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By Gary Evans, Medical Writer
A national containment strategy using powerful lab detection techniques and rapid intervention with infection control measures is blunting the emergence of pan-resistant pathogens, the Centers for Disease Control and Prevention reports.
Though it has implications for many multidrug-resistant organisms (MDROs), the CDC containment and intervention strategy1 is currently focusing on carbapenem-resistant Enterobacteriaceae (CRE).
With a mortality rate in the 50% range for vulnerable patients, CRE strains can be resistant to the full antibiotic formulary — including the last-line class from which it draws its name. For example, a hospitalized patient in Reno, NV, died in 2016 of a CRE strain that was resistant to 26 antibiotics.2 Of note, the patient had recently been hospitalized in India, where the specific enzyme conferring pan resistance — New Delhi metallo-beta-lactamase (NDM) — was first discovered.
The CDC is concerned that NDM and other unusual mechanisms of resistance will gain an endemic presence, and the report cites 221 cases — out of 5,776 CRE isolates tested — where particularly aggressive eradication efforts were taken.
“These results prompted an aggressive response including many infection control assessments and colonization screens,” Anne Schuchat, MD, CDC principal deputy director, said at a recent press conference. “The screenings showed that about one in 10 of these [CRE] could have continued spreading if left undetected.”
Picking up more than 200 CRE with unusual resistance mechanisms in nine months of lab surveillance data is a sobering finding, particularly when these bugs are viewed as the potential seeds of outbreaks.
“I was surprised by the numbers that we found,” she said. “That was more than I was expecting, but it’s the beginning of looking. We hope, though, that this won’t be an inevitable march upward. By finding them early when there’s only one in the facility, we can stop this from becoming common.”
Highly drug-resistant pathogens like CRE not only threaten fatal infections in single patients; they have an insidious reach beyond the clinical moment, undermining the general protective effect of antibiotics used prophylactically to keep infections from setting in after surgery, organ transplant, or cancer treatment that blasts the immune system.
The new CDC report focuses primarily on more recent data, but the CDC has been wary of CRE since it first appeared in the U.S. more than a decade ago. Efforts to respond to index cases and trace patient contacts are paying off.
Surveillance data show something unusual — a superbug in rare retreat. Though at least one type of CRE has been reported in all 50 states, overall the class of Enterobacteriaceae that are resistant to carbapenems has gone down over time, explained Arjun Srinivasan, MD, CDC associate director for healthcare-associated infections and prevention programs.
“That was a real encouraging finding,” he told Hospital Infection Control & Prevention. “We don’t typically see a drop in overall resistance, but we are seeing that with CRE.”
For example, in 2007 10.6% of all Enterobacteriaceae were carbapenem-resistant, but that dropped to 3.6% in 2015, the CDC reported.
“We have actually seen a dramatic reduction — about 15% per year — in the percent of Enterobacteriaceae that are carbapenem-resistant,” Srinivasan says. “It lends support to the containment strategy, which takes elements of what we have learned in our efforts to control CRE. This new infrastructure takes it to the next level because of the increased response capacity.”
The CDC has implemented the Antibiotic Resistance Lab Network (ARLN), which uses whole genome sequencing to rapidly detect MDROs and genetically describe their resistant mechanisms in great detail. Established in 2016, the network includes labs in 50 states, five cities, and Puerto Rico. The CDC also has state and local public health officials ready to implement containment measures once CRE is detected. The CDC says it is “encouraging healthcare facilities and public health authorities to respond to [even a single case] of an emerging antibiotic-resistant pathogen.”
“We need clinicians and labs in hospitals to be aware of this opportunity, to look for the resistant infections and recognize they can get help,” Schuchat said. “Many clinicians and facilities may not have been aware of this, or they may not have been looking because they weren’t able to keep up with the response strategy.”
Always savvy in public health messaging (the CDC has described pandemics in terms of zombie attacks), the agency previously dubbed CRE the “nightmare bacteria” because it can spread resistance to other organisms.
“The bottom line is that resistance genes with the capacity to turn regular germs into ‘nightmare’ bacteria have been introduced into many states,” Schuchat said. “But with an aggressive response, we have been able to stomp them out promptly and stop their spread between people, between facilities, and between other germs.”
The threat is not really overstated by the pulp fiction moniker, as CRE genes that can confer resistance to whole classes of antibiotics can be transferred via plasmids to other bacteria. That is a haunting shortcut compared to the evolution of resistance through a kind of natural selection, as antibiotics typically kill down the susceptible bugs and open a niche for those with inherent resistance to multiply. The plasmid problem means IPs and public health officials could awake to wonder if some extremely common pathogen — E. coli, for example — is becoming impervious to antibiotic treatment.
“The resistant plasmids pose the greatest threat,” Srinivasan told HIC. “That’s one of the reasons why we are so worried about this type of resistance in CRE. They don’t just move between strains of the same bacteria. It can be a Klebsiella donating to a Pseudomonas. There is a tremendous potential for spread when you are talking about a plasmid.”
Indeed, the CDC listed CRE as an urgent public health threat, its highest-level alert, in a previous report listing a murderer’s row of antibiotic resistant pathogens.
Though bacteria are endlessly resilient, it appears the CDC has come up with a promising strategy.
Using the ARLN labs and containment response, the CDC works with state and local health departments to assist healthcare facilities with CRE and other bugs of concern. The lab confirmation of CRE triggers a public infection control assessment of the facility by local public health officials under CDC guidance.
“These health departments will often go on site — this is not just a phone call,” Srinivasan said.
“In many instances, the health department staff will work directly with the infection experts and practitioners in the hospital to do observations of hand hygiene, contact precautions, and environmental cleaning.”
CRE and other MDROs are notorious for moving across the continuum, passing quietly through checkpoints from skilled nursing facilities, long-term care, hospitals and back again. If anything can overcome the CDC detection and containment strategy, it is probably a lack of communication and documentation by local facilities sharing patients.
“These weren’t just in hospitals,” he said. “I think that’s an important point. We know that the healthcare system is connected by patients. And when patients move, the resistant bacteria move with them.”
Long-term care is particularly vulnerable to CRE and similar gram negatives, as residents often are on antibiotics, interaction is encouraged, and isolation is difficult. In a previous modeling analysis, the CDC projected that 10 facilities sharing patients — but not collaborating — would see their overall level of CRE increase by 12% (2,000 infections) in five years.
“CDC estimates show if only 20% effective, the containment strategy can reduce the number of [CRE] by 76% over three years in one area,” Schuchat said. “That will let us bend the curve or slow the spread of rising resistance.”
Edward Septimus, MD, FIDSA, FACP, FSHEA, medical director of infection prevention and epidemiology at HCA Healthcare in Houston, gave a real-world example of how communication and collaboration with other facilities can prevent “silent transmission” of CRE. There is a CDC ARLN lab in Houston, explains Septimus, who was not involved in the CDC report.
“About six months ago, we had two patients come in to the hospital that were on ceftazidime/avibactam, which is one of the new beta-lactamase inhibitors that have high activity against CRE,” he told HIC.
The patients came in the same week, drawing the attention of an infection preventionist and a clinical pharmacist, who was monitoring use of the new antibiotic.
“It turned out they came from the same nursing home,” he said.
Septimus and colleagues contacted the nursing home to alert them to the situation, and began pre-emptively isolating patients who came in from the facility.
“They were immediately put in contact precautions and they were actively screened,” he said. “We were able to reach out and help the nursing home because they don’t have the same resources as an acute care hospital.”
Meanwhile, the isolates from the first two patients had been sent to a CDC network lab, enabling a detailed view of the resistance genes.
“They pick up a number of unique resistance genes that have not been commonly seen before because these labs actually do genomics on organisms,” he said. “I think it’s a real advantage to have the lab infrastructure that can assist in identifying these MDROs.”
Trying to find these mechanisms of resistance with the old microbiology techniques was difficult.
It took longer to identify pathogens and afforded less detail on transmission.
“You could have someone who had CRE, and it took five days in the laboratory to identify it,” Septimus said. “With molecular [tests] for certain genes, you can pick up these mechanisms much faster.”
Genomic details can show patterns of transmission, but in this case none occurred, in part because the index patients were in private rooms before the CRE was identified.
“This was unusual, but I’m happy to say we have not seen any more [CRE] from that nursing home,” he said.
“But we want to pick these people up early and not have silent transmission, because that’s what often happens,” he added. “With whole genomic sequencing, we can figure how it is being transmitted. Remember, we are in a global community.”
The CDC report described similar incidents, including one in Iowa, where a nursing home resident with a UTI was found to have CRE.
“Over the following weeks, the Iowa Department of Health and the nursing home did several on-site assessments to identify any gaps in the infection control that might have let this germ spread,” Schuchat noted at the press conference.
The patient had lived in the nursing home for several years, with no history of surgery or hospital care.
Given that, investigators suspected transmission was occurring within the facility.
A containment team was dispatched, and 30 residents were tested.
“Sure enough, five others were carrying the resistant gene,” Schuchat said.
“By following infection control protocols — simple steps like consistent use of gloves and gowns — workers at the facility were careful not to let [CRE] spread further,” she added.
In addition, last year the CDC and the Tennessee Department of Health identified an unusual CRE type, and an infection control assessment and screening of hospital contacts was completed within 48 hours.
“No transmission was identified,” the CDC concluded in the report.
“Because the index patient had a recent healthcare exposure in another country, ARLN regional laboratories expanded their services to perform CDC-recommended admission screening for patients with a history of overnight healthcare stays outside the United States during the preceding six months.”
The international aspect of this enforces the conventional wisdom in an era of emerging infections and global travel: Any bug anywhere can be just about anywhere else within 24 hours.
“It’s important to recognize that even in remote areas, the threat of highly resistant gram-negative pathogens is real,” Jay Butler, MD, past president of the Association of State and Territorial Health Officials, said at the CDC press conference.
“We can’t wait until one case becomes 10, or 10 cases become 100,” he added. “We can intervene early and aggressively to stop spread. Unusual resistance is relevant to all of us. These organisms don’t care about state or city lines.”
In addition to far-flung threats, the containment response and lab testing should work on other problem pathogens beyond CRE, including emerging multidrug-resistant Candida auris.
“The system is built that way,” Srinivasan says. “It is intended to respond to whatever is next. People ask me which resistant organism worries me — the one that worries me the most is the one I that don’t know about. Resistance always evolves.”
Financial Disclosure: Peer Reviewer Patrick Joseph, MD, reports that he is a consultant for Genomic Health Reference Laboratory, Siemens Clinical Laboratory, and CareDx Clinical Laboratory, Senior Writer Gary Evans, Editor Jesse Saffron, Editor Jill Drachenberg, Nurse Planner Patti Grant, RN, BSN, MS, CIC, and Editorial Group Manager Terrey L. Hatcher report no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.