User login
FDA approves drug to treat low sexual desire in women
The .
“There are women who, for no known reason, have reduced sexual desire that causes marked distress, and who can benefit from safe and effective pharmacologic treatment,” Hylton V. Joffe, MD, director of the Center for Drug Evaluation and Research’s Division of Bone, Reproductive, and Urologic Products, stated in a press release. “Today’s approval provides women with another treatment option for this condition.”
HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not caused by a medical or psychiatric condition. Acquired HSDD develops in a patient who previously experienced no problems with sexual desire, and generalized HSDD is a lack of desire that occurs regardless of the type of sexual activity, situation, or partner.
Vyleesi was studied in two 24-week, randomized, double-blind, placebo-controlled trials in 1,247 premenopausal women with acquired, generalized HSDD. The women used Vyleesi two or three times per month and no more than once a week. About one-quarter of patients treated with Vyleesi had an increase of 1.2 or more in their sexual desire score (scored on a range of 1.2 to 6.0, with higher scores indicating greater sexual desire), compared with about 17% of those who took placebo. About 35% of the patients treated with Vyleesi had a decrease of one or more in their distress score (scored on a range of 0-4, with higher scores indicating greater distress from low sexual desire) compared with about 31% of those who took placebo.
The drug is injected under the skin of the abdomen or thigh at least 45 minutes before anticipated sexual activity. Patients may decide the optimal time to use Vyleesi based on the duration of benefit and any side effects, such as nausea. Patients should not take more than one dose of Vyleesi within 24 hours, or more than eight doses per month. Patients should discontinue treatment after 8 weeks if they do not report an improvement in sexual desire and associated distress.
Vyleesi works by activating melanocortin receptors but the exact mechanism for improving sexual desire is unknown. Some side effects were reported. “The most common side effects of Vyleesi are nausea and vomiting, flushing, injection site reactions, and headache. About 40% of patients in the clinical trials experienced nausea, most commonly with the first Vyleesi injection, and 13% needed medications for the treatment of nausea. About 1% of patients treated with Vyleesi in the clinical trials reported darkening of the gums and parts of the skin, including the face and breasts, which did not go away in about half the patients after stopping treatment. Patients with dark skin were more likely to develop this side effect,” according to the press release.
A temporary increase in blood pressure in patients after dosing with Vyleesi was observed during the clinical trials and therefore the drug is not recommended in patients at high risk for cardiovascular disease. In addition, patients who take a naltrexone-containing medication by mouth to treat alcohol or opioid dependence should not use Vyleesi because it may significantly decrease the levels of naltrexone in the blood and could lead to naltrexone treatment failure.
The full press release can be found on the FDA website.
The .
“There are women who, for no known reason, have reduced sexual desire that causes marked distress, and who can benefit from safe and effective pharmacologic treatment,” Hylton V. Joffe, MD, director of the Center for Drug Evaluation and Research’s Division of Bone, Reproductive, and Urologic Products, stated in a press release. “Today’s approval provides women with another treatment option for this condition.”
HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not caused by a medical or psychiatric condition. Acquired HSDD develops in a patient who previously experienced no problems with sexual desire, and generalized HSDD is a lack of desire that occurs regardless of the type of sexual activity, situation, or partner.
Vyleesi was studied in two 24-week, randomized, double-blind, placebo-controlled trials in 1,247 premenopausal women with acquired, generalized HSDD. The women used Vyleesi two or three times per month and no more than once a week. About one-quarter of patients treated with Vyleesi had an increase of 1.2 or more in their sexual desire score (scored on a range of 1.2 to 6.0, with higher scores indicating greater sexual desire), compared with about 17% of those who took placebo. About 35% of the patients treated with Vyleesi had a decrease of one or more in their distress score (scored on a range of 0-4, with higher scores indicating greater distress from low sexual desire) compared with about 31% of those who took placebo.
The drug is injected under the skin of the abdomen or thigh at least 45 minutes before anticipated sexual activity. Patients may decide the optimal time to use Vyleesi based on the duration of benefit and any side effects, such as nausea. Patients should not take more than one dose of Vyleesi within 24 hours, or more than eight doses per month. Patients should discontinue treatment after 8 weeks if they do not report an improvement in sexual desire and associated distress.
Vyleesi works by activating melanocortin receptors but the exact mechanism for improving sexual desire is unknown. Some side effects were reported. “The most common side effects of Vyleesi are nausea and vomiting, flushing, injection site reactions, and headache. About 40% of patients in the clinical trials experienced nausea, most commonly with the first Vyleesi injection, and 13% needed medications for the treatment of nausea. About 1% of patients treated with Vyleesi in the clinical trials reported darkening of the gums and parts of the skin, including the face and breasts, which did not go away in about half the patients after stopping treatment. Patients with dark skin were more likely to develop this side effect,” according to the press release.
A temporary increase in blood pressure in patients after dosing with Vyleesi was observed during the clinical trials and therefore the drug is not recommended in patients at high risk for cardiovascular disease. In addition, patients who take a naltrexone-containing medication by mouth to treat alcohol or opioid dependence should not use Vyleesi because it may significantly decrease the levels of naltrexone in the blood and could lead to naltrexone treatment failure.
The full press release can be found on the FDA website.
The .
“There are women who, for no known reason, have reduced sexual desire that causes marked distress, and who can benefit from safe and effective pharmacologic treatment,” Hylton V. Joffe, MD, director of the Center for Drug Evaluation and Research’s Division of Bone, Reproductive, and Urologic Products, stated in a press release. “Today’s approval provides women with another treatment option for this condition.”
HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not caused by a medical or psychiatric condition. Acquired HSDD develops in a patient who previously experienced no problems with sexual desire, and generalized HSDD is a lack of desire that occurs regardless of the type of sexual activity, situation, or partner.
Vyleesi was studied in two 24-week, randomized, double-blind, placebo-controlled trials in 1,247 premenopausal women with acquired, generalized HSDD. The women used Vyleesi two or three times per month and no more than once a week. About one-quarter of patients treated with Vyleesi had an increase of 1.2 or more in their sexual desire score (scored on a range of 1.2 to 6.0, with higher scores indicating greater sexual desire), compared with about 17% of those who took placebo. About 35% of the patients treated with Vyleesi had a decrease of one or more in their distress score (scored on a range of 0-4, with higher scores indicating greater distress from low sexual desire) compared with about 31% of those who took placebo.
The drug is injected under the skin of the abdomen or thigh at least 45 minutes before anticipated sexual activity. Patients may decide the optimal time to use Vyleesi based on the duration of benefit and any side effects, such as nausea. Patients should not take more than one dose of Vyleesi within 24 hours, or more than eight doses per month. Patients should discontinue treatment after 8 weeks if they do not report an improvement in sexual desire and associated distress.
Vyleesi works by activating melanocortin receptors but the exact mechanism for improving sexual desire is unknown. Some side effects were reported. “The most common side effects of Vyleesi are nausea and vomiting, flushing, injection site reactions, and headache. About 40% of patients in the clinical trials experienced nausea, most commonly with the first Vyleesi injection, and 13% needed medications for the treatment of nausea. About 1% of patients treated with Vyleesi in the clinical trials reported darkening of the gums and parts of the skin, including the face and breasts, which did not go away in about half the patients after stopping treatment. Patients with dark skin were more likely to develop this side effect,” according to the press release.
A temporary increase in blood pressure in patients after dosing with Vyleesi was observed during the clinical trials and therefore the drug is not recommended in patients at high risk for cardiovascular disease. In addition, patients who take a naltrexone-containing medication by mouth to treat alcohol or opioid dependence should not use Vyleesi because it may significantly decrease the levels of naltrexone in the blood and could lead to naltrexone treatment failure.
The full press release can be found on the FDA website.
Medical cannabis laws appear no longer tied to drop in opioid overdose mortality
Correlations do not hold when analysis is expanded to 2017
Contrary to previous research indicating that medical cannabis laws reduced opioid overdose mortality, the association between these two has reversed, with opioid overdose mortality increased in states with comprehensive medical cannabis laws, according to Chelsea L. Shover, PhD, and associates.
The original research by Marcus A. Bachhuber, MD, and associates showed that the introduction of state medical cannabis laws was associated with a 24.8% reduction in opioid overdose deaths per 100,000 population between 1999 and 2010. In contrast, the new research – which looked at a longer time period than the original research did – found that the association between state medical cannabis laws and opioid overdose mortality reversed direction, from –21% to +23%.
“We find it unlikely that medical cannabis – used by about 2.5% of the U.S. population – has exerted large conflicting effects on opioid overdose mortality,” wrote Dr. Shover, of the department of psychiatry and behavioral sciences at Stanford (Calif.) University, and associates. “A more plausible interpretation is that this association is spurious.” Their study was published in the Proceedings of the National Academy of Sciences.
To conduct their analysis, Dr. Shover and associates extended the timeline reviewed by Dr. Bachhuber and associates to 2017. During 2010-2017, 32 states enacted medical cannabis laws, including 17 allowing only medical cannabis with low levels of tetrahydrocannabinol (THC), and 8 legalized recreational marijuana. In the expanded timeline during 1999-2017, states possessing a comprehensive medical marijuana law saw an increase in opioid overdose mortality of 28.2%. Meanwhile, states with recreational marijuana laws saw a decrease of 14.7% in opioid overdose mortality, and states with low-THC medical cannabis laws saw a decrease of 7.1%. However, the investigators noted that those values had wide confidence intervals, which indicates “compatibility with large range of true associations.”
Corporate actors with deep pockets have substantial ability to promote congenial results, and suffering people are desperate for effective solutions. Cannabinoids have demonstrated therapeutic benefits, but reducing population-level opioid overdose mortality does not appear to be among them,” Dr. Shover and associates noted.
Dr. Shover reported receiving support from National Institute on Drug Abuse and the Wu Tsai Neurosciences Institute. Another coauthor received support from the Veterans Health Administration, Wu Tsai Neurosciences Institute, and the Esther Ting Memorial Professorship at Stanford.
SOURCE: Shover CL et al. Proc Natl Acad Sci U S A. 2019 Jun 10. doi: 10.1073/pnas.1903434116.
Correlations do not hold when analysis is expanded to 2017
Correlations do not hold when analysis is expanded to 2017
Contrary to previous research indicating that medical cannabis laws reduced opioid overdose mortality, the association between these two has reversed, with opioid overdose mortality increased in states with comprehensive medical cannabis laws, according to Chelsea L. Shover, PhD, and associates.
The original research by Marcus A. Bachhuber, MD, and associates showed that the introduction of state medical cannabis laws was associated with a 24.8% reduction in opioid overdose deaths per 100,000 population between 1999 and 2010. In contrast, the new research – which looked at a longer time period than the original research did – found that the association between state medical cannabis laws and opioid overdose mortality reversed direction, from –21% to +23%.
“We find it unlikely that medical cannabis – used by about 2.5% of the U.S. population – has exerted large conflicting effects on opioid overdose mortality,” wrote Dr. Shover, of the department of psychiatry and behavioral sciences at Stanford (Calif.) University, and associates. “A more plausible interpretation is that this association is spurious.” Their study was published in the Proceedings of the National Academy of Sciences.
To conduct their analysis, Dr. Shover and associates extended the timeline reviewed by Dr. Bachhuber and associates to 2017. During 2010-2017, 32 states enacted medical cannabis laws, including 17 allowing only medical cannabis with low levels of tetrahydrocannabinol (THC), and 8 legalized recreational marijuana. In the expanded timeline during 1999-2017, states possessing a comprehensive medical marijuana law saw an increase in opioid overdose mortality of 28.2%. Meanwhile, states with recreational marijuana laws saw a decrease of 14.7% in opioid overdose mortality, and states with low-THC medical cannabis laws saw a decrease of 7.1%. However, the investigators noted that those values had wide confidence intervals, which indicates “compatibility with large range of true associations.”
Corporate actors with deep pockets have substantial ability to promote congenial results, and suffering people are desperate for effective solutions. Cannabinoids have demonstrated therapeutic benefits, but reducing population-level opioid overdose mortality does not appear to be among them,” Dr. Shover and associates noted.
Dr. Shover reported receiving support from National Institute on Drug Abuse and the Wu Tsai Neurosciences Institute. Another coauthor received support from the Veterans Health Administration, Wu Tsai Neurosciences Institute, and the Esther Ting Memorial Professorship at Stanford.
SOURCE: Shover CL et al. Proc Natl Acad Sci U S A. 2019 Jun 10. doi: 10.1073/pnas.1903434116.
Contrary to previous research indicating that medical cannabis laws reduced opioid overdose mortality, the association between these two has reversed, with opioid overdose mortality increased in states with comprehensive medical cannabis laws, according to Chelsea L. Shover, PhD, and associates.
The original research by Marcus A. Bachhuber, MD, and associates showed that the introduction of state medical cannabis laws was associated with a 24.8% reduction in opioid overdose deaths per 100,000 population between 1999 and 2010. In contrast, the new research – which looked at a longer time period than the original research did – found that the association between state medical cannabis laws and opioid overdose mortality reversed direction, from –21% to +23%.
“We find it unlikely that medical cannabis – used by about 2.5% of the U.S. population – has exerted large conflicting effects on opioid overdose mortality,” wrote Dr. Shover, of the department of psychiatry and behavioral sciences at Stanford (Calif.) University, and associates. “A more plausible interpretation is that this association is spurious.” Their study was published in the Proceedings of the National Academy of Sciences.
To conduct their analysis, Dr. Shover and associates extended the timeline reviewed by Dr. Bachhuber and associates to 2017. During 2010-2017, 32 states enacted medical cannabis laws, including 17 allowing only medical cannabis with low levels of tetrahydrocannabinol (THC), and 8 legalized recreational marijuana. In the expanded timeline during 1999-2017, states possessing a comprehensive medical marijuana law saw an increase in opioid overdose mortality of 28.2%. Meanwhile, states with recreational marijuana laws saw a decrease of 14.7% in opioid overdose mortality, and states with low-THC medical cannabis laws saw a decrease of 7.1%. However, the investigators noted that those values had wide confidence intervals, which indicates “compatibility with large range of true associations.”
Corporate actors with deep pockets have substantial ability to promote congenial results, and suffering people are desperate for effective solutions. Cannabinoids have demonstrated therapeutic benefits, but reducing population-level opioid overdose mortality does not appear to be among them,” Dr. Shover and associates noted.
Dr. Shover reported receiving support from National Institute on Drug Abuse and the Wu Tsai Neurosciences Institute. Another coauthor received support from the Veterans Health Administration, Wu Tsai Neurosciences Institute, and the Esther Ting Memorial Professorship at Stanford.
SOURCE: Shover CL et al. Proc Natl Acad Sci U S A. 2019 Jun 10. doi: 10.1073/pnas.1903434116.
FROM PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES
Rivaroxaban tied to higher GI bleeding than other NOACs
SAN DIEGO – Patients on rivaroxaban had significantly higher rates of GI bleeding, compared with those taking apixaban or dabigatran, results from a large population-based study showed.
“This may be due to the fact that rivaroxaban is administered as a single daily dose as opposed to the other two non–vitamin K anticoagulants [NOACs], which are given twice daily,” lead study author Arnar B. Ingason said at the annual Digestive Disease Week. “This may lead to a greater variance in plasma drug concentration, making these patients more susceptible to bleeding.”
Mr. Ingason, a medical student at the University of Iceland, Reykjavik, said that although several studies have compared warfarin with NOACs, it remains unclear which NOAC has the most favorable GI profile. In an effort to improve the research in this area, he and his associates performed a nationwide, population-based study during March 2014–Jan. 2018 to compare the GI bleeding risk of patients receiving rivaroxaban to that of a combined pool of patients receiving either apixaban or dabigatran. They drew from the Icelandic Medicine Registry, which contains all outpatient drug prescriptions in the country. Next, the researchers linked the personal identification numbers of patients to the Landspitali University diagnoses registry, which includes more than 90% of all patients hospitalized for GI bleeding. They used 1:1 nearest neighbor propensity score for matching and Kaplan-Meier survival estimates and Cox regression to compare rates of GI bleeding. The study outcome of interest was any clinically relevant GI bleeding.
Mr. Ingason reported that the baseline characteristics were similar between the rivaroxaban group and the apixaban/dabigatran group. They matched for several variables, including age, sex, Charlson score, the proportion being anticoagulant naive, moderate to severe renal disease, moderate to severe liver disease, any prior bleeding, and any prior thrombotic events.
During the study period, 3,473 patients received rivaroxaban, 1,901 received apixaban, and 1,086 received dabigatran. After propensity score matching, the researchers compared 2,635 patients who received rivaroxaban with 2,365 patients who received either apixaban or dabigatran. They found that patients in the rivaroxaban group had significantly higher rates of GI bleeding, compared with in the apixaban/dabigatran group (1.2 and. 0.6 events per 100 patient-years, respectively). This yielded a hazard ratio of 2.02, “which means that patients receiving rivaroxaban are twice as likely to get GI bleeding compared to patients on apixaban or dabigatran,” Mr. Ingason said. When the researchers examined the entire unmatched cohort of patients, the rivaroxaban group also had significantly higher rates of GI bleeding, compared with the apixaban/dabigatran group (1.0 and 0.6 events per 100 patient-years; HR, 1.75).
Mr. Ingason and his colleagues observed that patients in the rivaroxaban group had higher rates of GI bleeding, compared with the apixaban/dabigatran group, during the entire follow-up period. At the end of year 4, the rivaroxaban group had a 4% cumulative event rate of GI bleeding, compared with 1.8% for the apixaban/dabigatran group, a highly significant difference at P = .0057).
When a meeting attendee asked Mr. Ingason why patients taking apixaban or dabigatran were combined into one group, he said that it was done to increase the power of their study. “Our theory was that rivaroxaban was different because it is administered as a single daily dose, while the others are given twice daily,” he said. The researchers reported having no financial disclosures.
SAN DIEGO – Patients on rivaroxaban had significantly higher rates of GI bleeding, compared with those taking apixaban or dabigatran, results from a large population-based study showed.
“This may be due to the fact that rivaroxaban is administered as a single daily dose as opposed to the other two non–vitamin K anticoagulants [NOACs], which are given twice daily,” lead study author Arnar B. Ingason said at the annual Digestive Disease Week. “This may lead to a greater variance in plasma drug concentration, making these patients more susceptible to bleeding.”
Mr. Ingason, a medical student at the University of Iceland, Reykjavik, said that although several studies have compared warfarin with NOACs, it remains unclear which NOAC has the most favorable GI profile. In an effort to improve the research in this area, he and his associates performed a nationwide, population-based study during March 2014–Jan. 2018 to compare the GI bleeding risk of patients receiving rivaroxaban to that of a combined pool of patients receiving either apixaban or dabigatran. They drew from the Icelandic Medicine Registry, which contains all outpatient drug prescriptions in the country. Next, the researchers linked the personal identification numbers of patients to the Landspitali University diagnoses registry, which includes more than 90% of all patients hospitalized for GI bleeding. They used 1:1 nearest neighbor propensity score for matching and Kaplan-Meier survival estimates and Cox regression to compare rates of GI bleeding. The study outcome of interest was any clinically relevant GI bleeding.
Mr. Ingason reported that the baseline characteristics were similar between the rivaroxaban group and the apixaban/dabigatran group. They matched for several variables, including age, sex, Charlson score, the proportion being anticoagulant naive, moderate to severe renal disease, moderate to severe liver disease, any prior bleeding, and any prior thrombotic events.
During the study period, 3,473 patients received rivaroxaban, 1,901 received apixaban, and 1,086 received dabigatran. After propensity score matching, the researchers compared 2,635 patients who received rivaroxaban with 2,365 patients who received either apixaban or dabigatran. They found that patients in the rivaroxaban group had significantly higher rates of GI bleeding, compared with in the apixaban/dabigatran group (1.2 and. 0.6 events per 100 patient-years, respectively). This yielded a hazard ratio of 2.02, “which means that patients receiving rivaroxaban are twice as likely to get GI bleeding compared to patients on apixaban or dabigatran,” Mr. Ingason said. When the researchers examined the entire unmatched cohort of patients, the rivaroxaban group also had significantly higher rates of GI bleeding, compared with the apixaban/dabigatran group (1.0 and 0.6 events per 100 patient-years; HR, 1.75).
Mr. Ingason and his colleagues observed that patients in the rivaroxaban group had higher rates of GI bleeding, compared with the apixaban/dabigatran group, during the entire follow-up period. At the end of year 4, the rivaroxaban group had a 4% cumulative event rate of GI bleeding, compared with 1.8% for the apixaban/dabigatran group, a highly significant difference at P = .0057).
When a meeting attendee asked Mr. Ingason why patients taking apixaban or dabigatran were combined into one group, he said that it was done to increase the power of their study. “Our theory was that rivaroxaban was different because it is administered as a single daily dose, while the others are given twice daily,” he said. The researchers reported having no financial disclosures.
SAN DIEGO – Patients on rivaroxaban had significantly higher rates of GI bleeding, compared with those taking apixaban or dabigatran, results from a large population-based study showed.
“This may be due to the fact that rivaroxaban is administered as a single daily dose as opposed to the other two non–vitamin K anticoagulants [NOACs], which are given twice daily,” lead study author Arnar B. Ingason said at the annual Digestive Disease Week. “This may lead to a greater variance in plasma drug concentration, making these patients more susceptible to bleeding.”
Mr. Ingason, a medical student at the University of Iceland, Reykjavik, said that although several studies have compared warfarin with NOACs, it remains unclear which NOAC has the most favorable GI profile. In an effort to improve the research in this area, he and his associates performed a nationwide, population-based study during March 2014–Jan. 2018 to compare the GI bleeding risk of patients receiving rivaroxaban to that of a combined pool of patients receiving either apixaban or dabigatran. They drew from the Icelandic Medicine Registry, which contains all outpatient drug prescriptions in the country. Next, the researchers linked the personal identification numbers of patients to the Landspitali University diagnoses registry, which includes more than 90% of all patients hospitalized for GI bleeding. They used 1:1 nearest neighbor propensity score for matching and Kaplan-Meier survival estimates and Cox regression to compare rates of GI bleeding. The study outcome of interest was any clinically relevant GI bleeding.
Mr. Ingason reported that the baseline characteristics were similar between the rivaroxaban group and the apixaban/dabigatran group. They matched for several variables, including age, sex, Charlson score, the proportion being anticoagulant naive, moderate to severe renal disease, moderate to severe liver disease, any prior bleeding, and any prior thrombotic events.
During the study period, 3,473 patients received rivaroxaban, 1,901 received apixaban, and 1,086 received dabigatran. After propensity score matching, the researchers compared 2,635 patients who received rivaroxaban with 2,365 patients who received either apixaban or dabigatran. They found that patients in the rivaroxaban group had significantly higher rates of GI bleeding, compared with in the apixaban/dabigatran group (1.2 and. 0.6 events per 100 patient-years, respectively). This yielded a hazard ratio of 2.02, “which means that patients receiving rivaroxaban are twice as likely to get GI bleeding compared to patients on apixaban or dabigatran,” Mr. Ingason said. When the researchers examined the entire unmatched cohort of patients, the rivaroxaban group also had significantly higher rates of GI bleeding, compared with the apixaban/dabigatran group (1.0 and 0.6 events per 100 patient-years; HR, 1.75).
Mr. Ingason and his colleagues observed that patients in the rivaroxaban group had higher rates of GI bleeding, compared with the apixaban/dabigatran group, during the entire follow-up period. At the end of year 4, the rivaroxaban group had a 4% cumulative event rate of GI bleeding, compared with 1.8% for the apixaban/dabigatran group, a highly significant difference at P = .0057).
When a meeting attendee asked Mr. Ingason why patients taking apixaban or dabigatran were combined into one group, he said that it was done to increase the power of their study. “Our theory was that rivaroxaban was different because it is administered as a single daily dose, while the others are given twice daily,” he said. The researchers reported having no financial disclosures.
REPORTING FROM DDW 2019
Skin plus GI adverse events with checkpoint inhibitors linked to risk of additional adverse events
MILAN – Patients on checkpoint inhibitors who experience both dermatologic and gastrointestinal side effects may be at increased risk of further immune-related adverse events, even though they may have better odds of a favorable outcome on the cancer treatment, results of a study presented at the World Congress of Dermatology suggest.
The co-occurrence of dermatologic and gastrointestinal immune-related adverse events (irAEs), which was usually seen early in the course of treatment, was independently associated with favorable progression-free and overall survival in this study, said Gabriel E. Molina, a medical student at Harvard Medical School, Boston.
Compared with patients with colitis alone, those patients who had both immune checkpoint inhibitor-induced rash and colitis were at significantly increased risk of additional irAEs affecting other organ systems, according to Mr. Molina. As a result, patients with both dermatologic and gastrointestinal irAEs may warrant earlier or closer monitoring, and need prompt referral to specialty care at first sign of emerging toxicity.
“We are really excited by the possibility that this co-occurrence of rash and colitis may be a unique and early clinical marker of both high-risk irAE patients and favorable treatment response,” Mr. Molina said.
The single-center, retrospective cohort study reported by Mr. Molina included 67 patients treated with immune checkpoint inhibitors who subsequently developed colitis. Of that group, 28 (or about 42%) also had a rash induced by that treatment.
The median time from starting treatment to onset of rash was 32.5 days, according to this report. Median onset of gastrointestinal toxicity was roughly similar between the patients who also had rash, at 73 days, as compared with patients who did not have rash, at 64 days. Most rashes were grade 1-2 in severity, and were treated with topical corticosteroids in 50% of cases or with nothing at all in 43%, according to the report.
The odds of developing an additional irAE such as hepatitis or hypophysitis was 18.5 times higher in the patients who had rash and colitis as compared with those with colitis only, the researchers also found.
In multivariate analysis, the patients with both rash and colitis had longer progression-free survival (hazard ratio, 0.37; 95% confidence interval, 0.17-0.80; P = .012) and overall survival (HR, 0.20; 95% CI, 0.05-0.83; P = .026), as compared with those with just colitis, Mr. Molina reported.
This isn’t the first study to show that the occurrence of an irAE foreshadows a better prognosis. “One promising observation that has consistently emerged in the literature is that cancer patients who develop these toxicities may actually have better oncologic outcomes than those who don’t,” Mr. Molina said.
Harvard now has a multidisciplinary group, including a dermatologist, dedicated to evaluating irAEs, he said. To date, however, a minority of patients are being referred, at which point, the dermatologic toxicity may be quite severe. “There’s this belief – which is generally true – that the rashes are mild and can be treated with topical steroids. So there’s often a delay before they see us.”
While larger studies are needed to validate the findings, just tallying up toxicities isn’t going far enough, according to the investigator.
“Our ultimate goal is to bridge the translational research gap, and to use thoughtful specimen collection to one day identify, ideally at the individualized level, the irAE risk level of the patient as soon as they start their immune checkpoint inhibitor, and then reprognosticate them each time they present with a new toxicity,” Mr. Molina said.
Mr. Molina reported no conflicts of interest.
MILAN – Patients on checkpoint inhibitors who experience both dermatologic and gastrointestinal side effects may be at increased risk of further immune-related adverse events, even though they may have better odds of a favorable outcome on the cancer treatment, results of a study presented at the World Congress of Dermatology suggest.
The co-occurrence of dermatologic and gastrointestinal immune-related adverse events (irAEs), which was usually seen early in the course of treatment, was independently associated with favorable progression-free and overall survival in this study, said Gabriel E. Molina, a medical student at Harvard Medical School, Boston.
Compared with patients with colitis alone, those patients who had both immune checkpoint inhibitor-induced rash and colitis were at significantly increased risk of additional irAEs affecting other organ systems, according to Mr. Molina. As a result, patients with both dermatologic and gastrointestinal irAEs may warrant earlier or closer monitoring, and need prompt referral to specialty care at first sign of emerging toxicity.
“We are really excited by the possibility that this co-occurrence of rash and colitis may be a unique and early clinical marker of both high-risk irAE patients and favorable treatment response,” Mr. Molina said.
The single-center, retrospective cohort study reported by Mr. Molina included 67 patients treated with immune checkpoint inhibitors who subsequently developed colitis. Of that group, 28 (or about 42%) also had a rash induced by that treatment.
The median time from starting treatment to onset of rash was 32.5 days, according to this report. Median onset of gastrointestinal toxicity was roughly similar between the patients who also had rash, at 73 days, as compared with patients who did not have rash, at 64 days. Most rashes were grade 1-2 in severity, and were treated with topical corticosteroids in 50% of cases or with nothing at all in 43%, according to the report.
The odds of developing an additional irAE such as hepatitis or hypophysitis was 18.5 times higher in the patients who had rash and colitis as compared with those with colitis only, the researchers also found.
In multivariate analysis, the patients with both rash and colitis had longer progression-free survival (hazard ratio, 0.37; 95% confidence interval, 0.17-0.80; P = .012) and overall survival (HR, 0.20; 95% CI, 0.05-0.83; P = .026), as compared with those with just colitis, Mr. Molina reported.
This isn’t the first study to show that the occurrence of an irAE foreshadows a better prognosis. “One promising observation that has consistently emerged in the literature is that cancer patients who develop these toxicities may actually have better oncologic outcomes than those who don’t,” Mr. Molina said.
Harvard now has a multidisciplinary group, including a dermatologist, dedicated to evaluating irAEs, he said. To date, however, a minority of patients are being referred, at which point, the dermatologic toxicity may be quite severe. “There’s this belief – which is generally true – that the rashes are mild and can be treated with topical steroids. So there’s often a delay before they see us.”
While larger studies are needed to validate the findings, just tallying up toxicities isn’t going far enough, according to the investigator.
“Our ultimate goal is to bridge the translational research gap, and to use thoughtful specimen collection to one day identify, ideally at the individualized level, the irAE risk level of the patient as soon as they start their immune checkpoint inhibitor, and then reprognosticate them each time they present with a new toxicity,” Mr. Molina said.
Mr. Molina reported no conflicts of interest.
MILAN – Patients on checkpoint inhibitors who experience both dermatologic and gastrointestinal side effects may be at increased risk of further immune-related adverse events, even though they may have better odds of a favorable outcome on the cancer treatment, results of a study presented at the World Congress of Dermatology suggest.
The co-occurrence of dermatologic and gastrointestinal immune-related adverse events (irAEs), which was usually seen early in the course of treatment, was independently associated with favorable progression-free and overall survival in this study, said Gabriel E. Molina, a medical student at Harvard Medical School, Boston.
Compared with patients with colitis alone, those patients who had both immune checkpoint inhibitor-induced rash and colitis were at significantly increased risk of additional irAEs affecting other organ systems, according to Mr. Molina. As a result, patients with both dermatologic and gastrointestinal irAEs may warrant earlier or closer monitoring, and need prompt referral to specialty care at first sign of emerging toxicity.
“We are really excited by the possibility that this co-occurrence of rash and colitis may be a unique and early clinical marker of both high-risk irAE patients and favorable treatment response,” Mr. Molina said.
The single-center, retrospective cohort study reported by Mr. Molina included 67 patients treated with immune checkpoint inhibitors who subsequently developed colitis. Of that group, 28 (or about 42%) also had a rash induced by that treatment.
The median time from starting treatment to onset of rash was 32.5 days, according to this report. Median onset of gastrointestinal toxicity was roughly similar between the patients who also had rash, at 73 days, as compared with patients who did not have rash, at 64 days. Most rashes were grade 1-2 in severity, and were treated with topical corticosteroids in 50% of cases or with nothing at all in 43%, according to the report.
The odds of developing an additional irAE such as hepatitis or hypophysitis was 18.5 times higher in the patients who had rash and colitis as compared with those with colitis only, the researchers also found.
In multivariate analysis, the patients with both rash and colitis had longer progression-free survival (hazard ratio, 0.37; 95% confidence interval, 0.17-0.80; P = .012) and overall survival (HR, 0.20; 95% CI, 0.05-0.83; P = .026), as compared with those with just colitis, Mr. Molina reported.
This isn’t the first study to show that the occurrence of an irAE foreshadows a better prognosis. “One promising observation that has consistently emerged in the literature is that cancer patients who develop these toxicities may actually have better oncologic outcomes than those who don’t,” Mr. Molina said.
Harvard now has a multidisciplinary group, including a dermatologist, dedicated to evaluating irAEs, he said. To date, however, a minority of patients are being referred, at which point, the dermatologic toxicity may be quite severe. “There’s this belief – which is generally true – that the rashes are mild and can be treated with topical steroids. So there’s often a delay before they see us.”
While larger studies are needed to validate the findings, just tallying up toxicities isn’t going far enough, according to the investigator.
“Our ultimate goal is to bridge the translational research gap, and to use thoughtful specimen collection to one day identify, ideally at the individualized level, the irAE risk level of the patient as soon as they start their immune checkpoint inhibitor, and then reprognosticate them each time they present with a new toxicity,” Mr. Molina said.
Mr. Molina reported no conflicts of interest.
REPORTING FROM WCD2019
EULAR issues guidelines on managing rheumatic complications of cancer immunotherapies
MADRID – EULAR has issued recommendations to help rheumatologists address the increasingly common clinical issue of diagnosing and managing rheumatic-related adverse events associated with cancer immunotherapy.
“The rheumatic adverse events associated with immunotherapy represent a spectrum of new clinical entities, and they are challenging because they can be difficult to control while attempting to preserve the antitumor effects of oncological drugs,” Marie Kostine, MD, of the Centre Universitaire Hospitalier, Bordeaux, France, explained at the European Congress of Rheumatology.
The recommendations were drawn from the deliberations of an expert task force that identified the clinical issues to address and then developed a consensus about best practice recommendations. In addition to rheumatologists with expertise in this field, the task force included oncologists, allied health personnel, and two patient representatives.
The recommendations include four overarching principles and 10 recommendations.
“One of the overarching principles regards the importance of shared decision making between rheumatologists, oncologists, and patients,” Dr. Kostine said. Because of the expertise of rheumatologists in employing immunomodulatory therapies as they pertain to inflammation of the joints, the recommendations emphasize the value of their collaboration in clinical decisions.
The recommendations address patient referral, the assessment of preexisting rheumatic conditions, diagnosis, and therapeutic strategies.
“Rheumatologists should make themselves aware of the wide spectrum of potential clinical presentations of rheumatic adverse events following the initiation of immunotherapy,” Dr. Kostine said. While rheumatoid arthritis–like symptoms are common, the immune activation produced by checkpoint inhibitors and other immunotherapies can affect nearly every organ in the body, which includes diverse involvement of joint tissues.
In addition to joint pain, which has occurred in up to 40% of patients receiving a checkpoint inhibitor in some series, rheumatology-related events can include vasculitis, systemic sclerosis, and lupus. When associated with immunotherapy, these events sometimes develop in the absence of inflammatory markers or autoantibodies.
The new consensus guidelines emphasize that glucocorticoids can be “considered” to control rheumatic-related adverse events despite their immunosuppressive effect. However, because of their potential to attenuate the benefit of immune activation for treatment of the oncologic disease, such drugs, if used, “should be tapered to the lowest effective dose.”
The consensus recommendations were based on an extensive literature review, but Dr. Kostine acknowledged that prospective studies regarding the best practices for managing rheumatic-related adverse events of immunotherapies remain limited. She suggested that this knowledge gap was one reason for creating an expert task force.
“There has been an immunotherapy revolution, such that rheumatologists who have not yet seen these adverse events soon will,” said Dr. Kostine, noting that the number of approved immunotherapies and their clinical indications have been increasing rapidly.
The EULAR recommendations were created specifically for rheumatologists. In addition to guiding them toward best practice, the report from the task force provides background on the clinical issues raised by therapies that cause inflammatory side effects while stimulating immune function to treat malignancy.
MADRID – EULAR has issued recommendations to help rheumatologists address the increasingly common clinical issue of diagnosing and managing rheumatic-related adverse events associated with cancer immunotherapy.
“The rheumatic adverse events associated with immunotherapy represent a spectrum of new clinical entities, and they are challenging because they can be difficult to control while attempting to preserve the antitumor effects of oncological drugs,” Marie Kostine, MD, of the Centre Universitaire Hospitalier, Bordeaux, France, explained at the European Congress of Rheumatology.
The recommendations were drawn from the deliberations of an expert task force that identified the clinical issues to address and then developed a consensus about best practice recommendations. In addition to rheumatologists with expertise in this field, the task force included oncologists, allied health personnel, and two patient representatives.
The recommendations include four overarching principles and 10 recommendations.
“One of the overarching principles regards the importance of shared decision making between rheumatologists, oncologists, and patients,” Dr. Kostine said. Because of the expertise of rheumatologists in employing immunomodulatory therapies as they pertain to inflammation of the joints, the recommendations emphasize the value of their collaboration in clinical decisions.
The recommendations address patient referral, the assessment of preexisting rheumatic conditions, diagnosis, and therapeutic strategies.
“Rheumatologists should make themselves aware of the wide spectrum of potential clinical presentations of rheumatic adverse events following the initiation of immunotherapy,” Dr. Kostine said. While rheumatoid arthritis–like symptoms are common, the immune activation produced by checkpoint inhibitors and other immunotherapies can affect nearly every organ in the body, which includes diverse involvement of joint tissues.
In addition to joint pain, which has occurred in up to 40% of patients receiving a checkpoint inhibitor in some series, rheumatology-related events can include vasculitis, systemic sclerosis, and lupus. When associated with immunotherapy, these events sometimes develop in the absence of inflammatory markers or autoantibodies.
The new consensus guidelines emphasize that glucocorticoids can be “considered” to control rheumatic-related adverse events despite their immunosuppressive effect. However, because of their potential to attenuate the benefit of immune activation for treatment of the oncologic disease, such drugs, if used, “should be tapered to the lowest effective dose.”
The consensus recommendations were based on an extensive literature review, but Dr. Kostine acknowledged that prospective studies regarding the best practices for managing rheumatic-related adverse events of immunotherapies remain limited. She suggested that this knowledge gap was one reason for creating an expert task force.
“There has been an immunotherapy revolution, such that rheumatologists who have not yet seen these adverse events soon will,” said Dr. Kostine, noting that the number of approved immunotherapies and their clinical indications have been increasing rapidly.
The EULAR recommendations were created specifically for rheumatologists. In addition to guiding them toward best practice, the report from the task force provides background on the clinical issues raised by therapies that cause inflammatory side effects while stimulating immune function to treat malignancy.
MADRID – EULAR has issued recommendations to help rheumatologists address the increasingly common clinical issue of diagnosing and managing rheumatic-related adverse events associated with cancer immunotherapy.
“The rheumatic adverse events associated with immunotherapy represent a spectrum of new clinical entities, and they are challenging because they can be difficult to control while attempting to preserve the antitumor effects of oncological drugs,” Marie Kostine, MD, of the Centre Universitaire Hospitalier, Bordeaux, France, explained at the European Congress of Rheumatology.
The recommendations were drawn from the deliberations of an expert task force that identified the clinical issues to address and then developed a consensus about best practice recommendations. In addition to rheumatologists with expertise in this field, the task force included oncologists, allied health personnel, and two patient representatives.
The recommendations include four overarching principles and 10 recommendations.
“One of the overarching principles regards the importance of shared decision making between rheumatologists, oncologists, and patients,” Dr. Kostine said. Because of the expertise of rheumatologists in employing immunomodulatory therapies as they pertain to inflammation of the joints, the recommendations emphasize the value of their collaboration in clinical decisions.
The recommendations address patient referral, the assessment of preexisting rheumatic conditions, diagnosis, and therapeutic strategies.
“Rheumatologists should make themselves aware of the wide spectrum of potential clinical presentations of rheumatic adverse events following the initiation of immunotherapy,” Dr. Kostine said. While rheumatoid arthritis–like symptoms are common, the immune activation produced by checkpoint inhibitors and other immunotherapies can affect nearly every organ in the body, which includes diverse involvement of joint tissues.
In addition to joint pain, which has occurred in up to 40% of patients receiving a checkpoint inhibitor in some series, rheumatology-related events can include vasculitis, systemic sclerosis, and lupus. When associated with immunotherapy, these events sometimes develop in the absence of inflammatory markers or autoantibodies.
The new consensus guidelines emphasize that glucocorticoids can be “considered” to control rheumatic-related adverse events despite their immunosuppressive effect. However, because of their potential to attenuate the benefit of immune activation for treatment of the oncologic disease, such drugs, if used, “should be tapered to the lowest effective dose.”
The consensus recommendations were based on an extensive literature review, but Dr. Kostine acknowledged that prospective studies regarding the best practices for managing rheumatic-related adverse events of immunotherapies remain limited. She suggested that this knowledge gap was one reason for creating an expert task force.
“There has been an immunotherapy revolution, such that rheumatologists who have not yet seen these adverse events soon will,” said Dr. Kostine, noting that the number of approved immunotherapies and their clinical indications have been increasing rapidly.
The EULAR recommendations were created specifically for rheumatologists. In addition to guiding them toward best practice, the report from the task force provides background on the clinical issues raised by therapies that cause inflammatory side effects while stimulating immune function to treat malignancy.
REPORTING FROM EULAR 2019 CONGRESS
Teva expands its recall of losartan lots
The Food and Drug Administration has announced that , according to a release.
The recall for this and other angiotensin II receptor blockers was initiated by Teva on April 25, 2019, because of detection of unacceptable levels of the possibly cancer-causing impurity N-Nitroso-N-methyl-4-aminobutyric acid (NMBA). Teva expanded this recall on June 10, with another update issued on June 12.
Losartan is not the only ARB found to contain NMBA; a full list of all ARBs affected can be found on the FDA website and currently includes more than 1,100 lots being recalled. The list can be searched and sorted by such considerations as medicine in question, company involved, and lot number.
The Food and Drug Administration has announced that , according to a release.
The recall for this and other angiotensin II receptor blockers was initiated by Teva on April 25, 2019, because of detection of unacceptable levels of the possibly cancer-causing impurity N-Nitroso-N-methyl-4-aminobutyric acid (NMBA). Teva expanded this recall on June 10, with another update issued on June 12.
Losartan is not the only ARB found to contain NMBA; a full list of all ARBs affected can be found on the FDA website and currently includes more than 1,100 lots being recalled. The list can be searched and sorted by such considerations as medicine in question, company involved, and lot number.
The Food and Drug Administration has announced that , according to a release.
The recall for this and other angiotensin II receptor blockers was initiated by Teva on April 25, 2019, because of detection of unacceptable levels of the possibly cancer-causing impurity N-Nitroso-N-methyl-4-aminobutyric acid (NMBA). Teva expanded this recall on June 10, with another update issued on June 12.
Losartan is not the only ARB found to contain NMBA; a full list of all ARBs affected can be found on the FDA website and currently includes more than 1,100 lots being recalled. The list can be searched and sorted by such considerations as medicine in question, company involved, and lot number.
FDA approves trastuzumab-anns for HER2-positive breast, gastric cancer
The Food and Drug Administration has approved Amgen’s trastuzumab-anns as a trastuzumab biosimilar for the treatment of HER2-positive breast cancer and gastric cancer.
This biosimilar, to be marketed as Kanjinti, is the fifth trastuzumab biosimilar to be approved by the agency, according to the FDA.
Approval was based in part on the LILAC study, which demonstrated that the biosimilar, previously called ABP-980, had similar efficacy and comparable cardiac safety with trastuzumab.
In the phase 3 study, 725 patients with HER2-positive early breast cancer were randomized to neoadjuvant treatment with trastuzumab-anns or trastuzumab, plus paclitaxel, for four cycles following four cycles of chemotherapy. The primary pathological complete response endpoint was achieved in 48% of those in the biosimilar arm, compared with 40.5% in the trastuzumab arm. Patients then went on to receive adjuvant treatment with ABP 980 or trastuzumab every 3 weeks for up to 1 year following surgery.
Grade 3 or worse adverse events during the neoadjuvant phase occurred in 15% of patients in the ABP 980 group and 14% in the trastuzumab group. The most frequent grade 3 event in both study arms was neutropenia. In the adjuvant phase, grade 3 or worse adverse events occurred in 9% of those continuing ABP 980 and in 6% of those continuing trastuzumab. The most frequent events in both arms were infections, infestations, and neutropenia.
Trastuzumab-anns is indicated for adjuvant treatment of HER2-overexpressing node positive or node negative breast cancer, first-line treatment of HER2-overexpressing metastatic breast cancer, and first-line treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. The FDA indicates patients should be selected based on an FDA-approved companion diagnostic for a trastuzumab product.
The biosimilar includes a boxed warning for cardiomyopathy, infusion reactions, embryo-fetal toxicity, and pulmonary toxicity.
The Food and Drug Administration has approved Amgen’s trastuzumab-anns as a trastuzumab biosimilar for the treatment of HER2-positive breast cancer and gastric cancer.
This biosimilar, to be marketed as Kanjinti, is the fifth trastuzumab biosimilar to be approved by the agency, according to the FDA.
Approval was based in part on the LILAC study, which demonstrated that the biosimilar, previously called ABP-980, had similar efficacy and comparable cardiac safety with trastuzumab.
In the phase 3 study, 725 patients with HER2-positive early breast cancer were randomized to neoadjuvant treatment with trastuzumab-anns or trastuzumab, plus paclitaxel, for four cycles following four cycles of chemotherapy. The primary pathological complete response endpoint was achieved in 48% of those in the biosimilar arm, compared with 40.5% in the trastuzumab arm. Patients then went on to receive adjuvant treatment with ABP 980 or trastuzumab every 3 weeks for up to 1 year following surgery.
Grade 3 or worse adverse events during the neoadjuvant phase occurred in 15% of patients in the ABP 980 group and 14% in the trastuzumab group. The most frequent grade 3 event in both study arms was neutropenia. In the adjuvant phase, grade 3 or worse adverse events occurred in 9% of those continuing ABP 980 and in 6% of those continuing trastuzumab. The most frequent events in both arms were infections, infestations, and neutropenia.
Trastuzumab-anns is indicated for adjuvant treatment of HER2-overexpressing node positive or node negative breast cancer, first-line treatment of HER2-overexpressing metastatic breast cancer, and first-line treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. The FDA indicates patients should be selected based on an FDA-approved companion diagnostic for a trastuzumab product.
The biosimilar includes a boxed warning for cardiomyopathy, infusion reactions, embryo-fetal toxicity, and pulmonary toxicity.
The Food and Drug Administration has approved Amgen’s trastuzumab-anns as a trastuzumab biosimilar for the treatment of HER2-positive breast cancer and gastric cancer.
This biosimilar, to be marketed as Kanjinti, is the fifth trastuzumab biosimilar to be approved by the agency, according to the FDA.
Approval was based in part on the LILAC study, which demonstrated that the biosimilar, previously called ABP-980, had similar efficacy and comparable cardiac safety with trastuzumab.
In the phase 3 study, 725 patients with HER2-positive early breast cancer were randomized to neoadjuvant treatment with trastuzumab-anns or trastuzumab, plus paclitaxel, for four cycles following four cycles of chemotherapy. The primary pathological complete response endpoint was achieved in 48% of those in the biosimilar arm, compared with 40.5% in the trastuzumab arm. Patients then went on to receive adjuvant treatment with ABP 980 or trastuzumab every 3 weeks for up to 1 year following surgery.
Grade 3 or worse adverse events during the neoadjuvant phase occurred in 15% of patients in the ABP 980 group and 14% in the trastuzumab group. The most frequent grade 3 event in both study arms was neutropenia. In the adjuvant phase, grade 3 or worse adverse events occurred in 9% of those continuing ABP 980 and in 6% of those continuing trastuzumab. The most frequent events in both arms were infections, infestations, and neutropenia.
Trastuzumab-anns is indicated for adjuvant treatment of HER2-overexpressing node positive or node negative breast cancer, first-line treatment of HER2-overexpressing metastatic breast cancer, and first-line treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. The FDA indicates patients should be selected based on an FDA-approved companion diagnostic for a trastuzumab product.
The biosimilar includes a boxed warning for cardiomyopathy, infusion reactions, embryo-fetal toxicity, and pulmonary toxicity.
Immunotherapy drug teplizumab may stall onset of type 1 diabetes
, according to research presented at the annual scientific sessions of the American Diabetes Association.
In this study, 76 first-degree relatives of individuals with type 1 diabetes – who did not themselves have the disease but were considered at high risk because of antibodies and abnormal glucose tolerance tests – were randomized to a single two-week outpatient course of intravenous teplizumab or saline placebo. The patients, of whom 72% were 18 years of age or younger, were followed for a median of 745 days and had twice-yearly oral glucose tolerance testing.
Overall, 43% of the 44 patients who received teplizumab were diagnosed with type 1 diabetes during the course of the study, compared with 72% of the 32 who received the placebo. The treatment was associated with a 59% reduction in the hazard ratio for type 1 diabetes, even after adjusting for age, the results of a second oral glucose-tolerance testing before randomization, or the presence of anti-GAD65 antibodies.
The median time to diagnosis was 48.4 months in the teplizumab group and 24.4 months in the placebo group. The greatest effect was seen in the first year after randomization, during which only 7% of the teplizumab group were diagnosed with type 1 diabetes, compared with 44% of the placebo group. The findings were published simultaneously in the New England Journal of Medicine.
“The delay of progression to type 1 diabetes is of clinical importance, particularly for children, in whom the diagnosis is associated with adverse outcomes, and given the challenges of daily management of the condition,” said Dr. Kevan C. Herold, professor of immunobiology and medicine at Yale University, New Haven, Conn., and coauthors.
There were significantly more adverse events in the teplizumab group, compared with placebo, with three-quarters of the 20 grade 3 adverse events being lymphopenia during the first 30 days. In all but one participant, however, the lymphopenia resolved by day 45. Participants receiving teplizumab also reported a higher incidence of dermatologic adverse events, such as a spontaneously-resolving rash that was experienced by just over one-third of the group.
The researchers also looked for evidence of T-cell unresponsiveness, which has been previously seen in patients with new-onset type 1 diabetes who received treatment with teplizumab. They noted an increase in a particular type of CD8+ T cell associated with T-cell unresponsiveness at months 3 and 6 in participants treated with teplizumab.
Teplizumab is an Fc receptor-nonbinding monoclonal antibody that has been shown to reduce the loss of beta-cell function in patients with type 1 diabetes (Diabetes. 2013 Nov;62(11):3766-74).
The study was supported by the National Institutes of Health, the Juvenile Diabetes Research Foundation, and the American Diabetes Association, with the study drug and additional site monitoring provided by MacroGenics. Eight authors declared grants, personal fees, and other support from private industry, with one also declaring income and stock options from MacroGenics.
SOURCE: Herold K et al. NEJM. 2019 Jun 9. doi: 10.1056/NEJMoa1902226*
*Correction, 6/9/2019: An earlier version of this story misstated the doi number for the journal article. The number is 10.1056/NEJMoa1902226.
While the results of this trial are striking, there are several caveats that are important to note. The trial did show a significant delay in the onset of type 1 diabetes – with the greatest preventive benefit in the first year of the trial – but these results do not necessarily mean that immune modulation represents a potential cure.
They do, however, provide indirect evidence of the pathogenesis of beta-cell destruction and the potential for newer biologic agents to alter the course of this.
The study also was small and involved only a 2-week course of the treatment. As such, there are still questions to be answered about the duration of treatment, longer-term side effects, sub-groups of patients who may respond differently to treatment, and the longer clinical course of those who do respond to treatment.
Julie R. Ingelfinger, MD, is deputy editor of the New England Journal of Medicine, and Clifford J. Rosen, MD, is from the Maine Medical Center Research Institute and is associate editor of the journal. Their comments are adapted from an accompanying editorial (NEJM 2019, Jun 9. doi: 10.1056/NEJMe1907458). No conflicts of interest were declared.
While the results of this trial are striking, there are several caveats that are important to note. The trial did show a significant delay in the onset of type 1 diabetes – with the greatest preventive benefit in the first year of the trial – but these results do not necessarily mean that immune modulation represents a potential cure.
They do, however, provide indirect evidence of the pathogenesis of beta-cell destruction and the potential for newer biologic agents to alter the course of this.
The study also was small and involved only a 2-week course of the treatment. As such, there are still questions to be answered about the duration of treatment, longer-term side effects, sub-groups of patients who may respond differently to treatment, and the longer clinical course of those who do respond to treatment.
Julie R. Ingelfinger, MD, is deputy editor of the New England Journal of Medicine, and Clifford J. Rosen, MD, is from the Maine Medical Center Research Institute and is associate editor of the journal. Their comments are adapted from an accompanying editorial (NEJM 2019, Jun 9. doi: 10.1056/NEJMe1907458). No conflicts of interest were declared.
While the results of this trial are striking, there are several caveats that are important to note. The trial did show a significant delay in the onset of type 1 diabetes – with the greatest preventive benefit in the first year of the trial – but these results do not necessarily mean that immune modulation represents a potential cure.
They do, however, provide indirect evidence of the pathogenesis of beta-cell destruction and the potential for newer biologic agents to alter the course of this.
The study also was small and involved only a 2-week course of the treatment. As such, there are still questions to be answered about the duration of treatment, longer-term side effects, sub-groups of patients who may respond differently to treatment, and the longer clinical course of those who do respond to treatment.
Julie R. Ingelfinger, MD, is deputy editor of the New England Journal of Medicine, and Clifford J. Rosen, MD, is from the Maine Medical Center Research Institute and is associate editor of the journal. Their comments are adapted from an accompanying editorial (NEJM 2019, Jun 9. doi: 10.1056/NEJMe1907458). No conflicts of interest were declared.
, according to research presented at the annual scientific sessions of the American Diabetes Association.
In this study, 76 first-degree relatives of individuals with type 1 diabetes – who did not themselves have the disease but were considered at high risk because of antibodies and abnormal glucose tolerance tests – were randomized to a single two-week outpatient course of intravenous teplizumab or saline placebo. The patients, of whom 72% were 18 years of age or younger, were followed for a median of 745 days and had twice-yearly oral glucose tolerance testing.
Overall, 43% of the 44 patients who received teplizumab were diagnosed with type 1 diabetes during the course of the study, compared with 72% of the 32 who received the placebo. The treatment was associated with a 59% reduction in the hazard ratio for type 1 diabetes, even after adjusting for age, the results of a second oral glucose-tolerance testing before randomization, or the presence of anti-GAD65 antibodies.
The median time to diagnosis was 48.4 months in the teplizumab group and 24.4 months in the placebo group. The greatest effect was seen in the first year after randomization, during which only 7% of the teplizumab group were diagnosed with type 1 diabetes, compared with 44% of the placebo group. The findings were published simultaneously in the New England Journal of Medicine.
“The delay of progression to type 1 diabetes is of clinical importance, particularly for children, in whom the diagnosis is associated with adverse outcomes, and given the challenges of daily management of the condition,” said Dr. Kevan C. Herold, professor of immunobiology and medicine at Yale University, New Haven, Conn., and coauthors.
There were significantly more adverse events in the teplizumab group, compared with placebo, with three-quarters of the 20 grade 3 adverse events being lymphopenia during the first 30 days. In all but one participant, however, the lymphopenia resolved by day 45. Participants receiving teplizumab also reported a higher incidence of dermatologic adverse events, such as a spontaneously-resolving rash that was experienced by just over one-third of the group.
The researchers also looked for evidence of T-cell unresponsiveness, which has been previously seen in patients with new-onset type 1 diabetes who received treatment with teplizumab. They noted an increase in a particular type of CD8+ T cell associated with T-cell unresponsiveness at months 3 and 6 in participants treated with teplizumab.
Teplizumab is an Fc receptor-nonbinding monoclonal antibody that has been shown to reduce the loss of beta-cell function in patients with type 1 diabetes (Diabetes. 2013 Nov;62(11):3766-74).
The study was supported by the National Institutes of Health, the Juvenile Diabetes Research Foundation, and the American Diabetes Association, with the study drug and additional site monitoring provided by MacroGenics. Eight authors declared grants, personal fees, and other support from private industry, with one also declaring income and stock options from MacroGenics.
SOURCE: Herold K et al. NEJM. 2019 Jun 9. doi: 10.1056/NEJMoa1902226*
*Correction, 6/9/2019: An earlier version of this story misstated the doi number for the journal article. The number is 10.1056/NEJMoa1902226.
, according to research presented at the annual scientific sessions of the American Diabetes Association.
In this study, 76 first-degree relatives of individuals with type 1 diabetes – who did not themselves have the disease but were considered at high risk because of antibodies and abnormal glucose tolerance tests – were randomized to a single two-week outpatient course of intravenous teplizumab or saline placebo. The patients, of whom 72% were 18 years of age or younger, were followed for a median of 745 days and had twice-yearly oral glucose tolerance testing.
Overall, 43% of the 44 patients who received teplizumab were diagnosed with type 1 diabetes during the course of the study, compared with 72% of the 32 who received the placebo. The treatment was associated with a 59% reduction in the hazard ratio for type 1 diabetes, even after adjusting for age, the results of a second oral glucose-tolerance testing before randomization, or the presence of anti-GAD65 antibodies.
The median time to diagnosis was 48.4 months in the teplizumab group and 24.4 months in the placebo group. The greatest effect was seen in the first year after randomization, during which only 7% of the teplizumab group were diagnosed with type 1 diabetes, compared with 44% of the placebo group. The findings were published simultaneously in the New England Journal of Medicine.
“The delay of progression to type 1 diabetes is of clinical importance, particularly for children, in whom the diagnosis is associated with adverse outcomes, and given the challenges of daily management of the condition,” said Dr. Kevan C. Herold, professor of immunobiology and medicine at Yale University, New Haven, Conn., and coauthors.
There were significantly more adverse events in the teplizumab group, compared with placebo, with three-quarters of the 20 grade 3 adverse events being lymphopenia during the first 30 days. In all but one participant, however, the lymphopenia resolved by day 45. Participants receiving teplizumab also reported a higher incidence of dermatologic adverse events, such as a spontaneously-resolving rash that was experienced by just over one-third of the group.
The researchers also looked for evidence of T-cell unresponsiveness, which has been previously seen in patients with new-onset type 1 diabetes who received treatment with teplizumab. They noted an increase in a particular type of CD8+ T cell associated with T-cell unresponsiveness at months 3 and 6 in participants treated with teplizumab.
Teplizumab is an Fc receptor-nonbinding monoclonal antibody that has been shown to reduce the loss of beta-cell function in patients with type 1 diabetes (Diabetes. 2013 Nov;62(11):3766-74).
The study was supported by the National Institutes of Health, the Juvenile Diabetes Research Foundation, and the American Diabetes Association, with the study drug and additional site monitoring provided by MacroGenics. Eight authors declared grants, personal fees, and other support from private industry, with one also declaring income and stock options from MacroGenics.
SOURCE: Herold K et al. NEJM. 2019 Jun 9. doi: 10.1056/NEJMoa1902226*
*Correction, 6/9/2019: An earlier version of this story misstated the doi number for the journal article. The number is 10.1056/NEJMoa1902226.
REPORTING FROM ADA 2019
Key clinical point: Teplizumab may delay the onset of type 1 diabetes in individuals at risk.
Major finding: Templizumab treatment was associated with a 59% lower hazard ratio for the diagnosis of type 1 diabetes.
Study details: Phase 2, randomized, double-blind, placebo-controlled trial in 76 participants.
Disclosures: The study was supported by the National Institutes of Health, the Juvenile Diabetes Research Foundation, and the American Diabetes Association, with the study drug and additional site monitoring provided by MacroGenics. Eight authors declared grants, personal fees, and other support from private industry, with one also declaring income and stock options from MacroGenics.
Source: Herold K et al. NEJM 2019, June 9. DOI: 10.1065/NEJMoa1902226.
DOACs surpass warfarin in low-weight AFib patients
SAN FRANCISCO – The direct-acting anticoagulants, as a class, were more effective and at least as safe as warfarin in low-weight and very-low-weight patients with atrial fibrillation in an adjusted analysis of real-world outcomes data from more than 21,000 Korean patients.
The analysis also showed that the direct-acting oral anticoagulants (DOACs) had the best safety and efficacy on low-weight patients when used at the labeled dosages, with blunted efficacy and safety at dosages that either exceeded or fell short of labeled levels, So-Ryoung Lee, MD, said at the annual scientific sessions of the Heart Rhythm Society.
The overall superiority of DOACs by both efficacy and safety also generally extended to the subgroup of very-low-weight patients, those with weights of less than 50 kg. In this subgroup, which was 28% of the total population studied, the composite adverse event outcome occurred 33% less often among patients treated with a DOAC relative to patients treated with warfarin, a statistically significant difference, said Dr. Lee, a cardiologist at Seoul (South Korea) National University Hospital. Among all patients with weights of 60 kg (132 pounds) or less, the composite outcome occurred 34% less often in the DOAC-treated patients relative to the warfarin-treated patients, also a statistically significant difference.
Dr. Lee and colleagues used a Korean National Health Insurance database that included information on more than 600,000 adults with atrial fibrillation (AFib) as of January 2013. The researchers whittled this down to 21,678 patients who began for the first time treatment with an oral anticoagulant starting during or after January 2014; had no history of a stroke, intracranial hemorrhage, or gastrointestinal bleed; and weighed no more than 60 kg. This cohort included 7,575 (35%) who received warfarin treatment, and 14,103 (65%) who received a DOAC. Within the DOAC-treated group, 42% received rivaroxaban (Xarelto), 26% dabigatran (Pradaxa), 24% apixaban (Eliquis), and 8% edoxaban (Savaysa).
To account for baseline differences in demographics and comorbidities between the patients treated with a DOAC and those who received warfarin, Dr. Lee and her associates did propensity score adjustment, which resulted in similar cohorts of 6,692 patients treated with warfarin and 12,810 patients treated with a DOAC. The average age of these patients was 73 years, a third were men, and the average body mass index was just over 22 kg/m2.
The events that the researchers tallied during follow-up through December 2016 included rates of all-cause death, ischemic stroke, intracranial hemorrhage, hospitalization for GI bleeding, hospitalization for major bleeding, and the composite of these five outcomes.
In the propensity-score adjusted full cohort of all patients who weighed 60 kg or less, the rate of each of these five outcomes, as well as the composite outcome, occurred statistically significantly less often among the DOAC-treated patients than in those on warfarin. The reductions ranged from a 41% lower incidence of ischemic stroke on DOAC treatment compared with warfarin treatment, to an 18% reduced rate of hospitalization for a GI bleed, compared with warfarin-treated patients. In the subgroup of patients who weighed less than 50 kg (110 pounds), the reductions ranged from a 41% cut in ischemic stroke on a DOAC compared with warfarin to a 24% relative reduction in the rate of hospitalization for a major bleed, a difference that just reached statistical significance. The outcome of hospitalization for a GI bleed showed no significant between-group difference among very-low-weight patients, but the rates of intracranial hemorrhage and all-cause death also showed statistically significant lower rates among DOAC-treated patients.
Nearly two-thirds of the patients on a DOAC received the label-appropriate dose of the drug, but 31% received a dosage that was below the labeled level while 4% received a dosage above the labeled level. An analysis that divided the NOAC patients by the appropriateness of their treatment dosages showed that patients on the correct dosages fared best. For example, in the total cohort of patients who weighed 60 kg or less, those on the correct DOAC dosage had a 9.1% rate of the combined endpoint. Patients on a low DOAC dosage did about as well as did the patients on warfarin, with a combined event rate of 11.6% in each of these subgroups. The worst outcomes occurred among the small number of patients on an inappropriately-high DOAC dosage, with a combined event rate of 15.4%. The researchers found a similar pattern among patients who weighed less than 50 kg.
Dr. Lee had no disclosures.
SOURCE: Lee SR et al. HRS 2019, Abstract S-AB30-05.
SAN FRANCISCO – The direct-acting anticoagulants, as a class, were more effective and at least as safe as warfarin in low-weight and very-low-weight patients with atrial fibrillation in an adjusted analysis of real-world outcomes data from more than 21,000 Korean patients.
The analysis also showed that the direct-acting oral anticoagulants (DOACs) had the best safety and efficacy on low-weight patients when used at the labeled dosages, with blunted efficacy and safety at dosages that either exceeded or fell short of labeled levels, So-Ryoung Lee, MD, said at the annual scientific sessions of the Heart Rhythm Society.
The overall superiority of DOACs by both efficacy and safety also generally extended to the subgroup of very-low-weight patients, those with weights of less than 50 kg. In this subgroup, which was 28% of the total population studied, the composite adverse event outcome occurred 33% less often among patients treated with a DOAC relative to patients treated with warfarin, a statistically significant difference, said Dr. Lee, a cardiologist at Seoul (South Korea) National University Hospital. Among all patients with weights of 60 kg (132 pounds) or less, the composite outcome occurred 34% less often in the DOAC-treated patients relative to the warfarin-treated patients, also a statistically significant difference.
Dr. Lee and colleagues used a Korean National Health Insurance database that included information on more than 600,000 adults with atrial fibrillation (AFib) as of January 2013. The researchers whittled this down to 21,678 patients who began for the first time treatment with an oral anticoagulant starting during or after January 2014; had no history of a stroke, intracranial hemorrhage, or gastrointestinal bleed; and weighed no more than 60 kg. This cohort included 7,575 (35%) who received warfarin treatment, and 14,103 (65%) who received a DOAC. Within the DOAC-treated group, 42% received rivaroxaban (Xarelto), 26% dabigatran (Pradaxa), 24% apixaban (Eliquis), and 8% edoxaban (Savaysa).
To account for baseline differences in demographics and comorbidities between the patients treated with a DOAC and those who received warfarin, Dr. Lee and her associates did propensity score adjustment, which resulted in similar cohorts of 6,692 patients treated with warfarin and 12,810 patients treated with a DOAC. The average age of these patients was 73 years, a third were men, and the average body mass index was just over 22 kg/m2.
The events that the researchers tallied during follow-up through December 2016 included rates of all-cause death, ischemic stroke, intracranial hemorrhage, hospitalization for GI bleeding, hospitalization for major bleeding, and the composite of these five outcomes.
In the propensity-score adjusted full cohort of all patients who weighed 60 kg or less, the rate of each of these five outcomes, as well as the composite outcome, occurred statistically significantly less often among the DOAC-treated patients than in those on warfarin. The reductions ranged from a 41% lower incidence of ischemic stroke on DOAC treatment compared with warfarin treatment, to an 18% reduced rate of hospitalization for a GI bleed, compared with warfarin-treated patients. In the subgroup of patients who weighed less than 50 kg (110 pounds), the reductions ranged from a 41% cut in ischemic stroke on a DOAC compared with warfarin to a 24% relative reduction in the rate of hospitalization for a major bleed, a difference that just reached statistical significance. The outcome of hospitalization for a GI bleed showed no significant between-group difference among very-low-weight patients, but the rates of intracranial hemorrhage and all-cause death also showed statistically significant lower rates among DOAC-treated patients.
Nearly two-thirds of the patients on a DOAC received the label-appropriate dose of the drug, but 31% received a dosage that was below the labeled level while 4% received a dosage above the labeled level. An analysis that divided the NOAC patients by the appropriateness of their treatment dosages showed that patients on the correct dosages fared best. For example, in the total cohort of patients who weighed 60 kg or less, those on the correct DOAC dosage had a 9.1% rate of the combined endpoint. Patients on a low DOAC dosage did about as well as did the patients on warfarin, with a combined event rate of 11.6% in each of these subgroups. The worst outcomes occurred among the small number of patients on an inappropriately-high DOAC dosage, with a combined event rate of 15.4%. The researchers found a similar pattern among patients who weighed less than 50 kg.
Dr. Lee had no disclosures.
SOURCE: Lee SR et al. HRS 2019, Abstract S-AB30-05.
SAN FRANCISCO – The direct-acting anticoagulants, as a class, were more effective and at least as safe as warfarin in low-weight and very-low-weight patients with atrial fibrillation in an adjusted analysis of real-world outcomes data from more than 21,000 Korean patients.
The analysis also showed that the direct-acting oral anticoagulants (DOACs) had the best safety and efficacy on low-weight patients when used at the labeled dosages, with blunted efficacy and safety at dosages that either exceeded or fell short of labeled levels, So-Ryoung Lee, MD, said at the annual scientific sessions of the Heart Rhythm Society.
The overall superiority of DOACs by both efficacy and safety also generally extended to the subgroup of very-low-weight patients, those with weights of less than 50 kg. In this subgroup, which was 28% of the total population studied, the composite adverse event outcome occurred 33% less often among patients treated with a DOAC relative to patients treated with warfarin, a statistically significant difference, said Dr. Lee, a cardiologist at Seoul (South Korea) National University Hospital. Among all patients with weights of 60 kg (132 pounds) or less, the composite outcome occurred 34% less often in the DOAC-treated patients relative to the warfarin-treated patients, also a statistically significant difference.
Dr. Lee and colleagues used a Korean National Health Insurance database that included information on more than 600,000 adults with atrial fibrillation (AFib) as of January 2013. The researchers whittled this down to 21,678 patients who began for the first time treatment with an oral anticoagulant starting during or after January 2014; had no history of a stroke, intracranial hemorrhage, or gastrointestinal bleed; and weighed no more than 60 kg. This cohort included 7,575 (35%) who received warfarin treatment, and 14,103 (65%) who received a DOAC. Within the DOAC-treated group, 42% received rivaroxaban (Xarelto), 26% dabigatran (Pradaxa), 24% apixaban (Eliquis), and 8% edoxaban (Savaysa).
To account for baseline differences in demographics and comorbidities between the patients treated with a DOAC and those who received warfarin, Dr. Lee and her associates did propensity score adjustment, which resulted in similar cohorts of 6,692 patients treated with warfarin and 12,810 patients treated with a DOAC. The average age of these patients was 73 years, a third were men, and the average body mass index was just over 22 kg/m2.
The events that the researchers tallied during follow-up through December 2016 included rates of all-cause death, ischemic stroke, intracranial hemorrhage, hospitalization for GI bleeding, hospitalization for major bleeding, and the composite of these five outcomes.
In the propensity-score adjusted full cohort of all patients who weighed 60 kg or less, the rate of each of these five outcomes, as well as the composite outcome, occurred statistically significantly less often among the DOAC-treated patients than in those on warfarin. The reductions ranged from a 41% lower incidence of ischemic stroke on DOAC treatment compared with warfarin treatment, to an 18% reduced rate of hospitalization for a GI bleed, compared with warfarin-treated patients. In the subgroup of patients who weighed less than 50 kg (110 pounds), the reductions ranged from a 41% cut in ischemic stroke on a DOAC compared with warfarin to a 24% relative reduction in the rate of hospitalization for a major bleed, a difference that just reached statistical significance. The outcome of hospitalization for a GI bleed showed no significant between-group difference among very-low-weight patients, but the rates of intracranial hemorrhage and all-cause death also showed statistically significant lower rates among DOAC-treated patients.
Nearly two-thirds of the patients on a DOAC received the label-appropriate dose of the drug, but 31% received a dosage that was below the labeled level while 4% received a dosage above the labeled level. An analysis that divided the NOAC patients by the appropriateness of their treatment dosages showed that patients on the correct dosages fared best. For example, in the total cohort of patients who weighed 60 kg or less, those on the correct DOAC dosage had a 9.1% rate of the combined endpoint. Patients on a low DOAC dosage did about as well as did the patients on warfarin, with a combined event rate of 11.6% in each of these subgroups. The worst outcomes occurred among the small number of patients on an inappropriately-high DOAC dosage, with a combined event rate of 15.4%. The researchers found a similar pattern among patients who weighed less than 50 kg.
Dr. Lee had no disclosures.
SOURCE: Lee SR et al. HRS 2019, Abstract S-AB30-05.
REPORTING FROM HEART RHYTHM 2019
Probiotic Use for the Prevention of Antibiotic- Associated Clostridium difficile Infection
Clostridium difficile (C difficile) is a gram-positive, toxin-producing bacterium that is of increasing concern among health care providers and patients. Infection with C difficile can have manifestations ranging from mild diarrhea to severe toxic megacolon and can result in prolonged hospitalization with severe cases requiring admission to an intensive care unit.1 In 2014, the US was estimated to have more than 600,000 cases of C difficile infection (CDI), previously known as C difficile–associated diarrhea, and more than 44,000 associated deaths. The annual economic cost of CDI is thought to exceed $5 billion.1 According to studies of health care–associated illness, CDI rates are comparable to or have surpassed rates of methicillin-resistant Staphylococcus aureus infection within the US, including at US Department of Veterans Affairs (VA) acute care centers nationwide.2,3
C difficile has been shown to be the causative agent in 10% to 20% of antibiotic-associated diarrhea episodes.4 Colonization of C difficile is uncommon in healthy adults, but colonization rates are as high as 21% in hospitalized patients, with increasing rates proportional to increasing hospital length of stay.5,6 Although not all colonized patients develop clinically significant CDI, those who do may require multiple treatment courses, over months to years, because of the high risk of disease recurrence. An estimated 25% of patients have a single recurrent episode of CDI within 30 days after treatment completion, and 45% of those patients have additional recurrent infections.7,8 Although probiotics do not have an approved US Food and Drug Administration (FDA) indication, these supplements are often used to try to prevent CDI from developing during concomitant antibiotic use. Probiotics are microorganisms with potential health benefits, but the mechanisms of these benefits are not fully understood. Proposed mechanisms include reduced growth of pathogenic bacteria, modulation of the immune system, and support of the intestinal wall barrier.9 The many probiotic formulations currently marketed include Lactobacillus acidophilus (L acidophilus) capsules and various combinations of L acidophilus, Lactobacillus casei, Bifidobacterium lactis, Bifidobacterium longum, Streptococcus thermophilus, and other bacterial strains.
Dosing and Guidelines
Manufacturers’ suggested dosing for their Lactobacillus capsules, tablets, and packets varies from 1 unit daily to 4 units 4 times daily for dietary supplementation; the products’ labeling does not include any information regarding treatment duration.10-13 In addition, there are no published recommendations or product labeling guiding the dosing of probiotics or their duration of use in the primary prevention of CDI.
In 2017, the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) updated their CDI treatment guidelines.14 As these guidelines indicate that the data on probiotic use in CDI are inadequate, IDSA and SHEA make no recommendation for or against probiotic use in primary prevention of the disease. The guidelines point to several limitations in the literature, including variability in probiotic formulations studied, duration of probiotic administration, definitions of CDI, and duration of study follow-up.
Given the lack of consensus guidelines that clinicians can use when deciding which probiotic dosing and duration are appropriate for a patient for primary prevention of CDI, we evaluated the literature on the topic and summarize their findings here.
Review of Probiotoc Literature
Conflicting data exist about probiotics and their effect on CDI prevention. The literature reviewed was selected based on our assessment of its contribution to the topic and its potential utility to clinicians in determining appropriate probiotic therapies and recommendations. Included in our discussion is a large Cochrane Review of probiotic efficacy, 2 trials of probiotic dosing, the PLACIDE trial, and a systematic review of timely probiotic initiation. All of these studies attempted to determine the effect of probiotics on CDI incidence (Table).
In their 2017 Cochrane Review, Goldenberg and colleagues reviewed 39 trials that investigated the efficacy of probiotics in CDI prevention in 9,955 immunocompetent patients receiving antibiotics.15 The incidence of CDI was significantly lower in patients who received a probiotic than in patients who received placebo or no treatment (1.5% vs 4.0%; relative risk [RR], 0.40; 95% CI, 0.30-0.52; I2 = 0%). It is important to note that trials with a control-group CDI incidence of 0% to 2% (baseline CDI risk) found no statistically significant difference in CDI risk between patients using and not using probiotics (RR, 0.77; 95% CI, 0.45-1.32; I2 = 0%) and that the preceding statistically significant result may have been driven by the inclusion of trials with high baseline CDI risk (> 5%). Trials that enrolled patients who were at this risk level found a statistically significant 70% reduction in CDI risk in those using probiotics (vs no probiotics) while on concomitant antibiotic therapy (RR, 0.30; 95% CI, 0.21-0.42; I2 = 0%).
Probiotic therapy seems to be effective in reducing CDI risk in immunocompetent patients and may be particularly beneficial in patients at higher CDI risk, though Goldenberg and colleagues did not elaborate on what constitutes higher risk and based their conclusion on their control group’s high CDI incidence (> 5%). The most common adverse events (AEs) attributable to probiotics included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. The review’s findings are limited in that the inclusion of many small trials with high baseline CDI risk likely contributed to a statistically significant result, and 17 of the review’s 39 trials were industry-sponsored or were conducted by investigators with industry associations; another 12 lacked statements about funding or sponsorship.
Two of the trials in the Cochrane Review investigated whether probiotics have a dose effect on CDI prevention. Gao and colleagues randomly assigned 255 hospitalized Asian patients to 3 groups: those receiving placebo, 1 probiotic capsule daily, and 2 probiotic capsules daily.16 Each probiotic capsule contained 50 billion colony-forming units (CFUs) of Lactobacillus. Incidence of CDI was lower in patients taking 2 probiotic capsules daily than in those taking 1 probiotic capsule daily (1.2% vs 9.4%; P = .04) or placebo (1.2% vs 23.8%; P = .002). In the other trial, Ouwehand and colleagues randomly assigned 503 hospitalized Asian patients to 3 groups as well: those receiving placebo, low-dose probiotic (4.17 billion CFUs of Lactobacillus and Bifidobacterium), and high-dose probiotic (17 billion CFUs).17 The incidence of CDI in each probiotic group (low-dose, high-dose) was 1.8%, which was significantly lower than the 4.8% in the placebo group (P = .04).
The Cochrane Review’s largest and most rigorous trial was PLACIDE, a 2013 randomized controlled study of the effect of probiotics on CDI.18 Allen and colleagues randomly assigned 2,981 inpatients (aged ≥ 65 years; exposed to antibiotics within preceding 7 days) to 2 groups: those receiving either 1 probiotic capsule daily, or 1 placebo capsule daily, for 21 days. Results showed no difference in CDI incidence between the probiotic and placebo groups (0.8% vs 1.2%; RR, 0.71; 95% CI, 0.34-1.47; P = .35). Of note, this trial is free of industry sponsorship, is the largest probiotic trial to date, has a control-group baseline CDI rate consistent with the rate in hospital and ambulatory settings in the US, and found a negative result regarding probiotic use in CDI prevention. Findings are limited in that the study allowed for initiating probiotic therapy up to 7 days after the start of antibiotics, and patients were given 1 relatively low-dose capsule daily, which may have contributed to lack of an effect on CDI prevention. No serious AEs were attributed to probiotic use.
In a 2017 systematic meta-analysis of 19 studies, Shen and colleagues investigated whether timely use of probiotics prevented CDI in 6,261 hospitalized patients receiving antibiotics.19 The incidence of CDI was significantly lower in patients receiving vs not receiving probiotics (1.6% vs 3.9%; RR, 0.42; 95% CI, 0.30-0.57; I2 = 0%; P < .001).19 A subgroup analysis was performed to compare studies initiating probiotics within 2 days after the start of antibiotics with studies initiating probiotics more than 2 days after the start. CDI risk was reduced by 68% when probiotics were started within 2 days, vs 30% when started after 2 days (RR, 0.32; 95% CI, 0.22-0.48; I2 = 0% vs RR, 0.70; 95% CI, 0.40-1.23; I2 = 0%; P = .02). Of note, no difference was found in efficacy among the various probiotic formulations, and no significant AEs were noted in any study group.
Trials included in the Cochrane Review used many different probiotic regimens over various durations.15 All these trials continued probiotics for at least the duration of antibiotic therapy. The 2 trials that evaluated the effect of probiotic therapy over an extended period required probiotics be started within 48 hours after initiation of antibiotic therapy; one trial continued probiotics for 5 days after completion of antibiotics, and the other for 7 days after completion.16,20 In both trials, CDI was statistically significantly reduced among adults using probiotics compared with adults receiving placebo.
Probiotic Safety
The FDA has not approved probiotics for the prevention or treatment of any health problems. Most probiotics are FDA-regulated as dietary supplements and do not have to meet stringent drug-approval requirements. The FDA has given many strains of common probiotics the Generally Recognized as Safe designation for use in commercially available products and foods.21-23 Probiotic use has not been associated with significant AEs in clinical trials and generally has been considered safe in immunocompetent and otherwise healthy persons.15-19 However, clinical trials have been inadequate in reporting or investigating AEs; the alternative for evaluating the risks of probiotic therapy is case reports.24,25 Theoretical risks associated with probiotics include sepsis, deleterious effects on normal gut digestion, excessive immune stimulation, and possible transfer of antimicrobial resistance genes among microorganisms.26 Boyle and colleagues further described a handful of case reports of sepsis caused by probiotics in immunocompromised individuals; the other theoretical risks have not been reported outside animal studies.26
CDI Risk Factors
Many factors can increase a patient’s CDI risk. Specific antibiotics (eg, ampicillin, amoxicillin, cephalosporins, clindamycin, fluoroquinolones) confer higher risk.27,28 Other factors include inflammatory bowel disease, organ transplantation, chemotherapy, chronic kidney disease, and immunodeficiency. Advanced age increases CDI risk and can increase the severity of infection. The evidence regarding acid suppression and CDI risk is conflicting, though a recent meta-analysis found that use of proton pump inhibitors is associated with a 2-fold higher risk of developing CDI.29 Patient-specific risk factors should be evaluated when the risk–benefit ratio for probiotic use is being considered.
Conclusion
CDIs are becoming increasingly burdensome to the health care system. More research is needed on the role of probiotics in CDI prevention in patients taking antibiotics. Given the limited risk for AEs when probiotics are used in immunocompetent patients and the relatively low cost of these supplements, the risks likely are outweighed by the postulated benefits, and probiotics may be recommended in select patient populations.
The PLACIDE trial found no benefit of probiotics in preventing CDI in a population similar to that of a typical US hospital or ambulatory setting, but its intervention allowed late initiation of relatively low doses of probiotics. Therefore, probiotics may be recommended for CDI prevention in patients taking antibiotics, especially patients at high risk for developing CDI. When clinicians recommend probiotic use in this setting, the probiotic should be initiated within 2 days after the start of antibiotics and should be continued for the duration of antibiotic therapy and for up to 7 days after that therapy is completed. Optimal probiotic dosing, likely dependent on the product used, remains unclear. PLACIDE trial results suggest that a dosage of at least 1 probiotic capsule 2 times daily may confer additional efficacy.
1. Desai K, Gupta SB, Dubberke ER, Prabhu VS, Browne C, Mast TC. Epidemiological and economic burden of Clostridium difficile in the United States: estimates from a modeling approach. BMC Infect Dis. 2016;16:303.
2. Miller BA, Chen LF, Sexton DJ, Anderson DJ. Comparison of the burdens of hospital-onset, healthcare facility-associated Clostridium difficile infection and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospitals. Infect Control Hosp Epidemiol. 2011;32(4):387-390.
3. Evans ME, Kralovic SM, Simbartl LA, Jain R, Roselle GA. Effect of a Clostridium difficile infection prevention initiative in Veterans Affairs acute care facilities. Infect Control Hosp Epidemiol. 2016;37(6):720-722.
4. Bartlett JG. Clinical practice. Antibiotic-associated diarrhea. N Engl J Med. 2002;346(5):334-339.
5. Johnson S, Clabots CR, Linn FV, Olson MM, Peterson LR, Gerding DN. Nosocomial Clostridium difficile colonisation and disease. Lancet. 1990;336(8707):97-100.
6. McFarland LV, Mulligan ME, Kwok RY, Stamm WE. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med. 1989;320(4):204-210.
7. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002;97(7):1769-1775.
8. Kelly CP. Can we identify patients at high risk of recurrent Clostridium difficile infection? Clin Microbiol Infect. 2012;18(suppl 6):21-27.
9. Sartor RB. Probiotics for gastrointestinal diseases. https://www.uptodate.com/contents/probiotics-for-gastrointestinal-diseases. Updated September 4, 2018. Accessed April 4, 2019.
10. VSL#3 (Lactobacillus) [prescribing information]. Covington, LA: Alfasigma USA Inc; July 2017.
11. Culturelle Digestive Health Probiotic Capsules (Lactobacillus) [prescribing information]. Cromwell, CT: I-Health, Inc; 2015.
12. Flora-Q (Lactobacillus) [prescribing information]. Melville, NY: PharmaDerm; May 2012.
13. Lactinex (Lactobacillus) [prescribing information]. Franklin Lakes, NJ: Becton, Dickinson and Company; 2015
14. 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). Clin Infect Dis. 2018;66(7):987-994.
15. Goldenberg JZ, Yap C, Lytvyn L, et al. Probiotics for the prevention of Clostridium difficile–associated diarrhea in adults and children. Cochrane Database Syst Rev. 2017;(12):CD006095.
16. Gao XW, Mubasher M, Fang CY, Reifer C, Miller LE. Dose–response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile–associated diarrhea prophylaxis in adult patients. Am J Gastroenterol. 2010;105(7):1636-1641.
17. Ouwehand AC, DongLian C, Weijian X, et al. Probiotics reduce symptoms of antibiotic use in a hospital setting: a randomized dose response study. Vaccine. 2014;32(4):458-463.
18. Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2013;382(9900):1249-1257.
19. Shen NT, Maw A, Tmanova LL, et al. Timely use of probiotics in hospitalized adults prevents Clostridium difficile infection: a systematic review with meta-regression analysis. Gastroenterology. 2017;152(8):1889-1900.
20. Hickson M, D’Souza AL, Muthu N, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ. 2007;335(7610):80.
21. Center for Food Safety and Applied Nutrition. GRAS notice inventory. https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/default.htm. Updated September 26, 2018. Accessed November 1, 2018.
22. Mattia A, Merker R. Regulation of probiotic substances as ingredients in foods: premarket approval or “generally recognized as safe” notification. Clin Infect Dis. 2008;46(suppl 2):S115-S118.
23. Probiotics: in depth. https://nccih.nih.gov/health/probiotics/introduction.htm. Updated October 2016. Accessed January 15, 2019.
24. Doron S, Snydman DR. Risk and safety of probiotics. Clin Infect Dis. 2015;60(suppl 2):S129-S134.
25. Bafeta A, Koh M, Riveros C, Ravaud P. Harms reporting in randomized controlled trials of interventions aimed at modifying microbiota: a systematic review. Ann Intern Med. 2018;169(4):240-247.
26. Boyle RJ, Robins-Browne RM, Tang ML. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr. 2006;83(6):1256-1264.
27. Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015;372(16):1539-1548.
28. Brown KA, Khanafer N, Daneman N, Fisman DN. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemoth. 2013;57(5):2326-2332.
29. Oshima T, Wu L, Li M, Fukui H, Watari J, Miwa H. Magnitude and direction of the association between Clostridium difficile infection and proton pump inhibitors in adults and pediatric patients: a systematic review and meta-analysis. J Gastroenterol. 2018;53(1):84-94.
Clostridium difficile (C difficile) is a gram-positive, toxin-producing bacterium that is of increasing concern among health care providers and patients. Infection with C difficile can have manifestations ranging from mild diarrhea to severe toxic megacolon and can result in prolonged hospitalization with severe cases requiring admission to an intensive care unit.1 In 2014, the US was estimated to have more than 600,000 cases of C difficile infection (CDI), previously known as C difficile–associated diarrhea, and more than 44,000 associated deaths. The annual economic cost of CDI is thought to exceed $5 billion.1 According to studies of health care–associated illness, CDI rates are comparable to or have surpassed rates of methicillin-resistant Staphylococcus aureus infection within the US, including at US Department of Veterans Affairs (VA) acute care centers nationwide.2,3
C difficile has been shown to be the causative agent in 10% to 20% of antibiotic-associated diarrhea episodes.4 Colonization of C difficile is uncommon in healthy adults, but colonization rates are as high as 21% in hospitalized patients, with increasing rates proportional to increasing hospital length of stay.5,6 Although not all colonized patients develop clinically significant CDI, those who do may require multiple treatment courses, over months to years, because of the high risk of disease recurrence. An estimated 25% of patients have a single recurrent episode of CDI within 30 days after treatment completion, and 45% of those patients have additional recurrent infections.7,8 Although probiotics do not have an approved US Food and Drug Administration (FDA) indication, these supplements are often used to try to prevent CDI from developing during concomitant antibiotic use. Probiotics are microorganisms with potential health benefits, but the mechanisms of these benefits are not fully understood. Proposed mechanisms include reduced growth of pathogenic bacteria, modulation of the immune system, and support of the intestinal wall barrier.9 The many probiotic formulations currently marketed include Lactobacillus acidophilus (L acidophilus) capsules and various combinations of L acidophilus, Lactobacillus casei, Bifidobacterium lactis, Bifidobacterium longum, Streptococcus thermophilus, and other bacterial strains.
Dosing and Guidelines
Manufacturers’ suggested dosing for their Lactobacillus capsules, tablets, and packets varies from 1 unit daily to 4 units 4 times daily for dietary supplementation; the products’ labeling does not include any information regarding treatment duration.10-13 In addition, there are no published recommendations or product labeling guiding the dosing of probiotics or their duration of use in the primary prevention of CDI.
In 2017, the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) updated their CDI treatment guidelines.14 As these guidelines indicate that the data on probiotic use in CDI are inadequate, IDSA and SHEA make no recommendation for or against probiotic use in primary prevention of the disease. The guidelines point to several limitations in the literature, including variability in probiotic formulations studied, duration of probiotic administration, definitions of CDI, and duration of study follow-up.
Given the lack of consensus guidelines that clinicians can use when deciding which probiotic dosing and duration are appropriate for a patient for primary prevention of CDI, we evaluated the literature on the topic and summarize their findings here.
Review of Probiotoc Literature
Conflicting data exist about probiotics and their effect on CDI prevention. The literature reviewed was selected based on our assessment of its contribution to the topic and its potential utility to clinicians in determining appropriate probiotic therapies and recommendations. Included in our discussion is a large Cochrane Review of probiotic efficacy, 2 trials of probiotic dosing, the PLACIDE trial, and a systematic review of timely probiotic initiation. All of these studies attempted to determine the effect of probiotics on CDI incidence (Table).
In their 2017 Cochrane Review, Goldenberg and colleagues reviewed 39 trials that investigated the efficacy of probiotics in CDI prevention in 9,955 immunocompetent patients receiving antibiotics.15 The incidence of CDI was significantly lower in patients who received a probiotic than in patients who received placebo or no treatment (1.5% vs 4.0%; relative risk [RR], 0.40; 95% CI, 0.30-0.52; I2 = 0%). It is important to note that trials with a control-group CDI incidence of 0% to 2% (baseline CDI risk) found no statistically significant difference in CDI risk between patients using and not using probiotics (RR, 0.77; 95% CI, 0.45-1.32; I2 = 0%) and that the preceding statistically significant result may have been driven by the inclusion of trials with high baseline CDI risk (> 5%). Trials that enrolled patients who were at this risk level found a statistically significant 70% reduction in CDI risk in those using probiotics (vs no probiotics) while on concomitant antibiotic therapy (RR, 0.30; 95% CI, 0.21-0.42; I2 = 0%).
Probiotic therapy seems to be effective in reducing CDI risk in immunocompetent patients and may be particularly beneficial in patients at higher CDI risk, though Goldenberg and colleagues did not elaborate on what constitutes higher risk and based their conclusion on their control group’s high CDI incidence (> 5%). The most common adverse events (AEs) attributable to probiotics included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. The review’s findings are limited in that the inclusion of many small trials with high baseline CDI risk likely contributed to a statistically significant result, and 17 of the review’s 39 trials were industry-sponsored or were conducted by investigators with industry associations; another 12 lacked statements about funding or sponsorship.
Two of the trials in the Cochrane Review investigated whether probiotics have a dose effect on CDI prevention. Gao and colleagues randomly assigned 255 hospitalized Asian patients to 3 groups: those receiving placebo, 1 probiotic capsule daily, and 2 probiotic capsules daily.16 Each probiotic capsule contained 50 billion colony-forming units (CFUs) of Lactobacillus. Incidence of CDI was lower in patients taking 2 probiotic capsules daily than in those taking 1 probiotic capsule daily (1.2% vs 9.4%; P = .04) or placebo (1.2% vs 23.8%; P = .002). In the other trial, Ouwehand and colleagues randomly assigned 503 hospitalized Asian patients to 3 groups as well: those receiving placebo, low-dose probiotic (4.17 billion CFUs of Lactobacillus and Bifidobacterium), and high-dose probiotic (17 billion CFUs).17 The incidence of CDI in each probiotic group (low-dose, high-dose) was 1.8%, which was significantly lower than the 4.8% in the placebo group (P = .04).
The Cochrane Review’s largest and most rigorous trial was PLACIDE, a 2013 randomized controlled study of the effect of probiotics on CDI.18 Allen and colleagues randomly assigned 2,981 inpatients (aged ≥ 65 years; exposed to antibiotics within preceding 7 days) to 2 groups: those receiving either 1 probiotic capsule daily, or 1 placebo capsule daily, for 21 days. Results showed no difference in CDI incidence between the probiotic and placebo groups (0.8% vs 1.2%; RR, 0.71; 95% CI, 0.34-1.47; P = .35). Of note, this trial is free of industry sponsorship, is the largest probiotic trial to date, has a control-group baseline CDI rate consistent with the rate in hospital and ambulatory settings in the US, and found a negative result regarding probiotic use in CDI prevention. Findings are limited in that the study allowed for initiating probiotic therapy up to 7 days after the start of antibiotics, and patients were given 1 relatively low-dose capsule daily, which may have contributed to lack of an effect on CDI prevention. No serious AEs were attributed to probiotic use.
In a 2017 systematic meta-analysis of 19 studies, Shen and colleagues investigated whether timely use of probiotics prevented CDI in 6,261 hospitalized patients receiving antibiotics.19 The incidence of CDI was significantly lower in patients receiving vs not receiving probiotics (1.6% vs 3.9%; RR, 0.42; 95% CI, 0.30-0.57; I2 = 0%; P < .001).19 A subgroup analysis was performed to compare studies initiating probiotics within 2 days after the start of antibiotics with studies initiating probiotics more than 2 days after the start. CDI risk was reduced by 68% when probiotics were started within 2 days, vs 30% when started after 2 days (RR, 0.32; 95% CI, 0.22-0.48; I2 = 0% vs RR, 0.70; 95% CI, 0.40-1.23; I2 = 0%; P = .02). Of note, no difference was found in efficacy among the various probiotic formulations, and no significant AEs were noted in any study group.
Trials included in the Cochrane Review used many different probiotic regimens over various durations.15 All these trials continued probiotics for at least the duration of antibiotic therapy. The 2 trials that evaluated the effect of probiotic therapy over an extended period required probiotics be started within 48 hours after initiation of antibiotic therapy; one trial continued probiotics for 5 days after completion of antibiotics, and the other for 7 days after completion.16,20 In both trials, CDI was statistically significantly reduced among adults using probiotics compared with adults receiving placebo.
Probiotic Safety
The FDA has not approved probiotics for the prevention or treatment of any health problems. Most probiotics are FDA-regulated as dietary supplements and do not have to meet stringent drug-approval requirements. The FDA has given many strains of common probiotics the Generally Recognized as Safe designation for use in commercially available products and foods.21-23 Probiotic use has not been associated with significant AEs in clinical trials and generally has been considered safe in immunocompetent and otherwise healthy persons.15-19 However, clinical trials have been inadequate in reporting or investigating AEs; the alternative for evaluating the risks of probiotic therapy is case reports.24,25 Theoretical risks associated with probiotics include sepsis, deleterious effects on normal gut digestion, excessive immune stimulation, and possible transfer of antimicrobial resistance genes among microorganisms.26 Boyle and colleagues further described a handful of case reports of sepsis caused by probiotics in immunocompromised individuals; the other theoretical risks have not been reported outside animal studies.26
CDI Risk Factors
Many factors can increase a patient’s CDI risk. Specific antibiotics (eg, ampicillin, amoxicillin, cephalosporins, clindamycin, fluoroquinolones) confer higher risk.27,28 Other factors include inflammatory bowel disease, organ transplantation, chemotherapy, chronic kidney disease, and immunodeficiency. Advanced age increases CDI risk and can increase the severity of infection. The evidence regarding acid suppression and CDI risk is conflicting, though a recent meta-analysis found that use of proton pump inhibitors is associated with a 2-fold higher risk of developing CDI.29 Patient-specific risk factors should be evaluated when the risk–benefit ratio for probiotic use is being considered.
Conclusion
CDIs are becoming increasingly burdensome to the health care system. More research is needed on the role of probiotics in CDI prevention in patients taking antibiotics. Given the limited risk for AEs when probiotics are used in immunocompetent patients and the relatively low cost of these supplements, the risks likely are outweighed by the postulated benefits, and probiotics may be recommended in select patient populations.
The PLACIDE trial found no benefit of probiotics in preventing CDI in a population similar to that of a typical US hospital or ambulatory setting, but its intervention allowed late initiation of relatively low doses of probiotics. Therefore, probiotics may be recommended for CDI prevention in patients taking antibiotics, especially patients at high risk for developing CDI. When clinicians recommend probiotic use in this setting, the probiotic should be initiated within 2 days after the start of antibiotics and should be continued for the duration of antibiotic therapy and for up to 7 days after that therapy is completed. Optimal probiotic dosing, likely dependent on the product used, remains unclear. PLACIDE trial results suggest that a dosage of at least 1 probiotic capsule 2 times daily may confer additional efficacy.
Clostridium difficile (C difficile) is a gram-positive, toxin-producing bacterium that is of increasing concern among health care providers and patients. Infection with C difficile can have manifestations ranging from mild diarrhea to severe toxic megacolon and can result in prolonged hospitalization with severe cases requiring admission to an intensive care unit.1 In 2014, the US was estimated to have more than 600,000 cases of C difficile infection (CDI), previously known as C difficile–associated diarrhea, and more than 44,000 associated deaths. The annual economic cost of CDI is thought to exceed $5 billion.1 According to studies of health care–associated illness, CDI rates are comparable to or have surpassed rates of methicillin-resistant Staphylococcus aureus infection within the US, including at US Department of Veterans Affairs (VA) acute care centers nationwide.2,3
C difficile has been shown to be the causative agent in 10% to 20% of antibiotic-associated diarrhea episodes.4 Colonization of C difficile is uncommon in healthy adults, but colonization rates are as high as 21% in hospitalized patients, with increasing rates proportional to increasing hospital length of stay.5,6 Although not all colonized patients develop clinically significant CDI, those who do may require multiple treatment courses, over months to years, because of the high risk of disease recurrence. An estimated 25% of patients have a single recurrent episode of CDI within 30 days after treatment completion, and 45% of those patients have additional recurrent infections.7,8 Although probiotics do not have an approved US Food and Drug Administration (FDA) indication, these supplements are often used to try to prevent CDI from developing during concomitant antibiotic use. Probiotics are microorganisms with potential health benefits, but the mechanisms of these benefits are not fully understood. Proposed mechanisms include reduced growth of pathogenic bacteria, modulation of the immune system, and support of the intestinal wall barrier.9 The many probiotic formulations currently marketed include Lactobacillus acidophilus (L acidophilus) capsules and various combinations of L acidophilus, Lactobacillus casei, Bifidobacterium lactis, Bifidobacterium longum, Streptococcus thermophilus, and other bacterial strains.
Dosing and Guidelines
Manufacturers’ suggested dosing for their Lactobacillus capsules, tablets, and packets varies from 1 unit daily to 4 units 4 times daily for dietary supplementation; the products’ labeling does not include any information regarding treatment duration.10-13 In addition, there are no published recommendations or product labeling guiding the dosing of probiotics or their duration of use in the primary prevention of CDI.
In 2017, the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) updated their CDI treatment guidelines.14 As these guidelines indicate that the data on probiotic use in CDI are inadequate, IDSA and SHEA make no recommendation for or against probiotic use in primary prevention of the disease. The guidelines point to several limitations in the literature, including variability in probiotic formulations studied, duration of probiotic administration, definitions of CDI, and duration of study follow-up.
Given the lack of consensus guidelines that clinicians can use when deciding which probiotic dosing and duration are appropriate for a patient for primary prevention of CDI, we evaluated the literature on the topic and summarize their findings here.
Review of Probiotoc Literature
Conflicting data exist about probiotics and their effect on CDI prevention. The literature reviewed was selected based on our assessment of its contribution to the topic and its potential utility to clinicians in determining appropriate probiotic therapies and recommendations. Included in our discussion is a large Cochrane Review of probiotic efficacy, 2 trials of probiotic dosing, the PLACIDE trial, and a systematic review of timely probiotic initiation. All of these studies attempted to determine the effect of probiotics on CDI incidence (Table).
In their 2017 Cochrane Review, Goldenberg and colleagues reviewed 39 trials that investigated the efficacy of probiotics in CDI prevention in 9,955 immunocompetent patients receiving antibiotics.15 The incidence of CDI was significantly lower in patients who received a probiotic than in patients who received placebo or no treatment (1.5% vs 4.0%; relative risk [RR], 0.40; 95% CI, 0.30-0.52; I2 = 0%). It is important to note that trials with a control-group CDI incidence of 0% to 2% (baseline CDI risk) found no statistically significant difference in CDI risk between patients using and not using probiotics (RR, 0.77; 95% CI, 0.45-1.32; I2 = 0%) and that the preceding statistically significant result may have been driven by the inclusion of trials with high baseline CDI risk (> 5%). Trials that enrolled patients who were at this risk level found a statistically significant 70% reduction in CDI risk in those using probiotics (vs no probiotics) while on concomitant antibiotic therapy (RR, 0.30; 95% CI, 0.21-0.42; I2 = 0%).
Probiotic therapy seems to be effective in reducing CDI risk in immunocompetent patients and may be particularly beneficial in patients at higher CDI risk, though Goldenberg and colleagues did not elaborate on what constitutes higher risk and based their conclusion on their control group’s high CDI incidence (> 5%). The most common adverse events (AEs) attributable to probiotics included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. The review’s findings are limited in that the inclusion of many small trials with high baseline CDI risk likely contributed to a statistically significant result, and 17 of the review’s 39 trials were industry-sponsored or were conducted by investigators with industry associations; another 12 lacked statements about funding or sponsorship.
Two of the trials in the Cochrane Review investigated whether probiotics have a dose effect on CDI prevention. Gao and colleagues randomly assigned 255 hospitalized Asian patients to 3 groups: those receiving placebo, 1 probiotic capsule daily, and 2 probiotic capsules daily.16 Each probiotic capsule contained 50 billion colony-forming units (CFUs) of Lactobacillus. Incidence of CDI was lower in patients taking 2 probiotic capsules daily than in those taking 1 probiotic capsule daily (1.2% vs 9.4%; P = .04) or placebo (1.2% vs 23.8%; P = .002). In the other trial, Ouwehand and colleagues randomly assigned 503 hospitalized Asian patients to 3 groups as well: those receiving placebo, low-dose probiotic (4.17 billion CFUs of Lactobacillus and Bifidobacterium), and high-dose probiotic (17 billion CFUs).17 The incidence of CDI in each probiotic group (low-dose, high-dose) was 1.8%, which was significantly lower than the 4.8% in the placebo group (P = .04).
The Cochrane Review’s largest and most rigorous trial was PLACIDE, a 2013 randomized controlled study of the effect of probiotics on CDI.18 Allen and colleagues randomly assigned 2,981 inpatients (aged ≥ 65 years; exposed to antibiotics within preceding 7 days) to 2 groups: those receiving either 1 probiotic capsule daily, or 1 placebo capsule daily, for 21 days. Results showed no difference in CDI incidence between the probiotic and placebo groups (0.8% vs 1.2%; RR, 0.71; 95% CI, 0.34-1.47; P = .35). Of note, this trial is free of industry sponsorship, is the largest probiotic trial to date, has a control-group baseline CDI rate consistent with the rate in hospital and ambulatory settings in the US, and found a negative result regarding probiotic use in CDI prevention. Findings are limited in that the study allowed for initiating probiotic therapy up to 7 days after the start of antibiotics, and patients were given 1 relatively low-dose capsule daily, which may have contributed to lack of an effect on CDI prevention. No serious AEs were attributed to probiotic use.
In a 2017 systematic meta-analysis of 19 studies, Shen and colleagues investigated whether timely use of probiotics prevented CDI in 6,261 hospitalized patients receiving antibiotics.19 The incidence of CDI was significantly lower in patients receiving vs not receiving probiotics (1.6% vs 3.9%; RR, 0.42; 95% CI, 0.30-0.57; I2 = 0%; P < .001).19 A subgroup analysis was performed to compare studies initiating probiotics within 2 days after the start of antibiotics with studies initiating probiotics more than 2 days after the start. CDI risk was reduced by 68% when probiotics were started within 2 days, vs 30% when started after 2 days (RR, 0.32; 95% CI, 0.22-0.48; I2 = 0% vs RR, 0.70; 95% CI, 0.40-1.23; I2 = 0%; P = .02). Of note, no difference was found in efficacy among the various probiotic formulations, and no significant AEs were noted in any study group.
Trials included in the Cochrane Review used many different probiotic regimens over various durations.15 All these trials continued probiotics for at least the duration of antibiotic therapy. The 2 trials that evaluated the effect of probiotic therapy over an extended period required probiotics be started within 48 hours after initiation of antibiotic therapy; one trial continued probiotics for 5 days after completion of antibiotics, and the other for 7 days after completion.16,20 In both trials, CDI was statistically significantly reduced among adults using probiotics compared with adults receiving placebo.
Probiotic Safety
The FDA has not approved probiotics for the prevention or treatment of any health problems. Most probiotics are FDA-regulated as dietary supplements and do not have to meet stringent drug-approval requirements. The FDA has given many strains of common probiotics the Generally Recognized as Safe designation for use in commercially available products and foods.21-23 Probiotic use has not been associated with significant AEs in clinical trials and generally has been considered safe in immunocompetent and otherwise healthy persons.15-19 However, clinical trials have been inadequate in reporting or investigating AEs; the alternative for evaluating the risks of probiotic therapy is case reports.24,25 Theoretical risks associated with probiotics include sepsis, deleterious effects on normal gut digestion, excessive immune stimulation, and possible transfer of antimicrobial resistance genes among microorganisms.26 Boyle and colleagues further described a handful of case reports of sepsis caused by probiotics in immunocompromised individuals; the other theoretical risks have not been reported outside animal studies.26
CDI Risk Factors
Many factors can increase a patient’s CDI risk. Specific antibiotics (eg, ampicillin, amoxicillin, cephalosporins, clindamycin, fluoroquinolones) confer higher risk.27,28 Other factors include inflammatory bowel disease, organ transplantation, chemotherapy, chronic kidney disease, and immunodeficiency. Advanced age increases CDI risk and can increase the severity of infection. The evidence regarding acid suppression and CDI risk is conflicting, though a recent meta-analysis found that use of proton pump inhibitors is associated with a 2-fold higher risk of developing CDI.29 Patient-specific risk factors should be evaluated when the risk–benefit ratio for probiotic use is being considered.
Conclusion
CDIs are becoming increasingly burdensome to the health care system. More research is needed on the role of probiotics in CDI prevention in patients taking antibiotics. Given the limited risk for AEs when probiotics are used in immunocompetent patients and the relatively low cost of these supplements, the risks likely are outweighed by the postulated benefits, and probiotics may be recommended in select patient populations.
The PLACIDE trial found no benefit of probiotics in preventing CDI in a population similar to that of a typical US hospital or ambulatory setting, but its intervention allowed late initiation of relatively low doses of probiotics. Therefore, probiotics may be recommended for CDI prevention in patients taking antibiotics, especially patients at high risk for developing CDI. When clinicians recommend probiotic use in this setting, the probiotic should be initiated within 2 days after the start of antibiotics and should be continued for the duration of antibiotic therapy and for up to 7 days after that therapy is completed. Optimal probiotic dosing, likely dependent on the product used, remains unclear. PLACIDE trial results suggest that a dosage of at least 1 probiotic capsule 2 times daily may confer additional efficacy.
1. Desai K, Gupta SB, Dubberke ER, Prabhu VS, Browne C, Mast TC. Epidemiological and economic burden of Clostridium difficile in the United States: estimates from a modeling approach. BMC Infect Dis. 2016;16:303.
2. Miller BA, Chen LF, Sexton DJ, Anderson DJ. Comparison of the burdens of hospital-onset, healthcare facility-associated Clostridium difficile infection and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospitals. Infect Control Hosp Epidemiol. 2011;32(4):387-390.
3. Evans ME, Kralovic SM, Simbartl LA, Jain R, Roselle GA. Effect of a Clostridium difficile infection prevention initiative in Veterans Affairs acute care facilities. Infect Control Hosp Epidemiol. 2016;37(6):720-722.
4. Bartlett JG. Clinical practice. Antibiotic-associated diarrhea. N Engl J Med. 2002;346(5):334-339.
5. Johnson S, Clabots CR, Linn FV, Olson MM, Peterson LR, Gerding DN. Nosocomial Clostridium difficile colonisation and disease. Lancet. 1990;336(8707):97-100.
6. McFarland LV, Mulligan ME, Kwok RY, Stamm WE. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med. 1989;320(4):204-210.
7. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002;97(7):1769-1775.
8. Kelly CP. Can we identify patients at high risk of recurrent Clostridium difficile infection? Clin Microbiol Infect. 2012;18(suppl 6):21-27.
9. Sartor RB. Probiotics for gastrointestinal diseases. https://www.uptodate.com/contents/probiotics-for-gastrointestinal-diseases. Updated September 4, 2018. Accessed April 4, 2019.
10. VSL#3 (Lactobacillus) [prescribing information]. Covington, LA: Alfasigma USA Inc; July 2017.
11. Culturelle Digestive Health Probiotic Capsules (Lactobacillus) [prescribing information]. Cromwell, CT: I-Health, Inc; 2015.
12. Flora-Q (Lactobacillus) [prescribing information]. Melville, NY: PharmaDerm; May 2012.
13. Lactinex (Lactobacillus) [prescribing information]. Franklin Lakes, NJ: Becton, Dickinson and Company; 2015
14. 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). Clin Infect Dis. 2018;66(7):987-994.
15. Goldenberg JZ, Yap C, Lytvyn L, et al. Probiotics for the prevention of Clostridium difficile–associated diarrhea in adults and children. Cochrane Database Syst Rev. 2017;(12):CD006095.
16. Gao XW, Mubasher M, Fang CY, Reifer C, Miller LE. Dose–response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile–associated diarrhea prophylaxis in adult patients. Am J Gastroenterol. 2010;105(7):1636-1641.
17. Ouwehand AC, DongLian C, Weijian X, et al. Probiotics reduce symptoms of antibiotic use in a hospital setting: a randomized dose response study. Vaccine. 2014;32(4):458-463.
18. Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2013;382(9900):1249-1257.
19. Shen NT, Maw A, Tmanova LL, et al. Timely use of probiotics in hospitalized adults prevents Clostridium difficile infection: a systematic review with meta-regression analysis. Gastroenterology. 2017;152(8):1889-1900.
20. Hickson M, D’Souza AL, Muthu N, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ. 2007;335(7610):80.
21. Center for Food Safety and Applied Nutrition. GRAS notice inventory. https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/default.htm. Updated September 26, 2018. Accessed November 1, 2018.
22. Mattia A, Merker R. Regulation of probiotic substances as ingredients in foods: premarket approval or “generally recognized as safe” notification. Clin Infect Dis. 2008;46(suppl 2):S115-S118.
23. Probiotics: in depth. https://nccih.nih.gov/health/probiotics/introduction.htm. Updated October 2016. Accessed January 15, 2019.
24. Doron S, Snydman DR. Risk and safety of probiotics. Clin Infect Dis. 2015;60(suppl 2):S129-S134.
25. Bafeta A, Koh M, Riveros C, Ravaud P. Harms reporting in randomized controlled trials of interventions aimed at modifying microbiota: a systematic review. Ann Intern Med. 2018;169(4):240-247.
26. Boyle RJ, Robins-Browne RM, Tang ML. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr. 2006;83(6):1256-1264.
27. Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015;372(16):1539-1548.
28. Brown KA, Khanafer N, Daneman N, Fisman DN. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemoth. 2013;57(5):2326-2332.
29. Oshima T, Wu L, Li M, Fukui H, Watari J, Miwa H. Magnitude and direction of the association between Clostridium difficile infection and proton pump inhibitors in adults and pediatric patients: a systematic review and meta-analysis. J Gastroenterol. 2018;53(1):84-94.
1. Desai K, Gupta SB, Dubberke ER, Prabhu VS, Browne C, Mast TC. Epidemiological and economic burden of Clostridium difficile in the United States: estimates from a modeling approach. BMC Infect Dis. 2016;16:303.
2. Miller BA, Chen LF, Sexton DJ, Anderson DJ. Comparison of the burdens of hospital-onset, healthcare facility-associated Clostridium difficile infection and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospitals. Infect Control Hosp Epidemiol. 2011;32(4):387-390.
3. Evans ME, Kralovic SM, Simbartl LA, Jain R, Roselle GA. Effect of a Clostridium difficile infection prevention initiative in Veterans Affairs acute care facilities. Infect Control Hosp Epidemiol. 2016;37(6):720-722.
4. Bartlett JG. Clinical practice. Antibiotic-associated diarrhea. N Engl J Med. 2002;346(5):334-339.
5. Johnson S, Clabots CR, Linn FV, Olson MM, Peterson LR, Gerding DN. Nosocomial Clostridium difficile colonisation and disease. Lancet. 1990;336(8707):97-100.
6. McFarland LV, Mulligan ME, Kwok RY, Stamm WE. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med. 1989;320(4):204-210.
7. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002;97(7):1769-1775.
8. Kelly CP. Can we identify patients at high risk of recurrent Clostridium difficile infection? Clin Microbiol Infect. 2012;18(suppl 6):21-27.
9. Sartor RB. Probiotics for gastrointestinal diseases. https://www.uptodate.com/contents/probiotics-for-gastrointestinal-diseases. Updated September 4, 2018. Accessed April 4, 2019.
10. VSL#3 (Lactobacillus) [prescribing information]. Covington, LA: Alfasigma USA Inc; July 2017.
11. Culturelle Digestive Health Probiotic Capsules (Lactobacillus) [prescribing information]. Cromwell, CT: I-Health, Inc; 2015.
12. Flora-Q (Lactobacillus) [prescribing information]. Melville, NY: PharmaDerm; May 2012.
13. Lactinex (Lactobacillus) [prescribing information]. Franklin Lakes, NJ: Becton, Dickinson and Company; 2015
14. 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). Clin Infect Dis. 2018;66(7):987-994.
15. Goldenberg JZ, Yap C, Lytvyn L, et al. Probiotics for the prevention of Clostridium difficile–associated diarrhea in adults and children. Cochrane Database Syst Rev. 2017;(12):CD006095.
16. Gao XW, Mubasher M, Fang CY, Reifer C, Miller LE. Dose–response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile–associated diarrhea prophylaxis in adult patients. Am J Gastroenterol. 2010;105(7):1636-1641.
17. Ouwehand AC, DongLian C, Weijian X, et al. Probiotics reduce symptoms of antibiotic use in a hospital setting: a randomized dose response study. Vaccine. 2014;32(4):458-463.
18. Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2013;382(9900):1249-1257.
19. Shen NT, Maw A, Tmanova LL, et al. Timely use of probiotics in hospitalized adults prevents Clostridium difficile infection: a systematic review with meta-regression analysis. Gastroenterology. 2017;152(8):1889-1900.
20. Hickson M, D’Souza AL, Muthu N, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ. 2007;335(7610):80.
21. Center for Food Safety and Applied Nutrition. GRAS notice inventory. https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/default.htm. Updated September 26, 2018. Accessed November 1, 2018.
22. Mattia A, Merker R. Regulation of probiotic substances as ingredients in foods: premarket approval or “generally recognized as safe” notification. Clin Infect Dis. 2008;46(suppl 2):S115-S118.
23. Probiotics: in depth. https://nccih.nih.gov/health/probiotics/introduction.htm. Updated October 2016. Accessed January 15, 2019.
24. Doron S, Snydman DR. Risk and safety of probiotics. Clin Infect Dis. 2015;60(suppl 2):S129-S134.
25. Bafeta A, Koh M, Riveros C, Ravaud P. Harms reporting in randomized controlled trials of interventions aimed at modifying microbiota: a systematic review. Ann Intern Med. 2018;169(4):240-247.
26. Boyle RJ, Robins-Browne RM, Tang ML. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr. 2006;83(6):1256-1264.
27. Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015;372(16):1539-1548.
28. Brown KA, Khanafer N, Daneman N, Fisman DN. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemoth. 2013;57(5):2326-2332.
29. Oshima T, Wu L, Li M, Fukui H, Watari J, Miwa H. Magnitude and direction of the association between Clostridium difficile infection and proton pump inhibitors in adults and pediatric patients: a systematic review and meta-analysis. J Gastroenterol. 2018;53(1):84-94.