Fatal infection of NDM-1 included gene transfer

Eight cases now reported in Canada

Threatening to spread to North America after originating in hospitals in India, the pan-resistant New Delhi metallo-beta-lactamase (NDM-1) enzyme has been linked to a fatal infection in Canada.1 The patient in Vancouver had traveled to India, but there is also another new report of NDM-1 infection in a child in Europe who never left the continent.2 As more cases appear with unremarkable travel histories, concerns mount that NDM-1 is spreading beyond its suspected origins in India and Pakistan.

In the Canadian case, multidrug-resistant Klebsiella pneumoniae and Escherichia coli isolates harboring the NDM-1 enzyme — a mechanism that confers almost complete drug resistance — were recovered from a 76-year-old woman who died of apparent sepsis. She returned to Vancouver in early 2010 after spending approximately three months in northern India. A genetic transfer of drug-resistant plasmids apparently occurred within the patient, underscoring that NDM-1 has the ability to transfer its resistance capabilities to other pathogens.

"This [plasmid transference] was actually reported as well from one of the first reported cases of NDM-1 from a patient in Sweden," says Michael Mulvey, MD chief of antimicrobial resistance and nosocomial Infections at the National Microbiology Laboratory of the Public Health Agency of Canada. "That's another concern with this NDM-1. It is carried on a plasmid that is mobile and can move from one strain to another."

As this issue went to press, there had been eight cases of NDM-1-related infections reported in Canada and three by the official count thus far in the United States. The Centers for Disease Control and Prevention declined to update U.S. case counts for this report, explaining that NDM-1 is not a reportable infection and thus will be subject to periodic updates. The previously reported U.S. cases were patients who had Enterobacteriaceae NDM-1 isolates after recently receiving medical care in India. The three isolates — Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae — all carried blaNDM-1, which confers resistance to all beta-lactam agents except aztreonam (a monobactam antimicrobial). None of the U.S. cases included plasmid transference, but the general concern is that the phenomena could rapidly increase the presence of the NDM-1 in other gram negative strains.

"NDM-1 is just one of many beta-lactamases that hydrolyze [i.e., destroy] virtually all of the beta-lactam antibiotics," says Robert Rapp, PharmD, professor of pharmacy at the University of Kentucky Chandler Medical Center. "It is a metallo-beta-lactamase. Most of these are transferable, which means they are on plasmids rather than chromosomes of the bacteria. They are transferable from one genus of bacteria to other gram negatives through sexual conjugation."

In the Vancouver case, blood cultures were negative, but urine culture grew highly drug-resistant K. pneumoniae with intermediate resistance to chloramphenicol and susceptibility to colistin. Plasmids that harbor NDM-1 enzymes successfully transferred by conjugation between K. pneumoniae and E. coli within the patient, Mulvey and colleagues reported.

The case report

According to the case report, before the trip to India, the patient had been in good health with no coexisting conditions. In India, she developed persistent non-bloody diarrhea, but did not seek medical attention. One month after the diarrhea began, she was treated in an Indian hospital for hypertension and congestive heart failure. She was discharged from the hospital in India and transferred back to Canada, where she was hospitalized on Feb. 14, 2010 and eventually died with a final diagnosis of toxic metabolic leukoencephalopathy, likely related to sepsis.

The Centers for Disease Control & Prevention recommends that carbapenem-resistant isolates from patients who have received medical care within six months in India or Pakistan be forwarded through state public health laboratories to CDC for further characterization. Infection control interventions aimed at preventing transmission should be implemented when NDM-1-producing isolates are identified, even in areas where other carbapenem-resistance mechanisms are common among Enterobacteriaceae. These include recognizing carbapenem-resistant Enterobacteriaceae when cultured from clinical specimens, placing patients colonized or infected with these isolates in contact precautions, and in some circumstances, conducting point prevalence surveys or active-surveillance testing among other high-risk patients, the CDC recommends.

"It is certainly a concern that we are now beginning to see cases from so many different countries," says Mulvey. "There have been calls now for global surveillance of this to actually develop baseline levels for different countries for this organism. It is important to know when it is first identified in countries. If someone is entering your hospital and has been hospitalized in India or Pakistan, maybe they should be screened and monitored to make sure that we don't see this potentially spreading in hospitals. These tests are currently available. There are standard biologic procedures to screen and test for these organisms. But in Canada screening is left up to the individual hospital."

The cases in North America appear to all be related to travel to India and Pakistan, and more specifically medical treatment in the countries, he says.

"There still are a couple of antibiotics left to treat it," he says. "In some of the cases anyway — tigecycline and colistin have been used. But there are some isolates that have been reported that are pan resistant. Then you have a serious problem. This particular case was susceptible to tigecycline and colistin, but it was resistant to all of the standard front-line antimicrobials. [That means] your empiric therapy won't work."

Canadian hospitals have done better than many of their U.S. counterparts in staving off methicillin-resistant Staphylococcus aureus (MRSA), so the emergence of NDM-1 there will be viewed with interest. "So far to date in Canada we haven't seen nosocomial transmission," Mulvey says. "So these have been sporadic cases."

Report of two cases in Austria

Also slated for publication in the Jan. 2011 issue of Emerging Infectious Diseases, is a letter from investigators in Austria who reported two unrelated NDM-1 cases.2

In the first case, a 30-year-old Austrian man was admitted to University Hospital in Graz in November 2009. He had experienced multiple open fractures of his upper and lower left leg as well as rectal laceration because of a motorcycle accident in Pakistan. His treatment had taken place primarily in surgery departments in Pakistan and India. During his hospitalization in Austria, multiple resistant gram-negative bacteria were isolated, including highly resistant NDM-1–producing K. pneumoniae. After 5 months of recurrent hospitalizations with various infectious complications, multiple anti-infective regimens, and surgical interventions required to treat fractures resulting from the patient's motorcycle accident, the patient was released without further medical problems.

In August 2010, patient 2 — a 14-year-old boy who had undergone an appendectomy in Pristina, Kosovo — was transferred to the department of pediatrics at the same hospital with multiple intra-abdominal abscesses and peritonitis. His travel history was completely unremarkable.

On the day of admission, multiple-drug resistant K. pneumoniae was isolated from five sites (2 swab samples from the abdominal wound, 1 sample from the throat, 1 sample of secretion from an abdominal fistula, and 1 sample from stool). As of November 2010, the patient still required medical care and remained hospitalized.

Most plasmids with the carbapenemase enzyme blaNDM-1 were shown to be readily transferable and prone to rearrangement, which indicates a potential to spread among bacterial populations, the investigators noted. However, the strains detected in the two cases were distinctly different, lead investigator Andrea Grisold, MD, said in an email to Hospital Infection Control & Prevention.

"Not knowing other NDM-1 strains it is very difficult to discuss [whether this represents] 'independent' emergence, but at the moment our findings may implicate this," she noted. "Further investigations are surely necessary and will be very interesting. When any multidrug resistant organisms are detected infection control measures include contact precautions and patient isolation. There is no difference if it is NDM-1, MRSA, ESBL or MDR-Acinteobacter."

References

  1. Mulvey MR, Grant JM, Plewes K, et al. New Delhi metallo-β-lactamase in Klebsiella pnemoniae and Escherichia coli, Canada. Emerg Infect Dis. 2011 Jan; [Epub ahead of print].
  2. Zarfel G, Hoenigl M, Leitner E, et al. Emergence of New Delhi metallo-β-lactamase, Austria [letter]. Emerg Infect Dis. 2011 Jan; [Epub ahead of print].