Two subcutaneous dosages of the nerve growth factor–inhibitor tanezumab showed significant benefits in patients with osteoarthritic joint pain in a multicenter, randomized, phase 3 trial of 698 patients run primarily at U.S. centers.

The 16-week responses to two subcutaneous injections with tanezumab spaced 8 weeks apart showed statistically significant improvements in pain, physical function, and patient global self assessment, compared with placebo, the primary endpoints for the study, Pfizer and Lilly jointly reported. The two companies together are developing tanezumab for an indication for osteoarthritic pain, as well as for chronic lower back pain and pain from cancer metastases.

The company announcement said that patients showed good tolerance to the tanezumab treatments, with no new safety signals and no osteonecrosis seen. About 1% of patients on tanezumab stopped treatment because of an adverse effect, and less than 1.5% of patients on the drug had progressive osteoarthritis during treatment, compared with no patients in the placebo group.

The study enrolled patients at any one of 98 centers in the United States, Puerto Rico, or Canada with confirmed moderate or severe osteoarthritis of the knee or hip that either produced pain refractory to conventional pain medications or involved patients unable to take these medications. The researchers randomized patients to receive two 2.5-mg doses of tanezumab, a 2.5-mg dose followed 8 weeks later by a 5-mg dose, or two placebo doses. The primary outcomes were changes from baseline when measured 16 weeks after the start of treatment in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, the WOMAC physical function subscale, and patient’s global assessment of osteoarthritis. Both of the tested tanezumab regimens produced statistically significant improvements in each of the three measures, compared with the placebo control patients, the companies reported.

Tanezumab is a humanized monoclonal antibody that binds to and inhibits nerve growth factor. This inhibition may prevent pain signals from reaching the spinal cord and brain, according to the companies’ report. In June 2017, the two companies announced that development of tanezumab had received “Fast Track” designation from the Food and Drug Administration for the indications of treating chronic osteoarthritic pain and chronic lower back pain.

[email protected]

Two subcutaneous dosages of the nerve growth factor–inhibitor tanezumab showed significant benefits in patients with osteoarthritic joint pain in a multicenter, randomized, phase 3 trial of 698 patients run primarily at U.S. centers.

The 16-week responses to two subcutaneous injections with tanezumab spaced 8 weeks apart showed statistically significant improvements in pain, physical function, and patient global self assessment, compared with placebo, the primary endpoints for the study, Pfizer and Lilly jointly reported. The two companies together are developing tanezumab for an indication for osteoarthritic pain, as well as for chronic lower back pain and pain from cancer metastases.

The company announcement said that patients showed good tolerance to the tanezumab treatments, with no new safety signals and no osteonecrosis seen. About 1% of patients on tanezumab stopped treatment because of an adverse effect, and less than 1.5% of patients on the drug had progressive osteoarthritis during treatment, compared with no patients in the placebo group.

The study enrolled patients at any one of 98 centers in the United States, Puerto Rico, or Canada with confirmed moderate or severe osteoarthritis of the knee or hip that either produced pain refractory to conventional pain medications or involved patients unable to take these medications. The researchers randomized patients to receive two 2.5-mg doses of tanezumab, a 2.5-mg dose followed 8 weeks later by a 5-mg dose, or two placebo doses. The primary outcomes were changes from baseline when measured 16 weeks after the start of treatment in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, the WOMAC physical function subscale, and patient’s global assessment of osteoarthritis. Both of the tested tanezumab regimens produced statistically significant improvements in each of the three measures, compared with the placebo control patients, the companies reported.

Tanezumab is a humanized monoclonal antibody that binds to and inhibits nerve growth factor. This inhibition may prevent pain signals from reaching the spinal cord and brain, according to the companies’ report. In June 2017, the two companies announced that development of tanezumab had received “Fast Track” designation from the Food and Drug Administration for the indications of treating chronic osteoarthritic pain and chronic lower back pain.

[email protected]

Two subcutaneous dosages of the nerve growth factor–inhibitor tanezumab showed significant benefits in patients with osteoarthritic joint pain in a multicenter, randomized, phase 3 trial of 698 patients run primarily at U.S. centers.

The 16-week responses to two subcutaneous injections with tanezumab spaced 8 weeks apart showed statistically significant improvements in pain, physical function, and patient global self assessment, compared with placebo, the primary endpoints for the study, Pfizer and Lilly jointly reported. The two companies together are developing tanezumab for an indication for osteoarthritic pain, as well as for chronic lower back pain and pain from cancer metastases.

The company announcement said that patients showed good tolerance to the tanezumab treatments, with no new safety signals and no osteonecrosis seen. About 1% of patients on tanezumab stopped treatment because of an adverse effect, and less than 1.5% of patients on the drug had progressive osteoarthritis during treatment, compared with no patients in the placebo group.

The study enrolled patients at any one of 98 centers in the United States, Puerto Rico, or Canada with confirmed moderate or severe osteoarthritis of the knee or hip that either produced pain refractory to conventional pain medications or involved patients unable to take these medications. The researchers randomized patients to receive two 2.5-mg doses of tanezumab, a 2.5-mg dose followed 8 weeks later by a 5-mg dose, or two placebo doses. The primary outcomes were changes from baseline when measured 16 weeks after the start of treatment in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, the WOMAC physical function subscale, and patient’s global assessment of osteoarthritis. Both of the tested tanezumab regimens produced statistically significant improvements in each of the three measures, compared with the placebo control patients, the companies reported.

Tanezumab is a humanized monoclonal antibody that binds to and inhibits nerve growth factor. This inhibition may prevent pain signals from reaching the spinal cord and brain, according to the companies’ report. In June 2017, the two companies announced that development of tanezumab had received “Fast Track” designation from the Food and Drug Administration for the indications of treating chronic osteoarthritic pain and chronic lower back pain.

[email protected]

This year’s annual meeting of the Childhood Arthritis & Rheumatology Research Alliance (CARRA) saw a growing number of participants and new developments in collaborative research projects.

Dr. Klein-Gitelman is professor of pediatrics at Northwestern University, Chicago, and is a pediatric rheumatologist at the Ann & Robert H. Lurie Children’s Hospital of Chicago. Dr. Kimura is past president of CARRA and is chief of pediatric rheumatology at the Joseph M. Sanzari Children’s Hospital at Hackensack (N.J.) University Medical Center.

This year’s annual meeting of the Childhood Arthritis & Rheumatology Research Alliance (CARRA) saw a growing number of participants and new developments in collaborative research projects.

Dr. Klein-Gitelman is professor of pediatrics at Northwestern University, Chicago, and is a pediatric rheumatologist at the Ann & Robert H. Lurie Children’s Hospital of Chicago. Dr. Kimura is past president of CARRA and is chief of pediatric rheumatology at the Joseph M. Sanzari Children’s Hospital at Hackensack (N.J.) University Medical Center.

This year’s annual meeting of the Childhood Arthritis & Rheumatology Research Alliance (CARRA) saw a growing number of participants and new developments in collaborative research projects.

Dr. Klein-Gitelman is professor of pediatrics at Northwestern University, Chicago, and is a pediatric rheumatologist at the Ann & Robert H. Lurie Children’s Hospital of Chicago. Dr. Kimura is past president of CARRA and is chief of pediatric rheumatology at the Joseph M. Sanzari Children’s Hospital at Hackensack (N.J.) University Medical Center.

An 11-step plan to encourage innovation and competition in the development of biosimilars has been announced by the Food and Drug Administration.

Some of the actions include tools to enhance public information about the FDA’s evaluation of biosimilars, including more information about approved biological products in the Purple Book; exploring the potential for entering into new data sharing agreements with foreign regulators to facilitate the increased use of non–U.S.-licensed comparator products in certain studies to support a biosimilar application; releasing a series of videos that explain key concepts about biosimilar and interchangeable products; and requesting information from the public on additional policy steps the FDA should consider for enhancing the biosimilar program.

The FDA’s Biosimilar Action Plan is available here.

[email protected]

An 11-step plan to encourage innovation and competition in the development of biosimilars has been announced by the Food and Drug Administration.

Some of the actions include tools to enhance public information about the FDA’s evaluation of biosimilars, including more information about approved biological products in the Purple Book; exploring the potential for entering into new data sharing agreements with foreign regulators to facilitate the increased use of non–U.S.-licensed comparator products in certain studies to support a biosimilar application; releasing a series of videos that explain key concepts about biosimilar and interchangeable products; and requesting information from the public on additional policy steps the FDA should consider for enhancing the biosimilar program.

The FDA’s Biosimilar Action Plan is available here.

[email protected]

An 11-step plan to encourage innovation and competition in the development of biosimilars has been announced by the Food and Drug Administration.

Some of the actions include tools to enhance public information about the FDA’s evaluation of biosimilars, including more information about approved biological products in the Purple Book; exploring the potential for entering into new data sharing agreements with foreign regulators to facilitate the increased use of non–U.S.-licensed comparator products in certain studies to support a biosimilar application; releasing a series of videos that explain key concepts about biosimilar and interchangeable products; and requesting information from the public on additional policy steps the FDA should consider for enhancing the biosimilar program.

The FDA’s Biosimilar Action Plan is available here.

[email protected]

Deaths from cirrhosis of the liver in the United States increased by 65% during 1999-2016, while deaths from hepatocellular carcinoma more than doubled.

Cirrhosis mortality showed a sharp rise beginning in 2009, with a 3.6% annual increase driven entirely by a surge in alcoholic cirrhosis among young people aged 25-34 years, Elliot B. Tapper, MD, and Neehar D. Parikh, MD, reported in the BMJ. The uptick in hepatocellular carcinoma, however, was gradual and consistent, with a 2% annual increase felt mostly in older people, wrote Dr. Tapper and Dr. Parikh, both at the University of Michigan, Ann Arbor.

“The increasing mortality due to cirrhosis and hepatocellular carcinoma speaks to the expanding socioeconomic impact of liver disease,” the colleagues wrote. “Adverse trends in liver-related mortality are particularly unfortunate given that in most cases the liver disease is preventable. Understanding the factors associated with mortality due to these conditions will inform how best to allocate resources.”

The study extracted its data from the Vital Statistic Cooperative and the Centers for Disease Control and Prevention. The investigators not only examined raw mortality numbers, but analyzed them for demographic and geographic trends, in analyses that controlled for age.

Cirrhosis

During the study period, 460,760 patients died from cirrhosis (20,661 in 1999 and 34,174 in 2016, an increase of 65.4%).

Men were twice as likely to die from cirrhosis. Young people aged 25-34 years had the highest rate of increase (3.7% over the entire period and 10.5% from 2009 to 2016). This was directly driven by parallel increases in both alcohol use disorder and alcohol-related liver diseases, which increased by about 16% and 10%, respectively, in this group.

Native Americans had the highest mortality rate (25.8 per 100,000) followed by whites (12.7 per 100,000). “Notably, by 2016, cirrhosis accounted for 6.3% [up from 4.3% in 2009] and 7% [up from 5.8% in 2009] of deaths for Native Americans aged 25-34 and 35 or more, respectively,” and 2.3% of all deaths among adults aged 25-34 years, the authors wrote.

The increases were largely felt in the southern and western states (about 13 per 100,000 in each region). The greatest increases occurred in Kentucky (6.8%), New Mexico (6%), Arkansas (5.7%), Indiana (5%), and Alabama (5%). There was a statistically significant 1.2% decrease in deaths from cirrhosis in Maryland.

Hepatocellular carcinoma

Hepatocellular carcinoma accounted for 136,442 deaths during the study period (5,112 in 1999 and 11,073 in 2016 – an increase of 116.6%). This represented an average annual increase of 2%.

Men were four times more likely to die from hepatocellular carcinoma. The increase manifested mostly in older people, decreasing in those younger than 55 years. Mortality was highest among Asians and Pacific Islanders (6 per 100,000), followed by blacks (4.94 per 100,000).

The increases were largely felt in western states, with an overall increase of 4.2 per 100,000.

“Many of the same states with worsening cirrhosis-related mortality also experienced worsening mortality from hepatocellular carcinoma, including Oregon and Iowa,” the authors wrote. But mortality from the disease also increased significantly in Arizona (5.1%), Kansas (4.3%), Kentucky (4%), and Washington (3.9%).

“Potential explanations supported by these data include increasing early detection of hepatocellular carcinoma, application of curative or locoregional therapies, and, because hepatitis B is the principal cause of hepatocellular carcinoma worldwide and among Asian Americans, effectiveness of vaccination programs and the efficacy of antiviral therapy for hepatitis B in preventing the development of hepatocellular carcinoma.”

However, they noted, “it is unclear how these trends are, or will be, affected by direct-acting antivirals for hepatitis C virus ... eradication of hepatitis C virus will prevent the development of cirrhosis and its complications, potentially changing these trends in the next 5-10 years. However, therapy for hepatitis C viral infection cannot modify the statistically significant trends observed related to alcohol or the expected increase in the burden of nonalcoholic fatty liver disease.”

Neither author had any financial disclosure relevant to the work.

[email protected]

SOURCE: Tapper EB et al. BMJ 2018;362:k2817.

Deaths from cirrhosis of the liver in the United States increased by 65% during 1999-2016, while deaths from hepatocellular carcinoma more than doubled.

Cirrhosis mortality showed a sharp rise beginning in 2009, with a 3.6% annual increase driven entirely by a surge in alcoholic cirrhosis among young people aged 25-34 years, Elliot B. Tapper, MD, and Neehar D. Parikh, MD, reported in the BMJ. The uptick in hepatocellular carcinoma, however, was gradual and consistent, with a 2% annual increase felt mostly in older people, wrote Dr. Tapper and Dr. Parikh, both at the University of Michigan, Ann Arbor.

“The increasing mortality due to cirrhosis and hepatocellular carcinoma speaks to the expanding socioeconomic impact of liver disease,” the colleagues wrote. “Adverse trends in liver-related mortality are particularly unfortunate given that in most cases the liver disease is preventable. Understanding the factors associated with mortality due to these conditions will inform how best to allocate resources.”

The study extracted its data from the Vital Statistic Cooperative and the Centers for Disease Control and Prevention. The investigators not only examined raw mortality numbers, but analyzed them for demographic and geographic trends, in analyses that controlled for age.

Cirrhosis

During the study period, 460,760 patients died from cirrhosis (20,661 in 1999 and 34,174 in 2016, an increase of 65.4%).

Men were twice as likely to die from cirrhosis. Young people aged 25-34 years had the highest rate of increase (3.7% over the entire period and 10.5% from 2009 to 2016). This was directly driven by parallel increases in both alcohol use disorder and alcohol-related liver diseases, which increased by about 16% and 10%, respectively, in this group.

Native Americans had the highest mortality rate (25.8 per 100,000) followed by whites (12.7 per 100,000). “Notably, by 2016, cirrhosis accounted for 6.3% [up from 4.3% in 2009] and 7% [up from 5.8% in 2009] of deaths for Native Americans aged 25-34 and 35 or more, respectively,” and 2.3% of all deaths among adults aged 25-34 years, the authors wrote.

The increases were largely felt in the southern and western states (about 13 per 100,000 in each region). The greatest increases occurred in Kentucky (6.8%), New Mexico (6%), Arkansas (5.7%), Indiana (5%), and Alabama (5%). There was a statistically significant 1.2% decrease in deaths from cirrhosis in Maryland.

Hepatocellular carcinoma

Hepatocellular carcinoma accounted for 136,442 deaths during the study period (5,112 in 1999 and 11,073 in 2016 – an increase of 116.6%). This represented an average annual increase of 2%.

Men were four times more likely to die from hepatocellular carcinoma. The increase manifested mostly in older people, decreasing in those younger than 55 years. Mortality was highest among Asians and Pacific Islanders (6 per 100,000), followed by blacks (4.94 per 100,000).

The increases were largely felt in western states, with an overall increase of 4.2 per 100,000.

“Many of the same states with worsening cirrhosis-related mortality also experienced worsening mortality from hepatocellular carcinoma, including Oregon and Iowa,” the authors wrote. But mortality from the disease also increased significantly in Arizona (5.1%), Kansas (4.3%), Kentucky (4%), and Washington (3.9%).

“Potential explanations supported by these data include increasing early detection of hepatocellular carcinoma, application of curative or locoregional therapies, and, because hepatitis B is the principal cause of hepatocellular carcinoma worldwide and among Asian Americans, effectiveness of vaccination programs and the efficacy of antiviral therapy for hepatitis B in preventing the development of hepatocellular carcinoma.”

However, they noted, “it is unclear how these trends are, or will be, affected by direct-acting antivirals for hepatitis C virus ... eradication of hepatitis C virus will prevent the development of cirrhosis and its complications, potentially changing these trends in the next 5-10 years. However, therapy for hepatitis C viral infection cannot modify the statistically significant trends observed related to alcohol or the expected increase in the burden of nonalcoholic fatty liver disease.”

Neither author had any financial disclosure relevant to the work.

[email protected]

SOURCE: Tapper EB et al. BMJ 2018;362:k2817.

Deaths from cirrhosis of the liver in the United States increased by 65% during 1999-2016, while deaths from hepatocellular carcinoma more than doubled.

Cirrhosis mortality showed a sharp rise beginning in 2009, with a 3.6% annual increase driven entirely by a surge in alcoholic cirrhosis among young people aged 25-34 years, Elliot B. Tapper, MD, and Neehar D. Parikh, MD, reported in the BMJ. The uptick in hepatocellular carcinoma, however, was gradual and consistent, with a 2% annual increase felt mostly in older people, wrote Dr. Tapper and Dr. Parikh, both at the University of Michigan, Ann Arbor.

“The increasing mortality due to cirrhosis and hepatocellular carcinoma speaks to the expanding socioeconomic impact of liver disease,” the colleagues wrote. “Adverse trends in liver-related mortality are particularly unfortunate given that in most cases the liver disease is preventable. Understanding the factors associated with mortality due to these conditions will inform how best to allocate resources.”

The study extracted its data from the Vital Statistic Cooperative and the Centers for Disease Control and Prevention. The investigators not only examined raw mortality numbers, but analyzed them for demographic and geographic trends, in analyses that controlled for age.

Cirrhosis

During the study period, 460,760 patients died from cirrhosis (20,661 in 1999 and 34,174 in 2016, an increase of 65.4%).

Men were twice as likely to die from cirrhosis. Young people aged 25-34 years had the highest rate of increase (3.7% over the entire period and 10.5% from 2009 to 2016). This was directly driven by parallel increases in both alcohol use disorder and alcohol-related liver diseases, which increased by about 16% and 10%, respectively, in this group.

Native Americans had the highest mortality rate (25.8 per 100,000) followed by whites (12.7 per 100,000). “Notably, by 2016, cirrhosis accounted for 6.3% [up from 4.3% in 2009] and 7% [up from 5.8% in 2009] of deaths for Native Americans aged 25-34 and 35 or more, respectively,” and 2.3% of all deaths among adults aged 25-34 years, the authors wrote.

The increases were largely felt in the southern and western states (about 13 per 100,000 in each region). The greatest increases occurred in Kentucky (6.8%), New Mexico (6%), Arkansas (5.7%), Indiana (5%), and Alabama (5%). There was a statistically significant 1.2% decrease in deaths from cirrhosis in Maryland.

Hepatocellular carcinoma

Hepatocellular carcinoma accounted for 136,442 deaths during the study period (5,112 in 1999 and 11,073 in 2016 – an increase of 116.6%). This represented an average annual increase of 2%.

Men were four times more likely to die from hepatocellular carcinoma. The increase manifested mostly in older people, decreasing in those younger than 55 years. Mortality was highest among Asians and Pacific Islanders (6 per 100,000), followed by blacks (4.94 per 100,000).

The increases were largely felt in western states, with an overall increase of 4.2 per 100,000.

“Many of the same states with worsening cirrhosis-related mortality also experienced worsening mortality from hepatocellular carcinoma, including Oregon and Iowa,” the authors wrote. But mortality from the disease also increased significantly in Arizona (5.1%), Kansas (4.3%), Kentucky (4%), and Washington (3.9%).

“Potential explanations supported by these data include increasing early detection of hepatocellular carcinoma, application of curative or locoregional therapies, and, because hepatitis B is the principal cause of hepatocellular carcinoma worldwide and among Asian Americans, effectiveness of vaccination programs and the efficacy of antiviral therapy for hepatitis B in preventing the development of hepatocellular carcinoma.”

However, they noted, “it is unclear how these trends are, or will be, affected by direct-acting antivirals for hepatitis C virus ... eradication of hepatitis C virus will prevent the development of cirrhosis and its complications, potentially changing these trends in the next 5-10 years. However, therapy for hepatitis C viral infection cannot modify the statistically significant trends observed related to alcohol or the expected increase in the burden of nonalcoholic fatty liver disease.”

Neither author had any financial disclosure relevant to the work.

[email protected]

SOURCE: Tapper EB et al. BMJ 2018;362:k2817.

Using epinephrine for cardiac arrest improves 30-day survival by less than 1%, and nearly doubles the risk of severe brain damage among survivors, according to PARAMEDIC2, a randomized, double-blind trial in more than 8,000 patients in Great Britain.

It’s clear what patients want. “Our own work with patients and the public before starting the trial identified survival without brain damage [as] more important to patients than survival alone. The findings of this trial will require careful consideration by the wider community and those responsible for clinical practice guidelines for cardiac arrest,” lead investigator Gavin D. Perkins, MD, professor of critical care medicine at the University of Warwick, Coventry, England, and lead author of the study published in the New England Journal of Medicine, wrote in a statement.

In PARAMEDIC2, after initial attempts with CPR and defibrillation failed, 4,012 patients were given epinephrine 1 mg by intravenous or intraosseous infusion every 3-5 minutes for a maximum of 10 doses, and 3,995 were given a saline placebo in the same fashion. The median time from emergency call to ambulance arrival was just over 6 minutes in both groups, with a further 14 minutes until drug administration.

The heart restarted in a higher proportion of epinephrine patients (36.3% vs. 11.7%), and 3.2% of epinephrine patients were alive at 30 days, versus 2.4% in the placebo arm, a 39% increase.

However, that slight benefit came at a significant cost. Of the 126 epinephrine patients who survived to hospital discharge, 39 (31%) had severe brain damage, compared with 16 (17.8%) among the 90 placebo survivors. Severe brain damage meant inability to walk and tend to bodily functions, or a persistent vegetative state (modified Rankin scale grade 4 or 5).

The trial addresses a long-standing question in resuscitation medicine, the role of epinephrine in cardiac arrest. It’s a devil’s bargain: Epinephrine increases blood flow to the heart, so helps with resuscitation, but it also reduces blood flow in the brain’s microvasculature, increasing the risk of brain damage.

“The benefit of epinephrine on survival demonstrated in this trial should be considered in comparison with other treatments in the chain of survival.” Early cardiac arrest recognition saves 1 in every 11 patients, bystander CPR saves 1 in every 15, and early defibrillation saves 1 in 5, the investigators noted.

The trial did not collect data on prearrest neurologic status, but the number of subjects with impaired function was probably very small and balanced between the groups, according to the report.

On average, patients were aged just under 70 years, 65% were men, and bystander CPR was performed in about 60% in both groups. They were enrolled by five ambulance services in England and Wales. Informed consent was obtained, when possible, after resuscitation.

The trial was funded by the U.K. National Institute for Health Research. The researchers had no relevant disclosures to report.

[email protected]

SOURCE: Perkins GD et al. N Engl J Med. 2018 Jul 18. doi:10.1056/NEJMoa1806842.

Using epinephrine for cardiac arrest improves 30-day survival by less than 1%, and nearly doubles the risk of severe brain damage among survivors, according to PARAMEDIC2, a randomized, double-blind trial in more than 8,000 patients in Great Britain.

It’s clear what patients want. “Our own work with patients and the public before starting the trial identified survival without brain damage [as] more important to patients than survival alone. The findings of this trial will require careful consideration by the wider community and those responsible for clinical practice guidelines for cardiac arrest,” lead investigator Gavin D. Perkins, MD, professor of critical care medicine at the University of Warwick, Coventry, England, and lead author of the study published in the New England Journal of Medicine, wrote in a statement.

In PARAMEDIC2, after initial attempts with CPR and defibrillation failed, 4,012 patients were given epinephrine 1 mg by intravenous or intraosseous infusion every 3-5 minutes for a maximum of 10 doses, and 3,995 were given a saline placebo in the same fashion. The median time from emergency call to ambulance arrival was just over 6 minutes in both groups, with a further 14 minutes until drug administration.

The heart restarted in a higher proportion of epinephrine patients (36.3% vs. 11.7%), and 3.2% of epinephrine patients were alive at 30 days, versus 2.4% in the placebo arm, a 39% increase.

However, that slight benefit came at a significant cost. Of the 126 epinephrine patients who survived to hospital discharge, 39 (31%) had severe brain damage, compared with 16 (17.8%) among the 90 placebo survivors. Severe brain damage meant inability to walk and tend to bodily functions, or a persistent vegetative state (modified Rankin scale grade 4 or 5).

The trial addresses a long-standing question in resuscitation medicine, the role of epinephrine in cardiac arrest. It’s a devil’s bargain: Epinephrine increases blood flow to the heart, so helps with resuscitation, but it also reduces blood flow in the brain’s microvasculature, increasing the risk of brain damage.

“The benefit of epinephrine on survival demonstrated in this trial should be considered in comparison with other treatments in the chain of survival.” Early cardiac arrest recognition saves 1 in every 11 patients, bystander CPR saves 1 in every 15, and early defibrillation saves 1 in 5, the investigators noted.

The trial did not collect data on prearrest neurologic status, but the number of subjects with impaired function was probably very small and balanced between the groups, according to the report.

On average, patients were aged just under 70 years, 65% were men, and bystander CPR was performed in about 60% in both groups. They were enrolled by five ambulance services in England and Wales. Informed consent was obtained, when possible, after resuscitation.

The trial was funded by the U.K. National Institute for Health Research. The researchers had no relevant disclosures to report.

[email protected]

SOURCE: Perkins GD et al. N Engl J Med. 2018 Jul 18. doi:10.1056/NEJMoa1806842.

Using epinephrine for cardiac arrest improves 30-day survival by less than 1%, and nearly doubles the risk of severe brain damage among survivors, according to PARAMEDIC2, a randomized, double-blind trial in more than 8,000 patients in Great Britain.

It’s clear what patients want. “Our own work with patients and the public before starting the trial identified survival without brain damage [as] more important to patients than survival alone. The findings of this trial will require careful consideration by the wider community and those responsible for clinical practice guidelines for cardiac arrest,” lead investigator Gavin D. Perkins, MD, professor of critical care medicine at the University of Warwick, Coventry, England, and lead author of the study published in the New England Journal of Medicine, wrote in a statement.

In PARAMEDIC2, after initial attempts with CPR and defibrillation failed, 4,012 patients were given epinephrine 1 mg by intravenous or intraosseous infusion every 3-5 minutes for a maximum of 10 doses, and 3,995 were given a saline placebo in the same fashion. The median time from emergency call to ambulance arrival was just over 6 minutes in both groups, with a further 14 minutes until drug administration.

The heart restarted in a higher proportion of epinephrine patients (36.3% vs. 11.7%), and 3.2% of epinephrine patients were alive at 30 days, versus 2.4% in the placebo arm, a 39% increase.

However, that slight benefit came at a significant cost. Of the 126 epinephrine patients who survived to hospital discharge, 39 (31%) had severe brain damage, compared with 16 (17.8%) among the 90 placebo survivors. Severe brain damage meant inability to walk and tend to bodily functions, or a persistent vegetative state (modified Rankin scale grade 4 or 5).

The trial addresses a long-standing question in resuscitation medicine, the role of epinephrine in cardiac arrest. It’s a devil’s bargain: Epinephrine increases blood flow to the heart, so helps with resuscitation, but it also reduces blood flow in the brain’s microvasculature, increasing the risk of brain damage.

“The benefit of epinephrine on survival demonstrated in this trial should be considered in comparison with other treatments in the chain of survival.” Early cardiac arrest recognition saves 1 in every 11 patients, bystander CPR saves 1 in every 15, and early defibrillation saves 1 in 5, the investigators noted.

The trial did not collect data on prearrest neurologic status, but the number of subjects with impaired function was probably very small and balanced between the groups, according to the report.

On average, patients were aged just under 70 years, 65% were men, and bystander CPR was performed in about 60% in both groups. They were enrolled by five ambulance services in England and Wales. Informed consent was obtained, when possible, after resuscitation.

The trial was funded by the U.K. National Institute for Health Research. The researchers had no relevant disclosures to report.

[email protected]

SOURCE: Perkins GD et al. N Engl J Med. 2018 Jul 18. doi:10.1056/NEJMoa1806842.

Widespread opioid use disorder (OUD) has spawned new epidemics of hepatitis C virus (HCV) and HIV infections as well as increased hospitalizations for bacteremia, endocarditis, skin and soft tissue infections, and osteomyelitis, according to a report arising from a National Academies of Science, Engineering and Medicine (NASEM) workshop titled Integrating Infectious Disease Considerations with Response to the Opioid Epidemic.

Hailshadow/iStock/Getty Images

Optimal treatment of these infections is often impeded by untreated OUD, Sandra A. Springer, MD, and her colleagues wrote in an article published online in the Annals of Internal Medicine. Failing to address OUD can result in longer hospital stays; frequent readmissions because of a lack of adherence to antibiotic regimens; or reinfection, morbidity, and high costs. “Medical settings that manage such infections offer a potential means of engaging people in treatment of OUD; however, few providers and hospitals treating such infections have the needed resources and capabilities,” Dr. Springer, director, infectious disease outpatient clinic, Veterans Administration, Newington, and of Yale University, New Haven, both in Conn., and her colleagues wrote.

The authors outlined five action steps resulting from the NASEM workshop:

• Implement screening for OUD in all relevant health care settings.
• For patients with positive screening results, immediately prescribe effective medication for OUD and/or opioid withdrawal symptoms.
• Develop hospital-based protocols that facilitate OUD treatment initiation and linkage to community-based treatment upon discharge.
• Hospitals, medical schools, physician assistant schools, nursing schools, and residency programs should increase training to identify and treat OUD.
• Increase access to addiction care and funding to states to provide effective medications to treat OUD.

Opioid withdrawal and pain syndromes should be addressed with opioid agonist therapies to optimize infectious disease (ID) treatment and relieve pain, according to Dr. Springer and her colleagues. In addition, “Because ID specialists are likely to be consulted for anyone requiring long-term antibiotic therapy or patients with HIV and HCV infection, OUD screening should be a standard part of an ID consult assessment,” the authors wrote.

“All health care providers have a role in combating the OUD epidemic and its ID consequences. Those who treat infectious complications of OUD are well suited to screen for OUD and begin treatment with effective FDA-approved medications,” the authors concluded.

The workshop was held in March 2018 in Washington and videos and slide presentations from the meeting are available.

Dr. Springer and her colleagues reported grant funding from the National Institutes of Health, but no commercial conflicts.
 

[email protected]

SOURCE: Springer SA et al. Ann Intern Med. 2018 Jul 13. doi: 10.7326/M18-1203.

Widespread opioid use disorder (OUD) has spawned new epidemics of hepatitis C virus (HCV) and HIV infections as well as increased hospitalizations for bacteremia, endocarditis, skin and soft tissue infections, and osteomyelitis, according to a report arising from a National Academies of Science, Engineering and Medicine (NASEM) workshop titled Integrating Infectious Disease Considerations with Response to the Opioid Epidemic.

Hailshadow/iStock/Getty Images

Optimal treatment of these infections is often impeded by untreated OUD, Sandra A. Springer, MD, and her colleagues wrote in an article published online in the Annals of Internal Medicine. Failing to address OUD can result in longer hospital stays; frequent readmissions because of a lack of adherence to antibiotic regimens; or reinfection, morbidity, and high costs. “Medical settings that manage such infections offer a potential means of engaging people in treatment of OUD; however, few providers and hospitals treating such infections have the needed resources and capabilities,” Dr. Springer, director, infectious disease outpatient clinic, Veterans Administration, Newington, and of Yale University, New Haven, both in Conn., and her colleagues wrote.

The authors outlined five action steps resulting from the NASEM workshop:

• Implement screening for OUD in all relevant health care settings.
• For patients with positive screening results, immediately prescribe effective medication for OUD and/or opioid withdrawal symptoms.
• Develop hospital-based protocols that facilitate OUD treatment initiation and linkage to community-based treatment upon discharge.
• Hospitals, medical schools, physician assistant schools, nursing schools, and residency programs should increase training to identify and treat OUD.
• Increase access to addiction care and funding to states to provide effective medications to treat OUD.

Opioid withdrawal and pain syndromes should be addressed with opioid agonist therapies to optimize infectious disease (ID) treatment and relieve pain, according to Dr. Springer and her colleagues. In addition, “Because ID specialists are likely to be consulted for anyone requiring long-term antibiotic therapy or patients with HIV and HCV infection, OUD screening should be a standard part of an ID consult assessment,” the authors wrote.

“All health care providers have a role in combating the OUD epidemic and its ID consequences. Those who treat infectious complications of OUD are well suited to screen for OUD and begin treatment with effective FDA-approved medications,” the authors concluded.

The workshop was held in March 2018 in Washington and videos and slide presentations from the meeting are available.

Dr. Springer and her colleagues reported grant funding from the National Institutes of Health, but no commercial conflicts.
 

[email protected]

SOURCE: Springer SA et al. Ann Intern Med. 2018 Jul 13. doi: 10.7326/M18-1203.

Widespread opioid use disorder (OUD) has spawned new epidemics of hepatitis C virus (HCV) and HIV infections as well as increased hospitalizations for bacteremia, endocarditis, skin and soft tissue infections, and osteomyelitis, according to a report arising from a National Academies of Science, Engineering and Medicine (NASEM) workshop titled Integrating Infectious Disease Considerations with Response to the Opioid Epidemic.

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Optimal treatment of these infections is often impeded by untreated OUD, Sandra A. Springer, MD, and her colleagues wrote in an article published online in the Annals of Internal Medicine. Failing to address OUD can result in longer hospital stays; frequent readmissions because of a lack of adherence to antibiotic regimens; or reinfection, morbidity, and high costs. “Medical settings that manage such infections offer a potential means of engaging people in treatment of OUD; however, few providers and hospitals treating such infections have the needed resources and capabilities,” Dr. Springer, director, infectious disease outpatient clinic, Veterans Administration, Newington, and of Yale University, New Haven, both in Conn., and her colleagues wrote.

The authors outlined five action steps resulting from the NASEM workshop:

• Implement screening for OUD in all relevant health care settings.
• For patients with positive screening results, immediately prescribe effective medication for OUD and/or opioid withdrawal symptoms.
• Develop hospital-based protocols that facilitate OUD treatment initiation and linkage to community-based treatment upon discharge.
• Hospitals, medical schools, physician assistant schools, nursing schools, and residency programs should increase training to identify and treat OUD.
• Increase access to addiction care and funding to states to provide effective medications to treat OUD.

Opioid withdrawal and pain syndromes should be addressed with opioid agonist therapies to optimize infectious disease (ID) treatment and relieve pain, according to Dr. Springer and her colleagues. In addition, “Because ID specialists are likely to be consulted for anyone requiring long-term antibiotic therapy or patients with HIV and HCV infection, OUD screening should be a standard part of an ID consult assessment,” the authors wrote.

“All health care providers have a role in combating the OUD epidemic and its ID consequences. Those who treat infectious complications of OUD are well suited to screen for OUD and begin treatment with effective FDA-approved medications,” the authors concluded.

The workshop was held in March 2018 in Washington and videos and slide presentations from the meeting are available.

Dr. Springer and her colleagues reported grant funding from the National Institutes of Health, but no commercial conflicts.
 

[email protected]

SOURCE: Springer SA et al. Ann Intern Med. 2018 Jul 13. doi: 10.7326/M18-1203.

On September 18, 2014, President Barack Obama signed an executive order that made addressing antibiotic-resistant bacteria a national security policy.¹ This legislation resulted in the creation of a large multidepartment task force to combat the global and domestic problem of antimicrobial resistance. The order required hospitals and other inpatient health care delivery facilities, including the Department of Veterans Affairs (VA), to implement robust antimicrobial stewardship programs that adhere to best practices, such as those identified by the Centers for Disease Control and Prevention (CDC). More specifically, the VA was mandated to take steps to encourage other areas of health care, such as ambulatory surgery centers and outpatient clinics, to adopt antimicrobial stewardship programs.¹ This order also reinforced the importance for VA facilities to continue to develop, improve, and sustain efforts in antimicrobial stewardship.

Prior to the order, in 2012 the Richard L. Roudebush VA Medical Center (RRVAMC) in Indianapolis, Indiana, implemented an inpatient antimicrobial stewardship program that included thrice-weekly meetings to review inpatient records and make stewardship recommendations with an infectious diseases physician champion and clinical pharmacists. These efforts led to the improved use of antimicrobial agents on the inpatient side of the medical center. During the first 4 years of implementation, the program helped to decrease the defined daily doses of broad-spectrum antibiotics per 1,000 patient days nearly 36%, from 532 in 2012 to 343 in 2015, as well as decrease the days of therapy of fluoroquinolones per 1,000 patient days 28.75%, from 80 in 2012 to 57 in 2015. Additionally, the program showed a significant decrease in the standardized antimicrobial administration ratio, a benchmark measure developed by the CDC to reflect a facility’s actual antimicrobial use to the expected use of a similar facility based on bed size, number of intensive care unit beds, location type, and medical school affiliation.²

While the RRVAMC antimicrobial stewardship team has been able to intervene on most of the inpatients admitted to the medical center, the outpatient arena has had few antimicrobial stewardship interventions. Recognizing a need to establish and expand pharmacy services and for improvement of outpatient antimicrobial stewardship, RRVAMC leadership decided to establish a pharmacist-led outpatient antimicrobial surveillance program, starting specifically within the emergency department (ED).

Clinical pharmacists in the ED setting are uniquely positioned to improve patient care and encourage the judicious use of antimicrobials for empiric treatment of urinary tract infections (UTIs). The CDC’s Core Elements of Outpatient Antibiotic Stewardship recommends pharmacist availability in the ED setting, and previous literature has demonstrated pharmacist utility in ED postdischarge culture monitoring and surveillance.^3-5

This article will highlight one such program review at the RRVAMC and demonstrate the need for pharmacist-led antimicrobial stewardship and monitoring in the ED. The purpose of this study was to test the hypothesis that pharmacist intervention would be necessary to prospectively check for “bug-drug mismatch” and assure proper follow-up of urine cultures at this institution. The project was deemed to be quality improvement and thereby granted exemption by the RRVAMC Institutional Review Board.

Methods

This project took place at the RRVAMC, a 229-bed tertiary academic medical center that serves > 60,000 patients annually. The RRVAMC ED has 20 beds and received about 29,000 visits in 2014. Patients were eligible for initial evaluation if they had a urine culture collected in the ED within the 91-day period from September 1, 2015 to November 30, 2015. Patients were included for data analysis if it was documented that they were treated for actual or clinically suspected, based on signs and symptoms, uncomplicated UTI, complicated UTI, or UTI with pyelonephritis. Patients did not need to have a positive urine culture for inclusion, as infections could still be present despite negative culture results.⁶ Patients with positive cultures who were not clinically symptomatic of a UTI and were not treated as such by the ED provider (ie, asymptomatic bacteriuria) were excluded from the study.

Data collection took place via daily chart review of patient records in both the Computerized Patient Record System and Decentralized Hospital Computer Program medical applications as urine cultures were performed. Data were gathered and assessed by a postgraduate year-2 internal medicine pharmacy resident on rotation in the ED who reviewed cultures daily and made interventions based on the results as needed. The pharmacy resident was physically present within the ED during the first 30 days of the project. The pharmacy resident was not within the direct practice area during the final 61 days of the project but was in a different area of the hospital and available for consultation.

Primary data collected included urine culture results and susceptibilities, empiric antimicrobial choices, and admission status. Other data collected included duration of treatment and secondary antibiotics chosen, each of which specifically evaluated those patients who were not admitted to the hospital and were thus treated as outpatients. Additional data generated from this study were used to identify empiric antibiotics utilized for the treatment of UTIs and assess for appropriate selection and duration of therapy within this institution.

Results

During the study period, 722 urine cultures were collected in the ED and were included for initial evaluation. Of these, 127 were treated by the ED provider pursuant to one of the indications specified and were included in the data analysis. Treatment with an antimicrobial agent provided adequate coverage for the identified pathogen in 112 patients, yielding a match rate of 88%. As all included cultures were collected in suspicion of an infection, those cultures yielding no growth were considered to have been adequately covered. 

Nearly half (45%) of treatment plans included a fluoroquinolone. Of those treated on an outpatient basis, fluoroquinolones were even more frequently used, comprising 50 of 82 (61%) courses. Ciprofloxacin was the most frequently used treatment, used in 39 of the 82 outpatient regimens (48%). Cephalexin was the second most common and was used in 14 outpatient regimens (17%), followed by levofloxacin (15%) (Figure 1). 

Mismatched cultures, or those where the prescribed antibiotic did not provide adequate coverage of the identified pathogens based on susceptibilities, occurred at a rate of 12%. Follow-up on these cultures was determined largely by the patient’s admission status. The majority of mismatched cultures were addressed by the inpatient team (10/15) upon admission. 

Discussion

Empiric antibiotic selection for the treatment of UTIs continues to be the cornerstone of antibiotic management for the treatment of such a disease state.⁷ The noted drug-bug match rate of 88% in this study demonstrates effective initial empiric coverage and ensures a vast majority of veterans receive adequate coverage for identified pathogens. Additionally, this rate shows that the current system seems to be functioning appropriately and refutes the author’s preconceived ideas that the mismatch rate was higher at RRVAMC. However, these findings also demonstrate a predominant use of fluoroquinolones for empiric treatment in a majority of patients who could be better served with narrower spectrum agents. Only 2 of the outpatient regimens were for the treatment of pyelonephritis, the only indication in which a fluoroquinolone would be the standard of care per guideline recommendations.⁷

These findings were consistent with a similar study in which 83% of ED collected urine cultures ultimately grew bacteria susceptibleto empiric treatment.⁸ This number was similar to the current study despite the latter study consisting of predominantly female patients (93%) and excluding patients with a history of benign prostatic hypertrophy, catheter use, or history of genitourinary cancer, which are frequently found within the VA population. Thus, despite having a differing patient population at the current study’s facility with characteristics that would classify most to be treated as a complicated UTI, empiric coverage rates remained similar. The lower than anticipated intervention rate by the pharmacist on rotation in the ED can be directly attributed to this high empiric match rate, which could in turn be attributed to the extensive use of broad-spectrum antibiotics for treatment.

Empiric antimicrobial selection is based largely on local resistance patterns.⁷ Of particular importance is the resistance patterns of E coli, as it is the primary isolate responsible for UTIs worldwide. Thus, it is not unexpected that the most frequently isolated pathogen in the current study also was E coli. While clinical practice guidelines state that hospital-wide antibiograms often are skewed by cultures collected from inpatients or those with complicated infection, the current study found hospital-wide E coli resistance patterns, specifically those related to fluoroquinolone use, to be similar to those collected in the ED alone (78.5% hospital-wide susceptibility vs. 75% ED susceptibility). This was expected, as similar studies comparing E coli resistance patterns from ED-collected urine cultures to those institution-wide also have found similar rates of resistance.^8,9 These findings are of particular importance as E coli resistance is noted to be increasing, varies with geographic area, and local resistance patterns are rarely known.⁷ Thus, these findings may aid ED providers in their empiric antimicrobial selections.

Ciprofloxacin was the most frequently used medication for the treatment of UTIs. While overall empiric selections were found to have favorable resistance patterns, it is difficult to interpret the appropriateness of ciprofloxacin’s use in the present study. First, there is a distinct lack of US-based clinical practice guidelines for the treatment of complicated UTIs. As the majority of this study population was male, it is difficult to directly extrapolate from the current Infectious Diseases Society of America treatment guidelines for uncomplicated cystitis and apply to the study population. Although recommended for the treatment of pyelonephritis, it is unclear whether ciprofloxacin should be utilized as a first-line empiric option for the treatment of UTIs in males.

Despite the lack of disease-specific recommendations for ciprofloxacin, recommendations exist regarding its use when local resistance patterns are known.⁷ It is currently recommended that these agents not be used when resistance rates of E coli exceed 20% for trimethoprim-sulfamethoxazole or 10% for fluoroquinolones. As this study demonstrated a nearly 25% resistance rate for E coli to fluoroquinolones in both the ED and institution-wide sample populations, it could potentially be ascertained that ciprofloxacin is an inappropriate choice for the empiric treatment of UTIs in this patient population. However, as noted, it is unknown whether this recommendation would still be applicable when applied to the treatment of complicated cystitis and greater male population, as overall rates of susceptible cultures to all organisms was similar to other published studies.^8,9

While there is scant specific guidance related to the treatment of complicated UTIs, there is emerging guidance on the use of fluoroquinolones, both in general and specifically related to the treatment of UTIs. In July 2016, the FDA issued a drug safety communication regarding the use of and warnings for fluoroquinolones, which explicitly stated that “health care professionals should not prescribe systemic fluoroquinolones to patients who have other treatment options for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated UTIs because the risks outweigh the benefits in these patients.”¹⁰

This guidance has the potential to impact fluoroquinolone prescribing significantly at RRVAMC. Given the large number of fluoroquinolones prescribed for UTIs, the downstream effects that this shift in prescribing would have is unknown. As most nonfluoroquinolones used for UTI typically are narrower in antimicrobial spectrum (eg, trimethoprim/sulfamethoxazole, nitrofurantoin, cephalexin, etc) the possibility exists that the match rate for empiric therapy may decrease. Thus, a larger need for closer follow-up to assure adequate coverage may arise, posing a more expanded role for an ED-based pharmacist than was demonstrated in the current study.

This new guidance also may place providers in an area of larger uncertainty with regards to treating both complicated and uncomplicated cystitis. Given the enhanced warnings on fluoroquinolone use, it is unknown whether prescribers would gravitate to utilizing similar options as their peers as alternatives to fluoroquinolones. Similarly, duration of therapy with nonfluoroquinolone agents is unclear as well; as the present study demonstrated a large range in treatment duration of outpatients (3-14 days). While the average observed duration of 8.3 days is intuitively fitting, as the majority of cases were in males, no published guideline exists that affirms the appropriateness of this finding. Such uncertainty and potential inconsistency between providers affords a large opportunity for developing a standardized treatment pathway for the treatment of UTIs to ensure both effective and guideline concordant treatment for patients, specifically with regards to antimicrobial selection and duration of treatment.

It is noteworthy to mention that all follow-ups on positive cultures inadequately covered by empiric therapy took place on the day organism identification and susceptibility data were released. This finding was somewhat surprising, as it was originally theorized that most ED-collected urine cultures were not monitored to completion by a pharmacist and that would be necessary in order to ensure proper follow-up of culture results. What is not clear is whether there is a robust process for the follow-up of urine cultures in the ED. Most of the bug-drug mismatches coincidentally were admitted to the inpatient teams where there were appropriate personnel to follow up and adjust the antibiotic selection. If there was a bug-drug mismatch, and the patient was not admitted, it is unclear whether there is a consistent process for follow-up.

Given the limited number of mismatched cultures that required change in therapy, it is unknown if this role would expand if more narrow-spectrum agents were utilized, theoretically leading to a higher mismatch rate and necessitating closer follow-up. Furthermore, given the common practice of mailed prescriptions at the VA, it is all the more imperative that the cultures be acted upon on the day they were identified, as the mailing and processing time of prescriptions may limit the clinical utility in switching from a more broad-spectrum agent, to one more targeted for an identified organism. While a patient traveling back to the medical center for expedited prescription pickup at the pharmacy would alleviate this problem, many patients at the facility travel great distances or may not have readily available travel means to return to the medical center.

Future Directions

While minimal follow-up was required after a patient had left the ED, this study demonstrated a fundamental need for further refinements in antimicrobial stewardship activities within the ED. Duration of therapy, empiric selection, and proper dosing are key areas where the ED-based pharmacy resident was able to intervene during the time physically stationed in the ED. The data collected from this study demonstrated this and was ultimately combined with other ED-based interventions and utilized as supporting evidence in the pharmacy service business plan, outlining the necessity of a full-time pharmacy presence in the ED. The business plan submission, along with other ongoing RRVAMC initiatives, ultimately led to the approval for clinical pharmacy specialists to expand practice into the ED. These positions will continue to advance pharmacy practice within the ED, while affording opportunities for pharmacists to practice at the top of their licensure, provide individualized provider education, and deliver real-time antimicrobial stewardship interventions. Furthermore, as the majority of the study period was monitored outside of the ED, the project may provide a model for other VA institutions without full-time ED pharmacists to implement as a means to improve antimicrobial stewardship and further build an evidence base for expanding their pharmacy services to the ED.

Given the large number of fluoroquinolones utilized in the ED, this study has raised the question of what prescribing patterns look like with regards to outpatient UTI treatment within the realm of primary care at RRVAMC. Despite the great strides made with regards to antimicrobial stewardship at this facility on the inpatient side, no formal antimicrobial stewardship program exists for review in the outpatient setting, where literature suggests the majority of antibiotics are prescribed.^3,11 While more robust protocols are in place for follow-up of culture data in the primary care realm at this facility, the prescribing patterns are relatively unknown.

A recent study completed at a similar VA facility found that 60% of antibiotics prescribed for cystitis, pharyngitis, or sinusitis on an outpatient basis were guideline-discordant, and CDC guidance has further recommended specific focus should be undertaken with regards to outpatient stewardship practices in the treatment of genitourinary infections.^3,12 These findings highlight the need for outpatient antimicrobial stewardship and presents a compelling reason to further investigate outpatient prescribing within primary care at RRVAMC.

Strengths and Limitations

Strengths of the current study include the ability to monitor urine cultures in real time and to provide timely interventions in the event of a rare bug-drug mismatch. The evaluation of cultures in this study shows that the majority of cases had a drug selected with adequate coverage. The study did assure ED providers that, even though guidelines may suggest otherwise, urine cultures drawn in the ED at RRVAMC followed similar resistance patterns seen for the facility as a whole. Moreover, it is valuable as it captures data that are directly applicable to the VA patient population, in which there is little published data with regards to UTI treatment and no formal VA guidance.

A primary limitation of this study is the lack of differentiation between cultures collected from patients with or without indwelling catheters. However, only including patients who presented with signs and/or symptoms of a UTI limits the number of cultures that could potentially be deemed as colonization, thus minimizing the potential for nonpathogenic organisms to confound the results. This study also did not differentiate the setting from which the patient presented (eg, community, extended care facility, etc) that could have potentially provided guidance on resistance patterns for community-acquired UTIs and whether this may have differed from hospital-acquired or facility-acquired UTIs. Another limitation was the relatively short time frame for data collection. A data collection period greater than 91 days would allow for a larger sample size, thus making the data more robust and potentially allowing for the identification of other trends not seen in the current study. A longer data collection period also would have afforded the opportunity to track more robust clinical outcomes throughout the study, identifying whether treatment failure may have been linked to the use of certain classes or spectrums of activity of antibiotics.

Conclusion

Despite the E coli resistance rate to ciprofloxacin (> 20%), the empiric treatments chosen were > 85% effective, needing minimal follow-up once a patient left the ED. Nonetheless, a change in prescribing patterns based on recent national recommendations may provide expanded opportunities in antimicrobial stewardship for ED-based pharmacists. Further research is needed in antimicrobial stewardship within this facility’s outpatient primary care realm, potentially uncovering other opportunities for pharmacist intervention to assure guideline concordant care for the treatment of UTIs as well as other infections treated in primary care patients.

On September 18, 2014, President Barack Obama signed an executive order that made addressing antibiotic-resistant bacteria a national security policy.¹ This legislation resulted in the creation of a large multidepartment task force to combat the global and domestic problem of antimicrobial resistance. The order required hospitals and other inpatient health care delivery facilities, including the Department of Veterans Affairs (VA), to implement robust antimicrobial stewardship programs that adhere to best practices, such as those identified by the Centers for Disease Control and Prevention (CDC). More specifically, the VA was mandated to take steps to encourage other areas of health care, such as ambulatory surgery centers and outpatient clinics, to adopt antimicrobial stewardship programs.¹ This order also reinforced the importance for VA facilities to continue to develop, improve, and sustain efforts in antimicrobial stewardship.

Prior to the order, in 2012 the Richard L. Roudebush VA Medical Center (RRVAMC) in Indianapolis, Indiana, implemented an inpatient antimicrobial stewardship program that included thrice-weekly meetings to review inpatient records and make stewardship recommendations with an infectious diseases physician champion and clinical pharmacists. These efforts led to the improved use of antimicrobial agents on the inpatient side of the medical center. During the first 4 years of implementation, the program helped to decrease the defined daily doses of broad-spectrum antibiotics per 1,000 patient days nearly 36%, from 532 in 2012 to 343 in 2015, as well as decrease the days of therapy of fluoroquinolones per 1,000 patient days 28.75%, from 80 in 2012 to 57 in 2015. Additionally, the program showed a significant decrease in the standardized antimicrobial administration ratio, a benchmark measure developed by the CDC to reflect a facility’s actual antimicrobial use to the expected use of a similar facility based on bed size, number of intensive care unit beds, location type, and medical school affiliation.²

While the RRVAMC antimicrobial stewardship team has been able to intervene on most of the inpatients admitted to the medical center, the outpatient arena has had few antimicrobial stewardship interventions. Recognizing a need to establish and expand pharmacy services and for improvement of outpatient antimicrobial stewardship, RRVAMC leadership decided to establish a pharmacist-led outpatient antimicrobial surveillance program, starting specifically within the emergency department (ED).

Clinical pharmacists in the ED setting are uniquely positioned to improve patient care and encourage the judicious use of antimicrobials for empiric treatment of urinary tract infections (UTIs). The CDC’s Core Elements of Outpatient Antibiotic Stewardship recommends pharmacist availability in the ED setting, and previous literature has demonstrated pharmacist utility in ED postdischarge culture monitoring and surveillance.^3-5

This article will highlight one such program review at the RRVAMC and demonstrate the need for pharmacist-led antimicrobial stewardship and monitoring in the ED. The purpose of this study was to test the hypothesis that pharmacist intervention would be necessary to prospectively check for “bug-drug mismatch” and assure proper follow-up of urine cultures at this institution. The project was deemed to be quality improvement and thereby granted exemption by the RRVAMC Institutional Review Board.

Methods

This project took place at the RRVAMC, a 229-bed tertiary academic medical center that serves > 60,000 patients annually. The RRVAMC ED has 20 beds and received about 29,000 visits in 2014. Patients were eligible for initial evaluation if they had a urine culture collected in the ED within the 91-day period from September 1, 2015 to November 30, 2015. Patients were included for data analysis if it was documented that they were treated for actual or clinically suspected, based on signs and symptoms, uncomplicated UTI, complicated UTI, or UTI with pyelonephritis. Patients did not need to have a positive urine culture for inclusion, as infections could still be present despite negative culture results.⁶ Patients with positive cultures who were not clinically symptomatic of a UTI and were not treated as such by the ED provider (ie, asymptomatic bacteriuria) were excluded from the study.

Data collection took place via daily chart review of patient records in both the Computerized Patient Record System and Decentralized Hospital Computer Program medical applications as urine cultures were performed. Data were gathered and assessed by a postgraduate year-2 internal medicine pharmacy resident on rotation in the ED who reviewed cultures daily and made interventions based on the results as needed. The pharmacy resident was physically present within the ED during the first 30 days of the project. The pharmacy resident was not within the direct practice area during the final 61 days of the project but was in a different area of the hospital and available for consultation.

Primary data collected included urine culture results and susceptibilities, empiric antimicrobial choices, and admission status. Other data collected included duration of treatment and secondary antibiotics chosen, each of which specifically evaluated those patients who were not admitted to the hospital and were thus treated as outpatients. Additional data generated from this study were used to identify empiric antibiotics utilized for the treatment of UTIs and assess for appropriate selection and duration of therapy within this institution.

Results

During the study period, 722 urine cultures were collected in the ED and were included for initial evaluation. Of these, 127 were treated by the ED provider pursuant to one of the indications specified and were included in the data analysis. Treatment with an antimicrobial agent provided adequate coverage for the identified pathogen in 112 patients, yielding a match rate of 88%. As all included cultures were collected in suspicion of an infection, those cultures yielding no growth were considered to have been adequately covered. 

Nearly half (45%) of treatment plans included a fluoroquinolone. Of those treated on an outpatient basis, fluoroquinolones were even more frequently used, comprising 50 of 82 (61%) courses. Ciprofloxacin was the most frequently used treatment, used in 39 of the 82 outpatient regimens (48%). Cephalexin was the second most common and was used in 14 outpatient regimens (17%), followed by levofloxacin (15%) (Figure 1). 

Mismatched cultures, or those where the prescribed antibiotic did not provide adequate coverage of the identified pathogens based on susceptibilities, occurred at a rate of 12%. Follow-up on these cultures was determined largely by the patient’s admission status. The majority of mismatched cultures were addressed by the inpatient team (10/15) upon admission. 

Discussion

Empiric antibiotic selection for the treatment of UTIs continues to be the cornerstone of antibiotic management for the treatment of such a disease state.⁷ The noted drug-bug match rate of 88% in this study demonstrates effective initial empiric coverage and ensures a vast majority of veterans receive adequate coverage for identified pathogens. Additionally, this rate shows that the current system seems to be functioning appropriately and refutes the author’s preconceived ideas that the mismatch rate was higher at RRVAMC. However, these findings also demonstrate a predominant use of fluoroquinolones for empiric treatment in a majority of patients who could be better served with narrower spectrum agents. Only 2 of the outpatient regimens were for the treatment of pyelonephritis, the only indication in which a fluoroquinolone would be the standard of care per guideline recommendations.⁷

These findings were consistent with a similar study in which 83% of ED collected urine cultures ultimately grew bacteria susceptibleto empiric treatment.⁸ This number was similar to the current study despite the latter study consisting of predominantly female patients (93%) and excluding patients with a history of benign prostatic hypertrophy, catheter use, or history of genitourinary cancer, which are frequently found within the VA population. Thus, despite having a differing patient population at the current study’s facility with characteristics that would classify most to be treated as a complicated UTI, empiric coverage rates remained similar. The lower than anticipated intervention rate by the pharmacist on rotation in the ED can be directly attributed to this high empiric match rate, which could in turn be attributed to the extensive use of broad-spectrum antibiotics for treatment.

Empiric antimicrobial selection is based largely on local resistance patterns.⁷ Of particular importance is the resistance patterns of E coli, as it is the primary isolate responsible for UTIs worldwide. Thus, it is not unexpected that the most frequently isolated pathogen in the current study also was E coli. While clinical practice guidelines state that hospital-wide antibiograms often are skewed by cultures collected from inpatients or those with complicated infection, the current study found hospital-wide E coli resistance patterns, specifically those related to fluoroquinolone use, to be similar to those collected in the ED alone (78.5% hospital-wide susceptibility vs. 75% ED susceptibility). This was expected, as similar studies comparing E coli resistance patterns from ED-collected urine cultures to those institution-wide also have found similar rates of resistance.^8,9 These findings are of particular importance as E coli resistance is noted to be increasing, varies with geographic area, and local resistance patterns are rarely known.⁷ Thus, these findings may aid ED providers in their empiric antimicrobial selections.

Ciprofloxacin was the most frequently used medication for the treatment of UTIs. While overall empiric selections were found to have favorable resistance patterns, it is difficult to interpret the appropriateness of ciprofloxacin’s use in the present study. First, there is a distinct lack of US-based clinical practice guidelines for the treatment of complicated UTIs. As the majority of this study population was male, it is difficult to directly extrapolate from the current Infectious Diseases Society of America treatment guidelines for uncomplicated cystitis and apply to the study population. Although recommended for the treatment of pyelonephritis, it is unclear whether ciprofloxacin should be utilized as a first-line empiric option for the treatment of UTIs in males.

Despite the lack of disease-specific recommendations for ciprofloxacin, recommendations exist regarding its use when local resistance patterns are known.⁷ It is currently recommended that these agents not be used when resistance rates of E coli exceed 20% for trimethoprim-sulfamethoxazole or 10% for fluoroquinolones. As this study demonstrated a nearly 25% resistance rate for E coli to fluoroquinolones in both the ED and institution-wide sample populations, it could potentially be ascertained that ciprofloxacin is an inappropriate choice for the empiric treatment of UTIs in this patient population. However, as noted, it is unknown whether this recommendation would still be applicable when applied to the treatment of complicated cystitis and greater male population, as overall rates of susceptible cultures to all organisms was similar to other published studies.^8,9

While there is scant specific guidance related to the treatment of complicated UTIs, there is emerging guidance on the use of fluoroquinolones, both in general and specifically related to the treatment of UTIs. In July 2016, the FDA issued a drug safety communication regarding the use of and warnings for fluoroquinolones, which explicitly stated that “health care professionals should not prescribe systemic fluoroquinolones to patients who have other treatment options for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated UTIs because the risks outweigh the benefits in these patients.”¹⁰

This guidance has the potential to impact fluoroquinolone prescribing significantly at RRVAMC. Given the large number of fluoroquinolones prescribed for UTIs, the downstream effects that this shift in prescribing would have is unknown. As most nonfluoroquinolones used for UTI typically are narrower in antimicrobial spectrum (eg, trimethoprim/sulfamethoxazole, nitrofurantoin, cephalexin, etc) the possibility exists that the match rate for empiric therapy may decrease. Thus, a larger need for closer follow-up to assure adequate coverage may arise, posing a more expanded role for an ED-based pharmacist than was demonstrated in the current study.

This new guidance also may place providers in an area of larger uncertainty with regards to treating both complicated and uncomplicated cystitis. Given the enhanced warnings on fluoroquinolone use, it is unknown whether prescribers would gravitate to utilizing similar options as their peers as alternatives to fluoroquinolones. Similarly, duration of therapy with nonfluoroquinolone agents is unclear as well; as the present study demonstrated a large range in treatment duration of outpatients (3-14 days). While the average observed duration of 8.3 days is intuitively fitting, as the majority of cases were in males, no published guideline exists that affirms the appropriateness of this finding. Such uncertainty and potential inconsistency between providers affords a large opportunity for developing a standardized treatment pathway for the treatment of UTIs to ensure both effective and guideline concordant treatment for patients, specifically with regards to antimicrobial selection and duration of treatment.

It is noteworthy to mention that all follow-ups on positive cultures inadequately covered by empiric therapy took place on the day organism identification and susceptibility data were released. This finding was somewhat surprising, as it was originally theorized that most ED-collected urine cultures were not monitored to completion by a pharmacist and that would be necessary in order to ensure proper follow-up of culture results. What is not clear is whether there is a robust process for the follow-up of urine cultures in the ED. Most of the bug-drug mismatches coincidentally were admitted to the inpatient teams where there were appropriate personnel to follow up and adjust the antibiotic selection. If there was a bug-drug mismatch, and the patient was not admitted, it is unclear whether there is a consistent process for follow-up.

Given the limited number of mismatched cultures that required change in therapy, it is unknown if this role would expand if more narrow-spectrum agents were utilized, theoretically leading to a higher mismatch rate and necessitating closer follow-up. Furthermore, given the common practice of mailed prescriptions at the VA, it is all the more imperative that the cultures be acted upon on the day they were identified, as the mailing and processing time of prescriptions may limit the clinical utility in switching from a more broad-spectrum agent, to one more targeted for an identified organism. While a patient traveling back to the medical center for expedited prescription pickup at the pharmacy would alleviate this problem, many patients at the facility travel great distances or may not have readily available travel means to return to the medical center.

Future Directions

While minimal follow-up was required after a patient had left the ED, this study demonstrated a fundamental need for further refinements in antimicrobial stewardship activities within the ED. Duration of therapy, empiric selection, and proper dosing are key areas where the ED-based pharmacy resident was able to intervene during the time physically stationed in the ED. The data collected from this study demonstrated this and was ultimately combined with other ED-based interventions and utilized as supporting evidence in the pharmacy service business plan, outlining the necessity of a full-time pharmacy presence in the ED. The business plan submission, along with other ongoing RRVAMC initiatives, ultimately led to the approval for clinical pharmacy specialists to expand practice into the ED. These positions will continue to advance pharmacy practice within the ED, while affording opportunities for pharmacists to practice at the top of their licensure, provide individualized provider education, and deliver real-time antimicrobial stewardship interventions. Furthermore, as the majority of the study period was monitored outside of the ED, the project may provide a model for other VA institutions without full-time ED pharmacists to implement as a means to improve antimicrobial stewardship and further build an evidence base for expanding their pharmacy services to the ED.

Given the large number of fluoroquinolones utilized in the ED, this study has raised the question of what prescribing patterns look like with regards to outpatient UTI treatment within the realm of primary care at RRVAMC. Despite the great strides made with regards to antimicrobial stewardship at this facility on the inpatient side, no formal antimicrobial stewardship program exists for review in the outpatient setting, where literature suggests the majority of antibiotics are prescribed.^3,11 While more robust protocols are in place for follow-up of culture data in the primary care realm at this facility, the prescribing patterns are relatively unknown.

A recent study completed at a similar VA facility found that 60% of antibiotics prescribed for cystitis, pharyngitis, or sinusitis on an outpatient basis were guideline-discordant, and CDC guidance has further recommended specific focus should be undertaken with regards to outpatient stewardship practices in the treatment of genitourinary infections.^3,12 These findings highlight the need for outpatient antimicrobial stewardship and presents a compelling reason to further investigate outpatient prescribing within primary care at RRVAMC.

Strengths and Limitations

Strengths of the current study include the ability to monitor urine cultures in real time and to provide timely interventions in the event of a rare bug-drug mismatch. The evaluation of cultures in this study shows that the majority of cases had a drug selected with adequate coverage. The study did assure ED providers that, even though guidelines may suggest otherwise, urine cultures drawn in the ED at RRVAMC followed similar resistance patterns seen for the facility as a whole. Moreover, it is valuable as it captures data that are directly applicable to the VA patient population, in which there is little published data with regards to UTI treatment and no formal VA guidance.

A primary limitation of this study is the lack of differentiation between cultures collected from patients with or without indwelling catheters. However, only including patients who presented with signs and/or symptoms of a UTI limits the number of cultures that could potentially be deemed as colonization, thus minimizing the potential for nonpathogenic organisms to confound the results. This study also did not differentiate the setting from which the patient presented (eg, community, extended care facility, etc) that could have potentially provided guidance on resistance patterns for community-acquired UTIs and whether this may have differed from hospital-acquired or facility-acquired UTIs. Another limitation was the relatively short time frame for data collection. A data collection period greater than 91 days would allow for a larger sample size, thus making the data more robust and potentially allowing for the identification of other trends not seen in the current study. A longer data collection period also would have afforded the opportunity to track more robust clinical outcomes throughout the study, identifying whether treatment failure may have been linked to the use of certain classes or spectrums of activity of antibiotics.

Conclusion

Despite the E coli resistance rate to ciprofloxacin (> 20%), the empiric treatments chosen were > 85% effective, needing minimal follow-up once a patient left the ED. Nonetheless, a change in prescribing patterns based on recent national recommendations may provide expanded opportunities in antimicrobial stewardship for ED-based pharmacists. Further research is needed in antimicrobial stewardship within this facility’s outpatient primary care realm, potentially uncovering other opportunities for pharmacist intervention to assure guideline concordant care for the treatment of UTIs as well as other infections treated in primary care patients.

On September 18, 2014, President Barack Obama signed an executive order that made addressing antibiotic-resistant bacteria a national security policy.¹ This legislation resulted in the creation of a large multidepartment task force to combat the global and domestic problem of antimicrobial resistance. The order required hospitals and other inpatient health care delivery facilities, including the Department of Veterans Affairs (VA), to implement robust antimicrobial stewardship programs that adhere to best practices, such as those identified by the Centers for Disease Control and Prevention (CDC). More specifically, the VA was mandated to take steps to encourage other areas of health care, such as ambulatory surgery centers and outpatient clinics, to adopt antimicrobial stewardship programs.¹ This order also reinforced the importance for VA facilities to continue to develop, improve, and sustain efforts in antimicrobial stewardship.

Prior to the order, in 2012 the Richard L. Roudebush VA Medical Center (RRVAMC) in Indianapolis, Indiana, implemented an inpatient antimicrobial stewardship program that included thrice-weekly meetings to review inpatient records and make stewardship recommendations with an infectious diseases physician champion and clinical pharmacists. These efforts led to the improved use of antimicrobial agents on the inpatient side of the medical center. During the first 4 years of implementation, the program helped to decrease the defined daily doses of broad-spectrum antibiotics per 1,000 patient days nearly 36%, from 532 in 2012 to 343 in 2015, as well as decrease the days of therapy of fluoroquinolones per 1,000 patient days 28.75%, from 80 in 2012 to 57 in 2015. Additionally, the program showed a significant decrease in the standardized antimicrobial administration ratio, a benchmark measure developed by the CDC to reflect a facility’s actual antimicrobial use to the expected use of a similar facility based on bed size, number of intensive care unit beds, location type, and medical school affiliation.²

While the RRVAMC antimicrobial stewardship team has been able to intervene on most of the inpatients admitted to the medical center, the outpatient arena has had few antimicrobial stewardship interventions. Recognizing a need to establish and expand pharmacy services and for improvement of outpatient antimicrobial stewardship, RRVAMC leadership decided to establish a pharmacist-led outpatient antimicrobial surveillance program, starting specifically within the emergency department (ED).

Clinical pharmacists in the ED setting are uniquely positioned to improve patient care and encourage the judicious use of antimicrobials for empiric treatment of urinary tract infections (UTIs). The CDC’s Core Elements of Outpatient Antibiotic Stewardship recommends pharmacist availability in the ED setting, and previous literature has demonstrated pharmacist utility in ED postdischarge culture monitoring and surveillance.^3-5

This article will highlight one such program review at the RRVAMC and demonstrate the need for pharmacist-led antimicrobial stewardship and monitoring in the ED. The purpose of this study was to test the hypothesis that pharmacist intervention would be necessary to prospectively check for “bug-drug mismatch” and assure proper follow-up of urine cultures at this institution. The project was deemed to be quality improvement and thereby granted exemption by the RRVAMC Institutional Review Board.

Methods

This project took place at the RRVAMC, a 229-bed tertiary academic medical center that serves > 60,000 patients annually. The RRVAMC ED has 20 beds and received about 29,000 visits in 2014. Patients were eligible for initial evaluation if they had a urine culture collected in the ED within the 91-day period from September 1, 2015 to November 30, 2015. Patients were included for data analysis if it was documented that they were treated for actual or clinically suspected, based on signs and symptoms, uncomplicated UTI, complicated UTI, or UTI with pyelonephritis. Patients did not need to have a positive urine culture for inclusion, as infections could still be present despite negative culture results.⁶ Patients with positive cultures who were not clinically symptomatic of a UTI and were not treated as such by the ED provider (ie, asymptomatic bacteriuria) were excluded from the study.

Data collection took place via daily chart review of patient records in both the Computerized Patient Record System and Decentralized Hospital Computer Program medical applications as urine cultures were performed. Data were gathered and assessed by a postgraduate year-2 internal medicine pharmacy resident on rotation in the ED who reviewed cultures daily and made interventions based on the results as needed. The pharmacy resident was physically present within the ED during the first 30 days of the project. The pharmacy resident was not within the direct practice area during the final 61 days of the project but was in a different area of the hospital and available for consultation.

Primary data collected included urine culture results and susceptibilities, empiric antimicrobial choices, and admission status. Other data collected included duration of treatment and secondary antibiotics chosen, each of which specifically evaluated those patients who were not admitted to the hospital and were thus treated as outpatients. Additional data generated from this study were used to identify empiric antibiotics utilized for the treatment of UTIs and assess for appropriate selection and duration of therapy within this institution.

Results

During the study period, 722 urine cultures were collected in the ED and were included for initial evaluation. Of these, 127 were treated by the ED provider pursuant to one of the indications specified and were included in the data analysis. Treatment with an antimicrobial agent provided adequate coverage for the identified pathogen in 112 patients, yielding a match rate of 88%. As all included cultures were collected in suspicion of an infection, those cultures yielding no growth were considered to have been adequately covered. 

Nearly half (45%) of treatment plans included a fluoroquinolone. Of those treated on an outpatient basis, fluoroquinolones were even more frequently used, comprising 50 of 82 (61%) courses. Ciprofloxacin was the most frequently used treatment, used in 39 of the 82 outpatient regimens (48%). Cephalexin was the second most common and was used in 14 outpatient regimens (17%), followed by levofloxacin (15%) (Figure 1). 

Mismatched cultures, or those where the prescribed antibiotic did not provide adequate coverage of the identified pathogens based on susceptibilities, occurred at a rate of 12%. Follow-up on these cultures was determined largely by the patient’s admission status. The majority of mismatched cultures were addressed by the inpatient team (10/15) upon admission. 

Discussion

Empiric antibiotic selection for the treatment of UTIs continues to be the cornerstone of antibiotic management for the treatment of such a disease state.⁷ The noted drug-bug match rate of 88% in this study demonstrates effective initial empiric coverage and ensures a vast majority of veterans receive adequate coverage for identified pathogens. Additionally, this rate shows that the current system seems to be functioning appropriately and refutes the author’s preconceived ideas that the mismatch rate was higher at RRVAMC. However, these findings also demonstrate a predominant use of fluoroquinolones for empiric treatment in a majority of patients who could be better served with narrower spectrum agents. Only 2 of the outpatient regimens were for the treatment of pyelonephritis, the only indication in which a fluoroquinolone would be the standard of care per guideline recommendations.⁷

These findings were consistent with a similar study in which 83% of ED collected urine cultures ultimately grew bacteria susceptibleto empiric treatment.⁸ This number was similar to the current study despite the latter study consisting of predominantly female patients (93%) and excluding patients with a history of benign prostatic hypertrophy, catheter use, or history of genitourinary cancer, which are frequently found within the VA population. Thus, despite having a differing patient population at the current study’s facility with characteristics that would classify most to be treated as a complicated UTI, empiric coverage rates remained similar. The lower than anticipated intervention rate by the pharmacist on rotation in the ED can be directly attributed to this high empiric match rate, which could in turn be attributed to the extensive use of broad-spectrum antibiotics for treatment.

Empiric antimicrobial selection is based largely on local resistance patterns.⁷ Of particular importance is the resistance patterns of E coli, as it is the primary isolate responsible for UTIs worldwide. Thus, it is not unexpected that the most frequently isolated pathogen in the current study also was E coli. While clinical practice guidelines state that hospital-wide antibiograms often are skewed by cultures collected from inpatients or those with complicated infection, the current study found hospital-wide E coli resistance patterns, specifically those related to fluoroquinolone use, to be similar to those collected in the ED alone (78.5% hospital-wide susceptibility vs. 75% ED susceptibility). This was expected, as similar studies comparing E coli resistance patterns from ED-collected urine cultures to those institution-wide also have found similar rates of resistance.^8,9 These findings are of particular importance as E coli resistance is noted to be increasing, varies with geographic area, and local resistance patterns are rarely known.⁷ Thus, these findings may aid ED providers in their empiric antimicrobial selections.

Ciprofloxacin was the most frequently used medication for the treatment of UTIs. While overall empiric selections were found to have favorable resistance patterns, it is difficult to interpret the appropriateness of ciprofloxacin’s use in the present study. First, there is a distinct lack of US-based clinical practice guidelines for the treatment of complicated UTIs. As the majority of this study population was male, it is difficult to directly extrapolate from the current Infectious Diseases Society of America treatment guidelines for uncomplicated cystitis and apply to the study population. Although recommended for the treatment of pyelonephritis, it is unclear whether ciprofloxacin should be utilized as a first-line empiric option for the treatment of UTIs in males.

Despite the lack of disease-specific recommendations for ciprofloxacin, recommendations exist regarding its use when local resistance patterns are known.⁷ It is currently recommended that these agents not be used when resistance rates of E coli exceed 20% for trimethoprim-sulfamethoxazole or 10% for fluoroquinolones. As this study demonstrated a nearly 25% resistance rate for E coli to fluoroquinolones in both the ED and institution-wide sample populations, it could potentially be ascertained that ciprofloxacin is an inappropriate choice for the empiric treatment of UTIs in this patient population. However, as noted, it is unknown whether this recommendation would still be applicable when applied to the treatment of complicated cystitis and greater male population, as overall rates of susceptible cultures to all organisms was similar to other published studies.^8,9

While there is scant specific guidance related to the treatment of complicated UTIs, there is emerging guidance on the use of fluoroquinolones, both in general and specifically related to the treatment of UTIs. In July 2016, the FDA issued a drug safety communication regarding the use of and warnings for fluoroquinolones, which explicitly stated that “health care professionals should not prescribe systemic fluoroquinolones to patients who have other treatment options for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated UTIs because the risks outweigh the benefits in these patients.”¹⁰

This guidance has the potential to impact fluoroquinolone prescribing significantly at RRVAMC. Given the large number of fluoroquinolones prescribed for UTIs, the downstream effects that this shift in prescribing would have is unknown. As most nonfluoroquinolones used for UTI typically are narrower in antimicrobial spectrum (eg, trimethoprim/sulfamethoxazole, nitrofurantoin, cephalexin, etc) the possibility exists that the match rate for empiric therapy may decrease. Thus, a larger need for closer follow-up to assure adequate coverage may arise, posing a more expanded role for an ED-based pharmacist than was demonstrated in the current study.

This new guidance also may place providers in an area of larger uncertainty with regards to treating both complicated and uncomplicated cystitis. Given the enhanced warnings on fluoroquinolone use, it is unknown whether prescribers would gravitate to utilizing similar options as their peers as alternatives to fluoroquinolones. Similarly, duration of therapy with nonfluoroquinolone agents is unclear as well; as the present study demonstrated a large range in treatment duration of outpatients (3-14 days). While the average observed duration of 8.3 days is intuitively fitting, as the majority of cases were in males, no published guideline exists that affirms the appropriateness of this finding. Such uncertainty and potential inconsistency between providers affords a large opportunity for developing a standardized treatment pathway for the treatment of UTIs to ensure both effective and guideline concordant treatment for patients, specifically with regards to antimicrobial selection and duration of treatment.

It is noteworthy to mention that all follow-ups on positive cultures inadequately covered by empiric therapy took place on the day organism identification and susceptibility data were released. This finding was somewhat surprising, as it was originally theorized that most ED-collected urine cultures were not monitored to completion by a pharmacist and that would be necessary in order to ensure proper follow-up of culture results. What is not clear is whether there is a robust process for the follow-up of urine cultures in the ED. Most of the bug-drug mismatches coincidentally were admitted to the inpatient teams where there were appropriate personnel to follow up and adjust the antibiotic selection. If there was a bug-drug mismatch, and the patient was not admitted, it is unclear whether there is a consistent process for follow-up.

Given the limited number of mismatched cultures that required change in therapy, it is unknown if this role would expand if more narrow-spectrum agents were utilized, theoretically leading to a higher mismatch rate and necessitating closer follow-up. Furthermore, given the common practice of mailed prescriptions at the VA, it is all the more imperative that the cultures be acted upon on the day they were identified, as the mailing and processing time of prescriptions may limit the clinical utility in switching from a more broad-spectrum agent, to one more targeted for an identified organism. While a patient traveling back to the medical center for expedited prescription pickup at the pharmacy would alleviate this problem, many patients at the facility travel great distances or may not have readily available travel means to return to the medical center.

Future Directions

While minimal follow-up was required after a patient had left the ED, this study demonstrated a fundamental need for further refinements in antimicrobial stewardship activities within the ED. Duration of therapy, empiric selection, and proper dosing are key areas where the ED-based pharmacy resident was able to intervene during the time physically stationed in the ED. The data collected from this study demonstrated this and was ultimately combined with other ED-based interventions and utilized as supporting evidence in the pharmacy service business plan, outlining the necessity of a full-time pharmacy presence in the ED. The business plan submission, along with other ongoing RRVAMC initiatives, ultimately led to the approval for clinical pharmacy specialists to expand practice into the ED. These positions will continue to advance pharmacy practice within the ED, while affording opportunities for pharmacists to practice at the top of their licensure, provide individualized provider education, and deliver real-time antimicrobial stewardship interventions. Furthermore, as the majority of the study period was monitored outside of the ED, the project may provide a model for other VA institutions without full-time ED pharmacists to implement as a means to improve antimicrobial stewardship and further build an evidence base for expanding their pharmacy services to the ED.

Given the large number of fluoroquinolones utilized in the ED, this study has raised the question of what prescribing patterns look like with regards to outpatient UTI treatment within the realm of primary care at RRVAMC. Despite the great strides made with regards to antimicrobial stewardship at this facility on the inpatient side, no formal antimicrobial stewardship program exists for review in the outpatient setting, where literature suggests the majority of antibiotics are prescribed.^3,11 While more robust protocols are in place for follow-up of culture data in the primary care realm at this facility, the prescribing patterns are relatively unknown.

A recent study completed at a similar VA facility found that 60% of antibiotics prescribed for cystitis, pharyngitis, or sinusitis on an outpatient basis were guideline-discordant, and CDC guidance has further recommended specific focus should be undertaken with regards to outpatient stewardship practices in the treatment of genitourinary infections.^3,12 These findings highlight the need for outpatient antimicrobial stewardship and presents a compelling reason to further investigate outpatient prescribing within primary care at RRVAMC.

Strengths and Limitations

Strengths of the current study include the ability to monitor urine cultures in real time and to provide timely interventions in the event of a rare bug-drug mismatch. The evaluation of cultures in this study shows that the majority of cases had a drug selected with adequate coverage. The study did assure ED providers that, even though guidelines may suggest otherwise, urine cultures drawn in the ED at RRVAMC followed similar resistance patterns seen for the facility as a whole. Moreover, it is valuable as it captures data that are directly applicable to the VA patient population, in which there is little published data with regards to UTI treatment and no formal VA guidance.

A primary limitation of this study is the lack of differentiation between cultures collected from patients with or without indwelling catheters. However, only including patients who presented with signs and/or symptoms of a UTI limits the number of cultures that could potentially be deemed as colonization, thus minimizing the potential for nonpathogenic organisms to confound the results. This study also did not differentiate the setting from which the patient presented (eg, community, extended care facility, etc) that could have potentially provided guidance on resistance patterns for community-acquired UTIs and whether this may have differed from hospital-acquired or facility-acquired UTIs. Another limitation was the relatively short time frame for data collection. A data collection period greater than 91 days would allow for a larger sample size, thus making the data more robust and potentially allowing for the identification of other trends not seen in the current study. A longer data collection period also would have afforded the opportunity to track more robust clinical outcomes throughout the study, identifying whether treatment failure may have been linked to the use of certain classes or spectrums of activity of antibiotics.

Conclusion

Despite the E coli resistance rate to ciprofloxacin (> 20%), the empiric treatments chosen were > 85% effective, needing minimal follow-up once a patient left the ED. Nonetheless, a change in prescribing patterns based on recent national recommendations may provide expanded opportunities in antimicrobial stewardship for ED-based pharmacists. Further research is needed in antimicrobial stewardship within this facility’s outpatient primary care realm, potentially uncovering other opportunities for pharmacist intervention to assure guideline concordant care for the treatment of UTIs as well as other infections treated in primary care patients.

Young women may not want to hear it, but fat could be their friend. Researchers from the Premenopausal Breast Cancer Collaborative Group have found that women aged 18 – 24 years with high body fat have a lower risk of developing breast cancer before menopause.

The researchers pooled data from 19 different studies, involving about 800,000 women from around the world. Overall, 1.7% of the women developed breast cancer. The researchers found that the relative risk of premenopausal breast cancer dropped 12% to 23% for each 5-unit increase in body mass index, depending on age. They saw the strongest effect at ages 18 – 24 years: Very obese women in this age group were 4.2 times less likely to develop premenopausal breast cancer than women with low body mass index (BMI) at the same age.

The researchers do not know why high BMI might protect against breast cancer in some women. Breast cancer is relatively rare before menopause, although previous studies have suggested that the risk factors might be different for younger vs older women, says Dale Sandler, PhD, co-author of the group and head of the Epidemiology Branch at the National Institute of Environmental Health Sciences. For instance, it is well known that women who gain weight, particularly after menopause, have a higher risk. The fact that this study found that the risk not only is not increased, but actually decreased, in younger women points to the possibility that different biologic mechanisms are at work, Sandler says.

Nonetheless, the researchers caution that young women should not intentionally gain weight to offset the risk.

Source:
National Institutes of Health. https://www.nih.gov/news-events/news-releases/nih-study-associates-obesity-lower-breast-cancer-risk-young-women. Published June 27, 2018. Accessed July 18, 2018.

Young women may not want to hear it, but fat could be their friend. Researchers from the Premenopausal Breast Cancer Collaborative Group have found that women aged 18 – 24 years with high body fat have a lower risk of developing breast cancer before menopause.

The researchers pooled data from 19 different studies, involving about 800,000 women from around the world. Overall, 1.7% of the women developed breast cancer. The researchers found that the relative risk of premenopausal breast cancer dropped 12% to 23% for each 5-unit increase in body mass index, depending on age. They saw the strongest effect at ages 18 – 24 years: Very obese women in this age group were 4.2 times less likely to develop premenopausal breast cancer than women with low body mass index (BMI) at the same age.

The researchers do not know why high BMI might protect against breast cancer in some women. Breast cancer is relatively rare before menopause, although previous studies have suggested that the risk factors might be different for younger vs older women, says Dale Sandler, PhD, co-author of the group and head of the Epidemiology Branch at the National Institute of Environmental Health Sciences. For instance, it is well known that women who gain weight, particularly after menopause, have a higher risk. The fact that this study found that the risk not only is not increased, but actually decreased, in younger women points to the possibility that different biologic mechanisms are at work, Sandler says.

Nonetheless, the researchers caution that young women should not intentionally gain weight to offset the risk.

Source:
National Institutes of Health. https://www.nih.gov/news-events/news-releases/nih-study-associates-obesity-lower-breast-cancer-risk-young-women. Published June 27, 2018. Accessed July 18, 2018.

Young women may not want to hear it, but fat could be their friend. Researchers from the Premenopausal Breast Cancer Collaborative Group have found that women aged 18 – 24 years with high body fat have a lower risk of developing breast cancer before menopause.

The researchers pooled data from 19 different studies, involving about 800,000 women from around the world. Overall, 1.7% of the women developed breast cancer. The researchers found that the relative risk of premenopausal breast cancer dropped 12% to 23% for each 5-unit increase in body mass index, depending on age. They saw the strongest effect at ages 18 – 24 years: Very obese women in this age group were 4.2 times less likely to develop premenopausal breast cancer than women with low body mass index (BMI) at the same age.

The researchers do not know why high BMI might protect against breast cancer in some women. Breast cancer is relatively rare before menopause, although previous studies have suggested that the risk factors might be different for younger vs older women, says Dale Sandler, PhD, co-author of the group and head of the Epidemiology Branch at the National Institute of Environmental Health Sciences. For instance, it is well known that women who gain weight, particularly after menopause, have a higher risk. The fact that this study found that the risk not only is not increased, but actually decreased, in younger women points to the possibility that different biologic mechanisms are at work, Sandler says.

Nonetheless, the researchers caution that young women should not intentionally gain weight to offset the risk.

Source:
National Institutes of Health. https://www.nih.gov/news-events/news-releases/nih-study-associates-obesity-lower-breast-cancer-risk-young-women. Published June 27, 2018. Accessed July 18, 2018.

Image by Betty Pace

Results of a phase 3 trial showed that L-glutamine can reduce complications of sickle cell disease (SCD).

SCD patients who received pharmaceutical-grade L-glutamine (with or without hydroxyurea) had a reduction in sickle cell crises, hospitalizations, and acute chest syndrome (ACS) when compared to patients who received placebo (with or without hydroxyurea).

Gastrointestinal events and pain in the chest (noncardiac), back, and extremities were more frequent in L-glutamine recipients than controls.

Yutaka Niihara, MD, of Emmaus Medical, Inc., in Torrance, California, and his colleagues reported these results in NEJM. The research was sponsored by Emmaus Medical.

Dr Niihara noted that L-glutamine (Endari), which was approved by the US Food and Drug Administration last summer, is the first treatment approved to treat SCD in pediatric patients age 5 and older and the first SCD treatment approved for adults in nearly 20 years.

“Our hope in sharing the results [of the phase 3 trial] is to aid in increasing the awareness of sickle cell disease, a life-long hereditary blood disorder which commonly affects those of African descent, as well as those from Central and South America and people of Middle Eastern, Asian, Indian, and Mediterranean descent,” Dr Niihara said.

He and his colleagues enrolled 230 patients on the trial. One hundred and fifty-two were randomized to receive L-glutamine at 0.3 g/kg twice daily (maximum 30 g/day), and 78 were randomized to placebo (maltodextrin) at 0.3 g/kg twice daily for 48 weeks.

Baseline characteristics were similar between the treatment arms. Most patients had sickle cell anemia—89.5% (n=136) in the L-glutamine arm and 91% (n=71) in the placebo arm. Several patients had sickle B⁰ thalassemia—9.2% (n=14) and 9.0% (n=7), respectively. Two patients in the L-glutamine arm had B⁺ thalassemia, but 1 of these patients did not receive L-glutamine.

The median age was 19 (range, 5-57) in the L-glutamine arm and 17 (range, 5-58) in the placebo arm. There were more females than males in both arms—52% (n=79) and 57.7% (n=45), respectively.

Most patients received concomitant hydroxyurea—66.4% (n=101) in the L-glutamine arm and 66.7% (n=52) in the placebo arm.

Efficacy

Patients in the L-glutamine arm had 25% fewer pain crises than patients in the placebo arm. The median number of crises was 3 and 4, respectively (P=0.005).

The median time to a first crisis was 84 days in the L-glutamine arm and 54 days in the placebo arm (P=0.02). The median time to a second crisis was 212 days and 133 days, respectively (P=0.03).

The median number of hospitalizations was 2 in the L-glutamine arm and 3 in the placebo arm, which is a difference of 33% (P=0.005). The median cumulative number of days in the hospital was 6.5 and 11, respectively (P=0.02).

The incidence of ACS was significantly lower in the L-glutamine arm, with 8.6% of patients in that group having at least 1 episode of ACS and 23.1% of the placebo group having at least 1 episode (P=0.003).

Safety

The rate of adverse events (AEs) was 98% in the L-glutamine arm and 100% in the placebo arm. The rate of serious AEs was 78.2% and 87.1%, respectively.

AEs with a higher incidence in the L-glutamine arm (at least 5%) are listed in the table below.

Image by Betty Pace

Results of a phase 3 trial showed that L-glutamine can reduce complications of sickle cell disease (SCD).

SCD patients who received pharmaceutical-grade L-glutamine (with or without hydroxyurea) had a reduction in sickle cell crises, hospitalizations, and acute chest syndrome (ACS) when compared to patients who received placebo (with or without hydroxyurea).

Gastrointestinal events and pain in the chest (noncardiac), back, and extremities were more frequent in L-glutamine recipients than controls.

Yutaka Niihara, MD, of Emmaus Medical, Inc., in Torrance, California, and his colleagues reported these results in NEJM. The research was sponsored by Emmaus Medical.

Dr Niihara noted that L-glutamine (Endari), which was approved by the US Food and Drug Administration last summer, is the first treatment approved to treat SCD in pediatric patients age 5 and older and the first SCD treatment approved for adults in nearly 20 years.

“Our hope in sharing the results [of the phase 3 trial] is to aid in increasing the awareness of sickle cell disease, a life-long hereditary blood disorder which commonly affects those of African descent, as well as those from Central and South America and people of Middle Eastern, Asian, Indian, and Mediterranean descent,” Dr Niihara said.

He and his colleagues enrolled 230 patients on the trial. One hundred and fifty-two were randomized to receive L-glutamine at 0.3 g/kg twice daily (maximum 30 g/day), and 78 were randomized to placebo (maltodextrin) at 0.3 g/kg twice daily for 48 weeks.

Baseline characteristics were similar between the treatment arms. Most patients had sickle cell anemia—89.5% (n=136) in the L-glutamine arm and 91% (n=71) in the placebo arm. Several patients had sickle B⁰ thalassemia—9.2% (n=14) and 9.0% (n=7), respectively. Two patients in the L-glutamine arm had B⁺ thalassemia, but 1 of these patients did not receive L-glutamine.

The median age was 19 (range, 5-57) in the L-glutamine arm and 17 (range, 5-58) in the placebo arm. There were more females than males in both arms—52% (n=79) and 57.7% (n=45), respectively.

Most patients received concomitant hydroxyurea—66.4% (n=101) in the L-glutamine arm and 66.7% (n=52) in the placebo arm.

Efficacy

Patients in the L-glutamine arm had 25% fewer pain crises than patients in the placebo arm. The median number of crises was 3 and 4, respectively (P=0.005).

The median time to a first crisis was 84 days in the L-glutamine arm and 54 days in the placebo arm (P=0.02). The median time to a second crisis was 212 days and 133 days, respectively (P=0.03).

The median number of hospitalizations was 2 in the L-glutamine arm and 3 in the placebo arm, which is a difference of 33% (P=0.005). The median cumulative number of days in the hospital was 6.5 and 11, respectively (P=0.02).

The incidence of ACS was significantly lower in the L-glutamine arm, with 8.6% of patients in that group having at least 1 episode of ACS and 23.1% of the placebo group having at least 1 episode (P=0.003).

Safety

The rate of adverse events (AEs) was 98% in the L-glutamine arm and 100% in the placebo arm. The rate of serious AEs was 78.2% and 87.1%, respectively.

AEs with a higher incidence in the L-glutamine arm (at least 5%) are listed in the table below.

Image by Betty Pace

Results of a phase 3 trial showed that L-glutamine can reduce complications of sickle cell disease (SCD).

SCD patients who received pharmaceutical-grade L-glutamine (with or without hydroxyurea) had a reduction in sickle cell crises, hospitalizations, and acute chest syndrome (ACS) when compared to patients who received placebo (with or without hydroxyurea).

Gastrointestinal events and pain in the chest (noncardiac), back, and extremities were more frequent in L-glutamine recipients than controls.

Yutaka Niihara, MD, of Emmaus Medical, Inc., in Torrance, California, and his colleagues reported these results in NEJM. The research was sponsored by Emmaus Medical.

Dr Niihara noted that L-glutamine (Endari), which was approved by the US Food and Drug Administration last summer, is the first treatment approved to treat SCD in pediatric patients age 5 and older and the first SCD treatment approved for adults in nearly 20 years.

“Our hope in sharing the results [of the phase 3 trial] is to aid in increasing the awareness of sickle cell disease, a life-long hereditary blood disorder which commonly affects those of African descent, as well as those from Central and South America and people of Middle Eastern, Asian, Indian, and Mediterranean descent,” Dr Niihara said.

He and his colleagues enrolled 230 patients on the trial. One hundred and fifty-two were randomized to receive L-glutamine at 0.3 g/kg twice daily (maximum 30 g/day), and 78 were randomized to placebo (maltodextrin) at 0.3 g/kg twice daily for 48 weeks.

Baseline characteristics were similar between the treatment arms. Most patients had sickle cell anemia—89.5% (n=136) in the L-glutamine arm and 91% (n=71) in the placebo arm. Several patients had sickle B⁰ thalassemia—9.2% (n=14) and 9.0% (n=7), respectively. Two patients in the L-glutamine arm had B⁺ thalassemia, but 1 of these patients did not receive L-glutamine.

The median age was 19 (range, 5-57) in the L-glutamine arm and 17 (range, 5-58) in the placebo arm. There were more females than males in both arms—52% (n=79) and 57.7% (n=45), respectively.

Most patients received concomitant hydroxyurea—66.4% (n=101) in the L-glutamine arm and 66.7% (n=52) in the placebo arm.

Efficacy

Patients in the L-glutamine arm had 25% fewer pain crises than patients in the placebo arm. The median number of crises was 3 and 4, respectively (P=0.005).

The median time to a first crisis was 84 days in the L-glutamine arm and 54 days in the placebo arm (P=0.02). The median time to a second crisis was 212 days and 133 days, respectively (P=0.03).

The median number of hospitalizations was 2 in the L-glutamine arm and 3 in the placebo arm, which is a difference of 33% (P=0.005). The median cumulative number of days in the hospital was 6.5 and 11, respectively (P=0.02).

The incidence of ACS was significantly lower in the L-glutamine arm, with 8.6% of patients in that group having at least 1 episode of ACS and 23.1% of the placebo group having at least 1 episode (P=0.003).

Safety

The rate of adverse events (AEs) was 98% in the L-glutamine arm and 100% in the placebo arm. The rate of serious AEs was 78.2% and 87.1%, respectively.

AEs with a higher incidence in the L-glutamine arm (at least 5%) are listed in the table below.

Micrograph showing ALL

Researchers believe they have solved the mystery of how acute lymphoblastic leukemia (ALL) infiltrates the central nervous system (CNS).

Experiments in mice suggested that ALL enters the CNS not by breaching the blood-brain barrier but by evading it.

The researchers said they found that expression of the laminin receptor α6 integrin, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS.

“It’s a very unexpected way for cells to travel into the central nervous system,” said Dorothy Sipkins, MD, PhD, of Duke University in Durham, North Carolina.

She and her colleagues described the cells’ journey in Nature.

The researchers said they found that α6 integrin–laminin interactions mediate the migration of ALL cells toward the cerebrospinal fluid.

The team noted that α6 integrin is expressed in most cases of ALL, and laminin surrounds blood vessels that pass directly through the vertebrae to the meninges tissue that lines the spinal cord and brain.

Experiments indicated that ALL cells latch onto the laminin surrounding these blood vessels and travel down into the meninges region where cerebral spinal fluid circulates.

“Understanding how ALL gets into the central nervous system arms us with new ways to target this pathway and hopefully shut it down,” Dr Sipkins noted.

She and her colleagues found that treatment with a PI3Kδ inhibitor may be one way to do that.

The team tested the PI3Kδ inhibitor GS-649443 in a mouse model of CNS ALL (Nalm-6) and found the drug decreased α6 integrin expression on ALL cells.

Mice treated with the inhibitor had a 50% decrease in CNS disease burden compared to vehicle-treated controls. However, there was no significant difference between treated mice and controls when it came to bone marrow or splenic Nalm-6 disease burden or peripheral blood cell counts.

The researchers observed similar results in another model of CNS disease (RCH-ACV ALL).

The team also tested α6 integrin-neutralizing antibodies in Nalm-6-engrafted mice. There was no difference in peripheral disease burden between targeted and isotype control antibody-treated mice. However, anti-α6 integrin-treated mice had a reduction in cerebrospinal fluid blast counts.

This research was supported by the Duke Cancer Institute and Gilead Sciences, Inc., which provided the PI3Kδ inhibitor.

Micrograph showing ALL

Researchers believe they have solved the mystery of how acute lymphoblastic leukemia (ALL) infiltrates the central nervous system (CNS).

Experiments in mice suggested that ALL enters the CNS not by breaching the blood-brain barrier but by evading it.

The researchers said they found that expression of the laminin receptor α6 integrin, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS.

“It’s a very unexpected way for cells to travel into the central nervous system,” said Dorothy Sipkins, MD, PhD, of Duke University in Durham, North Carolina.

She and her colleagues described the cells’ journey in Nature.

The researchers said they found that α6 integrin–laminin interactions mediate the migration of ALL cells toward the cerebrospinal fluid.

The team noted that α6 integrin is expressed in most cases of ALL, and laminin surrounds blood vessels that pass directly through the vertebrae to the meninges tissue that lines the spinal cord and brain.

Experiments indicated that ALL cells latch onto the laminin surrounding these blood vessels and travel down into the meninges region where cerebral spinal fluid circulates.

“Understanding how ALL gets into the central nervous system arms us with new ways to target this pathway and hopefully shut it down,” Dr Sipkins noted.

She and her colleagues found that treatment with a PI3Kδ inhibitor may be one way to do that.

The team tested the PI3Kδ inhibitor GS-649443 in a mouse model of CNS ALL (Nalm-6) and found the drug decreased α6 integrin expression on ALL cells.

Mice treated with the inhibitor had a 50% decrease in CNS disease burden compared to vehicle-treated controls. However, there was no significant difference between treated mice and controls when it came to bone marrow or splenic Nalm-6 disease burden or peripheral blood cell counts.

The researchers observed similar results in another model of CNS disease (RCH-ACV ALL).

The team also tested α6 integrin-neutralizing antibodies in Nalm-6-engrafted mice. There was no difference in peripheral disease burden between targeted and isotype control antibody-treated mice. However, anti-α6 integrin-treated mice had a reduction in cerebrospinal fluid blast counts.

This research was supported by the Duke Cancer Institute and Gilead Sciences, Inc., which provided the PI3Kδ inhibitor.

Micrograph showing ALL

Researchers believe they have solved the mystery of how acute lymphoblastic leukemia (ALL) infiltrates the central nervous system (CNS).

Experiments in mice suggested that ALL enters the CNS not by breaching the blood-brain barrier but by evading it.

The researchers said they found that expression of the laminin receptor α6 integrin, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS.

“It’s a very unexpected way for cells to travel into the central nervous system,” said Dorothy Sipkins, MD, PhD, of Duke University in Durham, North Carolina.

She and her colleagues described the cells’ journey in Nature.

The researchers said they found that α6 integrin–laminin interactions mediate the migration of ALL cells toward the cerebrospinal fluid.

The team noted that α6 integrin is expressed in most cases of ALL, and laminin surrounds blood vessels that pass directly through the vertebrae to the meninges tissue that lines the spinal cord and brain.

Experiments indicated that ALL cells latch onto the laminin surrounding these blood vessels and travel down into the meninges region where cerebral spinal fluid circulates.

“Understanding how ALL gets into the central nervous system arms us with new ways to target this pathway and hopefully shut it down,” Dr Sipkins noted.

She and her colleagues found that treatment with a PI3Kδ inhibitor may be one way to do that.

The team tested the PI3Kδ inhibitor GS-649443 in a mouse model of CNS ALL (Nalm-6) and found the drug decreased α6 integrin expression on ALL cells.

Mice treated with the inhibitor had a 50% decrease in CNS disease burden compared to vehicle-treated controls. However, there was no significant difference between treated mice and controls when it came to bone marrow or splenic Nalm-6 disease burden or peripheral blood cell counts.

The researchers observed similar results in another model of CNS disease (RCH-ACV ALL).

The team also tested α6 integrin-neutralizing antibodies in Nalm-6-engrafted mice. There was no difference in peripheral disease burden between targeted and isotype control antibody-treated mice. However, anti-α6 integrin-treated mice had a reduction in cerebrospinal fluid blast counts.

This research was supported by the Duke Cancer Institute and Gilead Sciences, Inc., which provided the PI3Kδ inhibitor.