Analysis reveals mechanisms behind pan-resistant pathogen

Scientists with the US Centers for Disease Control and Prevention (CDC) have identified the resistance mechanisms in a strain of Klebsiella pneumoniae responsible for a deadly infection in a Nevada woman in 2016.

In a new study in mBio, the scientists report that whole-genome analysis of an isolate from the bacterial strain, which was resistant to all available antibiotics, identified several resistance genes and other resistance mechanisms that explain all the observed antibiotic resistance. They also found that the isolate belongs to a strain of multidrug-resistant K pneumoniae that has spread globally.

The K pneumoniae strain, and the unusual resistance mechanisms it harbored, is an example of the type of "nightmare" bacteria that the CDC says it recently detected in hospitals in more than 30 states.

Resistance to all available antibiotics

The Nevada woman was admitted to an acute care hospital with a diagnosis of systemic inflammatory response syndrome in August 2016 after she returned from an extended trip to India, where she had been hospitalized multiple times for leg and hip fractures. The infection was caused by carbapenem-resistant Enterobacteriaceae (CRE). None of the antibiotics that physicians used to treat the woman worked, and she died of septic shock in September 2016, less than 2 months after admission.

Additional antibiotic susceptibility testing of isolates from the patient by the CDC revealed that the CRE—which had been identified as K pneumoniae—was resistant to 26 different antibiotics. The agency reported the case in January 2017 in its Morbidity and Mortality Weekly Report, and CDC officials noted how rare it was to find a pan-resistant infection in the United States.

For this study, the CDC investigators extracted DNA from an isolate of the strain and analyzed and sequenced it to get a better understanding what made the pathogen pan-resistant. Genomic analysis revealed four beta-lactamase genes—NDM-1, CMY-6, CTX-M-15, and SHV-28—that were responsible for resistance to all beta-lactam antibiotics, including carbapenems. Two of these genes, NDM-1 and CMY-6, were carried on plasmids, which are mobile pieces of DNA that can be shared within and among bacterial species and can contribute to the rapid spread of drug resistance.

The analysis also found other resistance genes, efflux pumps, and chromosomal mutations that explained resistance to fluoroquinolones, tigecycline, tetracycline, colistin, and chloramphenicol. But the mobile colistin-resistance gene MCR-1 was not detected in the isolate.

In addition, the investigators suggest the presence of the NDM-1 (New Delhi metallo-beta-lactamase) gene would have likely made the strain resistant to newer drugs like meropenem-vaborbactam or imipenem-relebactam, which combine a carbapenem antibiotic with a beta-lactamase inhibitor. That's because beta-lactamase inhibitors in these drugs don't inactivate metallo-beta-lactamase genes. However, they did not test the isolate for susceptibility to these drugs.

The strain belonged to K pneumoniae ST15, a strain that is frequently resistant to beta-lactams and fluoroquinolones. When the investigators screened the whole-genome sequence against publicly available K pneumoniae isolates in the genome database at the National Center for Biotechnology Information, they found that it likely shares an ancestor with 140 other multidrug-resistant K pneumoniae strains found in Europe, South Asia, and the United States.

Analysis of the plasmids carried by the isolate revealed similarities with plasmids carried by gram-negative bacteria strains reported in China, Nepal, India, and Kenya. The authors suggest this finding could indicate the potential origins of the isolate and the plasmids. When the case was originally reported, scientists with Nevada's Washoe County Health District told CIDRAP News they believed the woman had acquired the infecting K pneumoniae strain while she was in India.

Unusual resistance genes have spread

The deadly strain of K pneumoniae described in this study is an example of the type of CRE infections that the CDC reported finding in its most recent Vital Signs report. The report, released Apr 3, said that public health departments in the CDC's Antibiotic Resistance Lab Network had identified 221 CRE isolates from infected patients that were highly resistant and carrying unusual carbapenem resistance genes in 2017.

NDM-1 is one of the genes that was detected. It was originally identified in 2009 in a Swedish patient who had been travelling in India, and has until now rarely been detected in the United States.

The fact that NDM-1 and other resistance genes found in highly drug-resistant pathogens in other parts of the world—but not commonly in the United States—have grabbed a foothold in US hospitals and other healthcare facilities highlights the fact that dangerous pathogens know no boundaries and can easily spread in an interconnected world. CDC officials said at a press conference that the agency is focused on keeping these pathogens from spreading further.

"We are working to get in front of them, before they do become common, in order to protect patients now and in the future," said CDC Principal Deputy Director Anne Schuchat, MD.

The authors of the study say that using advanced molecular detection techniques like whole-genome sequencing could help in this effort by providing a better understanding of the origins of resistance gene like NDM-1, how bacteria acquire them, and how they spread around the globe. It could also help epidemiologists identify which bacterial strains are likely to carry these genes and need to be contained quickly.

"Moreover, this provides further insight into not only detecting these highly resistant organisms but also preventing their spread," they write.

See also:

Apr 3 mBio study

Apr 3 CIDRAP News story "CDC says its steps have limited the spread of 'nightmare bacteria'"

Jan 13, 2017, CIDRAP News story "Pan-resistant CRE reported in Nevada"

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