Response changes as gram neg HAIs rise

IPs should ask lab about new breakpoints

The U.S. public health system is trying to catch up with the explosion of infections with multidrug resistant gram negative rods (MDR-GNR) by standardizing surveillance definitions and changing laboratory breakpoints.

How fast are these pathogens emerging? Consider that the first U.S. case of Klebsiella pneumoniae carbapenemase (KPC) infection was diagnosed a little more than a decade ago.

"In fact, the first [KPC] isolate was identified in 2001 from a patient in North Carolina," says David Calfee, MD, MS, chief hospital epidemiologist at New York (City)-Presbyterian Hospital. "In 10 years we now have at least 36 states identifying at least one KPC isolate. They have become highly prevalent in some parts of the country, particularly in the Northeast U.S. Certainly, other parts of the country are experiencing similar increases."

Looking at the level of resistance that may be seen in a single infected patient, Calfee cites an antibiogram of an isolate of K. pneumoniae that was fully resistant to 18 antibiotics. "This is a pretty bad organism to be infected with," he said recently in Baltimore at the annual conference of the Association for Professionals in Infection Control and Epidemiology. "With this patient, tigecycline, gentamicin and tetracycline were the only antibiotics that were felt — in the laboratory — to perhaps have good activity against this isolate."

With no new drugs against the rising tide of gram negatives expected any time soon, patients must rely on infection preventionists to stop transmission of these pathogens across the health care continuum.

"We really haven't had a great new addition of new classes of antibiotics with activity against some of these highly resistant gram negative pathogens — leaving some people to talk about us heading back into the pre-antibiotic era when it comes to some of these infections (i.e., KPC)," Calfee says.

Interestingly, in global outbreaks of KPC many countries are tracing the index case to a patient who traveled from the U.S., Calfee noted. Similarly, patients from India and Pakistan are spreading another gram negative of major concern: New Delhi Metallo — Lactamase — 1 (NDM-1), which confers resistance to all beta–lactams.

"What has been particularly concerning about NDM-1 is that it has really quickly spread this [resistance] among different bacteria," he says. "Our KPC problem has mostly been in Klebsiella pneumoniae — there has been clonal spread of a KPC-possessing strain throughout the country and the world. With this NDM-1 there has been a lot of transmission of the gene itself, from one bacteria to another."

Though only a few cases have been detected in the U.S., it's hard to imagine that IPs won't be dealing with NDM-1 at some point. The resistance mechanism has spread to a variety of bacteria, including species of Klebsiella, Escherichia coli, Enterobacter and Acinetobacter.

"That is very concerning, particularly if we get NDM-1 in a lot of E. coli isolates in the community," Calfee says. "Can you imagine if we have people coming in with community acquired UTIs — infections that are almost untreatable with all of our oral antibiotics. That's why I think this has gotten more press than even KPC, which is actually at this point more prevalent, particularly in the United States."

In a situation somewhat analogous to MRSA, an increasing proportion of some of the MDR-GNRs are becoming resistant. In Centers for Disease Control and Prevention surveillance data from 2006-2007, 59% of Acinetobacter isolates causing HAIs were resistant to at least three classes of antibiotics. "When you look at the others, they kind of pale in comparison, but it's still pretty dramatic to think that 14% of Klebsiella isolates were resistant to three classes of antibiotics and 6% were resistant to four or more classes," Calfee says. "Especially if you consider, a couple of decades ago these [infections] were easily treated by almost any antibiotic that you would expect to have activity against gram negatives."

New surveillance definitions

As mentioned, Calfee cited data from 2007, and by all signs the situation has certainly not improved since. However, definitions for MDR-GNR can vary widely by facility, leaving the true national picture obscured. "[It's] far from standardized," Calfee said. To address the problem, the CDC's National Healthcare Safety Network (NHSN) recently added new definitions for multidrug resistance for Klebsiella, E. coli and Acinetobacter.

"They updated the MDRO module and gave us four different gram negative pathogens that we can monitor through NSHN," he said. "Obviously, I think we all recognize that these are the important ones, but they may not be the only ones we care about in our institutions."

While the NHSN change may help standardize national surveillance for these emerging pathogens, a more subtle change in the clinical lab could actually have a more direct effect on day-to-day infection prevention. The Clinical and Laboratory Standards Institute (CLSI) has changed some of the breakpoints that determine susceptibility and resistance. As a result, cultures once labeled susceptible could now meet the definition of resistant, Calfee explained. IPs should check with lab staff to make sure everybody is on the same page, he advised.

The CLSI changes enacted last year apply to antibiotic susceptibility testing and reporting for the bacteria Enterobacteriaceae, which include E. coli and Klebsiella.

"The CLSI recommended that laboratories lower the minimum inhibitory concentration (MIC) used to determine resistance or susceptibility for several of the cephalosporins, aztreonam and carbapenems," Calfee told APIC attendees. "This means that organisms that were previously called susceptible might now be called intermediate or resistant. It's not a change in the organism, it's a change in the definition of what is considered susceptible and what's considered resistant. These lower breakpoints might result in increased number of isolates that get classified as non-susceptible. [That could] lead to an increased number of patients that might require contact precautions and single rooms. Do you know whether your laboratory has implemented these changes or not? It's something to ask if you don't know."

At the same time, the CLSI said one result of the new breakpoints is that labs no longer have to test for extended-spectrum ß-Lactamases (ESBLs), which can be used as a marker for resistance. "We think these new break points clinically are more useful to the clinician than knowing the mechanism of resistance," Calfee said. "This actually gives you clinical data that you can use."

However, again, if infection prevention and the lab are not communicating, the change in practice could be misread epidemiologically. "First, if your lab is using ESBL production as a definition of MDR gram negative pathogens — and the lab stops testing for ESBL production — how are you going to define your MDRs?" Calfee said. "You might think, 'Wow, my ESBL problem went away — I haven't had one in months.' It may just be because your lab stopped telling you about it."

It's important to know whether you have MDR-GNRs in you facility. A patient with a MDR-GNR infection is roughly at a four-fold greater risk of death than someone infected with a drug susceptible version of the same organism, said Calfee, who has considerable experience with KPC as a hospital epidemiologist in New York City.

"We found that almost 40% of patients with [KPC] died of their infection — as compared to just over 10% of patients who had a carbapenem-susceptible Klebsiella infection," he said. In addition, MDR-GNRs increase the risk of treatment failure, increase length of hospital stay and increase hospital costs, he added. "There are a lot of reasons — very important patient-centered reasons — why we need to worry about these organisms and prevent their transmission," he said.

The increasing severity of outcomes is not necessarily in direct relation to virulence. With the notable exception of community-associated MRSA, resistant bacteria have generally not been more virulent than susceptible strains of the same pathogen, he said.

"These adverse outcomes are more likely due to delays in initiating effective therapy," he said. "Because we are not expecting this isolate to be resistant to our empiric regimen. It also may be that we have less effective or more toxic antimicrobial therapy. Some of these [MDR-GNR] are what we call pan-resistant. Some people are using the term XDR, extremely drug resistant pathogens."