Supercharged bacteria a concern for infectious disease physicians

Bacteria are usually described as “moving targets,” but infectious disease physicians typically have had at least one or two medications in their armamentarium that could somewhat clip part of the target and make an impact.

Yet, there is one genetic element that is quickly reshaping that landscape and making these supercharged bacteria which have acquired it, “a cause for global concern,” according to a recent editorial in The New England Journal of Medicine.

In the editorial, Robert C. Moellering Jr., MD, department of medicine, Beth Israel Deaconess Medical Center, Boston, Mass., discussed that supercharged resistance determinant which encodes a new broad spectrum beta-lactamase, New Delhi metallo-beta-lactamase 1, or NDM-1. This transmissible genetic element, which encodes multiple resistance genes including NDM-1, was initially isolated from a strain of Klebsiella obtained from a patient who acquired the organism in New Delhi, India, in 2008. By 2009, Moellering noted, “a study in Mumbai revealed 24 carbapenem-resistant Enterobacteriaceae, 22 of which were NDM-1 producers. Of these 22 organisms, 10 were Klebsiella species, nine were Escherichia coli, two were enterobacter species, and one was Morganella morganii — illustrating the ability of the plasmid to spread rapidly among strains of Enterobacteriaceae.”

Since that time, widespread distribution of this problematic element has been noted across the world, with five patients noted in the United States, although that number is likely underestimated because there are currently no active surveillance protocols for these types of bacteria. The US patients had three different bacterial species; K. pneumoniae, E. coli and Enterobacter cloacae, CDC researcher Alex Kallen, MD, told Infectious Disease News. Although most patients who have become ill due to bacteria with NDM-1 have spent time in Indian hospitals, it is this element’s ability to spread so rapidly that has health officials so concerned.

Johann Pitout, MD, of the University of Calgary in Alberta, Canada, told Infectious Disease News that although there have not been any deaths, as of yet, stemming directly from this supercharged bacteria, data are limited.

“The problem is that it can be transferred very easily between patients,” Pitout said. “This definitely has the potential to cause a pandemic, if it is not already, with few, if any, treatment choices.”

Resistance factors

Research into how NDM-1 first emerged in India is ongoing. “The fact that there is widespread nonprescription use of antibiotics in India, a country in which some areas have less than ideal sanitation and a high prevalence of diarrheal disease and crowding, sets the ideal stage for the development of such resistance,” Moellering said. As research continues into how this genetic element first arose in India, infection control experts grapple with how to slow the spread.

There are also numerous theories as to how these supercharged bacteria spread throughout the globe. In the United Kingdom, several researchers have noted NDM-1-charged bacteria in tourists who traveled to the Indian subcontinent for elective medical procedures. In the United States, however, CDC researchers Kallen and Brandi Limbago, PhD, said although four of the five patients had lived in or had been hospitalized in India or Pakistan and were there to obtain medical care — none of the US patients were there for elective procedures.

Limbago said although the NDM-1 mechanism is a new player, the United States has been struggling with carbapenem resistance for some time. Carbapenems have been used in clinical practice to treat many infections. They are known as the “go to” agent when multi-drug resistant organisms are of concern. Currently, the United States is in the midst of an outbreak of multiresistant Klebsiella containing KPC enzymes, which are capable of hydrolyzing betalactams including carbapenems. Kallen said these bacteria, which are being found in increasing numbers of Enterobacteriaceae, are making some community-acquired urinary tract infections (UTIs) trickier to treat.

The index NDM-1 patient was a Swedish patient of Indian origin who traveled to New Delhi and acquired a UTI, and this UTI was resistant to all antimicrobial agents tested except colistin. Although this medication has been around for some time, it has a high toxicity profile, and there are little data about this product’s use in children.

“This class renders all of the beta-lactams ineffective, which pretty much leaves us with the older medications like colistin,” Limbago said. She noted that although CDC researchers had not noted, as of press time, any panresistant NDM-producing strains here in the United States, panresistance has been noted in other countries.

“We are very concerned about the potential for panresistance,” Kallen said.

And, Limbago said, all three clinical isolates seen in the United States are resistant to aztreonam, which is important to note because this means the bacteria affected by this mechanism carry the potential to become multidrug resistant.

Bad bugs, no drugs

Although the emergence of the NDM-1 genetic element is new and changing the landscape of certain bacteria, many health officials are quick to point out those resistant bacteria, even multidrug-resistant bacteria, are nothing new. As Moellering said in his editorial, “[Bacteria] overwhelm us with their superior numbers, they reproduce with remarkable speed, and they develop extremely efficient ways to exchange and promulgate resistance genes.”

Limbago and Kallen said, at least for now, it seems that transmission of carbapenem-resistant Enterobacteriaceae can be limited by using proper infection-control methods, including hand washing, limiting antibiotic use and increasing recognition of carbapenem-resistant strains. CDC officials have asked infectious disease physicians who identify patients who have received medical care in India or Pakistan and who have carbapenem-resistant Enterobacteriaceae to forward this information to their state health officials.

Meanwhile, several medical organizations continue to call for more research into antibiotic development. Before the NDM-1 related bacteria were even identified, the Infectious Diseases Society of America had named K. pneumoniae as one of the most troublesome hospital-associated infections. IDSA has also identified several bugs, called the “ESKAPE” pathogens, which cause the most US hospital-associated infections and are resistant to many antibacterial drugs. These are:

• Enterococcus faecium
• Staphylococcus aureus
• Klebsiella pneumoniae
• Acinetobacter baumannii
• Pseudomonas aeruginosa
• Enterobacter species

In a paper last year, the IDSA also took issue with several policies that it said constituted “excessive regulatory oversight,” which may be hindering antibiotic development for these top-offending resistant bugs. As it stands now, research into new antibiotics is extremely limited, and the short-term antibiotic development pipeline is scarce.

In a report released last year, the IDSA identified several problem areas that it said are straining institutional review boards, confusing prospective study participants, perplexing scientists conducting pediatric research and unduly lengthening the research process. Reducing redundant data review and increasing funding for the Office for Human Research Protections are two target areas that may help “restore the balance” between equal needs for research and oversight, according to the IDSA. Clarifying regulatory terms used to classify pediatric research and streamlining the process by which regulatory panels provide guidance for pediatric trials are other steps, IDSA officials wrote.

The IDSA has also outlined a goal to have 10 new antibiotics launched by 2020 with its “10 by ’20” initiative. This initiative is designed to encourage public-private partnerships, which would help overcome the financial and scientific barriers to new drug development. The comprehensive plan calls on a global core of economic, industry, intellectual, medical, philanthropic, political, regulatory and scientific leaders to meet research and development challenges. The project is a collaborative effort, involving the American Academy of Pediatrics, American Gastroenterological Association, Trust for America’s Health, the Society for Healthcare Epidemiology of America, the Pediatric Infectious Diseases Society, the Michigan Antibiotic Resistance Reduction Coalition, the National Foundation for Infectious Diseases and the European Society of Clinical Microbiology and Infectious Diseases.

IDSA officials said they hope that collaborative efforts among global stakeholders will incentivize sustainable research and development infrastructure. This infrastructure will, in turn, replenish a skilled scientific workforce that has steadily declined in the past 2 decades as a result of industry abandonment of antimicrobial development projects.

In the meantime, limiting excessive and inappropriate antibiotic use remains the best way to prevent further drug resistance and to conserve existing therapies until a sustainable antibacterial research and development infrastructure is secured.

The CDC’s multifaceted Get Smart programs aim to create awareness among physicians and the public about judicious antibiotic use. A major objective of the Get Smart program, which launched an initial media campaign in 2003, and just recently launched one arm of the campaign directed at educating providers about proper prescribing practices, is to get the word out about adhering to treatment guidelines and prescribing antibiotics only when they are called for.

Get Smart officials are also partnering with state health departments to implement electronic medical record prompts that would improve physicians’ ability to accurately diagnose diseases and determine if antibiotic therapy is appropriate.

Physicians also contend with patients who visit their offices intent on obtaining antibiotics despite diagnoses. Therefore, tools to aid providers in addressing patients’ concerns are also key components of the Get Smart program.

Although concerns about antimicrobial resistance are not new, as Moellering said, infection control may be the best weapon the infectious diseases community has, but, he admits, even that may not be good enough.

“As of 50 years ago, most of the important principles concerning the nature, dissemination and potential control of antibiotic resistance were known, the role of inappropriate antibiotic use in selecting resistant organisms, the ability of resistant organisms to spread in the hospital setting, and the value of limiting antibiotic use in the hospital as a control measure,” Moellering wrote. “Despite such knowledge and vigorous worldwide attempts to initiate methods to prevent and control antibiotic resistance, our success has been limited at best.” – by Colleen Zacharyczuk

For more information:

• Infectious Diseases Society of America. Clin Infect Dis. 2009;49:328-335

• Moellering RC. N Engl J Med. 2010;363:2377-2379.

Disclosures: Drs. Kallen, Limbago and Moellering have no relevant financial disclosures.

Do the NDM-1 bacteria have the potential to spread to the community?

We are keeping a close eye on it

We’re very worried about NDM-1.

The organisms that this genetic material travels in and the characteristics of resistance that it carries make it very dangerous. We’re keeping a close eye on this because the type of attributes that NDM-1 has make it very likely to catch on in the community, like MRSA, compared with other resistant organisms, like Acinetobacter baumannii. Unlike Acinetobacter, this material travels in bacteria, like Escherichia coli, which is part of the body’s normal bacteria. The body recognizes E. coli and tolerates it, whereas Acinetobacter is not one of the body’s normal bacteria.

There is also a concern that once this gets into larger hospital populations, it would affect the neonatal population and you would see early and late onset sepsis caused by this plasmid-containing bacteria.

John Bradley, MD, is director of infectious diseases at Rady Children’s Hospital. Disclosure: There are no products or companies mentioned that would require financial disclosure.

NDM-1 will spread

You will definitely see this NDM-1 spread. Similar to the outbreak of multiresistant Klebsiella containing KPC enzymes, which are capable of causing resistance problems, this is going to cause a huge problem in patients that are very sick.

Selective pressure has let these NDM-1 bacteria, similar to MRSA, just explode. And as we’ve seen with MRSA, just because you have good infection control measures does not necessarily mean you are going to guarantee the safety of the community. All it takes is one person to come back from a community whose infection control measures are not as complete, and this spreads like crazy — or not. That’s the thing; these bacteria continue to surprise us.

James R. Johnson, MD, can be reached at Infectious Diseases, VA Medical Center, Minneapolis, Minn. Disclosure: There are no products or companies mentioned that would require financial disclosure.