March 2010

Keeping MRSA in check: Are you doing enough?

Marc Ginsburg, DPM, of Albany, NY, examines a patient with diabetes who underwent amputation following an MRSA infection. Photo by Dino Petrocelli (www.dinopetrocelli.com). All other photos courtesy of Jeffrey Ross, DPM, MD.

The spread of methicillin-resistant Staphylococcus aureus has clinicians, especially those who treat patients with diabetes, rethinking the way they practice. Experts offer tips for treatment and prevention, starting with what not to wear.

by Cary Groner

Before he visits inpatients at Ben Taub Hospital in Houston, Jeffrey Ross, DPM, MD, usually doffs his jacket and his tie, then puts on latex gloves. Ross, chief of the hospital’s diabetic foot clinic, also wears surgical greens almost all the time he’s in his office. Doctors in the U.K. are adapting to a new dress code promulgated in 2007 by health secretary Alan Johnson, instructing them to get rid of long-sleeved shirts and lab coats, and lose their neckties to boot.1 They can still wear bow ties if they insist on having something around their necks other than a stethoscope, however.

At the University of Arizona Medical Center in Tucson, David Armstrong, DPM, MD, PhD, isn’t quite ready to give up his tie, but he acknowledges the day may be coming. Armstrong, a professor of surgery at the UA College of Medicine and director of the Southern Arizona Limb Salvage Alliance, does, however, put on a disposable paper gown almost every time he goes into a patient’s room.

What’s driving these changes in physician fashion isn’t a sudden shift toward informality or a dictate from a diva designer in Paris. It’s a tiny pathogen known as methicillin-resistant Staphylococcus aureus, or MRSA, which has spread swiftly from the hospitals in which it arose to communities around the world. In healthy people, the bacterium usually poses no great threat. But to those with compromised immunity or other health problems, and those recovering from surgery, it can be lethal.

Hence the change in the hospital dress code: in one study, six of 40 physician’s neckties (15%) carried a substantial concentration of S aureus and one was colonized with MRSA.2 Given that doctors reported that they washed their ties an average of twice a year, a surprising new vector for disease was uncovered literally under their noses.

Scary numbers

In 2007, researchers reported in the Journal of the American Medical Association3 that almost two-thirds of hospital-acquired S aureus infections in U.S. intensive-care units had become methicillin resistant by 2003; the percentage has likely climbed since then. The same study found that community-acquired (CA) MRSA, a distinct strain, had become the most frequent cause of skin and soft-tissue infections presenting to emergency departments. In 2005, there were roughly 94,360 invasive MRSA infections in the U.S., and 18,650 of those cases (20%) were fatal. What’s more, given that only about 7% of MRSA infections are considered invasive, these statistics suggest that there may be as many as 13.5 million overall MRSA infections annually in this country alone.

As a result, the changes sweeping hospitals around the world go far beyond the sartorial. They include infection control measures, a close look at decisions about prescribing antibiotics, and innovative approaches to debriding wounds.

The medical community has also responded by developing and publishing a variety of treatment protocols—though application of them is, so far, uneven. One reason is that MRSA rates vary widely by geographic region. The JAMA paper reported that between 2001 and 2005, the incidence of invasive MRSA in Atlanta grew from 19.3  to 33 per 100,000; in Baltimore incidence rose from 40.4 to 116.7 per 100,000; but in Connecticut, by contrast, the rate rose from a mere 2.5 per 100,000 in 1998 to just 2.8 in 2005. Overall, MRSA comprised 50% to 70% of S aureus infections in the U.S. in 2006, according to a study by the Association for Professionals in Infection Control & Epidemiology.4 Clinicians interviewed by LER said that percentage is almost certainly higher in many areas by now.

Statistics about the proportion of S aureus that is methicillin resistant show similarly wide variation worldwide. In Europe, between 1999 and 2002, the percentage ranged from a high of 48.6% in Greece to a low of 0.2% in Norway, with most countries hovering in the 20th-percentile range.5

Such drastic differences explain why treatment protocols are applied unevenly; they also point to the efficacy of strict infection control and antibiotic prescribing protocols implemented early in Scandinavian countries, to which other countries are now playing close attention.

“We’re washing down rooms a lot more than we used to,” Ross said. “We now keep a red bucket so we can dispose of anything that might pose a risk: not just sharps, but Q-tips and gauzes, so there is no exposure.”

MRSA and diabetes

MRSA presents a particular danger to diabetes patients because diabetes itself impairs immunity, and comorbidities such as neuropathy and peripheral vascular disease drastically increase the risk for, and severity of, foot ulcers that may be colonized by MRSA. Dreaded sequelae include amputation and death.

Up to a quarter of diabetes patients will develop foot ulceration during their lives,6 and more than 70,000 amputations are performed in these patients annually in the U.S.7 This risk is up to 30 times greater than that of amputation in nondiabetic people.6 In response to this threat, the Infectious Disease Society of America (IDSA) has published comprehensive, PDA-downloadable guidelines for assessing and treating these infections.8

“Between twenty and thirty percent of our hospital’s diabetic foot infections are colonized with MRSA,” said Sandra Nelson, MD, an instructor of medicine at Harvard Medical School who practices at Massachusetts General Hospital. Nelson published a paper last year outlining a comprehensive approach, similar to the IDSA’s, for managing diabetic foot infections given the rise of microbial resistance.9 The article emphasizes both prevention  and treatment along the following lines:

“The prevalence of MRSA affects our empirical management because we have to consider the possibility that it’s present before we have culture data,” Nelson explained. “This is particularly true in patients with higher risk factors—if they’ve been in the hospital, if they have had a lot of antibiotics without improvement, if they’ve had MRSA in other settings.”

Antibiotic regimens

The increase in MRSA has led to modifications in antibiotic therapy. In her practice at Mass General, Nelson favors starting with vancomycin, though she always gets an MIC from the lab first.

MIC, or “minimum inhibitory concentration,” is the lowest concentration of a given antibiotic that will kill or disable the target organism in vitro. According to Warren Joseph, DPM, author of the Handbook of Lower Extremity Infections, part of the problem with vancomycin for treating MRSA is that over the past 10 years this number has risen from roughly 0.5 mcg/ml to 1 mcg/ml, and in some cases to 2 mcg/ml, which means ever-higher doses of the drug must be given to achieve the same result, increasing the risk of side effects.10

If factors such as the pathogen’s MIC or a patient’s hypersensitivity suggest other drugs, Nelson goes first to daptomycin, then to linezolid.

“I use the primary agents for about six weeks, then sometimes extend the course with an oral drug, usually doxycycline or sulfa,” she said.

Do tissue concentrations matter?

Recently, researchers have proposed that factors other than MIC creep may influence a given antibiotic’s effectiveness in diabetes patients. A paper published in January suggests that too little is known about the effect of diminished concentrations of antibiotics in the ischemic tissue of the diabetic foot.11 The authors note that impaired peripheral circulation affects these values, and that the pharmacokinetics and pharmacodynamics of orally administered drugs are altered in diabetes patients.

Among drugs commonly prescribed for MRSA, for example, the ratio of site to serum concentration was 68% for daptomycin, 40% for telavancin, 74% for tigecycline, 104% for linezolid, and 37% for sulfamethoxazole. The authors concluded that “an understanding of the pharmacokinetics of the therapeutic agents under consideration are essential components in the effective management of infection in the diabetic population.”

Other experts were uncertain about the relevance of such findings, however.

“It makes sense that a drug without good tissue penetration would work less well in vivo, but there are really no data to guide us and this hasn’t translated yet into clinical practice,” Armstrong said. “Better tissue penetration may help, but it’s not going to be the thing that causes someone to decide on one agent versus another.”

Kevin Grimes, MD, MPH, an infectious disease specialist at Methodist Hospital in Houston, agreed.

“I don’t think this kind of data will affect prescribing patterns,” he said. “What influences those decisions are the susceptibility patterns of the organisms, ease of administration, and cost.”

Ross pointed out another problem—that there is so much variation in the peripheral circulation between diabetes patients that there may be no such thing as “average concentration” in their tissues.

“The question is, which drug is going to kill better? Which has a better MIC value? You have to look at the patient, the comorbidities, and the costs,” Ross said.

Research in Austria, however, suggests that issues related to tissue penetration warrant further attention. Scientists there studied vancomycin penetration in diabetic and nondiabetic patients after cardiac surgery. They found that the median concentration was about 10% in patients with diabetes and 30% in those without diabetes, and concluded that “vancomycin penetration into target tissues is substantially impaired in diabetic patients…[and] insufficient tissue concentrations could therefore possibly contribute to failure of antibiotic treatment and the development of antimicrobial resistance in diabetic patients.”12

Pharmacy management and costs

Although physicians frequently cite cost considerations in decisions about antibiotic therapy, Armstrong pointed out that figuring out costs is more complicated than it may seem.

“Linezolid is an expensive drug, but it comes out cheaper than vancomycin if you add in all the other things like a peripherally inserted catheter and the potential complications associated with that,” he said. “Patients hate having a line in their arm, so it’s nice to give them an oral agent [e.g., linezolid] rather than a parenteral one if we can.”

Out of concerns about resistance, Armstrong’s colleagues in infectious disease dislike it when clinicians dole out linezolid too often. Armstrong respects this concern, but he finds it frustrating to be constrained by insurance companies when he feels a certain drug is the right one for a patient.

“We have to have targeted treatment and common sense mixed in with clinical acumen, and that’s what will win the day,” he said.

Research suggests one reason linezolid may be a popular MRSA drug for many years despite the cost, however; after almost 10 years of clinical use, the current resistance rates of MRSA to the drug remain at a very low 0.03%.13 Of course, it’s a question of the chicken and the egg: are resistance rates low because of some inherent characteristic of the drug, or because linezolid has been managed so carefully? The jury is out.

Vital collaboration

Most podiatrists and orthopedists stress the importance of collaboration when making decisions about treating diabetic foot ulcers.

“We need to be cautious and work closely in a team approach,” Ross said. “Our infectious disease doctors are really important to us, as are our endocrinologists and vascular specialists. We need them not only to evaluate the patient during the course of treatment but to prevent recurrence.”

Michael Pinzur, MD, professor of orthopedic surgery and rehabilitation at Loyola University Medical Center in Maywood, IL, agrees.

“If a diabetic has a superficial foot infection that I can’t get good cultures on, I’ll treat with a first-generation cephalosporin,” he said. “But if it’s anything of any complexity—a Wagner Grade 3 or higher—they are going to the operating room for surgical debridement and to obtain tissue culture specimens. At that point it’s best to work with an infectious disease specialist to establish whether there are appropriate oral choices, or whether they need parenteral antibiotics.”

Pinzur emphasizes the importance of basing such decisions on the best available evidence.

“You have to be careful about what is opinion and what is evidence-based,” he said. “In Columbus’s day, the smartest people in the world said the world was flat. Diabetes patients with severe foot infections are very sick, and that ulcer can be the first step in a spiral that puts them in the grave.”

Reevaluations

In areas with high MRSA rates, physicians are reevaluating longstanding approaches to empirical antibiotic therapy.

“You can’t always go with risk factors anymore,” said Warren Joseph, who is also a consultant for lower extremity infectious diseases at Roxborough Memorial Hospital in Philadelphia.

At Roxborough, almost all staph infections are now MRSA, but clinicians can still be surprised. Joseph recently had a previously healthy 36-year-old with no history of hospitalizations or antibiotic use present with MRSA; in the same week, an 85-year-old nursing home patient came in with a susceptible strain of S aureus.

“I mean, come on!” exclaimed Joseph. “The risk factors from just five years ago don’t apply anymore.”

As a result, Joseph has shifted from escalation to de-escalation therapy. In escalation therapy, the physician chooses the narrowest spectrum antibiotic against the organism suspected of causing the infection. Until recently, Joseph wouldn’t have included MRSA in that list, figuring he could always add an antibiotic if MRSA cultured out.             All that’s changed: now he starts the vast majority of patients as if they have MRSA and then de-escalates if cultures show they don’t have it.

Other aspects of his practice haven’t altered much, however.

“If I’m considering a minor debridement and learn that my patient has MRSA, do I have to consider a more major debridement?” he asks. “No. I think that the basics of good surgical incision, drainage, and debridement are going to hold no matter what the organism is. MRSA has virulence factors you need to be concerned about, but just because you have it doesn’t mean you’re doomed to a worse outcome.”

Yes, maggots

The severity of diabetic foot wounds has led to a few surprising therapeutic approaches. Joseph reported that occasionally patients will present with wounds so neglected that they are infested with maggots.

“In those cases, believe it or not, the wound always looks wonderful,” Joseph said. “When you clear the maggots away, it’s nice and clean.”

The reason, of course, is that maggots are naturals at debridement; they eat dead tissue and leave the rest intact. A British study14 found that larval therapy eliminated MRSA colonization in 12 of 13 (92%) patients with diabetic foot ulcers, most of which were neuroischemic. Mean therapy duration was 19 days, far shorter than the average 28-week duration for conventional MRSA decontamination in such ulcers.

This capability has not gone unnoticed at other medical centers. At the University of Arizona, David Armstrong and his team have been using medical maggots to debride wounds for a more than a decade.

“They complement our surgical debridement very well,” he explained. “We use them in patients when we are unable to keep up with the amount of debridement we need to do, or in frail patients we can’t aggressively debride. They’re a stopgap and they do a phenomenal job.”

Armstrong laughingly describes his team as “larvaephilic,” noting that the patients, who become familiar with the benefits of the process firsthand, are often less grossed out by the creatures than the doctors and nurses are. The bugs also offer advantages over medical students, Armstrong noted.

“Maggots don’t complain, they don’t need insurance, there are no OSHA considerations, they work 24/7, and you don’t have to teach them anything,” he joked. “Also, after three days, you can kill them, which we can’t legally do with our medical students in Pima County.”

Remaining challenges

Levity aside, however, Armstrong emphasized that MRSA in diabetic foot wounds is associated with increased morbidity, extended hospital stays, higher costs, and elevated amputation rates. Although clinical protocols are adapting to the evolution of this challenging pathogen, clinicians will need to remain vigilant.

Cary Groner is a freelance writer based in Northern California.

References

1. Barbieri RL. The hospital has a new dress code for its vectors – er, doctors. OBG Management 2008;20(11):6-8.

2. Ditchburn I. Should doctors wear ties? J Hosp Infect 2006;63(2):227–228.

3. Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 2007;298(15): 1763–1771.

4. Jarvis WR, Schlosser J, Chinn RY, et al. National prevalence of methicillin-resistant Staphylococcus aureus in inpatients at US health care facilities, 2006. Am J Infect Control 2007;35(10):631-637.

5. MRSA: Statistics in UK and Europe. Available at www.privatehealth.co.uk/hospitaltreatment/treatment-abroad/mrsa-europe. Accessed Feb. 24, 2010.

6. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA 2005;293(2):217–228.

7. NIDDK. National diabetes statistics, 2007. Available at http://diabetes.niddk.nih.gov/DM/PUBS/statistics. Accessed Feb. 24, 2010.

8. ISDA guidelines on diagnosis and treatment of diabetic foot infections. Available at www.idsociety.org/Content.aspx?id=5908. Accessed Feb. 24, 2010.

9. Nelson SB. Management of diabetic foot infections in an era of increasing microbial resistance. Curr Infect Dis Rep 2009;11(5):375–382.

10.  Steinkraus G, White R, Friedrich L. Vancomycin MIC creep in non-vancomycin-intermediate Staphylococcus aureus (VISA), vancomycin-susceptible clinical methicillin-resistant S. aureus (MRSA) blood isolates from 2001-05. J Antimicrob  Chemother 2007;60(4):788-794.

11.  Nicolau DP, Stein GE. Therapeutic options for diabetic foot infections. J Am Podiatr Med Assoc 2010;100(1):52–63.

12.  Skhirtladze K, Hutschala D, Fleck T, et al. Impaired target site penetration of vancomycin in diabetes patients following cardiac surgery. Antimicrob Agents Chemother 2006;50(4):1372–1375.

13.  Joseph WS. Lower extremity handbook of infections companion blog. October 3, 2009. Available at: www.leinfections.com/category/diabetic-foot.

14.  Bowling F, Salgami E, Boulton A. Larval therapy: a novel treatment in eliminating MRSA from diabetic foot ulcers. Diabetes Care 2007;30(2):370–1.

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2 Responses to Keeping MRSA in check: Are you doing enough?

  1. I am interested to know what the Medical Communitty thinks about Patients with diabetes who are being told they are border line.
    In our practice i find they them do not take the disease seriouly.
    We try to stress that they can be supceptible to the same complications.
    Any further advice on how to tackle this issue?

  2. Dwight L. Bates, DPM says:

    If it does not hurt do not expect any patient to co-operate. Dr, Paul Brand said ”the gift of pain” must be present if you will live..

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