Searching for weapons in the war on MRSA

Vancomycin hasn't had it easy. First developed in the 1950s, the drug was widely ignored for the first 30 years of its existence. Then, in the early 1980s, its heyday began.

“Use really took off at that point, fueled by the twin epidemics” of Clostridium difficile and methicillin-resistant Staphylococcus aureus (MRSA), said James C. Pile, FACP, interim division director of hospital medicine as well as an infectious diseases specialist at Case Western Reserve University/MetroHealth Medical Center in Cleveland.

Dr. Pile spoke about the latter epidemic—MRSA—and its treatment options, especially vancomycin, during the Society of Hospital Medicine's annual meeting. A decade ago, vancomycin was considered a reasonably effective treatment for MRSA, but times have changed, according to Dr. Pile.

“In 2010, we are lot less sanguine about the performance of vancomycin for serious MRSA infections. In fact, vancomycin is really in rough seas, with some experts saying the era of vancomycin as the primary therapy for MRSA infections is over, or at least rapidly passing,” Dr. Pile said.

Resistant strains pose challenge

One of the main concerns has been the emergence of resistant types of S. aureus, known as VISA (vancomycin-intermediate) and VRSA (vancomycin-resistant). “Fortunately, both of these have been very uncommon to date, although that could change in coming years. A bigger problem is heteroresistance,” said Dr. Pile. Unfortunately, there's no way to watch for heteroresistance (in which subpopulations of a MRSA isolate that appears sensitive are actually resistant) because current lab technology doesn't pick it up.

What labs should be able to do is provide accurate minimal inhibitory concentrations (MICs), assuming that they're using the latest technology. Otherwise, hospitalists should be suspicious of the findings. “The reported MIC may actually be an understimate, if it's not determined by E-testing or other state-of-the-art methods,” said Dr. Pile.

Getting an accurate MIC matters because the number predicts the likelihood of treatment failure with vancomycin; one study found that rates ranged from 20% failure at an MIC of 0.5 to 50% at an MIC of 2 (which is still considered sensitive). “If your lab is still giving an R or S only for vancomycin sensitivity, you really need to hold their feet to the fire and insist they give you the actual MIC,” said Dr. Pile.

Once you've got the MIC, you can dose the medication. Dr. Pile, citing guidelines published jointly in Clinical Infectious Diseases and the American Journal of Health-System Pharmacy last year, called for getting fairly aggressive.

“The authors said traditional doses of vancomycin are almost certainly insufficient in most cases of serious MRSA infection. The guidelines also made the formal recommendation to shoot for troughs of 15 to 20 [mcg/mL]. A lot of us have been doing this for the past few years anyway,” Dr. Pile said.

Evidence is still lacking, but the guidelines, based on expert opinion, call for patients with normal renal function to get an initial dose of 15 mg every 8 hours or 20 mg every 12 hours; for critically ill patients, a loading dose of 25 to 30 mg may be considered. “We need to avoid troughs less than 10 mcg/mL because there's a growing sense that this has helped to drive tolerance,” said Dr. Pile.

However, the downside of these higher doses is greater risk of side effects. “Multiple studies over the last several years have shown that, especially with the higher vancomycin troughs we're shooting for, there almost certainly is significant nephrotoxicity,” said Dr. Pile. In addition, he cited a recent study suggesting that older patients who take the drug for two weeks or more face a risk of irreversible ototoxicity.

Clearly, vancomycin leaves room for improvement in the treatment of MRSA. “For an MIC of 2, at least in serious infections, consider choosing another agent,” suggested Dr. Pile.

Alternatives to vancomycin

The only problem is that there's no guidance, and not much evidence, to support agents besides vancomycin. A study in the early 1990s found that trimethoprim/sulfamethoxazole was fairly effective for serious MRSA infections, although arguably less so than vancomycin; Dr. Pile suspects the dynamic may have changed with the emergence of vancomycin tolerance issues. “My own suspicion is that trimethoprim/sulfa today might perform just as well as vancomycin in the treatment of serious MRSA infections,” he said. More research would be helpful, but is unlikely to be of interest to pharmaceutical companies, he noted.

There are almost no data on the other commonly used older drugs, tetracycline and clindamycin. The newer agent daptomycin has shown promise, but its dosing is controversial. “Daptomycin is the one that most of us will initially turn to, if we're concerned about possible or potential vancomycin failure,” said Dr. Pile. “The FDA approved 6 mg/kg once a day. There's been increasing concern that perhaps that's not a high enough dose.” For a deep-seated infection, he increases the dose to 8 mg/kg, he said.

Linezolid is another potential option, and is favored over vancomycin by some clinicians for the treatment of MRSA pneumonia, Dr. Pile said, but he's waiting to see how it does in the ZEPHYR study, which is currently under way. “There's hope that we're going to have definite guidance on the optimal treatment of MRSA pneumonia soon. Until then, we're on our own.”

Telavancin has the advantage of not requiring serum monitoring, but the risk of possibly being nephrotoxic. It's currently awaiting FDA approval for use in nosocomial pneumonia. Tigecycline, on the other hand, has too broad a spectrum for many clinical scenarios, and peak serum concentrations may be suboptimal for serious MRSA infections, Dr. Pile advised.

There is some hope in the pipeline, provided particularly by the fifth-generation cephalosporins. If they prove to provide the type of efficacy against MRSA that beta-lactams have for methicillin-sensitive Staphylococcus aureus, it could be a “game changer,” said Dr. Pile. Ceftobiprole is on the market in Canada, but FDA concerns make its U.S. approval uncertain. Ceftaroline could go on the market here as soon as the coming year, he predicted.

Iclaprim, “a souped-up version of trimethoprim,” is under review by the FDA, and oritavancin, a drug similar to telavancin, is in phase III trials. Finally, carbapenems with MRSA activity show promise, but appear to be farther from commercial availability.

Of course, these drug choice dilemmas would be less pressing if the spread of MRSA could be slowed. At the end of his talk, Dr. Pile reminded hospitalists that an important strategy is basic hand hygiene.

“It seems so simple,” Dr. Pile said. “I think there's a place for us as hospitalists to get involved, to make sure that we're supporting hand hygiene efforts and maybe helping to lead them in our institutions.”