Flagship superdrug slams into VRE iceberg
Flagship superdrug slams into VRE iceberg
Patients had perfect scenario’ for resistance
A recent report of emerging linezolid resistance provides a striking profile of the patients most likely to succumb to similar infections in the future, a leading epidemiologist tells Hospital Infection Control.
Hailed last year as the flagship entry of the first new class (oxazolidinone) of antibiotics in 35 years, linezolid is getting a rude welcome from one of its prime pathogenic targets: vancomycin-resistant enterococci (VRE). A recent report in Lancet describes five patients with infections due to linezolid-resistant vancomycin-resistant Enterococcus faecium (VREF) in three hospitals during the last three months of 2000.1 (See cases, p. 75.)
"Anybody who thought that there would never be resistance to this drug failed to read the history of every antibiotic," says Richard Wenzel, MD, professor and chairman of the department of internal medicine at Virginia Commonwealth University in Richmond. Infection control professionals should be wary of linezolid-resistant VRE developing in patients who are immune-compromised, have some type of abscess, and are under prolonged therapy with the drug, he advised.
"Finding resistant isolates to a new antibiotic reminds us that bacteria always adapt to new challenges," Wenzel says. "In this very small series [of cases], one walks away with the impression that the high-risk patient may be the one with both immune suppression and abscesses. I think that may be a very important clinical portrait."
Drug holding steady against MRSA
Distributed under the brand name Zyvox by Pharmacia and Upjohn in Kalamazoo, MI, linezolid was approved last year for treating infections with two of the most troublesome nosocomial pathogens in U.S. hospitals: VREF and methicillin-resistant Staphylococcus aureus (MRSA). Indeed, emerging linezolid resistance in VRE immediately brings up the question of possible resistance in MRSA. Fortunately, a recent national study found that all MRSA isolates reviewed were 100% susceptible to linezolid.2 However, the study also found that MRSA is increasing "relentlessly," meaning treatment with linezolid will likely increase as well as clinicians grapple with their limited antibiotic options. (See related story, p. 75.)
That scenario, and clear evidence the resistance is emerging in VRE, is concerning, says the lead researcher of the MRSA study, Daniel J. Diekema, MD, MSc, hospital epidemiologist at Iowa City (IA) Veterans Affairs Medical Center.
"Anyone who thinks there is a new agent to which MRSA will never become resistant is fooling [himself]," he says.
While MRSA has remained susceptible in both clinical trials and post-market use, there were early signs that VRE might pose problems for the new drug. Wenzel’s epidemiological analysis was borne out in reviewing the brief history of linezolid resistance. The drug information posted on the web site of Pharmacia and Upjohn (www. zyvox.com/) describes cases that occurred before marketing approval. Six patients developed resistance in clinical trials, but four of them were on a subtherapeutic dose that probably favored selection of resistant organisms.
In a compassionate-use program, resistance developed in nine patients (eight E. faecium; one E. faecalis). "All patients had either unremoved prosthetic devices or undrained abscesses," the company states.
In the cases recently reported, four were transplant patients receiving protracted courses of the drug (21-40 days). In all, three cases were associated with treatment failure, says Ronald D. Gonzales, MD, a fellow at the University of Illinois at Chicago and lead author of the Lancet report.
"I think prolonged use is a risk factor," he tells HIC. "All five cases were immunocompromised patients, so from our point of view [resistance] is only seen for now on difficult or selected patients who are admitted to the hospital for a prolonged period of time. [In addition], one patient had an abdominal graft that was done for an aortic aneurysm. That was the source of prolonged infection, and that definitely must have contributed to the resistance in the linezolid."
The perfect scenario
The patient developed an abscess around the graft, creating ideal conditions for both VRE organisms to proliferate and drug penetration to become more difficult, Wenzel notes.
"A very low quantity of drug will get into the abscess, and as a result, it is easier to select for resistance," he says. "There are a huge number of organisms and a modest amount of the drug. It is the perfect scenario for selecting resistance. The combination of having an abscess with a huge number of organisms, poor blood supply — meaning low drug [penetration] — and weeks and weeks of selecting [for resistant strains], probably conspired to create resistance."
Thus clinicians should be cautious in treating patients that fit the patient profile, he says. "Not only were four of five transplant patients, but four of five had major abscesses for which they were being treated," he says. "This may be the group that we should have a high caution about in terms of looking for resistance. So your choices are to go ahead with linezolid but know that you have to be extremely vigilant or chose an alternative."
Three of five patients had an initial clinical response to linezolid but were switched to quinupristin-dalfopristin (Synercid) after resistance was noted. The other major new antibiotic approved in the last few years, quinupristin-dalfopristin, also remained active against all of linezolid-resistant isolates in vitro. However, it is not as simple as switching out drugs, because the patient numbers are too small to draw broad conclusions, Wenzel notes.
"There aren’t many solutions," Wenzel says. "One is that all abscesses need to be drained first of all, if possible. Second, we don’t have too many drugs that can get into white cells and abscesses and are also going to get VRE. I can’t say from this study that Synercid is the answer."
Gonzales urges clinicians using linezolid for VRE infections to measure susceptibility of all isolates at the start of therapy, pay attention to proper dosing, and promptly remove infected devices.
"Initially, we were not doing linezolid susceptibility testing on onset of treatment, because we were told the chances of the bug developing resistance to linezolid are so low," he says. "But during the treatment, we noticed that patients were not responding, or patients might have persistent organisms in whatever site, for example, the blood. After treating for some period of time, we said, Enough is enough. We should test for susceptibly.’ Lo and behold, we found these cases. [Clinicians] should do the susceptibility test right from the start of therapy so if the isolate develops resistance, then they can say definitely that the linezolid induces the emergence of resistance."
The emergence of resistant also raises a litany of other questions, including possible nosocomial spread of such strains and genetic transfer of the resistance mechanism to other organisms. "It is only a postulation," Gonzales says. "It is too early to say that this might be a source of resistance for other bugs. There may been an issue of infection control in one of the patients, but I cannot confirm it. It was possibly nosocomial."
What lesson will be learned?
While preventing the spread of linezolid-resistant strains as they arise is critical, it is also important to thwart VRE transmission in general so the need for the new drug will be minimized.
"From an ICP’s perspective, we don’t prescribe the antibiotics, so we may just shrug our shoulders and say, Oh well,’" says Ruth Carrico, RN, MA, CIC, director of infection control at the University of Louisville (KY) Hospital. "However, there is an element of infection prevention in this. We can work on stopping transmission. It’s not surprising that resistance has developed. To me, the question is what is the lesson we need to learn from this? We cannot have antibiotic prescribing practices willy-nilly in any health care facility."
Carrico’s hospital has tight controls initially on such drugs and uses "crop rotation" antibiotic cycling to try to prevent resistance from prolonged exposures, she adds. Still, the issue is complicated because all indications are that these were the very patients the drug should be used on. The cases strike right at the crux of the antibiotic resistance dilemma when efforts to save an individual patient conflict with preserving the antibiotic’s efficacy for others.
"This was not a proliferate use," says William Schaffner, MD, chairman of the department of preventive medicine at Vanderbilt University Medical School in Nashville. "These uses appear to be within the general scope of what we consider saving the drug for the patients who need it the most. Even under those circumstances, if you have to give therapy for a prolonged period of time, resistance may occur. We have a paradox. The very sort of circumstance where you have an indication of the drug, in fact for prolonged use, is the kind of circumstance in which resistance is likely to develop."
The key is to act before linezolid even comes into play by trying to prevent the development of VRE though antibiotic controls, and then once that barrier falls, muster full infection control resources to try and prevent subsequent transmission, he says. For example, VRE seems to occur largely among very sick patients who are exposed to a lot of antimicrobials, particularly third-generation cephalosporins. Use of vancomycin also sets up a selective pressure for emergence of VRE, Schaffner says.
"So we are all well-advised to try and be as careful as possible about the use of all of these drugs, and then also obviously to use the best possible infection control practices in order to limit the spread of VRE," he says. "The point is if there are indications for prolonged use, that is the circumstance in which resistance is likely to occur. And these are the sorts of patients in which enterococci obviously can do damage."
The question also arises whether linezolid-resistant strains will eventually merge into the so-called VRE iceberg — the description often used to underscore that identified infections only represent a small portion of the undetected VRE below the surface. An unanswerable query at this point, but as the drug/bug combination continues to define itself, few doubt additional cases of linezolid-resistant VRE will be reported.
"My crystal ball is cloudy, but it would be an extraordinary event if we didn’t see, hither and yon, further reports of resistance," Schaffner says. "You’re betting against evolutionary biology if you think resistance won’t occur."
References
1. Gonzales RD, Schreckenberger PC, Graham MB, et al. Infections due to vancomycin-resistant Enterococcus faecium resistant to linezolid. Lancet 2001; 357:1,179
2. Diekema D, Beach M, Pfaller M, et al. Nosocomial Staphylococcus aureus bacteremia: A four-year update from the SENTRY antimicrobial surveillance program (United States and Canada) Abstract 237. Presented at the Society for Healthcare Epidemiology of America. Toronto; April 2001.