CRE and other antibiotic resistant microorganisms: a research update

Aug. 18, 2014

A new report by the World Health Organization (WHO)—the first it has created that looks at antimicrobial resistance, including antibiotic resistance, globally—reveals that this serious threat is no longer a prediction for the future; it is happening right now, in every region of the world. Antibiotic resistance is increasingly being recognized for what it is: a major threat to public health.

Keiji Fukuda, MD, who serves as WHO’s Assistant Director-General for Health Security, has raised the specter of “a post-antibiotic era, in which common infections and minor injuries which have been treatable for decades can once again kill,” and recommended “urgent, coordinated action by many stakeholders” to avoid this dystopian scenario. “Effective antibiotics have been one of the pillars allowing us to live longer, live healthier, and benefit from modern medicine,” he continues. “Unless we take significant actions to improve efforts to prevent infections and also change how we produce, prescribe, and use antibiotics, the world will lose more and more of these global public health goods and the implications will be devastating.”

Key findings from the WHO

The report, “Antimicrobial resistance: global report on surveillance,”1 notes that resistance is occurring across many different infectious agents but focuses on antibiotic resistance in seven different bacteria responsible for common, serious diseases such as sepsis, diarrhea, pneumonia, urinary tract infections, and gonorrhea. It documents resistance to antibiotics, especially “last resort” antibiotics, in all regions of the world. Key findings include:

Resistance to carbapenem antibiotics, the treatment of last resort for life-threatening infections caused by the common intestinal bacteria Klebsiella pneumoniae, has spread to all regions of the world. K. pneumoniae is a major cause of hospital-acquired infections such as pneumonia, bloodstream infections, and infections in newborns and intensive-care unit patients. In some countries, because of resistance, carbapenem antibiotics will not work in more than half of people treated for K. pneumoniae infections. Enterobacteriaceae that produce any β-lactamase that hydrolyzes carbapenems (any or all of ertapenem, doripenem, imipenem, and meropenem) can be resistant to all of the following third-generation cephalosporins: ceftriaxone, cefotaxime, and ceftazidime.

Treatment failure of cephalosporins, which are also the drugs of last resort for gonorrhea, has been confirmed in Austria, Australia, Canada, France, Japan, Norway, Slovenia, South Africa, Sweden, and the United Kingdom. 

Resistance to fluoroquinolones, one of the most widely used classes of antibacterial medicines for the treatment of urinary tract infections caused by E. coli, is very widespread. In the 1980s, when these drugs were first introduced, resistance was virtually zero. Today, there are countries in many parts of the world where this treatment also is ineffective in more than half of patients. 

Antibiotic resistance causes people to be sick for longer and increases the risk of death. For example, people with MRSA (methicillin-resistant Staphylococcus aureus) are estimated to be 64% more likely to die than people with a non-resistant form of the infection. Resistance also increases the cost of healthcare, with lengthier hospital stays and more intensive care required.

This report is kick-starting a global effort led by WHO to address drug resistance. This will involve the development of tools and standards and improved collaboration around the world to track drug resistance, measure its health and economic impacts, and design targeted solutions. WHO is also calling attention to the need to develop new diagnostics, antibiotics, and other tools to allow healthcare professionals to stay ahead of emerging resistance.

Recent research

In fact, researchers are attacking antibiotic resistance, particularly carbapenem resistance, on a number of fronts. 

According to a study published in a recent issue of the American Journal of Infection Control,2 orally administered, nonabsorbable antibiotics were effective in eradicating CRE colonization. Researchers at Rambam Health Care Campus, a 1,000-bed, tertiary care center in Haifa, Israel, examined isolates from 152 patients who were identified as CRE carriers (colonized with the organism but not yet showing disease) over a 24-month period. The 50 patients in the treatment group received one of three drug regimens based on antibiotic sensitivities of their isolates: nonabsorbable gentamicin (26), colistin (16), or a combination of the two. Patients received treatment until cultures were negative for CRE, or for a maximum of 60 days. Patients not sensitive to either antibiotic, or those who did not give consent (102), comprised the control group and were also followed (median=140 days) in order to determine the spontaneous eradication rate. 

CRE was eradicated in 42% of patients taking gentamicin (11/26), 50% taking colistin (8/16), and 37.5% taking a combined treatment (3/8), for an overall eradication rate for patients on all treatment regimens of 44% (22/50). This compares to a 7% (7/102) eradication rate in the control group. In patients where colonization was stamped out, regardless of whether they received treatment, there were fewer deaths than in those where colonization persisted (17% vs. 49% respectively). 

“Treatment with oral nonabsorbable antibiotics, to which CRE is susceptible, appears to be safe and effective for eradication of the CRE carrier state,” say the Rambam researchers. “Reducing the reservoir of CRE carriers in healthcare facilities may thereby reduce patient-to-patient transmission and the incidence of clinical infection with this difficult-to-treat organism. When the mortality rate in patients who had successful eradication of the carrier state (either spontaneous or on treatment) was compared with that of patients failing eradication, significantly lower mortality was found in the former group. This could point toward a real reduction of mortality attributed to the eradication of CRE carrier state.”

In a second study, National Institutes of Health (NIH) scientists and their colleagues have tracked the evolution of the antibiotic-resistant bacterium K. pneumoniae sequence type 258 (ST258), an important agent of hospital-acquired infections. While researchers had previously thought that ST258 K. pneumoniae strains spread from a single ancestor, the NIH team showed that the strains arose from at least two different lineages. The investigators also found that the key difference between the two groups lies in the genes involved in production of the bacterium’s outer coat, the primary region that interacts with the human immune system.

Scientists from the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and their colleagues sequenced the complete genomes of ST258 K. pneumoniae strains collected from two patients in New Jersey hospitals. By comparing these reference genomes with gene sequences from an additional 83 clinical ST258 K. pneumoniae isolates, the researchers found that the strains divided broadly into two distinct groups, each with its own evolutionary history. Further analysis revealed that most differences between the two groups occur in a single “hotspot” of the genome containing genes that produce parts of the bacterium’s outer shell. The investigators plan to further study how these genetic differences may affect the bacterium’s ability to evade the immune system. The results, which appear online in Proceedings of the National Academy of Sciences,3 may help guide the development of new strategies to diagnose, prevent, and treat K. pneumonia.

Researchers at Canada’s McMaster University are offering results of a study that suggests a new approach: they have unearthed a fungus-derived molecule that could prove to be a secret weapon against antibiotic resistance. The molecule, known as AMA, is able to disarm one of the most dangerous antibiotic-resistance genes, NDM-1 or New Delhi Metallo-beta-Lactamase-1, identified by the WHO as a global public health threat. The McMaster team, working with colleagues from Cardiff University in Wales, created a sophisticated screening method to take the NDM-1 gene, combine it with harmless E. coli bacteria and then isolate a molecule capable of stopping NDM-1 in its tracks. NMD-1 requires zinc to thrive, but finding a way to remove zinc from it without causing a toxic effect in humans was a daunting task, until the discovery of the fungal molecule, which appears to perform the job naturally and harmlessly.

Scientists then tested the theory on mice infected with an NDM-1 expressing superbug. The mice that received a combination of the AMA molecule and a carbapenem antibiotic survived, while those that received either an antibiotic or AMA alone to fight the infection did not survive. The study was published online recently in the journal Nature.4

The researchers assert that seeking an answer to the riddle of resistance in the natural environment is a more promising approach than trying to discover new antibiotics, a challenge which has perplexed scientists for decades. No new classes of antibiotics have been discovered since the late 1980s, leaving physicians with very few new tools.

At the very least, the Canadian and Welsh researchers have opened a promising new front in an ongoing war with some of humanity’s ancient enemies—enemies that we thought, incorrectly, we had vanquished forever.


  1. WHO. Antimicrobial resistance: global report on surveillance. July 3, 2014.
  2. Oren I, Specher H, Finkelstein R, et al.  Eradication of carbapenem-resistant Enterobacteriaceae gastrointestinal colonization with nonabsorbable oral antibiotic treatment: A prospective controlled trial. Amer J Infect Contr. 2013;41(12):1167-1172.
  3. DeLeo FR, Chen L, Porcella SF, et al. Molecular dissection of the evolution of carbapenem-resistant ST258 Klebsiella pneumoniae. PNAS. DOI:10.1073/PNAS.1321364111. Accessed July 3, 2014. 
  4. King MA, Reid-Yu SA, Wang W, et al., Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance. Nature. 510,503–506. doi:10.1038/nature13445. Accessed July 3, 2014.