By Carol A. Kemper, MD, FACP

Dr. Kemper reports no financial relationships relevant to this field of study.

Multi-Modal Interventions for Controlling CRE: Which Is Best?

SOURCES: Tomczyk S, Zanichelli V, Grayson ML, et al. Control of carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa in healthcare facilities: A systemic review and reanalysis of quasi-experimental studies. Clin Infect Dis 2019;68:873-884;
Bleasdale SC. Do we need another study to control carbapenem-resistant organisms, or do we just need to get better at the basics? Clin Infect Dis 2019;68:885-886.

No one doubts that the emergence of carbapenem-resistant Gram-negative organisms (CRO), specifically carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Acinetobacter baumannii (CRAB), and carbapenem-resistant Pseudomonas aeruginosa (CRPA), presents a serious threat to healthcare facilities, resulting in outbreaks and increased mortality. A United Kingdom Review on Antimicrobial Resistance published in May 2015 estimated that 10 million people will die annually by the year 2050 because of antimicrobial resistance and ineffective antimicrobials. Some of this resistance has the potential for widespread transmission based on the presence of mobile plasmids, which can readily jump strains of bacteria, while others persist in the environment and successfully resist ordinary cleaning measures.

Hospitals are under siege as patients unwittingly carry these organisms with them into the hospital. The trick is, who are these people and what do we do about it before transmission or an outbreak actually occurs?

Both the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) have urged measures to stop the spread of carbapenem-resistant organisms within healthcare facilities, although clear guidelines, based on rigorous research, are lacking about how to best accomplish this task. For one reason, infection prevention (IP) strategies aimed at reducing infection do not readily lend themselves to randomization, and even the largest hospitals would not be able to produce a clinical trial with sufficient statistical power. Tomczyk and colleagues performed a systematic analysis of published articles and abstracts on carbapenem-resistance IP measures, yielding 76 articles with meaningful data, most of which were performed in the United States and Europe (46 concerning CRE, 26 on CRAB, and 13 on CRPA). Seventeen of these studies were non-randomized before-and-after or interrupted time series studies, providing an opportunity to assess the effect of bundled IP interventions on outcomes. The most common outcome in these studies was the incidence of infection. Hardly a meta-analysis, the interventions were too varying and the data were “of low or very low quality.” The authors termed their effort a “quasi-analysis.”

Most of these studies combined three or more IP interventions in a “multi-modal strategy,” including 10 (91%) CRE studies, four (80%) CRAB studies, and three (100%) CRPA studies. Interventions included contact precautions (variously defined, but at a minimum including gowns and gloves) in 90%, active surveillance (80%), monitoring, audit and feedback (80%), isolation of patients in private rooms (or cohorting; 70%), hand hygiene (50%), and environmental measures (40%). Active surveillance strategies varied but included culture of feces or rectal swabs from all patients (e.g., ICU) or high-risk patients (e.g., those with previous colonization or infection), either on admission or at various intervals. Hand hygiene may have been included as a stated intervention in only half of the studies since it was considered a baseline or standard of care measure and not explicitly an intervention. Contact precautions in some studies were described as “strict” or “enhanced.”

All of these IP measures were observed to reduce the incidence of outcomes significantly over time. The most effective strategy reported at several facilities appeared to be a combination of active surveillance, pre-emptive contact precautions with isolation pending those results, contact isolation measures, and healthcare worker education with renewed focus on hand hygiene. Another successful study combined an even broader range of interventions, including active surveillance of at-risk patients, pre-emptive isolation for all patients, patient and staff cohorting, chlorhexidine bathing, limiting public access to rooms and common areas, terminal cleaning, audit and feedback on hand hygiene, contact isolation, environmental cleaning, and antibiotic stewardship. (Our facility does all of this.) Even with this extensive effort, the effect was perhaps a 50% reduction in outcome. Other less commonly used interventions included chart flagging, alerts, temporary ward closure, task force meetings, and analysis of workflow to examine how equipment is passed from patient to staff to patient.

The intervention with the strongest supportive evidence appeared to be active surveillance for CRE, although surveillance strategies varied between studies, the types of cultures performed varied, and the targeted populations differed. At-risk patients were defined most often as those with a history of an overnight stay in a healthcare setting in the past 12 months; dialysis dependence; receipt of cancer chemotherapy; known previous infection or colonization in the previous 12 months; or linkage to another recognized CRE case. In addition, patients presenting from long-term care or with long-term mechanical ventilation were targeted by some as high risk. Studies that favored active surveillance also often pre-emptively isolated high-risk patients pending the results. (Our facility does this.)

Only three (30%) of the CRE studies, three (60%) of the CRAB studies, and two (70%) of the CRPA studies included environmental cleaning measures in their interventions. Again, various strategies were employed, but as part of a bundle of interventions, they appeared to reduce the incidence of outcomes over time.

Although bundled interventions uniformly had some beneficial effect on reducing outcomes, the contribution of any particular intervention remains cloudy. An interesting question remains whether a combined approach is truly necessary to achieve a beneficial outcome, or whether performing one good intervention really well 100% of the time is sufficient. Although the latter approach may have appeal, it is my opinion (having worked in this area for years) that a combined approach is necessary. How can you best isolate the highest risk patients but not perform some kind of surveillance? What good is isolation if your staff have lax hand hygiene, or if the bedrails, tray tables, and sinks are not well cleaned?

Perhaps our success with controlling hospital-onset Clostridioides difficile (HO-CD) infection can best illustrate this point. Once a facility with the highest HO-CD rate in California, our hospital implemented 10 years of successive IP interventions that have resulted in a clear step-wise reduction in our rate. These interventions began with a hand hygiene campaign in 2009-2010, an effort to strengthen contact precautions in 2012-2013, and then continued with active surveillance of high-risk individuals and pre-emptive isolation in 2013-2015. Gradually, our rate was cut by > 75%. But it was not until we implemented more aggressive daily and terminal cleaning measures, including UVC of all C. diff. and ICU rooms, in 2016 that we saw our rates drop by > 90%. More recently, we implemented a nurse-driven protocol for pre-emptive isolation and testing of patients with diarrhea. I hesitate to confess that this 10-year effort was not conducted with logic of forethought, but, as the editorialist suggested, more of a “hierarchy of hazard control” with step-wise implementation of interventions as they gained support in the literature and were driven by need. Using this combined approach, our HO-CD rates are the best in California.

Although everyone knows that something obviously needs to be done with CRO, it is not entirely clear what works best for hospitals. Our very own success story with CD is my best justification for a multi-modal approach for controlling CRO in our facility.

Antimicrobial Resistance Genes — in the Arctic

SOURCE: Antibiotic resistance — Norway: (Svalbard) NDM, high arctic region. ProMED-mail post. International Society for Infectious Diseases. Feb. 7, 2019. Available at: Accessed April 8, 2019.

For a recent study, researchers combined sophisticated geochemistry and high throughput qPCR technique to examine the frequency of antimicrobial resistance genes (ARGs) and mobile genetic elements (plasmids) in the remote Kongsfjorden region of Svalbard, Norway. Surprisingly, in this remote region, researchers found several ARGs, including the blaNDM-1 gene, which was first detected in India in 2008. Soil samples from eight areas yielded detectable levels of ARGs much higher than chance would allow. The levels of ARGs ranged from 10 (-6) to 10 (-4) copies/16s rRNA gene copy, suggesting these bits of genetic material were not naturally occurring but had been introduced into the area. Soil clusters with higher levels of ARGs showed elevated secondary nutrients, whereas soil clusters with lower readings were more likely to be consistent with rock with low nutrient levels. These results led to the supposition that bird or other wildlife guano, or dissemination of human waste, somehow had resulted in the dissemination of these resistance genes to this northern outpost.

Svalbard is a cluster of islands in the Arctic Ocean, directly north of continental Norway and about 810 miles south of the North Pole. Remarkably, it is not barren of human life, but it sports a longstanding mining community, a local government, and a research station. A secure seed bank is sequestered there, buried in a local mountain. It is also apparently a tourist “end-destination” for those interested in dog sledding or glacier watching. How many people populate the area in a year, and how human waste is managed, is not clear from this article. I was curious to know how much CRO-colonized guano or human waste theoretically could result in this miniscule environmental finding.

Updated PEP Guidelines for Hepatitis A Vaccine

SOURCE: Nelson NP, Link-Gelles R, Hofmeister MG, et al. Update: Recommendations of the Advisory Committee on Immunization Practices for the use of hepatitis A vaccine for postexposure prophylaxis and for preexposure prophylaxis for international travel. MMWR Morb Mortal Wkly Rep 2018;67:1216-1220.

In November 2018, the Advisory Committee on Immunization Practices provided updated guidelines on the use of hepatitis A (HAV) vaccine and immune globulin (IG) for postexposure prophylaxis (PEP) and for pre-travel prophylaxis. Previous recommendations for PEP included HAV for those 12 months and 40 years of age, at which point, IG was to be administered to older adults > 40 years of age. Children < 12 months also received IG, since HAV has not been licensed for infants. However, the administration of IG for pre-travel prophylaxis often precludes the receipt of other necessary vaccines, such as measles, mumps, and rubella (MMR), which is increasingly necessary for travel abroad.

Updated recommendations include:

  1. Postexposure prophylaxis with a single dose of HAV vaccine within two weeks of exposure for children and adults 12 months of age, including those older than 40 years of age;
  2. In addition to HAV vaccine, individuals > 40 years of age also may receive IG depending on the provider’s risk assessment of the exposure;
  3. Children 6-11 months of age also may receive HAV vaccine for travel outside of the United States to areas of HAV risk; this travel dose does not count toward their later routine two-dose HAV vaccination;
  4. For those adults and children 12 months of age or older who have not completed the usual two-dose HAV vaccine series, a second dose of HAV vaccine should be administered at least six months after the first dose to complete their vaccine series;
  5. Adults and children 12 months of age or older with compromised immunity or chronic liver disease who have not completed the usual two-dose HAV vaccine series should receive both HAV vaccine and IG.

When administered within two weeks of exposure, the HAV vaccine’s protection historically has approached that of IG in healthy adults and children. However, there are concerns that IG for HAV prophylaxis may be losing its efficacy, based on diminishing antibody titers. Therefore, a higher dose of IG (0.1 mL/kg) was recommended in 2017, which has been updated throughout these recommendations. IG should be administered in an area separate from HAV vaccine when given concurrently.