (MRSA) may need vancomycin, experts stress the need to determine susceptibilities as quickly as possible and to change drugs accordingly.
To do so, experts recommend the following strategies:
● Culture all you can. Hospitalists need to become adept at taking tissue cultures, experts say. And while skin abscesses were rarely cultured in the past, "it has become important to do that now," says James Pile, MD, a hospitalist and infectious diseases specialist at MetroHealth Medical Center in Cleveland.
● Speed is of the essence. Treating a patient with a severe pneumonia with the wrong antibiotic for 48 hours is bad for the patient as well as for the community.
To that end, the VA Medical Center in Pittsburgh, Pa., as part of a project to identify all cases of MRSA that come into its facility, has invested in technology that can analyze swabs from the nose or from any open wound by fast PCR testing, rather than slower culturing. "We run that twice a day, so that usually we get same-day results, as opposed to 48 hours later," said Robert Muder, MD, the center's chief of infectious diseases. The results are used to isolate patients with MRSA and, if findings show that the bug causing the infection is not methicillin-resistant, "then we can change the patient over quickly from vancomycin to a beta-lactam."
● Treat as briefly as possible. "We have a tendency to treat for too long," says Daniel Kaul, MD, assistant professor of infectious diseases at the University of Michigan in Ann Arbor. For example, he points out, most cases of hospital-acquired pneumonia can be treated for eight days, and "we used to treat for as long as three weeks."
● Get your lab to make changes. Experts say that labs need to lower the breakpoint for routinely reporting minimum inhibitory concentrations (MICs). Although "strains with an MIC of 4 often are heteroresistant and fail vancomycin therapy," says Robert C. Moellering Jr., MD, an infectious diseases specialist at Boston's Beth Israel Deaconess Medical Center, new information indicates that even lower MICs will contain resistant subpopulations as well. That may explain why some patients, whose organisms are thought to be susceptible, don't do as well as expected.
● Pay attention to proper dosage. "The standard dosing regimen worked perfectly well" in the past, but "as the MICs have edged up, you probably need higher doses of vancomycin to achieve the same ends," Dr. Moellering says. Debate continues, however, over whether higher doses will achieve better results and not be too toxic to patient's kidneys.
● Change to a more narrow spectrum drug as quickly as possible. In culturing all infections, you need to quickly determine whether the S. aureus causing the illness is methicillin-resistant or methicillin sensitive (MSSA). "Vancomycin clearly is inferior to the beta-lactams for treating serious MSSA infection," Dr. Pile says. "You need to switch the patient to a more appropriate choice if the isolate proves to be methicillin-sensitive."