NDM-1: An Update

Earlier this year, the medical community began hearing reports of a new "superbug," but in actuality, it was the emergence of a new resistance mechanism in the form of what is now called New Delhi metallo-beta-lactamase (NDM-1). Encouraging this resistance mechanism is the widespread use of carbapenems, the only agents reliably active against extended-spectrum Beta-lactamase producing Enterobacteriaceae strains.

According to Zarfel, et al. (2010), NDM-1 was first detected in a Klebsiella pneumoniae isolate in 2008 from a Swedish patient of Indian origin; it has since been reported in increasing numbers of infections in patients from India, Pakistan, and the United Kingdom. As many as 77 cases of NDM-1 have now been detected in 13 European countries, and eight cases have appeared in Canada, according to the latest news reports.

Carbapenemresistant Enterobacteriaceae (CRE) and Klebsiella pneumoniae carbapenemase (KPCs) infections, which were once seen in limited locations in the United States, are now spread throughout the country. According to the Centers for Disease Control and Prevention (CDC), KPC-producing organisms were originally found in only one U.S. state, North Carolina, but have now spread to 35 states.

The importance of NDM-1 is explained by Zarfel, et al. (2010), who note, " the emergence of NDM-1 poses the risk of plasmid-mediated transfer of the carbapenemase enzyme blaNDM-1 between different bacterial strains, which could lead to serious public health issues."

The June 25, 2010 issue of Morbidity and Mortality Weekly Report (MMWR) reported that from January 2010 to June 2010, three Enterobacteriaceae isolates carrying NDM-1 were identified from three U.S. states at the CDC antimicrobial susceptibility laboratory. This was the first report of NDM-1 in the United States, and the first report of metallo-beta-lactamase carriage among Enterobacteriaceae in the U.S.

These isolates, which include Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae, carry blaNDM-1, which confers resistance to all beta-lactam agents (except aztreonam). In the United Kingdom, where these organisms are increasingly common, carriage of Enterobacteriaceae containing blaNDM-1 has been closely linked to receipt of medical care in India and Pakistan, and all three U.S. isolates were from patients who received recent medical care in India. According to the CDC, Carbapenem resistance and carbapenemase production conferred by blaNDM-1 is detected reliably with phenotypic testing methods currently recommended by the Clinical and Laboratory Standards Institute (CLSI); carbapenem resistance in all three of these isolates was detected in the course of routine testing.

Current CDC infection prevention and control guidance for carbapenem-resistant Enterobacteriaceae also is appropriate for NDM-1 producing isolates. This includes 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 says that laboratory identification of the carbapenem-resistance mechanism is not necessary to guide treatment or infection control practices but should instead be used for surveillance and epidemiologic purposes.

According to the aforementioned June 2010 MMWR report, "Clinicians should be aware of the possibility of NDM-1 producing Enterobacteriaceae in patients who have received medical care in India and Pakistan, and should specifically inquire about this risk factor when carbapenem-resistant Enterobacteriaceae are identified. CDC asks 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, as outlined in current guidance from the CDC in March 2009, should be implemented when NDM-1 producing isolates are identified, even in areas where other carbapenem-resistance mechanisms are common among Enterobacteriaceae.

In its guidelines for the control of CRE or carbapenemase-producing Enterobacteriaceae in acute-care facilities, the CDCs Healthcare Infection Control Practices Advisory Committee (HICPAC) recommends an aggressive infection control strategy, including managing all patients with CRE using contact precautions and implementing CLSI guidelines for detection of carbapenemase production. In areas where CRE are not endemic, facilities should review microbiology records for the preceding six to 12 months to determine whether CRE have been recovered at the facility; if the review finds previously unrecognized CRE, perform a point prevalence culture survey in high-risk units to look for other cases of CRE, and perform active surveillance cultures of patients with epidemiologic links to persons from whom CRE have been recovered. In areas where CRE are endemic, an increased likelihood exists for imporation of CRE, and facilities should consider additional strategies to reduce rates of CRE.

NDM-1 underscores the need for antibiotic stewardship to help curb the growing threat of resistance, experts say. Taking or prescribing antibiotics when they are not needed creates additional health risks. And, antibiotic use can lead to antibiotic resistance -- when bacteria change in a way that reduces or eliminates the effectiveness of antibiotics. As resistance increases, a patient's risk of complications or death from an infection also increases. Additionally, antibiotic-resistant bacteria have the potential to spread between people and cause severe infections. Reducing unnecessary antibiotic use can reduce avoidable adverse events including Clostridium difficile infections and allergic reactions.

"Antibiotics are essential to combat life-threatening bacterial infections," says Thomas Frieden, MD, director of the CDC. "Unfortunately, misuse of antibiotics is widespread and contributes to resistance. We have to better promote appropriate use of antibiotics to preserve these life-saving tools."

Data from published studies show that:

-- Approximately 50 percent of antibiotics are unnecessarily prescribed or inappropriate.

-- More than $1.1 billion are spent annually on unnecessary antibiotic prescriptions for respiratory infections in adults.

-- Antibiotic-resistant infections lead to worse outcomes for patients, including higher mortality.

The World Health Organization (WHO) suggests that countries should be prepared to implement hospital infection control measures to limit the spread of multidrugresistant strains and to reinforce national policy on prudent use of antibiotics, reducing the generation of antibiotic resistant bacteria. WHO strongly recommends that governments focus control and prevention efforts in four main areas:

1. Surveillance for antimicrobial resistance

2. Rational antibiotic use, including education of healthcare workers and the public in the appropriate use of antibiotics

3. Introducing or enforcing legislation related to stopping the sale of antibiotics without prescription

4. Strict adherence to infection prevention and control measures, including the use of handwashing measures, particularly in healthcare facilities.

Successful control of multidrugresistant microorganisms has been documented in many countries, and the existing and wellknown infection prevention and control measures can effectively reduce transmission of multidrugresistant organisms if rigorously and systematically implemented.

References:

Zarfel G, Hoenigl M, Leitner E, Salzer HJF, Feierl G, Masoud L, et al. Emergence of New Delhi metallo--lactamase, Austria. Emerg Infect Dis. January 2011.

Centers for Disease Control and Prevention. Guidance for control of infections with carbapenem-resistant or carbapenemase-producing Enterobacteriaceae in acute care facilities. Morb Mortal Wkly Rep (MMWR). 2009;58:256--60.

Centers for Disease Control and Prevention. Detection of Enterobacteriaceae isolates carrying metallo-beta-lactamase.United States, 2010. Morb Mortal Wkly Rep. (MMWR). 2010;59:750.