NASHVILLE—Multiple sclerosis (MS) traditionally has been considered a chronic inflammatory autoimmune disease, but inflammation decreases as the disease progresses. Many other biologic processes are dysregulated in MS, such as myelin signal transport, mitochondrial function, and iron metabolism. Lipid metabolism affects all of these processes, including inflammation, and thus could be a valuable therapeutic target, according to research presented at the 2018 CMSC Annual Meeting.

“MS is not an inflammatory disease,” said John D. Nieland, PhD, Associate Professor of Health Science and Technology at Aalborg University in Denmark. “The inflammatory response is important, but it is not the only component. If you do not focus on the other components, you will never be able to treat the disease.”

The Role of Lipids in the CNS

Healthy brains have a high amount of glucose metabolism, but glucose metabolism is reduced in MS and other neurologic disorders such as Parkinson’s disease and Alzheimer’s disease. “If glucose metabolism is downregulated, something else has to be taking over,” said Dr. Nieland. He and his colleagues hypothesize that lipid metabolism replaces glucose metabolism in MS. They further hypothesize that MS fundamentally is a dysfunction of lipid metabolism.

Lipids have an essential role in the CNS. Proper signal transduction requires lipids to be bound to the myelin sheath. The proteins that compose myelin sheaths are highly immunogenic, and lipids shield them from exposure to the immune system. The half-life of lipids attached to the myelin sheath is three days, so these lipids must be replaced constantly. In addition, lipids are essential for the function of glutamate, cannabinoid, and insulin receptors.

An increase in lipid metabolism decreases glucose metabolism and induces the production of prostaglandin E2, which is a key molecule in the inflammatory response. In the early stages of MS, inflammation attacks the myelin sheath and other brain proteins. Increased lipid metabolism decreases lipid concentrations in the CNS, including around myelin. When lipids are removed from the myelin sheath, they expose the immunogenic proteins that compose it, thus provoking an immune response. Dysregulated lipid metabolism also contributes to oxidative stress, mitochondrial dysfunction, demyelination, and neuronal loss.

Chemical Inhibition of Lipid Metabolism

Dr. Nieland and colleagues hypothesized that blocking lipid metabolism would reverse the inflammatory response and other harmful processes that occur in MS. Previous research by Shriver and colleagues indicated that inhibition of carnitine palmitoyltransferase 1 (CPT1), a molecule essential to lipid metabolism, in encephalitogenic T cells increases apoptosis and reduces the production of inflammatory cytokines. Two of the molecule’s three isoforms, CPT1A and CPT1C, are upregulated in MS. Stress prompts an increase in CPT1 expression, which spurs a shift to lipid metabolism. “If you block CPT1, you jam lipid metabolism,” Dr. Nieland said. “There is no way around it.” Dr. Nieland’s group thus chose CPT1 as its target.

The investigators first conducted studies using etomoxir, which inhibits CPT1 and blocks long-chain fatty acids from entering the mitochondria for beta oxidation. Through these effects, etomoxir causes cells to shift to glucose metabolism.

The researchers immunized 42 mice with myelin oligodendrocyte glycoprotein (MOG35–55) to induce experimental autoimmune encephalopathy (EAE). When the animals first exhibited symptoms at Day 10, they were randomized to receive subcutaneous etomoxir or placebo daily. Disease score decreased significantly in the treated animals, compared with the control animals. On Day 24, more than 50% of the treated mice exhibited normal behavior, compared with approximately 20% of control mice.

In another study, the investigators immunized 47 rats with myelin basic protein to induce EAE. The animals began having symptoms at Day 7, and the investigators randomized them to daily treatment with subcutaneous etomoxir or placebo. At Day 11, disease score was significantly lower among treated animals, compared with control animals. Body weight was significantly higher among rats that received etomoxir, compared with controls, at that time point. Also, 25% of treated animals exhibited normal behavior, but no controls did.

In a third study, the investigators compared etomoxir, interferon beta, and placebo in a rat model of EAE. Each treatment group included 10 rats, and etomoxir had superior effects on disease score and body weight, compared with interferon beta and placebo. When the investigators examined the rats’ serum, they found that levels of antibodies against brain antigens common in EAE were lower in rats treated with etomoxir, compared with those treated with interferon beta or placebo.

Biologic Inhibition of Lipid Metabolism

In addition to pharmacologic treatment, genetic mutations affect CPT1 function. The Hutterites, an ethnoreligious group in Canada, have a mutation in CPT1A that almost completely blocks the molecule’s activity. Similarly, the Inuit have a mutation in CPT1A that reduces its activity to approximately 22%. The prevalence of MS is one in 1,100 among the Hutterites and one in 50,000 among the Inuit, compared with one in 350 in the Canadian population. These observations suggest that gene therapy could be another way to block CPT1.

Dr. Nieland’s group collaborated with the Netherlands Cancer Institute to develop mouse strains with two distinct mutations in CPT1A. The first mutation mimics that found among the Hutterites, and the other mimics that found among the Inuit. In a preliminary study, the investigators induced EAE in three wild-type mice and two mice with the CPT1A mutation similar to that of the Inuit. The mice were 10 weeks old at the time of immunization.

At 24 days, disease score was lower in the CPT1A mutant mice, compared with the wild-type mice. Furthermore, body weight was higher in the mutant mice, compared with the wild-type mice. The investigators also measured the mice’s grip strength at Day 2 and Day 24. Grip strength decreased in the wild-type mice but remained the same in the mutant mice. At Day 24, grip strength was significantly higher among mutant mice than among wild-type mice.

“These results indicate an interaction of the lipid metabolism in the brain and in the immune system, which supports our hypothesis regarding MS pathology,” said Anne Skøttrup Mørkholt, a doctoral student at Aalborg University, who collaborated with Dr. Nieland on these animal studies. “MS is not a disease of the immune system, but a systemic disease with dysregulation of multiple components.”

Lipid Metabolism in Other Neurologic Diseases

Data suggest that lipid metabolism may contribute to other neurologic diseases such as amyotrophic lateral sclerosis (ALS) as well. Huang et al found a correlation between serum triglyceride levels and the development of ALS. Dupuis et al observed upregulated lipid metabolism and downregulated glucose metabolism in SOD1 mouse models of the disease, as did subsequent researchers. In addition, a 2015 study by Palamiuc et al found that CPT1B was significantly increased in the muscle tissue of SOD1 mice.

To investigate whether suppressing lipid metabolism affected ALS, Dr. Nieland’s group examined a SOD1 mouse model of the disease. The mice developed symptoms at Day 70 and were randomized at Day 100 to etomoxir or placebo. Etomoxir was associated with less weight loss and better neurologic score, compared with placebo. Etomoxir also was associated with better performance on the wire hanging and rotarod tests, compared with placebo. “It seems like etomoxir was able to slow down the disease progression,” said Michael Sloth Trabjerg, MD, a doctoral student at Aalborg University.

—Erik Greb

Suggested Reading

Dodge JC, Treleaven CM, Fidler JA, et al. Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis. Proc Natl Acad Sci U S A. 2013;110(26):10812-10817.

Dupuis L, Oudart H, René F, et al. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004;101(30):11159-11164.

Huang R, Guo X, Chen X, et al. The serum lipid profiles of amyotrophic lateral sclerosis patients: A study from south-west China and a meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):359-365.

Kim SM, Kim H, Kim JE, et al. Amyotrophic lateral sclerosis is associated with hypolipidemia at the presymptomatic stage in mice. PLoS One. 2011;6(3):e17985.

Lieury A, Chanal M, Androdias G, et al. Tissue remodeling in periplaque regions of multiple sclerosis spinal cord lesions. Glia. 2014;62(10):1645-1658.

Mørkholt AS, Kastaniegaard K, Trabjerg MS, et al. Identification of brain antigens recognized by autoantibodies in experimental autoimmune encephalomyelitis-induced animals treated with etomoxir or interferon-β. Sci Rep. 2018;8(1):7092.

Palamiuc L, Schlagowski A, Ngo ST, et al. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Mol Med. 2015;7(5):526-546.

Shriver LP, Manchester M. Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis. Sci Rep. 2011;1:79.

van der Windt GJ, Everts B, Chang CH, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68-78.

NASHVILLE—Multiple sclerosis (MS) traditionally has been considered a chronic inflammatory autoimmune disease, but inflammation decreases as the disease progresses. Many other biologic processes are dysregulated in MS, such as myelin signal transport, mitochondrial function, and iron metabolism. Lipid metabolism affects all of these processes, including inflammation, and thus could be a valuable therapeutic target, according to research presented at the 2018 CMSC Annual Meeting.

“MS is not an inflammatory disease,” said John D. Nieland, PhD, Associate Professor of Health Science and Technology at Aalborg University in Denmark. “The inflammatory response is important, but it is not the only component. If you do not focus on the other components, you will never be able to treat the disease.”

The Role of Lipids in the CNS

Healthy brains have a high amount of glucose metabolism, but glucose metabolism is reduced in MS and other neurologic disorders such as Parkinson’s disease and Alzheimer’s disease. “If glucose metabolism is downregulated, something else has to be taking over,” said Dr. Nieland. He and his colleagues hypothesize that lipid metabolism replaces glucose metabolism in MS. They further hypothesize that MS fundamentally is a dysfunction of lipid metabolism.

Lipids have an essential role in the CNS. Proper signal transduction requires lipids to be bound to the myelin sheath. The proteins that compose myelin sheaths are highly immunogenic, and lipids shield them from exposure to the immune system. The half-life of lipids attached to the myelin sheath is three days, so these lipids must be replaced constantly. In addition, lipids are essential for the function of glutamate, cannabinoid, and insulin receptors.

An increase in lipid metabolism decreases glucose metabolism and induces the production of prostaglandin E2, which is a key molecule in the inflammatory response. In the early stages of MS, inflammation attacks the myelin sheath and other brain proteins. Increased lipid metabolism decreases lipid concentrations in the CNS, including around myelin. When lipids are removed from the myelin sheath, they expose the immunogenic proteins that compose it, thus provoking an immune response. Dysregulated lipid metabolism also contributes to oxidative stress, mitochondrial dysfunction, demyelination, and neuronal loss.

Chemical Inhibition of Lipid Metabolism

Dr. Nieland and colleagues hypothesized that blocking lipid metabolism would reverse the inflammatory response and other harmful processes that occur in MS. Previous research by Shriver and colleagues indicated that inhibition of carnitine palmitoyltransferase 1 (CPT1), a molecule essential to lipid metabolism, in encephalitogenic T cells increases apoptosis and reduces the production of inflammatory cytokines. Two of the molecule’s three isoforms, CPT1A and CPT1C, are upregulated in MS. Stress prompts an increase in CPT1 expression, which spurs a shift to lipid metabolism. “If you block CPT1, you jam lipid metabolism,” Dr. Nieland said. “There is no way around it.” Dr. Nieland’s group thus chose CPT1 as its target.

The investigators first conducted studies using etomoxir, which inhibits CPT1 and blocks long-chain fatty acids from entering the mitochondria for beta oxidation. Through these effects, etomoxir causes cells to shift to glucose metabolism.

The researchers immunized 42 mice with myelin oligodendrocyte glycoprotein (MOG35–55) to induce experimental autoimmune encephalopathy (EAE). When the animals first exhibited symptoms at Day 10, they were randomized to receive subcutaneous etomoxir or placebo daily. Disease score decreased significantly in the treated animals, compared with the control animals. On Day 24, more than 50% of the treated mice exhibited normal behavior, compared with approximately 20% of control mice.

In another study, the investigators immunized 47 rats with myelin basic protein to induce EAE. The animals began having symptoms at Day 7, and the investigators randomized them to daily treatment with subcutaneous etomoxir or placebo. At Day 11, disease score was significantly lower among treated animals, compared with control animals. Body weight was significantly higher among rats that received etomoxir, compared with controls, at that time point. Also, 25% of treated animals exhibited normal behavior, but no controls did.

In a third study, the investigators compared etomoxir, interferon beta, and placebo in a rat model of EAE. Each treatment group included 10 rats, and etomoxir had superior effects on disease score and body weight, compared with interferon beta and placebo. When the investigators examined the rats’ serum, they found that levels of antibodies against brain antigens common in EAE were lower in rats treated with etomoxir, compared with those treated with interferon beta or placebo.

Biologic Inhibition of Lipid Metabolism

In addition to pharmacologic treatment, genetic mutations affect CPT1 function. The Hutterites, an ethnoreligious group in Canada, have a mutation in CPT1A that almost completely blocks the molecule’s activity. Similarly, the Inuit have a mutation in CPT1A that reduces its activity to approximately 22%. The prevalence of MS is one in 1,100 among the Hutterites and one in 50,000 among the Inuit, compared with one in 350 in the Canadian population. These observations suggest that gene therapy could be another way to block CPT1.

Dr. Nieland’s group collaborated with the Netherlands Cancer Institute to develop mouse strains with two distinct mutations in CPT1A. The first mutation mimics that found among the Hutterites, and the other mimics that found among the Inuit. In a preliminary study, the investigators induced EAE in three wild-type mice and two mice with the CPT1A mutation similar to that of the Inuit. The mice were 10 weeks old at the time of immunization.

At 24 days, disease score was lower in the CPT1A mutant mice, compared with the wild-type mice. Furthermore, body weight was higher in the mutant mice, compared with the wild-type mice. The investigators also measured the mice’s grip strength at Day 2 and Day 24. Grip strength decreased in the wild-type mice but remained the same in the mutant mice. At Day 24, grip strength was significantly higher among mutant mice than among wild-type mice.

“These results indicate an interaction of the lipid metabolism in the brain and in the immune system, which supports our hypothesis regarding MS pathology,” said Anne Skøttrup Mørkholt, a doctoral student at Aalborg University, who collaborated with Dr. Nieland on these animal studies. “MS is not a disease of the immune system, but a systemic disease with dysregulation of multiple components.”

Lipid Metabolism in Other Neurologic Diseases

Data suggest that lipid metabolism may contribute to other neurologic diseases such as amyotrophic lateral sclerosis (ALS) as well. Huang et al found a correlation between serum triglyceride levels and the development of ALS. Dupuis et al observed upregulated lipid metabolism and downregulated glucose metabolism in SOD1 mouse models of the disease, as did subsequent researchers. In addition, a 2015 study by Palamiuc et al found that CPT1B was significantly increased in the muscle tissue of SOD1 mice.

To investigate whether suppressing lipid metabolism affected ALS, Dr. Nieland’s group examined a SOD1 mouse model of the disease. The mice developed symptoms at Day 70 and were randomized at Day 100 to etomoxir or placebo. Etomoxir was associated with less weight loss and better neurologic score, compared with placebo. Etomoxir also was associated with better performance on the wire hanging and rotarod tests, compared with placebo. “It seems like etomoxir was able to slow down the disease progression,” said Michael Sloth Trabjerg, MD, a doctoral student at Aalborg University.

—Erik Greb

Suggested Reading

Dodge JC, Treleaven CM, Fidler JA, et al. Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis. Proc Natl Acad Sci U S A. 2013;110(26):10812-10817.

Dupuis L, Oudart H, René F, et al. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004;101(30):11159-11164.

Huang R, Guo X, Chen X, et al. The serum lipid profiles of amyotrophic lateral sclerosis patients: A study from south-west China and a meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):359-365.

Kim SM, Kim H, Kim JE, et al. Amyotrophic lateral sclerosis is associated with hypolipidemia at the presymptomatic stage in mice. PLoS One. 2011;6(3):e17985.

Lieury A, Chanal M, Androdias G, et al. Tissue remodeling in periplaque regions of multiple sclerosis spinal cord lesions. Glia. 2014;62(10):1645-1658.

Mørkholt AS, Kastaniegaard K, Trabjerg MS, et al. Identification of brain antigens recognized by autoantibodies in experimental autoimmune encephalomyelitis-induced animals treated with etomoxir or interferon-β. Sci Rep. 2018;8(1):7092.

Palamiuc L, Schlagowski A, Ngo ST, et al. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Mol Med. 2015;7(5):526-546.

Shriver LP, Manchester M. Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis. Sci Rep. 2011;1:79.

van der Windt GJ, Everts B, Chang CH, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68-78.

NASHVILLE—Multiple sclerosis (MS) traditionally has been considered a chronic inflammatory autoimmune disease, but inflammation decreases as the disease progresses. Many other biologic processes are dysregulated in MS, such as myelin signal transport, mitochondrial function, and iron metabolism. Lipid metabolism affects all of these processes, including inflammation, and thus could be a valuable therapeutic target, according to research presented at the 2018 CMSC Annual Meeting.

“MS is not an inflammatory disease,” said John D. Nieland, PhD, Associate Professor of Health Science and Technology at Aalborg University in Denmark. “The inflammatory response is important, but it is not the only component. If you do not focus on the other components, you will never be able to treat the disease.”

The Role of Lipids in the CNS

Healthy brains have a high amount of glucose metabolism, but glucose metabolism is reduced in MS and other neurologic disorders such as Parkinson’s disease and Alzheimer’s disease. “If glucose metabolism is downregulated, something else has to be taking over,” said Dr. Nieland. He and his colleagues hypothesize that lipid metabolism replaces glucose metabolism in MS. They further hypothesize that MS fundamentally is a dysfunction of lipid metabolism.

Lipids have an essential role in the CNS. Proper signal transduction requires lipids to be bound to the myelin sheath. The proteins that compose myelin sheaths are highly immunogenic, and lipids shield them from exposure to the immune system. The half-life of lipids attached to the myelin sheath is three days, so these lipids must be replaced constantly. In addition, lipids are essential for the function of glutamate, cannabinoid, and insulin receptors.

An increase in lipid metabolism decreases glucose metabolism and induces the production of prostaglandin E2, which is a key molecule in the inflammatory response. In the early stages of MS, inflammation attacks the myelin sheath and other brain proteins. Increased lipid metabolism decreases lipid concentrations in the CNS, including around myelin. When lipids are removed from the myelin sheath, they expose the immunogenic proteins that compose it, thus provoking an immune response. Dysregulated lipid metabolism also contributes to oxidative stress, mitochondrial dysfunction, demyelination, and neuronal loss.

Chemical Inhibition of Lipid Metabolism

Dr. Nieland and colleagues hypothesized that blocking lipid metabolism would reverse the inflammatory response and other harmful processes that occur in MS. Previous research by Shriver and colleagues indicated that inhibition of carnitine palmitoyltransferase 1 (CPT1), a molecule essential to lipid metabolism, in encephalitogenic T cells increases apoptosis and reduces the production of inflammatory cytokines. Two of the molecule’s three isoforms, CPT1A and CPT1C, are upregulated in MS. Stress prompts an increase in CPT1 expression, which spurs a shift to lipid metabolism. “If you block CPT1, you jam lipid metabolism,” Dr. Nieland said. “There is no way around it.” Dr. Nieland’s group thus chose CPT1 as its target.

The investigators first conducted studies using etomoxir, which inhibits CPT1 and blocks long-chain fatty acids from entering the mitochondria for beta oxidation. Through these effects, etomoxir causes cells to shift to glucose metabolism.

The researchers immunized 42 mice with myelin oligodendrocyte glycoprotein (MOG35–55) to induce experimental autoimmune encephalopathy (EAE). When the animals first exhibited symptoms at Day 10, they were randomized to receive subcutaneous etomoxir or placebo daily. Disease score decreased significantly in the treated animals, compared with the control animals. On Day 24, more than 50% of the treated mice exhibited normal behavior, compared with approximately 20% of control mice.

In another study, the investigators immunized 47 rats with myelin basic protein to induce EAE. The animals began having symptoms at Day 7, and the investigators randomized them to daily treatment with subcutaneous etomoxir or placebo. At Day 11, disease score was significantly lower among treated animals, compared with control animals. Body weight was significantly higher among rats that received etomoxir, compared with controls, at that time point. Also, 25% of treated animals exhibited normal behavior, but no controls did.

In a third study, the investigators compared etomoxir, interferon beta, and placebo in a rat model of EAE. Each treatment group included 10 rats, and etomoxir had superior effects on disease score and body weight, compared with interferon beta and placebo. When the investigators examined the rats’ serum, they found that levels of antibodies against brain antigens common in EAE were lower in rats treated with etomoxir, compared with those treated with interferon beta or placebo.

Biologic Inhibition of Lipid Metabolism

In addition to pharmacologic treatment, genetic mutations affect CPT1 function. The Hutterites, an ethnoreligious group in Canada, have a mutation in CPT1A that almost completely blocks the molecule’s activity. Similarly, the Inuit have a mutation in CPT1A that reduces its activity to approximately 22%. The prevalence of MS is one in 1,100 among the Hutterites and one in 50,000 among the Inuit, compared with one in 350 in the Canadian population. These observations suggest that gene therapy could be another way to block CPT1.

Dr. Nieland’s group collaborated with the Netherlands Cancer Institute to develop mouse strains with two distinct mutations in CPT1A. The first mutation mimics that found among the Hutterites, and the other mimics that found among the Inuit. In a preliminary study, the investigators induced EAE in three wild-type mice and two mice with the CPT1A mutation similar to that of the Inuit. The mice were 10 weeks old at the time of immunization.

At 24 days, disease score was lower in the CPT1A mutant mice, compared with the wild-type mice. Furthermore, body weight was higher in the mutant mice, compared with the wild-type mice. The investigators also measured the mice’s grip strength at Day 2 and Day 24. Grip strength decreased in the wild-type mice but remained the same in the mutant mice. At Day 24, grip strength was significantly higher among mutant mice than among wild-type mice.

“These results indicate an interaction of the lipid metabolism in the brain and in the immune system, which supports our hypothesis regarding MS pathology,” said Anne Skøttrup Mørkholt, a doctoral student at Aalborg University, who collaborated with Dr. Nieland on these animal studies. “MS is not a disease of the immune system, but a systemic disease with dysregulation of multiple components.”

Lipid Metabolism in Other Neurologic Diseases

Data suggest that lipid metabolism may contribute to other neurologic diseases such as amyotrophic lateral sclerosis (ALS) as well. Huang et al found a correlation between serum triglyceride levels and the development of ALS. Dupuis et al observed upregulated lipid metabolism and downregulated glucose metabolism in SOD1 mouse models of the disease, as did subsequent researchers. In addition, a 2015 study by Palamiuc et al found that CPT1B was significantly increased in the muscle tissue of SOD1 mice.

To investigate whether suppressing lipid metabolism affected ALS, Dr. Nieland’s group examined a SOD1 mouse model of the disease. The mice developed symptoms at Day 70 and were randomized at Day 100 to etomoxir or placebo. Etomoxir was associated with less weight loss and better neurologic score, compared with placebo. Etomoxir also was associated with better performance on the wire hanging and rotarod tests, compared with placebo. “It seems like etomoxir was able to slow down the disease progression,” said Michael Sloth Trabjerg, MD, a doctoral student at Aalborg University.

—Erik Greb

Suggested Reading

Dodge JC, Treleaven CM, Fidler JA, et al. Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis. Proc Natl Acad Sci U S A. 2013;110(26):10812-10817.

Dupuis L, Oudart H, René F, et al. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004;101(30):11159-11164.

Huang R, Guo X, Chen X, et al. The serum lipid profiles of amyotrophic lateral sclerosis patients: A study from south-west China and a meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):359-365.

Kim SM, Kim H, Kim JE, et al. Amyotrophic lateral sclerosis is associated with hypolipidemia at the presymptomatic stage in mice. PLoS One. 2011;6(3):e17985.

Lieury A, Chanal M, Androdias G, et al. Tissue remodeling in periplaque regions of multiple sclerosis spinal cord lesions. Glia. 2014;62(10):1645-1658.

Mørkholt AS, Kastaniegaard K, Trabjerg MS, et al. Identification of brain antigens recognized by autoantibodies in experimental autoimmune encephalomyelitis-induced animals treated with etomoxir or interferon-β. Sci Rep. 2018;8(1):7092.

Palamiuc L, Schlagowski A, Ngo ST, et al. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Mol Med. 2015;7(5):526-546.

Shriver LP, Manchester M. Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis. Sci Rep. 2011;1:79.

van der Windt GJ, Everts B, Chang CH, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68-78.

PARIS – Technical success rates were high and major adverse events impressively low with a two-stent culotte strategy using contemporary drug-eluting stents for coronary bifurcation lesions in the randomized CELTIC Bifurcation Study.

Bruce Jancin/MDedge News

“Many of us use the DK [double kissing] crush technique,” another panelist said. “It’s very popular. But if you look at bench testing, perhaps culotte is a better approach by many parameters. So I think it was important for you to highlight the value of culotte and how it can be done properly.”

Discussant James Nolan, MD, a cardiologist at the University Hospital of North Staffordshire (England), said, “The most critical thing with these bifurcation procedures is the operators and how they do it. So you have to do the culotte to the standard done in this trial. If you do a sloppy culotte, it’s not going to be great. It’s probably more important to deliver an excellently performed procedure, whatever it is. You’ll get a better result if you’re good at what you’re doing rather than selecting one procedure or another.”

Dr. Foley agreed, adding: “In some of the DK crush versus culotte randomized trials, I’m not convinced that culotte was done the way I would suggest it should be done.”

Operators in the CELTIC Bifurcation Study were asked to follow a standardized culotte procedure: predilate both limbs of the bifurcation, keep both wires in place, deploy the first stent in the side branch unless the main branch was awkwardly angulated, then cross by going from distally into the optimized first stent, and placing the second stent proximal to the first stent so that the two stents overlap in the proximal main vessel.

“We call that ‘nailing it down,’ ” he explained.

The procedure is completed by sequential high-pressure kissing balloon dilatation of both branches, with intravascular ultrasound or optical coherence tomography recommended but not required.

Simultaneously with this presentation, the study results were published online (EuroIntervention 2018 Jun 8;14[3]:e318-24).

The CELTIC Bifurcation Study was funded by an unrestricted grant from Boston Scientific. Dr. Foley reported having no financial conflicts of interest regarding the study.

bjancin@mdedge.com

PARIS – Technical success rates were high and major adverse events impressively low with a two-stent culotte strategy using contemporary drug-eluting stents for coronary bifurcation lesions in the randomized CELTIC Bifurcation Study.

Bruce Jancin/MDedge News

“Many of us use the DK [double kissing] crush technique,” another panelist said. “It’s very popular. But if you look at bench testing, perhaps culotte is a better approach by many parameters. So I think it was important for you to highlight the value of culotte and how it can be done properly.”

Discussant James Nolan, MD, a cardiologist at the University Hospital of North Staffordshire (England), said, “The most critical thing with these bifurcation procedures is the operators and how they do it. So you have to do the culotte to the standard done in this trial. If you do a sloppy culotte, it’s not going to be great. It’s probably more important to deliver an excellently performed procedure, whatever it is. You’ll get a better result if you’re good at what you’re doing rather than selecting one procedure or another.”

Dr. Foley agreed, adding: “In some of the DK crush versus culotte randomized trials, I’m not convinced that culotte was done the way I would suggest it should be done.”

Operators in the CELTIC Bifurcation Study were asked to follow a standardized culotte procedure: predilate both limbs of the bifurcation, keep both wires in place, deploy the first stent in the side branch unless the main branch was awkwardly angulated, then cross by going from distally into the optimized first stent, and placing the second stent proximal to the first stent so that the two stents overlap in the proximal main vessel.

“We call that ‘nailing it down,’ ” he explained.

The procedure is completed by sequential high-pressure kissing balloon dilatation of both branches, with intravascular ultrasound or optical coherence tomography recommended but not required.

Simultaneously with this presentation, the study results were published online (EuroIntervention 2018 Jun 8;14[3]:e318-24).

The CELTIC Bifurcation Study was funded by an unrestricted grant from Boston Scientific. Dr. Foley reported having no financial conflicts of interest regarding the study.

bjancin@mdedge.com

PARIS – Technical success rates were high and major adverse events impressively low with a two-stent culotte strategy using contemporary drug-eluting stents for coronary bifurcation lesions in the randomized CELTIC Bifurcation Study.

Bruce Jancin/MDedge News

“Many of us use the DK [double kissing] crush technique,” another panelist said. “It’s very popular. But if you look at bench testing, perhaps culotte is a better approach by many parameters. So I think it was important for you to highlight the value of culotte and how it can be done properly.”

Discussant James Nolan, MD, a cardiologist at the University Hospital of North Staffordshire (England), said, “The most critical thing with these bifurcation procedures is the operators and how they do it. So you have to do the culotte to the standard done in this trial. If you do a sloppy culotte, it’s not going to be great. It’s probably more important to deliver an excellently performed procedure, whatever it is. You’ll get a better result if you’re good at what you’re doing rather than selecting one procedure or another.”

Dr. Foley agreed, adding: “In some of the DK crush versus culotte randomized trials, I’m not convinced that culotte was done the way I would suggest it should be done.”

Operators in the CELTIC Bifurcation Study were asked to follow a standardized culotte procedure: predilate both limbs of the bifurcation, keep both wires in place, deploy the first stent in the side branch unless the main branch was awkwardly angulated, then cross by going from distally into the optimized first stent, and placing the second stent proximal to the first stent so that the two stents overlap in the proximal main vessel.

“We call that ‘nailing it down,’ ” he explained.

The procedure is completed by sequential high-pressure kissing balloon dilatation of both branches, with intravascular ultrasound or optical coherence tomography recommended but not required.

Simultaneously with this presentation, the study results were published online (EuroIntervention 2018 Jun 8;14[3]:e318-24).

The CELTIC Bifurcation Study was funded by an unrestricted grant from Boston Scientific. Dr. Foley reported having no financial conflicts of interest regarding the study.

bjancin@mdedge.com

WASHINGTON – For male patients with sickle cell disease, priapism can be more than just painful and embarrassing. The prolonged erections prompted by vasoocclusive events in the penis may lead to irreversible impotence, but little is known about risk factors for priapism, which remains a difficult-to-treat complication of the disease.

In males with HbSS sickle cell disease (SCD) and priapism, RBC adhesion is increased in hypoxic conditions, according to preliminary findings from work using a newly developed biochip that mimics microvascular conditions in SCD. This significant level of adhesion prompted by hypoxia was not seen in men who did not have priapism, according to study coauthor Erina Quinn, a research assistant in hematology and oncology at Case Western Reserve University, Cleveland, who presented the results at the annual meeting of the Foundation for Sickle Cell Disease Research.

When hemoglobin desaturation occurs, polymerization can be increased, leading to increased end-organ damage, Ms. Quinn said. The biochip is “an effort to measure cellular adhesion in a clinically meaningful way.” The tool can detect hemoglobin phenotype, differentiating among HbSS, HbSbeta+, and HbSC. It can also measure the degree of hemolysis and RBC deformability.

The biochip “mimics postcapillary flow conditions in microchannels,” Ms. Quinn said. The device forces blood samples through microchannels that are at the diameter of smaller venules, approximately 50 mcm, and at a physiological flow rate ranging from 1-13 mm/sec. The microfluidic channels are coated with laminin, a subendothelial matrix protein implicated in RBC adhesion. A second microfluidic biochip mimics hypoxic conditions.

The study enrolled 26 men with the HbSS genotype, 14 of whom reported priapism, and assessed RBC adhesion in blood samples run though both the SCD-modeled biochip and the hypoxia biochip. Investigators also assessed contemporaneous in vivo hemoglobin desaturation, and looked for associations with the in vitro biochip findings.

Of the 26 participants, 16 also had either nocturnal or exertional hemoglobin desaturation. In addition, 10 participants had both priapism and desaturations. These data were collected by retrospective chart review and patient survey.

Patients with priapism were a mean age of 34 years, compared with a mean age of 29 years for the other participants, a nonsignificant difference. There were no significant differences in mean hemoglobin or bilirubin levels, or in reticulocyte counts, between the two groups.

However, white blood count, absolute neutrophil count, and lactate dehydrogenase levels were significantly higher for men with priapism (P = .022, .037, and .008, respectively). Ferritin levels were higher as well, at a mean 2,433 (plus or minus 2,234) mcg/L for those with priapism, compared with a mean 269 (plus or minus 3,015) mcg/L for those without priapism (P = .031).

When absolute reticulocyte count was mapped against lactate dehydrogenase levels to create a measure of degree of hemolysis, “individuals with priapism had a more hemolytic lab profile,” said Ms. Quinn (P = .0186).

Though 10 of 14 men with priapism had hemoglobin desaturation, compared with 5 of 12 who did not have priapism, the difference was not statistically significant.

When the researchers compared microchip analysis of RBC adhesion, though, they found marked differences in RBC adhesion in hypoxic versus nonhypoxic conditions. Significantly more RBCs were adherent under hypoxic conditions – in the hypoxic biochip – for the patients with priapism than for patients without priapism (mean, 529 vs. 3,268 adherent cells; P = .016).

koakes@mdedge.com

WASHINGTON – For male patients with sickle cell disease, priapism can be more than just painful and embarrassing. The prolonged erections prompted by vasoocclusive events in the penis may lead to irreversible impotence, but little is known about risk factors for priapism, which remains a difficult-to-treat complication of the disease.

In males with HbSS sickle cell disease (SCD) and priapism, RBC adhesion is increased in hypoxic conditions, according to preliminary findings from work using a newly developed biochip that mimics microvascular conditions in SCD. This significant level of adhesion prompted by hypoxia was not seen in men who did not have priapism, according to study coauthor Erina Quinn, a research assistant in hematology and oncology at Case Western Reserve University, Cleveland, who presented the results at the annual meeting of the Foundation for Sickle Cell Disease Research.

When hemoglobin desaturation occurs, polymerization can be increased, leading to increased end-organ damage, Ms. Quinn said. The biochip is “an effort to measure cellular adhesion in a clinically meaningful way.” The tool can detect hemoglobin phenotype, differentiating among HbSS, HbSbeta+, and HbSC. It can also measure the degree of hemolysis and RBC deformability.

The biochip “mimics postcapillary flow conditions in microchannels,” Ms. Quinn said. The device forces blood samples through microchannels that are at the diameter of smaller venules, approximately 50 mcm, and at a physiological flow rate ranging from 1-13 mm/sec. The microfluidic channels are coated with laminin, a subendothelial matrix protein implicated in RBC adhesion. A second microfluidic biochip mimics hypoxic conditions.

The study enrolled 26 men with the HbSS genotype, 14 of whom reported priapism, and assessed RBC adhesion in blood samples run though both the SCD-modeled biochip and the hypoxia biochip. Investigators also assessed contemporaneous in vivo hemoglobin desaturation, and looked for associations with the in vitro biochip findings.

Of the 26 participants, 16 also had either nocturnal or exertional hemoglobin desaturation. In addition, 10 participants had both priapism and desaturations. These data were collected by retrospective chart review and patient survey.

Patients with priapism were a mean age of 34 years, compared with a mean age of 29 years for the other participants, a nonsignificant difference. There were no significant differences in mean hemoglobin or bilirubin levels, or in reticulocyte counts, between the two groups.

However, white blood count, absolute neutrophil count, and lactate dehydrogenase levels were significantly higher for men with priapism (P = .022, .037, and .008, respectively). Ferritin levels were higher as well, at a mean 2,433 (plus or minus 2,234) mcg/L for those with priapism, compared with a mean 269 (plus or minus 3,015) mcg/L for those without priapism (P = .031).

When absolute reticulocyte count was mapped against lactate dehydrogenase levels to create a measure of degree of hemolysis, “individuals with priapism had a more hemolytic lab profile,” said Ms. Quinn (P = .0186).

Though 10 of 14 men with priapism had hemoglobin desaturation, compared with 5 of 12 who did not have priapism, the difference was not statistically significant.

When the researchers compared microchip analysis of RBC adhesion, though, they found marked differences in RBC adhesion in hypoxic versus nonhypoxic conditions. Significantly more RBCs were adherent under hypoxic conditions – in the hypoxic biochip – for the patients with priapism than for patients without priapism (mean, 529 vs. 3,268 adherent cells; P = .016).

koakes@mdedge.com

WASHINGTON – For male patients with sickle cell disease, priapism can be more than just painful and embarrassing. The prolonged erections prompted by vasoocclusive events in the penis may lead to irreversible impotence, but little is known about risk factors for priapism, which remains a difficult-to-treat complication of the disease.

In males with HbSS sickle cell disease (SCD) and priapism, RBC adhesion is increased in hypoxic conditions, according to preliminary findings from work using a newly developed biochip that mimics microvascular conditions in SCD. This significant level of adhesion prompted by hypoxia was not seen in men who did not have priapism, according to study coauthor Erina Quinn, a research assistant in hematology and oncology at Case Western Reserve University, Cleveland, who presented the results at the annual meeting of the Foundation for Sickle Cell Disease Research.

When hemoglobin desaturation occurs, polymerization can be increased, leading to increased end-organ damage, Ms. Quinn said. The biochip is “an effort to measure cellular adhesion in a clinically meaningful way.” The tool can detect hemoglobin phenotype, differentiating among HbSS, HbSbeta+, and HbSC. It can also measure the degree of hemolysis and RBC deformability.

The biochip “mimics postcapillary flow conditions in microchannels,” Ms. Quinn said. The device forces blood samples through microchannels that are at the diameter of smaller venules, approximately 50 mcm, and at a physiological flow rate ranging from 1-13 mm/sec. The microfluidic channels are coated with laminin, a subendothelial matrix protein implicated in RBC adhesion. A second microfluidic biochip mimics hypoxic conditions.

The study enrolled 26 men with the HbSS genotype, 14 of whom reported priapism, and assessed RBC adhesion in blood samples run though both the SCD-modeled biochip and the hypoxia biochip. Investigators also assessed contemporaneous in vivo hemoglobin desaturation, and looked for associations with the in vitro biochip findings.

Of the 26 participants, 16 also had either nocturnal or exertional hemoglobin desaturation. In addition, 10 participants had both priapism and desaturations. These data were collected by retrospective chart review and patient survey.

Patients with priapism were a mean age of 34 years, compared with a mean age of 29 years for the other participants, a nonsignificant difference. There were no significant differences in mean hemoglobin or bilirubin levels, or in reticulocyte counts, between the two groups.

However, white blood count, absolute neutrophil count, and lactate dehydrogenase levels were significantly higher for men with priapism (P = .022, .037, and .008, respectively). Ferritin levels were higher as well, at a mean 2,433 (plus or minus 2,234) mcg/L for those with priapism, compared with a mean 269 (plus or minus 3,015) mcg/L for those without priapism (P = .031).

When absolute reticulocyte count was mapped against lactate dehydrogenase levels to create a measure of degree of hemolysis, “individuals with priapism had a more hemolytic lab profile,” said Ms. Quinn (P = .0186).

Though 10 of 14 men with priapism had hemoglobin desaturation, compared with 5 of 12 who did not have priapism, the difference was not statistically significant.

When the researchers compared microchip analysis of RBC adhesion, though, they found marked differences in RBC adhesion in hypoxic versus nonhypoxic conditions. Significantly more RBCs were adherent under hypoxic conditions – in the hypoxic biochip – for the patients with priapism than for patients without priapism (mean, 529 vs. 3,268 adherent cells; P = .016).

koakes@mdedge.com

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.

mzoler@mdedge.com

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.

mzoler@mdedge.com

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.

mzoler@mdedge.com

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.

mdales@mdedge.com

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.

mdales@mdedge.com

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.

mdales@mdedge.com

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.

msullivan@mdedge.com

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.

msullivan@mdedge.com

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.

msullivan@mdedge.com

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.

aotto@mdedge.com

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.

aotto@mdedge.com

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.

aotto@mdedge.com

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.
 

mlesney@mdedge.com

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.
 

mlesney@mdedge.com

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.
 

mlesney@mdedge.com

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.