Can We Ever Get Rid of C. Diff?

Last spring, investigators with the Centers for Disease Control and Prevention (CDC) had some good news to report about an infection that had for years sat at the top of the threat list: Clostridioides difficile. The estimated national burden of C difficile infection (CDI) and associated hospitalizations, they said, had dropped 24% between 2011 and 2017, “owing to a decline in health care-associated infections [HAIs].”1

Despite that welcome decline, though, recurrent CDI remains one of the most important treatment challenges. In 2017, for instance, there were an estimated 38,500 health care–associated cases.2 Since the early 2000s, CDI has multiplied in incidence and severity, becoming the most common nosocomial infection.3 Part of that increase is due to more sensitive testing, which can contribute to higher case detection. And although health care-associated C difficile has been trending downward, the same is not true of community-acquired C difficile, which is on the rise.

C difficile infection is costly—both in economic and human terms. Between 1986 and 2013, CDI was among the top 5 most expensive HAIs in the United States.3 The burden of CDI adds an estimated 3 to 20 extra hospital days per patient with an additional cost of $1 billion in the US.3

Avalere Health, a health care consulting firm, conducted a retrospective cohort study of more than 268,000 Medicare recipients diagnosed with C difficile and recurrent CIDs (rCIDs) from 2010 through 2016. The investigators evaluated health care resource utilization and all-cause, direct medical costs associated with the infection. They found that 1 in 3 patients with C difficile had a recurrence within 12 months, and more than half of the patients with at least 1 recurrence experienced 2 or more after that first episode. Patients with C difficile spent 18 days in the hospital on average compared with 13 days for those with no recurrence.4

Admission Rates

Total all-cause, direct medical costs per patient over 12 months were highest in those with 3 or more recurrent episodes, primarily driven by hospitalizations. Inpatient costs were $31,614 per patient with 3+ recurrences versus $22,722 per patient without an rCDI episode. Recurrent CDI was also associated with higher overall health care costs and higher out-of-pocket costs for patients.

“Significantly,” the Avalere investigators say, “during the 12-month follow-up period, hospital admission rates increased in parallel with the number of recurrences”: 13% of patients with CDI experienced 4 or more hospitalizations within 12 months, while 25% of those with 3 or more recurrences were hospitalized 4 or more times.

C difficile carries a hefty price tag: $5 billion in direct health care costs annually.5 Most of the cost is due to morbidity and mortality. Between 1998 and 2008, the proportion of patients with complicated disease (eg, megacolon, perforation) jumped from 7% to 18%, and 30-day mortality nearly doubled, from 4.7% to 13.8%.3 More than 15,000 people die of CDI every year in the US; CDI and recurrent CDI is the seventeenth leading cause of death in people 65 and older.4,5

Co-infections are another complicating factor. COVID-19, for instance, manifests with GI symptoms similar to those of CDI.6 In a small Mayo Clinic study of 21 patients given a diagnosis of COVID-19 and CDI within 4 weeks of each other, 30-day mortality was 19%, mostly in the elderly. “Whether co-infection results in worsening mortality or more complications remains unanswered,” the investigators write. They note that the patients were not treated with antibiotics for COVID-19, and CDI seemed to have developed due to prior antibiotic exposure for other indications.

Sepsis takes the harmful potential of C difficile and turbocharges it. In an online interview with HCPLive®7 about an Avalere study of patients with CDI, economist Christie Teigland, PhD, vice president, Advanced Analytics, Avalere Health, said, “The main takeaways [from the study] were really the very high rates of sepsis among patients who get C difficile and particularly those who have recurring instances of C difficile. And that carried through with all of the health care resource utilization metrics we looked at, from inpatient stays to post-acute care use, lots of skilled nursing facility use, where they also have a high risk of sepsis and C. difficile, and longer stays in the ICU.

“The costs are strikingly high for these patients—$42,000 a year for patients with recurrent C difficile, with sepsis, and those were the patients who died, but the costs were even high in patients who did not die. For those who died, the follow-up was really short. I think the shortest was 12 days. These patients, once they have C difficile and sepsis, have higher odds of dying. So, the whole message here is what can we do to, number 1, prevent C difficile and number 2, sepsis, because the combination of those two is deadly.”

Many current estimates of the poor outcomes and costs associated with CDI “do not take into account the underlying severity of illness among patients who develop CDI and may overestimate the true attributable outcomes,” according to a 2020 meta-analysis that found a pooled incidence of hospital-onset CDI of 8.3 cases per 10,000 patient-days.8

CDI Management

This June, the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) released a new clinical practice guideline on management of CDI in adults. Since 2017, the authors say, when the guideline was last published, “new relevant evidence has emerged for treatment options.” This 2021 “focused update” specifically addresses the use of fidaxomicin and bezlotoxumab (a monoclonal antibody that targets toxin B produced by C difficile). Both agents have increased clinical efficacy and other advantages over older agents, the authors say, but implementation may be challenging because of initial monetary cost and logistics.

The new guideline also notes that the FDA has published 3 separate safety alerts on fecal microbiota transplantation (FMT) (which is recommended, although only for patients with multiple recurrences of CDI for whom antibiotic treatments have failed, and where appropriate screening has been performed). Two alerts document transmission of pathogenic Escherichia coli from donor to FMT recipients. The other alert concerns the potential for transmission of SARS-CoV-2. According to researchers from Mayo Clinic, with appropriate screening, FMT is safe to perform during the pandemic. In their study of 57 patients who underwent FMT for rCDI, none developed COVID-19.9

CDI is an old enemy and health care professionals have gathered an armamentarium of weapons against it, but it can be relentless. “Clearly,” says Teigland, “we know that hospitals and nursing homes take precautions to prevent sepsis and prevent C difficile.… The impact is just so devastating in this frail elderly population, you know, they’re already suffering from multiple chronic conditions, hypothyroidism, hypertension, diabetes, asthma, COPD, many comorbidities. C difficile and sepsis on top of all that is just devastating. Ultimately, more attention needs to be paid to those high-risk patients.” But, she adds, “We can predict who’s high risk because we know what the preceding risk factors are. Our study even looked at what the risk factors were in the most recent 7 to 12 months, right before the C difficile happened. Their conditions got much worse in the 6 months right before they had their first case of C difficile. So when you see those worsening effects happening, you really need to pay much more attention to the protocols that they have in place already. We know hospitals have protocols in place to prevent sepsis and C difficile, you really need to pay attention to these patients because it’s still happening way too much.”

The bedside is still a good place to keep watch. A paper-based bedside C difficile screening tool to reduce inappropriate testing could make a big cost difference to the 25% of hospitals that don’t use clinical decision support in their electronic health records, say investigators from Adventist Health-Simi Valley. Nurses used the screening tool to determine whether stool should be sent for C difficile testing. The researchers collected data on the number of C difficle stool tests performed before and after the intervention: They found a 31% drop in the mean monthly number of tests performed and a 56% reduction in CDI diagnoses.10

In an intervention tested at Hospital General Universitario Gregorio Marañón, in Madrid, after a positive C difficile test, patients immediately received a bedside visit from an infectious disease physician. The timely visit allowed for more targeted treatment, reducing overdiagnosis. Identifying the patients who do not meet the criteria for diarrhea and are simply carriers makes it possible to withdraw treatment from a large contingent, the researchers say.11

The ID physician was instrumental in identifying 29 cases as only colonized with C difficile, in which fecal sample collection was unnecessary. In 22 of those cases (76%), physicians in charge accepted the ID consultants’ recommendations to stop or not initiate CDI treatment in asymptomatic patients. Unnecessary non-CDI antibiotics were discontinued in 19% of cases. Only in 13% of the 214 cases were the ID recommendations not accepted by physicians in charge.

The cost of the intervention was estimated at €6800 (approximately $7800) during the study period, while the estimated costs of savings from antimicrobial discontinuations only were estimated at €1799 (approximately $2000).

Less Is More

The CDC investigators who reported on the decline in health care-associated C difficile infection say several factors were probably involved, including a decline in the epidemic strain ribo-type 027, which might be partly driven by reduced fluoroquinolone use.1 They cite a 2020 study that found hospitals that reduced fluoroquinolone use by 30% also saw a 19% reduction in hospital-onset CDI. They also point to a “greater emphasis on diagnostic stewardship” and reducing inappropriate testing.

Sometimes, less is more. Most hospitals implement interventions simultaneously in “bundles,” say researchers from the University of Michigan and the University of Wisconsin, and more than half of the bundles in a recent review included at least 6 components. But that may be costly overkill.

In their economic evaluation study, these researchers used an agent-based simulation of C difficile transmission at a 200-bed model tertiary acute care hospital to compare the cost effectiveness of nine single-intervention strategies and 8 multi-intervention bundles. They defined cost effectiveness by two measures: cost per hospital-onset CDI averted and cost per quality-adjusted life-year (QALY).5

Five of 9 enhanced-level strategies were “dominant,” reducing cost, increasing QALYs and averting CDI: Daily cleaning was the “most clinically effective and cost-effective intervention by far,” saving $358,268 and 36.8 QALYs annually, while averting 26 CDIs. Next came health care worker hand hygiene, patient hand hygiene, terminal cleaning, and reducing intrahospital patient transfers. (Daily cleaning prevented more than 16 times as many infections as the patient transfer intervention.) Contact precautions, while a mainstay of CDI prevention programs, are based on slim evidence, the researchers say, given that C difficile-targeted studies are lacking. In their study, they found neither health care worker nor visitor contact precautions were cost effective. Enhanced-level health care worker contact precautions cost $123,264 per QALY, and the ideal-level implementation $136,135 per QALY. “The results were even worse,” they say, for the visitor contact precaution interventions, with the ideal level costing $1,669,089 per QALY.

The bundles were only as cost effective as the parts they assembled. For instance, adding patient hand hygiene to the health care worker hand hygiene intervention saved a mean of $32,588 and 4.2 QALYs annually. When screening, health care worker hand hygiene and patient hand hygiene interventions were sequentially added to daily cleaning to form bundles, the incremental cost-effectiveness ratios for the additions were $29,616, $50,196, and $146,792 per QALY, respectively. Patient hand-hygiene, which, the researchers point out, is “rarely incorporated into C difficile bundles,” was cost saving at both the enhanced and ideal levels. Their back-to-basics advice: Institutions should “seek to streamline their infection control initiatives and prioritize a smaller number of highly cost-effective interventions.” Daily sporicidal cleaning, for example, they suggest, might be more useful and money-saving than minimally effective, costly strategies, such as visitor contact precautions.

Suggesting using fewer (albeit highly effective) interventions “runs contrary to the current infection control climate,” the researchers acknowledge. And while many of the interventions in their study saved money, they were not without upfront costs. Even at the enhanced level, each intervention required additional infection control nursing staff.

“Hospital administrative buy-in and financial support is key,” they emphasize, “to both the initial implementation of an intervention and sustaining its long-term success.” Throwing more money at the problem isn’t the solution—but throwing the right kind of money could be.

JAN DYER is a writer and editor specializing in clinical topics. She lives in Suffern, New York.

References:

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2. Johnson S, Lavergne V, Skinner AM, Gonzales-Luna AJ, Garey KW, Kelly CP, Wilcox MH. Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults. Clin Infect Dis 2021;14 June 2021, ciab549, https://doi.org/10.1093/cid/ciab549. Accessed 07/26/21.
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