Gina Battaglia, PhD

COVID-19 booster shots play a critical role in protecting against infection, hospitalization, and death related to COVID-19 infection, according to infectious disease experts who participated in a recent 

professor of medicine and anesthesiology, Columbia University Vagelos College of Physicians and Surgeons, New York City, New York. However, the panelists added that achieving herd immunity with vaccination may be difficult with the widespread vaccine hesitancy and lack of access to vaccines in developing countries. The panelists reviewed the importance of COVID-19 booster shots for promoting durable immunity, the benefits of COVID-19 vaccination on the individual and public health levels, and the role of booster shots in protecting against new virus variants.

The purpose of the COVID-19 booster is to potentiate the immune system and provide an additional layer of protection from infection, hospitalization, and death, according to 

associate professor of microbiology and immunology at Meharry Medical College and adjunct associate professor of pathology, microbiology, and immunology at Vanderbilt University School of Medicine in Nashville, TN. Salgo said that the public may question if the need for booster shots will ever end, but 

, research scientist III at the Vaccine and Infectious Disease Organization in Saskatchewan, Canada, noted that vaccines for many other diseases (such as measles, poliomyelitis, and hepatitis B virus infection) have multiple-shot regimens and that the optimal dosing regimen for the COVID-19 vaccines remains to be seen.

“It’s probably correct that we will get to a point where you’ve been sufficiently boosted, that you have very responsive protective long-term–memory immunity to this virus,” Rasmussen said. “Because these vaccines were expedited to the clinic, we don’t really know what the optimal dosing regimen is, but I think it’s very unlikely that we’re going to be needing COVID-19 boosters every 6 months for the rest of our lives.”

Rasmussen added that although the mRNA technology platform used with SARS-CoV-2 vaccines is unique, the fundamental effects of these vaccines on the immune system are similar to those of vaccines with other technology platforms such as adenovirus vectors.

“They expose your immune system to the antigen, in this case the spike protein from SARS-CoV-2, the same way that a protein subunit vaccine would and the same way that an inactivated virus would,” she said. “I don’t that there’s anything fundamentally different to this technology that would necessitate constant boosters. The data that we do have suggest that there are immune responses to both the mRNA and the adenovirus-vectored vaccines that are compatible with long-term–memory immunity.”

, associate dean of academic affairs, professor and chair of the Department of Pharmacy Practice at Chapman University School of Pharmacy, in Irvine, CA, added that natural disease has not been shown to lead to long-term immunity and that vaccination will be important to possibly achieve herd immunity.

“What we’re seeing is that the human is just not able to develop a long-lasting response, whether we’re using vaccine or natural disease,” he said. “When you start talking about the role of the booster and how many we may need going forward, a lot of it has to do with how well we do with getting the primary series in and now getting the booster in 6 months later because vaccination to herd immunity is going to be critical moving forward.”

HOW COVID-19 BOOSTER SHOTS AFFECT IMMUNITY

The effectiveness of COVID-19 vaccines should be looked at on both the public health and individual levels, according to 

professor, clinical specialist, infectious diseases, and director of the PGY2 Residency in Infectious Diseases Pharmacy at the Temple University School of Pharmacy, in Philadelphia, PA. He said that although “there’s no doubt” about the benefits of a booster following the initial 2-dose regimen from an individual standpoint, providing countries and individuals with their first vaccine doses is the ideal strategy from the public health standpoint. Additionally, the deployment of the vaccines amid a pandemic to try to change its trajectory is unprecedented, Gallagher noted. “We are learning as we go,” he said.

Alcendor said that the vaccine has “yet to let us down” in accomplishing its primary goals of protecting against severe disease, hospitalizations, and death. However, he noted that he has observed a “tremendous amount” of vaccine hesitancy and resistance in several areas of the country, such as in the rural counties of Tennessee where he lives, that is likely to persist and may eliminate the possibility of achieving herd immunity with vaccination.

“We are also dealing with antivaxxers who are putting out misinformation and helping support conspiracy theories around [ill-founded] ideas about vaccine efficacy and safety,” Alcendor said. “We are getting breakthrough infections, and we are getting the evolution of variants that we don’t know if we can control with existing immunity, so we are in a holding place when it comes to herd immunity.”

Alcendor added that even if a country such as the United States has a high vaccination rate, global vaccination is necessary to ensure widespread protection. He said that the low vaccine availability in developing countries, such as those in Africa, is a critical barrier that needs to be addressed.

“Those countries cannot afford vaccine contracts. Vaccine contracts are paid for before the vaccine is even made,” he said. “You’re looking at rich countries having more than 60% of the vaccine supply. What you need to do is this: You need to bring vaccine manufacturing and distribution local to those communities, and that must be done through public-private partnership with vaccine companies and the governments. The World Health Organization must be involved.”

The panelists agreed that booster shots are necessary, and Rasmussen added that turning down a booster shot in countries of high vaccine access, such as the United States or Canada, does not increase vaccine access to other countries in need.

“I think that the boosters may be necessary for everybody for long-term immunity,” she said. “Are they necessary now to prevent the severe disease that Donald [Alcendor] was talking about earlier? For a lot of people, probably not. Are these really 3-shot vaccine regimens, at least for the mRNA vaccines, and a 2-dose regimen for the adenovirus-vectored vaccines? I do think that they are. The question really is: At what point do you need to deliver those boosters to make sure that everybody is safe? At what point is it urgently needed? I would argue that in people who are low risk for severe COVID-19, boosters are not urgently needed, even though long term they may be needed for that duration of immunity.”

Alcendor added that the push to provide boosters in the United States was likely prompted by data from Israel showing the occurrence of breakthrough infections and decreases in antibody levels over time, but he noted that the effects of T-cell or cell-mediated immunity on the immune response against COVID-19 infection is often overlooked. According to Alcendor, T cells play a critical role in B cell differentiation and synthesis of antibodies, as well as activation of cytotoxic T cells and improving their ability to kill infected cells.

“We are using antibody levels as a surrogate marker for immunity,” Alcendor said. “We never talk about T-cell or cell-mediated immunity as a clear marker that must be looked at.”

However, Goad countered that higher antibody levels may be important for protection against new variants, such as the Omicron variant, that are likely to continue to develop in countries with limited access to vaccination.

“Without…changing the makeup of the vaccines, we can also overwhelm the virus by a higher antibody titer that we’re getting with the booster,” he said. “There may be some protection here that we’re overlooking, especially with new variants coming out.”

Columbia University Vagelos College of Physicians and Surgeons

Associate Professor of Microbiology and Immunology, Meharry Medical College

Adjunct Associate Professor of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine

Associate Dean of Academic Affairs, Professor and Chair of the Department of Pharmacy Practice at Chapman University School of Pharmacy,

Clinical Professor, Clinical Specialist, Infectious Diseases, and Director of the PGY2 Residency in Infectious Diseases Pharmacy

Research scientist III, Vaccine and Infectious Disease Organization

Articles

Medical professionals discuss how they affect immunity as well as the necessity of these additional vaccinations.

COVID-19 Expectations on the Rollout of the Booster Shots

Although treatment options and life expectancy of patients living with HIV have increased in recent years, age-related comorbidities (particularly obesity and diabetes) and quality-of-life issues continue to be of concern, according to panelists in a 

panel moderated by Grace McComsey, MD FIDSA. The panelists discussed approaches for screening and management of comorbidities, optimizing antiretroviral therapy (ART) regimens based on viral genotype and patient factors, discussing quality-of-life issues with patients, and addressing the relationship between HIV, obesity, and diabetes.

Comorbid diseases and clinical events associated with aging often occur at a younger age in patients living with HIV compared with the general population, and educating patients on screenings and intervals is imperative to ensure these comorbidities are diagnosed early, said Todd Brown, MD, PhD. He added that the higher burden of comorbidities in patients with HIV is in part related to the persistent effects of previous ART, noting that stavudine (Zerit) is commonly associated with lipoatrophy that can persist for several years after discontinuing the medication. Even if HIV infection is well treated, the HIV disease process itself results in increased systemic inflammation that can drive comorbidities, said Brown. “We have this confluence of inflammation related to HIV and inflammation related to aging, which is important in these aging-related comorbidities,” he said.

Brown emphasized the importance of a long-term approach for screening and management of comorbidities and said preventing major clinical events is crucial for aging well. “Over the long term, you think about a patient who’s middle-aged…you’re trying to prevent events so the person can age well, so they can maintain their physical function, their cognitive function, their quality of life,” he said. “What we know is that these events that happen—whether it be myocardial infarction, a stroke, or a fracture— can have major effects on these trajectories. Trying to be proactive and prevent these events is critical in the overall aging process.”

John Koethe, MD, said that although viral suppression is the easiest measure of treatment success with HIV infection, durable suppression of the virus that is refractory to breakthrough and resistance using a regimen that fits the patient’s comorbidities and other personal factors is likely a better gauge of success.

“The principal goal of ART has always been the same…to maintain viral suppression or a level of plasma virus below 50 copies/mL, and thus allow CD4 reconstitution and ideally protect us from opportunistic infections within the environment,” said Koethe. “There [are] several routes to getting there, and the 2 things that we need to separate when we think about how we’re going to approach this is, [first], matching the regimen to the preexisting patterns of viral resistance, and then also matching the regimen within that same idea to the likelihood that this [individual] is not going to take it sufficiently and is going to develop viral resistance.”

Koethe said selection of a treatment regimen is guided by the viral genotype and often uses concatenated databases (such as the International AIDS Society) to identify the optimal agent(s) among protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors, and nucleoside reverse treatment options and life expectancy of patients living with HIV have increased in recent years, age-related comorbidities (particularly obesity and diabetes) and quality-of-life issues continue to be of concern, according to panelists in a 

Koethe said selection of a treatment regimen is guided by the viral genotype and often uses concatenated databases (such as the International AIDS Society) to identify the optimal agent(s) among protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors, and nucleoside reverse 

transcriptase inhibitors. Even if a regimen appears appropriate for a patient’s genotype, he said he may adjust it if he predicts that barriers will prevent the patient from adhering to once-per-day or twice-per-day dosing.

“We may select something with a higher barrier to resistance…for example, a boosted protease inhibitor such as darunavir…or it could be a newer-generation integrase inhibitor,” he said. “For somebody who might be extremely adherent, that would probably be less [of] a question.”

Koethe added that tailoring the regimen to minimize adverse or unwanted effects is important and involves considering the patient’s neuropsychiatric profile (including depression), underlying comorbidities (eg, cardiovascular disease, insulin resistance, diabetes or hyperlipidemia, and current overweight or obesity status), and patient preferences for dosing, and Brown emphasized the importance of awareness of potential drug-drug interactions, notably between boosted PIs and statins and those between dolutegravir and metformin.

Issues related to quality of life are important to address and can prevent patients from continuing with care, according to Tavell Kindall, PhD, DNP, APRN, FNP. “In my experience here in New Orleans, there have been some individuals who have been out of care because they felt as though they weren’t treated well,” he said. “When they come to see me, they now have an opportunity to be on the newer medications that weren’t available to them at the time when they [received their diagnosis]. It’s amazing because they say things like, ‘I can’t believe [it]. If they would’ve had this 10, 15 years ago, I would’ve never fallen out of care, because the whole thing was, I don’t want to take anything that will have me sick and making me feel bad.’”

Kindall added that conversations about quality of life should start at the first meeting with the patient, but the provider should expect to take time to get the patient’s full story.

“You must be patient and allow the journey to have patients share things with you, and then that way you can address different things,” he said. “One of the things right now that I have been talking a lot about with patients is, they tell you things like, ‘Look, I’m afraid to tell [individuals] because I don’t know how they’re going to treat me,’ or, ‘What does this mean? Am I going to go to jail if somebody finds out that I have HIV and I didn’t share my status with them?’ Certainly anxiety, depression, if they were present before the diagnosis, [are] likely exacerbated on the other side of it, so that’s always a concern.”

Kindall added that employment, education, and finances are common concerns among patients, and many still believe a diagnosis of HIV infection means imminent death. “I try to address it along the journey, and I share with them right up front, ‘This is a journey. This is a partnership that you and I have together, and we’ll be talking about a lot of things,’” such as housing, transportation, employment, ability to care for oneself, and internalized stigma. “Because of the history of HIV and how [individuals] have been treated, some of those quality-of-life things are challenging,” said Kindall.

RELATIONSHIP BETWEEN HIV, OBESITY, AND DIABETES

According to Osama Hamdy, MD, PhD, individuals living with HIV are 4 to 5 times more likely to develop type 2 diabetes compared with the general population. “When we see any patient with HIV, we must think of diabetes,” he said.

Hamdy said that from a pathophysiologic perspective, the disease process as well as some HIV treatments are responsible for this increase in risk. “Our research, many years ago, showed that once you introduce inflammation in the adipose tissue and you have provocation from TNF-α [tumor necrosis factor α], IL-6, MCP-1 [monocyte chemoattractant protein 1], and all those provocative inflammatory cytokines, you will see all kinds of metabolic problems, including insulin resistance, endothelial dysfunction, and then atherosclerosis,” he said.

Hamdy said medications, particularly older medications, may also contribute to diabetes. He added that patients who started treatment with protease inhibitors between 1997 and 2014 have an approximately 50-fold increase in risk for type 2 diabetes, and patients who used these drugs, even for a short time, are still presenting today because of the longer life span of patients living with HIV.

“Diabetes is something that you should think of all the time when you have anyone with HIV,” he concluded, adding that weight gain and related health issues, such as obstructive sleep apnea, arthritis, and worsening of diabetes, cardiovascular disease, and pulmonary issues introduce a major health burden for patients with HIV and diabetes.

Endocrinologist and Professor of Medicine

Endocrinologist and Associate Professor of Medicine

Division of Infectious Disease at Vanderbilt University Medical Center

For people living with HIV, age-related comorbidities, such as obesity and diabetes, as well as quality-of-life issues remain challenges. Our Peer Exchange panel discusses clinical approaches for this patient population and trying to keep them in good health.

Age-Related Comorbidities and Quality-of-Life Issues in Patients Living With HIV

When used in conjunction with antibiotic therapy, bezlotoxumab (Zinplava) has shown promising efficacy in reducing recurrence of 

 infection (CDI) in patients who are at high risk for recurrence, but the high cost of the therapy limits widespread use in clinical practice, according to infectious disease experts who participated in a 

, concluded the panel with an overview of the need for microbiome- and metabolome-sparing treatments for recurrent CDI.

Bezlotoxumab, an intravenously administered human monoclonal antibody that binds to 

 toxin B, was approved as an adjunct to antibacterial drug treatment for patients at least 18 years of age who are at high risk for recurrent CDI.1 This approval was supported by data from the MODIFY I and II trials (NCT01241552 and NCT01513239, respectively), which showed that the rate of recurrent CDI was significantly lower with bezlotoxumab than it was with placebo (MODIFY I: 17% vs 28%; adjusted difference, –10.1 percentage points; 95% CI, –15.9 to –4.3; 

 < .001. MODIFY II: 16% vs 26%; adjusted difference, –9.9 percentage points; 95% CI, –15.5 to –4.3; 

 < .001).2 Bezlotoxumab plus actoxumab, a human monoclonal antibody targeting 

toxin A, was also associated with lower rates of recurrent CDI than placebo (MODIFY I: 16% vs 28%; adjusted difference, –11.6 percentage points; 95% CI, –17.4 to –5.9; 

 < .001. MODIFY II: 15% vs 26%; adjusted difference, −10.7 percentage points; 95% CI, –16.4 to –5.1; 

 < .001), but the addition of actoxumab did not improve efficacy over bezlotoxumab alone.2

“[Bezlotoxumab’s] sole purpose is to reduce the recurrence rate,” said 

Gerding was the first author on a post hoc analysis of participants in the MODIFY I and II trials, which analyzed the efficacy of bezlotoxumab in patients with risk factors for recurrent CDI, including aged 65 years or older, history of CDI, compromised immunity, severe CDI, and ribotype 027/078/244.3

“The target [of this study] was to determine which patient is most likely to respond to the use of bezlotoxumab in terms of having a significant reduction in recurrence,” said Gerding.

Among the participants who received placebo and achieved an initial clinical cure, more than 30% of participants within each of the prespecified risk groups had recurrent CDI during the 12-week follow-up period, and the proportion of patients who had a recurrence increased with an increasing number of risk factors (from 20.9% among patients with no risk factors to 46.1% among patients with 3 or more risk factors).3 Bezlotoxumab was associated with lower rates of recurrent CDI than placebo for all of the prespecified groups, with a statistically significant difference in all except the ribotype 027/078/244 subgroup (aged 65 years or older, 19.3% vs 39.4%; history of CDI, 31.6% vs 49.5%; immunocompromised status, 19.0% vs 36.0%; severe CDI, 15.9% vs 31.5%; ribotype 027/078/244, 28.2% vs 41.1%).3 Furthermore, treatment with bezlotoxumab reduced rate of recurrent CDI among patients with at least 1 risk factor (relative reductions 45.3%, −34.5%, and −53.9% for patients with 1, 2, and 3 or more risk factors, respectively).3 Of the patients with no risk factors, the proportion with recurrent CDI was similar between the bezlotoxumab and placebo groups (18.8% and 20.9%, respectively).3

“The significant takeaway is that if patients did not have any of these risk factors…they did not appear to benefit from bezlotoxumab in terms of lowering [the recurrence rate] any further,” said Gerding. “We now know that if patients have any of these risk factors, and particularly if they have multiple risk factors, that [they] have a high risk for recurrence, and the likelihood is very high that they’re going to respond to bezlotoxumab.”

, added that reductions in recurrence for patients at high risk for recurrence are clinically significant, but cost continues to be a major barrier to widespread uptake. “This is another treatment option that seems to significantly decrease recurrences, which we should certainly be concerned about; it decreases the recurrences in patients who had CDI. Similar to fidaxomicin, the number needed to treat in MODIFY I and II was about 10…but if we target certain patients, like patients over the age of 65 years or those that had a prior history of CDI in that study, that number dropped to about 6. It’s an impactful treatment option. Cost seems to be a barrier for using this drug.”

added that whether bezlotoxumab should be used with fidaxomicin, another high-cost drug, remains an unanswered question because the combination may be cost-prohibitive. Data from the MODIFY I and II trials showing that only 4% of participants received fidaxomicin2 strongly suggests that cost is a key barrier to access, according to Lodise. Lodise added that most of the data on fidaxomicin and bezlotoxumab are from patients who have had only a single recurrence, and whether these data can be extrapolated to patients with multiple recurrences is currently unclear, especially because such a small proportion of patients in the MODIFY trials used fidaxomicin with bezlotoxumab. “How do you support the argument for using 2 [premium-]priced agents [when] only 50 people received fidaxomicin in the MODIFY trials?” he said.

, said that the lack of effective treatment options for recurrent CDI remains a big gap in the research. “

 remains an urgent threat to public health in general, and we want newer treatments that are targeted toward the microbiome and are microbiome-sparing,” she said. She also stressed the importance of colonization sparing in the microbiome when treating recurrent CDI and how the newer therapies such as fecal transplantation are generally better in that respect than conventional treatments. “Newer therapies that are sparing the microbiome are definitely much better,” she said. “We want to make sure that we have a lot of diversity in our gut microbiome, and this diversity decreases as we age.”

Chopra added that the diversity in the gut microbiome is low in patients with recurrent CDI and may reach “a point of no return” in which the microbiome is unable to overcome the colonization, and additional therapies are urgently needed for this subset of patients.

The metabolome is also thought to be affected by CDI, according to Chopra. One study of a mouse model of CDI showed that carbohydrates and amino acids, particularly proline and the branched-chain amino acids, decrease throughout colonization and infection, and 

gene expression was consistent with the utilization of these nutrients.4 Another study showed that had a significant effect on the metabolic environment in the guts of mice pretreated with cefoperazone or streptomycin, and metagenome-enabled metatranscriptomics showed that infected animals had reductions in transcripts for genes associated with carbon and energy acquisition (which suggests that the niches were occupied by 

), with the largest changes observed in the least abundant species.5 According to the study authors, the results suggest that 

promotes persistent infection by restructuring the nutrient-niche landscape.5 Chopra concluded that the changes in the gut metabolome that occur with recurrent CDI is an area that needs further research.


Columbia University Irving Medical Center
New York, New York


Wayne State University School of Medicine
Detroit, Michigan


Yale New Haven Hospital
New Haven, Connecticut


Edward Hines Jr Veterans Affairs Hospital
Chicago, Illinois


Albany College of Pharmacy and Health Sciences
Albany, New York


AtlantiCare Regional Medical Center
Galloway, New Jersey

1. Zinplava. Prescribing information. Merck Sharp & Dohme Corp. Updated October 2016. Accessed August 8, 2021. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761046s000lbl.pdf

2. Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of recurrent 

. 2017;376(4):305-317. doi:10.1056/NEJMoa1602615

3. Gerding DN, Kelly CP, Rahav G, et al. Bezlotoxumab for prevention of recurrent 

 infection in patients at increased risk for recurrence. 

. 2018;67(5):649-656. doi:10.1093/cid/ciy171

4. Fletcher JR, Erwin S, Lanzas C, Theriot CM. Shifts in the gut metabolome and 

 transcriptome throughout colonization and infection in a mouse model. 

. 2018;3(2):e00089-18. doi:10.1128/mSphere.00089-18

5. Jenior ML, Leslie JL, Young VB, Schloss PD. 

 alters the structure and metabolism of distinct cecal microbiomes during initial infection to promote sustained colonization. 

. 2018;3(3):e00261-18. doi:10.1128/mSphere.00261-18

Expert Perspectives on Advances in the Management of Clostrioides difficile: Bezlotoxumab and Unmet Needs

 has shifted toward more targeted, microbiome-sparing approaches to decrease recurrence and improve clinical outcomes. Demonstrating the return on investment will be important to increase the uptake of these new, more expensive agents, according to panelists who participated in a 

: Updates to Clinical Practice Guidelines

, noted that an update to the Infectious Diseases Society of America/Society for Healthcare Epidemiology of America (IDSA/SHEA) guidelines prioritized fidaxomicin as the primary agent recommended for patients with initial and recurrent episodes of CDI. The update was based on data showing lower rates of recurrence with fidaxomicin than with vancomycin, including from the initial phase 3 trial (NCT00314951)1 in patients with clinically diagnosed CDI (initial or recurrent) and the phase 3b/4 EXTEND trial (NCT02254967) that used an extended-pulsed fidaxomicin in hospitalized patients 60 years or older.2 The update was delivered as provisional recommendations at IDWeek 2020.

“Fidaxomicin seems to come to the forefront for treatments with the initial episode,” said 

. “When fidaxomicin came out, I don’t think many people were familiar with the term ‘sustained clinical response.’ That seems to be the advantage of using [fidaxomicin] in many patients, that they are less likely to have recurrences.”

Lodise added that the provisional IDSA/SHEA recommendations included an additional recommendation for bezlotoxumab, a human monoclonal antibody that targets toxin B, in individuals who are at high risk for recurrence, aged 65 or older, are immunosuppressed, have a history of CDI, or have severe CDI. The MODIFY I and MODIFY II trials (NCT01241552 and NCT01513239) showed that bezlotoxumab was associated with lower rates of recurrence in multiple prespecified subgroups, including patients who were 65 years or older, had immunocompromised status or severe CDI, or who had had a CDI episode within the past 6 months.3

Adequate treatment of CDI is particularly challenging because it requires eradicating the 

 organism while attempting to restore the microbiota, according to 

. He added that optimally effective treatment involves antimicrobial therapy (such as vancomycin or fidaxomicin) followed by modulation of the immune system with bezlotoxumab or microbiota restoration therapy to “give 

Most patients who receive either fidaxomicin or vancomycin will respond and will get better,” said Feuerstadt. “What we’re talking about with other therapies are those subgroups that are at greater risk: age over 65, history of immune suppression, history of 

, the NAP1/B1/027 strain, severe infection, patients on PPIs [proton pump inhibitors], [and] patients who received concomitant antimicrobials. Those are the individuals that we’re really focusing on [to gain a] better understanding of how we get rid of this.”

Feuerstadt added that the “entire clinical gestalt” of a patient should be considered in the approach to therapy; factors that may affect management decisions include source of infection (community or health care setting) and presence of multiple risk factors for recurrence, severe disease, and high white blood cell count and creatinine.

“Deciding between vancomycin and fidaxomicin to me really boiled down to those factors and risk factors for recurrence,” said Feuerstadt. “Fidaxomicin’s sweet spot is that it is associated with statistically significant reduction in rates of recurrence. Patients who have multiple high-risk factors for recurrence would benefit from that product.”

Fidaxomicin is a macrolide-like antibiotic that inhibits RNA synthesis by binding to bacterial RNA polymerase4 and has potent activity against CDI, according to Lodise. He added that the more targeted approach, less disruption of the gut microbiota, and lower minimum inhibitory concentration with fidaxomicin likely contribute to the lower rates of recurrence compared with vancomycin. “It’s that prolonged disruption of the microbiota [with vancomycin] that drives a lot of the adverse outcomes we see in some of our CDI patients,” he said.

“When we think about treating CDI from a stewardship standpoint, our thought [is], ‘How do we stop that event from moving forward?’ Although we appreciate the similar clinical response, we were very impressed with a lot of the lower recurrence data and particularly with some of the altered dosing with fidaxomicin in one of their 2 trials.”

Lodise noted that the tapered and pulsed regimen of fidaxomicin may be beneficial for treating a recurrent episode while facilitating recovery of the microbiota, but that developing additional methods to replenish the microbiota will be important moving forward.

Reilly noted that although the data appear to support the use of fidaxomicin in the first-line setting, the high acquisition cost of the drug relative to vancomycin remains a concern. However, he and Salgo agreed that using the more expensive fidaxomicin could reduce overall costs of care in the long run and improve patient outcomes by reducing readmission rates and other comorbidities.

“It’s that silo budget mentality, just looking at how much we’re spending and not looking at the outcomes,” said Reilly. “If I spend more money and it’s saved somewhere else by decreasing admissions that might lose money…people often don’t take that into consideration.”

, said that patient-centered outcome research could help demonstrate the overall improvement in clinical outcomes and cost savings with fidaxomicin. Chopra and her colleagues performed an analysis of a patient discharge database that showed that the 30-day readmission rate was higher for patients with CDI than those without CDI (30.1% vs 14.4%).5 In addition, results from a single-center retrospective study demonstrated that, on average, treatment with fidaxomicin saved the hospital $3207 per patient compared with vancomycin treatment (even though the drug costs were higher with fidaxomicin), largely attributable to the lower readmission costs associated with fidaxomicin.6

Lodise noted that the financial penalties associated with high rates of CDI and readmission and the escalating costs associated with multiple recurrences should encourage the shift toward fidaxomicin. He added that the 2020 IDSA/SHEA provisional recommendations were an important step forward in the acknowledgment of return on investment by including the number needed to treat.

“I think we need to stop talking about drugs in terms of dollars and cents, which we’re never going to get away from, and rather say, ‘If I do this, these are the adverse events I’m going to prevent,’” said Lodise. “We must change the script a bit. Cost is always going to be the common denominator, but we need to talk about how, with this investment, this is going to be [the] return, and we must make that return in terms of dollars and cents as well.”

Choosing Between Vancomycin and Fidaxomicin for 

Feuerstadt highlighted the fact that the lower recurrence rates observed in multiple trials comparing fidaxomicin with vancomycin were also observed in real-world data from the United Kingdom.7 This study, which assessed recurrence rates in the year before and after local introduction of fidaxomicin in 7 UK hospitals, showed that 2 hospitals that used fidaxomicin in the first-line setting for all primary and recurrent infections had a decrease in recurrence rate (10.6% to 3.1% and 16.3% to 3.1% for hospitals “A” and “B,” respectively).7 Feuerstadt noted that even the hospital that used fidaxomicin only for first recurrences (hospital “D”) had a decrease in recurrence rate (12.5% vs 21.1%, prior to fidaxomicin), suggesting that the real-world data reflect the results observed in phase 3 clinical trials.7

“What we’re seeing is no matter how fidaxomicin is being used, if a health care system commits to it, it seems to remarkably reduce those rates of recurrence,” concluded Feuerstadt.

Louie TJ, Miller MA, Mullane KM, et al; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. 

. 2011;364(5):422-431. doi:10.1056/NEJMoa0910812

Guery B, Menichetti F, Anttila VJ, et al; EXTEND Clinical Study Group. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial. 

. 2018;18(3):296-307. doi:10.1016/S1473-3099(17)30751-X

Wilcox MH, Gerding DN, Poxton IR, et al; MODIFY I and MODIFY II Investigators. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. 

Dificid. Prescribing information. Merck & Co, Inc; 2020. Accessed June 18, 2021. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213138lbl.pdf

Chopra T, Neelakanta A, Dombecki C, et al. Burden of Clostridium difficile infection on hospital readmissions and its potential impact under the Hospital Readmission Reduction Program. 

. 2015;43(4):314-317. doi:10.1016/j.ajic.2014.11.004

Gallagher JC, Reilly JP, Navalkele B, Downham G, Haynes K, Trivedi M. Clinical and economic benefits of fidaxomicin compared to vancomycin for Clostridium difficile infection. 

. 2015;59(11):7007-7010. doi:10.1128/AAC.00939-15

Goldenberg SD, Brown S, Edwards L, et al. The impact of the introduction of fidaxomicin on the management of Clostridium difficile infection in seven NHS secondary care hospitals in England: a series of local service evaluations. 

. 2016;35(2):251-259. doi:10.1007/s10096-015-2538-z

Paradigm Shift in the Management of Clostridioides difficile Infections


Columbia University Irving Medical Center
New York, NY


School of Medicine—Wayne State University
Detroit, MI


Edward Hines Jr Veterans Affairs Hospital
Chicago, IL


Albany College of Pharmacy and Health Sciences
Albany, NY


AtlantiCare Regional Medical Center
Atlantic City, NJ

Identification of patients to undergo testing for 

 infection (CDI) is largely based on a high index of suspicion, although the role of asymptomatic carriage in transmission highlights the importance of infection control in inpatient and outpatient settings, according to experts who participated in a 

, also discussed recommendations for treatment of recurrent CDI and considerations for selecting the most appropriate treatment method.

The 2017 guidelines from the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) state that patients with unexplained and recent onset of at least 3 unformed stools in a 24-hour period are the “preferred target population for testing” of CDI.1 However, 

 noted that presentation of CDI can range from mild symptoms to severe sepsis, fulminating colitis, or death and that clinical judgment is the most important consideration when selecting patients for testing. She said that presence of risk factors for CDI along with fever, elevated white blood cell (WBC) count, and frequent diarrheal stools increases suspicion; however, she added that diarrhea can also be associated with antibiotics, parasites, or consumption of contaminated food or water and that testing every patient with diarrhea would likely lead to overdiagnosis because individuals may be colonized with nontoxigenic forms of 

, noted that with the increase in pay-for-performance initiatives and public reporting of CDI rates, hospitals are particularly motivated to ensure that the CDI rates are low to prevent financial penalties and that positive tests for patients who are colonized with nontoxigenic 

, added that, rather than testing for CDI in any patient with diarrhea as a “knee-jerk reaction,” clinicians should broaden the differential diagnosis and evaluate the clinical presentation, such as assessing for the presence of blood in the diarrhea or whether the diarrhea is secretory or osmotic.

He added that irritable bowel syndrome (IBS) and postinfection IBS can complicate the clinical picture and that it is important to determine whether another bout of diarrhea indicates a recurrent infection or an alternative issue in a patient with a history of CDI to direct therapy appropriately. However, Feuerstadt said that patients with inflammatory bowel disease (IBD) are an exception, so all patients with IBD who experience an exacerbation should undergo testing for CDI because of the high incidence in this population.

Feuerstadt said that in addition to the IDSA/SHEA guidelines that provide recommendations for selecting candidates for testing, factors such as WBC count, creatinine level, and recent history of antimicrobials are also helpful to consider.

“If a patient has loose stools and recently received antimicrobials, they’re in the [intensive care unit], and their white [blood cell] count is 40,000, you probably know what’s going on there,” he said. “That might be a circumstance where time is of the essence and you might send off a stool assay before starting antimicrobials, but you may also want to empirically start antimicrobials due to your suspicion that [

, also pointed out that the work-up for a patient with community-acquired diarrhea needs to be different than for a patient with health care–associated diarrhea, in which CDI is high on the list of probable causes. For example, he recommended a multiplex polymerase chain reaction platform for patients with community-associated diarrhea to rule out multiple other potential causes.

In general, tests for CDI detect the organism itself or its primary toxins (toxin A and/or B). Commonly available options include toxigenic culture, nucleic acid amplification test (NAAT), glutamate dehydrogenase (GDH) assay, cell culture cytotoxicity neutralization assay, and toxin A and B enzyme immunoassays. Gerding noted, however, that the cell culture cytotoxicity neutralization assay has become obsolete because it is time consuming and difficult to perform.1

The NAAT is among the more commonly used tests in the United States and detects several toxin gene targets in the organism, although it has a low to moderate specificity and may pick up cases of patients colonized with 

, according to Gerding. He added that specific toxin tests, typically performed using enzyme immunoassays for toxin A and/or B, identify toxigenic 

 strains but have low sensitivity and that GDH assays are commonly used but need paired with another diagnostic test because GDH is found in toxigenic and nontoxigenic strains.

The IDSA/SHEA guidelines recommend using a stool toxin test as part of a multistep algorithm for diagnosis, which may involve GDH plus toxin test, GDH plus toxin test followed by NAAT as an arbitration test, or NAAT plus toxin test.1 However, Gerding noted that the difference in diagnostic yield among the algorithms may be introducing inconsistencies with diagnosis of CDI in current practice.

According to Chopra, asymptomatic carriage is an important consideration because carriers can act as reservoirs of transmission and probable vehicles of transmission to other patients. She added that the rate of asymptomatic carriage varies, with rates as high as 50% among older adults and approximately 5% to 10% among healthy adults.

“It’s important that we understand and realize that...these asymptomatic carriers don’t have diarrhea, but we are detecting [

 and they can transmit it,” she said, emphasizing the importance of infection control with hand hygiene and contact precautions in outpatient care settings and dialysis units and in inpatient care settings.

However, Chopra added that testing asymptomatic patients for carriage in the hospital setting is not routinely performed and would be a poor use of resources, and even hospitalized patients with risk factors for asymptomatic carriage are only put in contact isolation to prevent transmission if the hospital is facing an outbreak. Gerding noted that the data are currently insufficient to recommend universal screening for CDI, in part, because testing is invasive and isolation of positive patients would use a large number of isolation rooms. “I think we need more data before we jump on the colonization bandwagon, even in hospitals,” he said.

 Clinical Practice Guidelines and Treatment Options

According to the 2018 IDSA/SHEA guidelines, the recommendations for management of the first recurrence of CDI are a prolonged tapered and pulsed vancomycin regimen or fidaxomicin (if a standard vancomycin regimen was used previously) or a standard vancomycin regimen (if metronidazole was used for the previous infection).1 However, 

, noted that metronidazole has largely fallen out of favor for CDI infection because it has a broad spectrum of coverage (likely eliminating gut bacteria that are protective against CDI) and has been shown to have lower rates of efficacy than vancomycin. The inferior response rate of metronidazole to vancomycin was demonstrated in a pooled analysis of 2 multinational trials designed to compare clinical success of tolevamer, a nonantibiotic toxin-binding polymer, with vancomycin and metronidazole, respectively, in patients with CDI.2 Tolevamer was found to be inferior to both antibiotics, and rates of clinical success were higher with vancomycin than with metronidazole (81.1% vs 72.7%).2

“That’s what built up this concept on the clinical side [that] metronidazole is less targeted and alters the gut microbiota, which leads to higher risk for recurrence,” Feuerstadt said.

For second or subsequent recurrences, regimens recommended by the 2018 IDSA/SHEA guidelines include tapered and pulsed regimen of vancomycin, standard vancomycin regimen followed by rifaximin, fidaxomicin (if not used for prior infections), and microbiota replacement therapy or fecal microbiota transplantation (although the expert panel recommended appropriate antibiotic regimens for at least 3 episodes of CDI prior to trying this strategy).1

Feuerstadt noted that these recommendations in the 2018 guidelines have changed substantially from 2010, as metronidazole was largely removed from 2018 guidelines in favor of vancomycin or fidaxomicin in the first-line setting and fidaxomicin was introduced as an option for treatment of first recurrence.

Reilly concluded that assessing likelihood of patient compliance with the regimens, particularly the 8-week pulsed tapered vancomycin regimen, is important when selecting a treatment plan. He said in his experience, compliance tends to drop off after getting past the twice-per-day portion of the regimen. Salgo added that compliance is particularly difficult when dosing frequency drops to once every 2 to 3 days.

“We have to think about the patients we see who have [

 infection],” Reilly said. “Are they going to be compliant with this, taking vancomycin 4 times per day for possibly 2 weeks, then another 2 times per day for a week, once per day for another week, and every 2 to 3 days for up to 8 weeks? That’s a demanding regimen that we have to put a patient on. I understand the efficacy behind it, but we shouldn’t approach it and say, ‘Oh, I’ll just use that’ when there’s an alternative available that might be easier [and] that the patient might be more compliant with.”

McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). 

. 2018;66(7):e1-e48. doi:10.1093/cid/cix1085

Johnson S, Louie TJ, Gerding DN, et al; Polymer Alternative for CDI Treatment (PACT) investigators. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. 

. 2014;59(3):345-354. doi:10.1093/cid/ciu313

Investigators apply guidelines into practical management strategies.

Clostridioides difficile Infection: Diagnosis, Testing, Screening, and Treatment

Clostridioides difficile (C difficile) infection

, particularly in the recurrent setting, is associated with substantial disease and economic burdens for patients and health care systems. Utilizing patient care strategies that minimize infection risk is vital, according to experts who participated in a recent 

 infection (CDI) is “huge.” An estimated 462,100 cases of CDI occurred in the United States in 2017,1 and the economic cost of CDI was estimated to be $5.4 billion overall ($4.7 billion in health care settings) in 2014, according to a decision-analytic model.2 Recurrence is common and can be debilitating for patients, according to 

“I’ve had patients who’ve had recurrent disease, and they’ve [lost] jobs because of the nuisance it causes with the diarrhea they experience,” she said.

Feuerstadt added that although much of the focus is on the vegetative stage, during which the spores germinate to produce toxins that cause symptoms, the pathogen is hardier and more easily spread in the spore phase, because the spores are resistant to gastric acid and alcohol-based hand sanitizers.

“When we swallow the spore phase, it can get through our gastric acid, it gets to our small bowel,” Feuerstadt said. “In the small bowel, there’s a convergence to the vegetative phase where the vegetative phase multiplies, divides, and multiplies some more.”

Feuerstadt added that CDI risk factors include age greater than 65 years; female gender; immunocompromised state such as chronic kidney disease, HIV infection, or inflammatory bowel disease; recent use of antimicrobials, proton pump inhibitors, or histamine blockers; and residence in a skilled nursing facility or prolonged hospital stay. Chopra added that highly virulent toxigenic strains, such as the North American strain that caused outbreaks in the United States and Canada, are also of concern when considering transmission in the hospital or community setting.

 have been identified, although toxin-producing strains are the only ones associated with illness.3 Colonization by toxigenic strains leads to production of toxin A and toxin B in the gut, which leads to the diarrhea associated with CDI.3 Mortality is relatively higher and may exceed 5% with ribotypes 027 and 078, which have been epidemic since 2000, according to 

. He attributed the high mortality rate in part to the fact that the strain tends to infect older and immunocompromised patients, with the highest rates of mortality reported in patients in their 80s and 90s.

, said that the mortality rate increases substantially in patients older than 65 years, with an estimated rate of 10%. Chopra noted that CDI has been labeled as an urgent threat by the Centers for Disease Control and Prevention (CDC) because of the high rate of associated morbidity and mortality. She added that, although the rate of hospital-acquired infections has plateaued in recent years, the increase in community-acquired infection indicates the need for improvement in community stewardship programs.

 spores are ubiquitous in the environment and even are present at low levels in meat, root vegetables, and lettuce, but health care environments are more contaminated with the spores, Gerding said. A news release from the CDC stated that 82% of patients with community-associated CDI had been in an outpatient setting (eg, doctor’s or dentist’s office, chronic dialysis unit, or ambulatory surgery unit) in the 12 weeks prior to receiving a diagnosis of CDI.4 Gerding attributed this risk to the high rate of patients being prescribed antibiotics as well as the high level of contamination of 

 spores also contributes to their ability to spread infection.

“Those spores can live for a significant period of time on many surfaces, even when exposed to sunlight,” he said. “You’ll see some data that say, ‘Alcohol and certain products can kill the spores,’ but they really have to be used properly, [to have] the liquid [sit] on a surface for a significant period of time to have effect. The fact that the spores can be taken home with you on your lab coat and [remain] in your house and on surfaces for 6 months, a year, or longer, certainly puts [individuals] at risk.”

Recurrence of symptomatic CDI is relatively common, difficult to treat effectively, and a cause of significant morbidity and economic costs. Recurrence occurs in 20% to 30% of cases, with higher rates reported with each subsequent episode.5

“If we saw 100 patients with [CDI] and we treated them all…about 25 patients would come back with their first recurrence,” Reilly said. “If we treated those 25 successfully, about 40% of those patients would come back with their second recurrence. And if we treated those patients successfully, about 60% would come back for their third recurrence. So, for every 100 patients we treat, you wind up [with much more than 100 visits], which is the nature of the beast.”

Lodise added that the level of risk varies among antibiotics and increases with longer duration spent in a health care setting. He said that fluoroquinolones and third-generation cephalosporins are among the most commonly used antibiotics and have a higher risk for selecting for CDI compared with other drugs. “One thing I would say with antibiotics is that every day matters,” he said. “Even 1 dose of an antibiotic can put a patient at a greater risk for [CDI] relative to no antibiotics. That risk increases substantially after 3 days of antibiotics.”

He added that for patients who are older and have a high risk of mortality, morbidity, or recurrences, keeping them on an antibiotic without an indication is “often the worst thing you can do” because the risk of CDI is elevated for at least 3 months after taking antibiotics. Through his stewardship efforts, Lodise communicates how important it is to get patients off antibiotics, particularly broad-spectrum antibiotics.

According to Feuerstadt, the burden of disease with recurrent CDI is significant. Physical manifestations include abdominal cramps, diarrhea, dehydration, and syncope related to the frequent loose stools. There also are psychological, adaptation, relational, and productivity effects. He added that these effects are observed in patients with active disease as well as those with a distant history of infection.

“One of the concepts that is very important is to acknowledge for patients is that this is real and that what they’re going through is not just them,” Feuerstadt said. “[Patients] feel stressed about this. They have posttraumatic stress disorder; they feel anxiety or depression. Sometimes they feel [as though] they can’t be the person they were before. Educating ourselves as clinicians about this disease, both the physical manifestations and the emotional manifestations, will make all of us better clinicians and better equipped to approach these individuals and help them get better physically and emotionally.”


Professor of Anesthesiology
Columbia University Irving Medical Center
New York, New York


Professor of Internal Medicine, Division of Infectious Diseases
Wayne State University School of Medicine
Detroit, Michigan

Experts discuss the bacteria’s transmission in the community setting, how to reduce disease and economic burdens, and ways to improve quality of life for patients.

Gina Battaglia, PhD

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