By Gary Evans, Senior Staff Writer
In a Canadian study1 that produced stunning results against arguably the greatest infection threat to patient safety, researchers showed that detecting and isolating asymptomatic carriers of Clostridium difficile prevented more than 60% of subsequent infections in hospital patients.
There are questions and caveats, of course, and the approach runs counter to the increasingly popular “horizontal” interventions that emphasize standard precautions and isolating less patients. Some U.S. epidemiologists and infection preventionists have found isolating a greater number of patients logistically challenging and warned of the deleterious effects on those left in isolation indefinitely.
That said, redoubled efforts against C. diff in the U.S. have yielded only grudging, incremental reductions for years. Some 500,000 people acquire C. diff annually in the U.S., and 29,000 of them die within 30 days of the initial diagnosis. Even if that death toll is winnowed down to some 15,000 deaths “directly attributable”2 to C. diff annually, that is still considerably more than the 11,325 people killed by Ebola in an outbreak that lasted more than two years. A confluence of events has led to the C. diff epidemic, including the emergence of the highly virulent NAP1 strain, the misuse and overuse of antibiotics, and the difficulty of removing C. diff spores from healthcare worker hands and contaminated surfaces. The alcohol rubs now ubiquitous in healthcare settings have little effect on the spores, and traditional soap-and-water hand hygiene doesn’t fare that much better. (See Hospital Infection Control & Prevention, April 2015.)
“Despite this menace, there have been no major advances in C. difficile prevention over the last 20 years,” says lead author Yves Longtin, MD, FRCPC, chair of the infection prevention and control unit at Jewish General Hospital in Montreal. “Institutions use the same armamentarium to control C. difficile in 2015 as they did in 1995, prior to the onset of the NAP1 epidemic. For these reasons, there was a need to identify new avenues to control the spread of this pathogen, and I think that the potential risks of isolation should not be overemphasized.”
Moreover, the CDC recently reported an 8% decrease in C. diff infections (CDIs) between 2011 and 2014. Certainly heading in the right direction, but recall that last year the White House issued a “National Action Plan for Combatting Antibiotic-Resistant Bacteria” that calls for a decrease of 50% in the number of CDIs by 2020.
“Although laudable, this ambitious goal will be nearly impossible to achieve with current infection control measures,” Longtin tells HIC. “The U.S. has been fighting against CDI for more than a decade with limited success. For the number of C. difficile infections to be cut by half within the next four years, a novel approach to infection control may be required that would need to be highly effective, safe, easy to implement on a large scale, and affordable. The detection and isolation of [asymptomatic] C. difficile carriers may represent such a promising avenue that certainly deserves to be further studied.”
Indeed, while raising several questions and caveats, a CDC commentary3 accompanying the article makes this bottom-line point: “The severity of disease and complications associated with CDI can result in tremendous distress among patients and substantial increases in cost. Preventing transmission of C. difficile is critical to limiting its serious effects, which might be more effectively achieved by targeting asymptomatic carriers in addition to symptomatic patients with CDI.”
Bottom of the berg
Current infection control measures do not generally target asymptomatic C. diff carriers, but there has been growing suspicion that they play a greater role in transmission than originally suspected. For example, a study4 in 2013 found through genomic sequencing of clinical isolates of hospital patients that only 35% of C. diff cases were genetically linked to a diagnosed case. The source for the rest was not definitively determined, but asymptomatic carriers were certainly high on the list of suspects. In that sense, the study by Longin and colleagues underscores the notion that asymptomatic C. diff carriers can contaminate the hospital environment and healthcare workers’ hands and potentially transmit C. diff to other patients.
To investigate the effect of detecting and isolating C. diff asymptomatic carriers at hospital admission on the incidence of healthcare-associated CDI, the researchers performed a controlled study between November 19, 2013 and March 7, 2015 at Jewish General. Admission screening was conducted by detecting a marker gene via PCR using rectal swabs. C. diff carriers were placed under a modified version of contact isolation precautions during their hospitalization.
“When we designed our intervention, we purposefully designed an infection control bundle that would be easier to implement than ‘traditional’ ones,” Longtin says. “For example, we did not require healthcare workers to use an isolation gown when caring for carriers, and we allowed carriers to be housed in two-patient rooms with the privacy curtain drawn. These decisions were taken to facilitate uptake in our institution.”
Changes in CDI incidence level during the intervention period (17 periods of four weeks each) were compared with the pre-intervention control period (120 periods of four weeks each) by regression analysis and statistical modeling. The control group, where the intervention was not adopted, included some 100 other institutions in the province of Québec.
Overall, 7,599 patients were screened, among whom 368 (4.8%) were identified as C. diff carriers and placed in the modified isolation. During the intervention, 38 patients (3 per 10,000 patient-days) developed a CDI compared with 416 patients (6.9 per 10,000 patient-days) during the pre-intervention control period. There was no immediate change in the level of CDIs on implementation, but there was a significant decreasing trend over time of 7% per four-week period. The researchers estimated that the intervention prevented 63 (62.4%) of the 101 expected cases. By contrast, no significant decrease in CDI rates occurred in the control group hospitals.
To put the results into perspective, the hospital now has the lowest CDI incidence rate among 22 academic institutions in the province of Québec. “The intervention is simple and could be easily implemented in other institutions,” the authors concluded. “If confirmed in subsequent studies, isolating asymptomatic carriers could potentially prevent thousands of cases of CDI every year in North America.”
If the results are confirmed in further studies, the question of large-scale implementation will certainly be raised, Longtin says.
“Overall, the bundle in our study is simply an adaptation of the contact precautions already in use in most hospitals to prevent the spread of other multi-resistant pathogens such as vancomycin-resistant Enterococcus and Carbapenemase-producing enterobacteriaceae,” he tells HIC. “Most hospitals are already using similar strategies for other purposes, so they should also be able to implement the measures contained in our bundle.”
In an accompanying commentary3 to the study, CDC C. diff expert L. Clifford McDonald, MD, credited the researchers for the striking success, but also warned against adopting sweeping measures based on one study.
“There are a lot questions,” McDonald tells HIC. “Is it feasible? What does it cost in terms of isolation, and in terms of patients in isolation? Of course, it’s a modified isolation, but it’s one study and it’s not a randomized controlled trial. Both the feasibility and the adverse effects of [patient isolation] are considerations.”
Isolation has been shown to negatively affect patients’ quality of life and can cause anxiety and depression, particularly in patients on long-term isolation, the CDC authors noted. “Using a modified approach to isolation precautions, as was done in the study … might mitigate some of the negative psychological effect, although the effectiveness of this strategy requires further evaluation,” they wrote.
Risk and reward
Given these concerns, HIC asked Longtin if the risk of negative effects of isolation is worth the reduction in infections.
“This question is a very complex one,” he says. “Some retrospective studies suggest that the use of isolation precautions may be associated with an increase in preventable adverse events. On the other hand, a large prospective randomized-controlled trial5 did not detect any difference in the rate of adverse events between isolated [gloves and gowns] and non-isolated patients.”
The question of risk vs. benefit of isolation precautions is thus difficult to answer, but given the toll of C. diff and the difficulty of preventing it, Longtin and colleagues make a compelling case for their approach.
“Regardless of the uncertainties, the benefits of the intervention in our institution are — in my humble opinion — greater than the risks of isolation,” he says. “We [determined] that that the intervention prevented 63 healthcare-associated cases over the course of 15 months.”
Though the study did not measure the effect of the intervention on morbidity and mortality, other studies have estimated that 10% of CDI cases require admission to the ICUs and assign an attributable mortality of approximately 5%, he adds.
“If we apply these numbers to our population of patients, preventing 63 cases over the course of 15 months would have prevented six admissions to the ICU and would have prevented three deaths,” Longtin says. “If this is the case — and further studies are required to confirm our findings — then the benefits of detecting and isolating C. difficile carriers most probably outweighs the risks of isolation.”
The CDC commentary pointed out — as was reported in the paper — that for every single CDI case prevented, 121 patients had to be screened, and six asymptomatic carriers had to be isolated. Looking purely at costs, it would seem the approach may be too expensive for some institutions, but then the value of the prevented infections has to be calculated into the equation.
Though conceding it was a preliminary estimate, Longtin and colleagues said the intervention was cost-effective. The intervention cost $130,000 in U.S. dollars but prevented approximately 63 cases. Because each case costs between $3,427 to $9,960, the savings in averted CDIs would range from $216,000 to $627,000 – both exceeding the costs of the intervention.
“The savings in averted cases could be even greater if we factor in the fact that preventing CDI cases also ultimately prevents recurrences,” Longin says. “Preventing 63 cases also probably prevented between six and 10 recurrences, but we did not [factor that] in our cost-effectiveness analysis. The main cost of this strategy is the cost of the screening. Commercial PCR [tests] that can be used to detect carriers are relatively expensive at the moment, but prices could drop in the future due to improvement in technology and economies of scale. It should be emphasized that current PCRs are not approved [by the FDA] at the moment for the detection of C. difficile carriers.”
The CDC made that point as well, adding that there is no standardized method for detecting asymptomatic carriage of C. diff. Likewise, McDonald is well aware of the possible pushback from enthusiasts for “horizontal” infection control, who argue it is better to take standard measures to prevent all infections rather than “vertical” approaches aimed at single pathogens.
“This is an intense vertical intervention where you are going after one type of [pathogen] by capturing all of the colonized patients,” he says. “There’s other things you can do [to reduce C. diff] like antibiotic stewardship. It was a good study though. They actually had a little increase in antibiotic use and yet they saw this decrease.”
Prior studies have suggested as much as 60% of CDI cannot be traced back to a symptomatic case, he notes. “There have also been important studies suggesting that in endemic situations — where you are not having an outbreak and you have been doing things to control transmission from symptomatic cases — then fewer and fewer new cases are due to previously infected patients.”
There is also the fact that the most basic of horizontal measures — hand hygiene — has little effect on C. diff.
“We know that is the Achilles heel with the alcohol-based hand sanitizers that are widely used,” McDonald says. “So this would be one way to identify who the [C. diff patients] are and maybe use gloves in addition to hand hygiene. Also, if you wanted to be selective in the use of sporicidal disinfectants, you could be selective with these patients as well.”
In addition, chlorhexidine bathing — another common horizontal measure — has not been shown to decrease the incidence of C. diff infections, probably because chlorhexidine does not destroy spores, Longtin says.
“Overall, horizontal strategies could be attractive if they were able to destroy C. difficile spores,” he says. “If, on the other hand, the horizontal measures fail to limit the spread of spores, they may be of limited use to contain C. difficile.”
Although the study design was not as rigorous as a cluster randomized approach, multiple statistical methods were used to measure the effect of the intervention, McDonald noted in the commentary. Larger, well-designed studies are ultimately needed to confirm the effectiveness of the strategy. Similar investigations need to be conducted in long-term care settings, where there can be a larger reservoir of asymptomatic C. diff colonization. Further efforts are also needed to explore other strategies for reducing transmission of C. diff from asymptomatic carriers, including decolonization, enhanced disinfection of the skin and environment to reduce the burden of spores, and decreased use of antibiotics, he noted in the commentary.
The CDC is interested in performing follow-up studies and McDonald says other researchers may follow suit to see if the promising findings can be repeated.
“With this kind of result I think it should be done somewhere,” he says.
- Longtin Y, Paquet-Bolduc B, Gilca R, et al. Effect of Detecting and Isolating Clostridium difficile Carriers at Hospital Admission on the Incidence of C difficile Infections: A Quasi-Experimental Controlled Study. JAMA Intern Med. Published Online: April 25, 2016. doi:10.1001/jamainternmed.2016.0177.
- Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile Infection in the United States. N Engl J Med 2015; 372:825-834.
- Guh AY, McDonald LC. Active Surveillance and Isolation of Asymptomatic Carriers of Clostridium difficile at Hospital Admission: Containing What Lies Under the Waterline. JAMA Intern Med. Published online April 25, 2016. doi:10.1001/jamainternmed.2016.1118.
- Eyre DW, Cule ML, Wilson DJ, et al. Diverse Sources of C. difficile Infection Identified on Whole-Genome Sequencing. N Engl J Med 2013;369:1195-1205.
- Croft LD, Harris AD, Pineles L, et al. The Effect of Universal Glove and Gown Use on Adverse Events in Intensive Care Unit Patients. Clin Infect Dis 2015;15:61(4):545-553.