What can we learn from a recent outbreak of highly-antibiotic-resistant bacterial infections at one of the most prestigious research hospitals in the US?

Kevin Lyons

Carbapenem-resistant Enterobacteriaceae (CRE)

In 2013, the Centers for Disease Control and Prevention (CDC) published an extensive report entitled Antibiotic Resistance Threats in the United States which included a list of the most problematic antibiotic-resistant microbes in the US. Virtually all of these so-called “superbugs” were bacteria, except for the fluconazole-resistant Candida yeasts. In addition to simply listing these organisms, each species (or group of species) on the list was assigned one of three threat-levels of increasing severity: concerning, serious or urgent. Two individual bacterial species, Clostridium difficile and drug-resistant Neisseria gonorrhoeae, were classed as urgent threats – as was a group of bacteria known as the carbapenem-resistant Enterobacteriaceae (CRE). All of the species in the urgent category are examples of Gram-negative bacteria: a group associated with significant intrinsic antibiotic resistance due to the presence of – among other things – a notably impermeable double-layered cell envelope, as well as cell-envelope-associated efflux pumps which actively drive certain antibiotic molecules out of the bacterial cell, thereby minimizing their efficacy.

cre-cdc

Carbapenems are often the ‘antibiotics of last resort’ to treat infections involving multidrug-resistant (MDR) Enterobacteriaceae. Hence, the emergence of carbapenem-resistant Enterobacteriaceae poses a considerable threat to public health (Image Source)

β-lactam antibiotics such as carbapenems, penicillins, cephalosporins and monobactams are broad-spectrum antimicrobial drugs used to treat infections involving Gram-positive or Gram-negative bacteria. These antibiotics are characterized by a core β-lactam ring, which, in resistant strains, can be cleaved by the action of bacterial enzymes known as β-lactamases. Carbapenemases are a subset of β-lactamases capable of cleaving carbapenems – which are often the antibiotics of last resort when treating infections involving multidrug-resistant (MDR) Enterobacteriaceae. Hence, CRE strains – which have typically acquired, via horizontal gene transfer, the ability to produce an effective carbapenemase – can cause extremely serious infections that are often untreatable. In a 2013 press release Dr. Tom Frieden, current director of the CDC, referred to members of the CRE group as “nightmare bacteria” – a description which might have been dismissed as an exaggeration had it originated in the tabloid press, but which coming directly from the CDC is quite worrying.  In the US, some of the most common CRE infections are caused by carbapenem-resistant strains of Klebsiella pneumoniae which carry the plasmid-encoded K. pneumoniae carbapenemase (KPC) gene.

Outbreak at the NIH

In 2011, an outbreak of KPC+ carbapenem-resistant K. pneumoniae took place at one of the top research hospitals in the US – the Clinical Center at the National Institutes of Health (NIH) in Bethesda, Maryland. On the 13th of June, a 43-year-old female patient known to be colonized with KPC+ carbapenem-resistant K. pneumoniae was transferred from a New York City hospital to the intensive care unit (ICU) of the Clinical Center with complications from a lung transplant. Although she soon recovered and was discharged, during the following months 17 other people became infected, and 6 died as a direct result of infection. The outbreak was eventually brought under control by enforcing strict contact-isolation protocols and surveillance mechanisms, as well as by developing an algorithm to construct a transmission map for the outbreak based on (i) data from whole-genome sequencing (WGS) of bacterial isolates, and (ii) epidemiological data obtained by tracking the location of every patient during his/her hospital stay (Snitkin et al., 2012).

These were drastic, cutting-edge infection control measures. For example, this was the first time a WGS approach was used to track patient-to-patient transmission during a hospital-associated outbreak; an approach which would have been far too slow and expensive a few years earlier. Although reliant on rapid, next-generation DNA sequencing technologies which are not yet available in all hospitals – e.g. Illumina sequencing – the WGS approach has many advantages. Perhaps the ‘take-home message’ here is that comparing the genetic similarities and differences between bacterial isolates from various infected patients with data from epidemiological investigations can lead to the construction of a more accurate transmission map than if epidemiological data were used on their own. In other words, epidemiological investigations based on questions like “Were patient X and Y seen by the same doctor?” and “When, and for how long did patient Y and Z share a room?” can be cross-referenced with WGS data, reducing the likelihood of an epidemiological wild goose chase.

1

Map of potential transmission routes between numbered patients, constructed by tracking the location of every patient during his/her hospital stay. Red arrows are routes predicted by WGS data. (Snitkin et al., 2012)

2

Most likely pattern of transmission, constructed by cross-referencing WGS data with data regarding the location of every patient during his/her hospital stay. (Snitkin et al., 2012)

Speaking openly about outbreaks of antibiotic-resistant bacterial infections in hospitals can be problematic for hospital representatives, due to the fact that revealing the details of these outbreaks can put both the privacy of individual patients and the reputation of the hospital at risk. Having said that, it is widely accepted that the increasing prevalence of these infections and the near-total lack of antimicrobial drugs in development is cause for serious alarm – and it was with this in mind that the scientists and hospital representatives central to the NIH outbreak decided to document and share their experiences.

As of 2016, every incoming patient at the NIH Clinical Center is tested for the presence of CRE bacteria, and if a CRE organism is found, the patient is immediately put in isolation. Since the end of the outbreak there has been no transmission of KPC+ carbapenem-resistant K. pneumoniae in the hospital. However, it would be a mistake to think that the bacteria have been completely eradicated from the facility. In 2012, a young man was admitted due to complications from a bone marrow transplant, became infected with KPC+ carbapenem-resistant K. pneumoniae, and died as a result of the infection. This case proved the need for continued surveillance of patients and the hospital environment for KPC+ carbapenem-resistant K. pneumoniae. In addition, the isolation of other Gram-negative bacteria which have acquired the KPC gene – for example, Citrobacter freundii and Enterobacter cloacae – from sink drains in the hospital, further complicates the problem (Conlan et al., 2014). These bacteria could potentially act as a resistance reservoir, passing the KPC gene (and with it, carbapenem resistance) to other bacterial pathogens that are currently susceptible to carbapenems.

Find out more

Anyone who has read my earlier blog-posts will know that I am a big fan of the American Society for Microbiology’s Microbes After Hours event series. Back in June of 2015, one of the principal investigators in the NIH outbreak, Dr. Julie Segre, discussed the outbreak in great detail as part of the 2015 Elizabeth O. King Lecture on Antibiotic Resistant Bacteria (recorded for Microbes After Hours). The outbreak was also featured in an episode of Frontline – the popular public affairs TV documentary series – entitled Hunting the Nightmare Bacteria, which is available for free online. To coincide with the release of the Frontline episode, the Public Broadcasting Service (PBS) also produced a useful summary of the NIH outbreak on their website, which is well worth a look.

References:

  1. Snitkin, E.S., Zelazny, A.M., Thomas, P.J., Stock, F., NISC Comparative Sequencing Program Group, Henderson, D.K., Palmore, T.N., Segre, J.A. (2012) Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing. Science Translational Medicine. 4(148), 148ra116.
  2. Conlan, S., Thomas, P.J., Deming, C., Park, M., Lau, A.F., Dekker, J.P., Snitkin, E.S., Clark, T.A., Luong, K., Song, Y., Tsai, Y.C., Boitano, M., Dayal, J., Brooks, S.Y., Schmidt, B., Young, A.C., Thomas, J.W., Bouffard, G.G., Blakesley, R.W., NISC Comparative Sequencing Program, Mullikin, J.C., Korlach, J., Henderson, D.K., Frank, K.M., Palmore T.N., Segre, J.A. (2014) Single-molecule sequencing to track plasmid diversity of hospital-associated carbapenemase-producing Enterobacteriaceae. Science Translational Medicine. 6(254), 254ra126.
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