Children’s Research Hospital

Many young children with sickle cell anemia (SCA) may not be taking the recommended antibiotics to prevent invasive pneumococcal disease (IPD), according to research published in Pediatrics.

Results of a previous study indicated that daily treatment with penicillin could reduce the risk of IPD by 84% in young children with SCA.

In the current study, only 18% of young SCA patients received daily penicillin or an equivalent antibiotic as IPD prophylaxis.

“Most children with sickle cell anemia are not getting the antibiotics they should be to adequately protect against potentially deadly infections,” said study author Sarah Reeves, PhD, of the University of Michigan Medical School in Ann Arbor.

“Long-standing recommendations say children with sickle cell anemia should take antibiotics daily for their first 5 years of life. It can be life-saving.”

For this study, Dr Reeves and her colleagues analyzed data on 2821 SCA patients, ages 3 months to 5 years, living in Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas.

The patients were continuously enrolled in the Medicaid program for at least 1 calendar year between 2005 and 2012. The researchers evaluated the receipt of antibiotics through the insurance claims for filled prescriptions.

The team found that, overall, 18% of patients received at least 300 days of antibiotics.

Sixteen percent of patients received at least 300 days of penicillin; 16% received at least 300 days of penicillin or erythromycin; 18% received at least 300 days of penicillin, erythromycin, or amoxicillin; and 22% received at least 300 days of any antibiotic to prevent Streptococcus pneumoniae.

On average, patients received 162 days of penicillin; 164 days of penicillin or erythromycin; 178 days of penicillin, erythromycin, or amoxicillin; and 193 days of any antibiotic to prevent S pneumoniae.

Multivariable analysis suggested that medical visits and a patient’s state of residence were associated with receiving at least 300 days of antibiotics.

The researchers said that each additional SCA-related outpatient visit and well-child visit was associated with incrementally increased odds of receiving at least 300 days of antibiotics. The odds ratio (OR) was 1.01 for SCA-related outpatient visits and 1.08 for well-child visits (P<0.05 for both).

Patients in Florida (OR=0.51, P<0.05), Louisiana (OR=0.57, P<0.05), Michigan (OR=0.60, P<0.05), and South Carolina (OR=0.62, P<0.05) had lower odds of receiving at least 300 days of antibiotics than patients in Illinois (OR=1.00) or Texas (OR=1.01).

The researchers did not investigate why children were not receiving recommended antibiotics, but Dr Reeves identified possible barriers to compliance. She noted that caregiver challenges include picking up prescriptions every 2 weeks from a pharmacy as well as remembering to administer an antibiotic to a young, healthy-appearing child twice a day.

“The types of challenges involved in making sure children get the recommended dose of antibiotics is exacerbated by the substantial burden of care already experienced by families to help control the symptoms of this disease,” Dr Reeves said.

She added that future studies should more deeply explore barriers preventing families from getting antibiotics and potential interventions to improve the rate of children receiving recommended prescriptions.

“Interventions to improve the receipt of antibiotics among children with sickle cell anemia should include enhanced collaboration between healthcare providers, pharmacists, and families,” Dr Reeves said.

“Doctors need to repeatedly discuss the importance of taking antibiotics with families of children with sickle cell anemia. Social factors that may impact receiving filled prescriptions should also be considered, such as the availability of transportation and time to travel to pharmacies to pick up the prescriptions.”

Children’s Research Hospital

Many young children with sickle cell anemia (SCA) may not be taking the recommended antibiotics to prevent invasive pneumococcal disease (IPD), according to research published in Pediatrics.

Results of a previous study indicated that daily treatment with penicillin could reduce the risk of IPD by 84% in young children with SCA.

In the current study, only 18% of young SCA patients received daily penicillin or an equivalent antibiotic as IPD prophylaxis.

“Most children with sickle cell anemia are not getting the antibiotics they should be to adequately protect against potentially deadly infections,” said study author Sarah Reeves, PhD, of the University of Michigan Medical School in Ann Arbor.

“Long-standing recommendations say children with sickle cell anemia should take antibiotics daily for their first 5 years of life. It can be life-saving.”

For this study, Dr Reeves and her colleagues analyzed data on 2821 SCA patients, ages 3 months to 5 years, living in Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas.

The patients were continuously enrolled in the Medicaid program for at least 1 calendar year between 2005 and 2012. The researchers evaluated the receipt of antibiotics through the insurance claims for filled prescriptions.

The team found that, overall, 18% of patients received at least 300 days of antibiotics.

Sixteen percent of patients received at least 300 days of penicillin; 16% received at least 300 days of penicillin or erythromycin; 18% received at least 300 days of penicillin, erythromycin, or amoxicillin; and 22% received at least 300 days of any antibiotic to prevent Streptococcus pneumoniae.

On average, patients received 162 days of penicillin; 164 days of penicillin or erythromycin; 178 days of penicillin, erythromycin, or amoxicillin; and 193 days of any antibiotic to prevent S pneumoniae.

Multivariable analysis suggested that medical visits and a patient’s state of residence were associated with receiving at least 300 days of antibiotics.

The researchers said that each additional SCA-related outpatient visit and well-child visit was associated with incrementally increased odds of receiving at least 300 days of antibiotics. The odds ratio (OR) was 1.01 for SCA-related outpatient visits and 1.08 for well-child visits (P<0.05 for both).

Patients in Florida (OR=0.51, P<0.05), Louisiana (OR=0.57, P<0.05), Michigan (OR=0.60, P<0.05), and South Carolina (OR=0.62, P<0.05) had lower odds of receiving at least 300 days of antibiotics than patients in Illinois (OR=1.00) or Texas (OR=1.01).

The researchers did not investigate why children were not receiving recommended antibiotics, but Dr Reeves identified possible barriers to compliance. She noted that caregiver challenges include picking up prescriptions every 2 weeks from a pharmacy as well as remembering to administer an antibiotic to a young, healthy-appearing child twice a day.

“The types of challenges involved in making sure children get the recommended dose of antibiotics is exacerbated by the substantial burden of care already experienced by families to help control the symptoms of this disease,” Dr Reeves said.

She added that future studies should more deeply explore barriers preventing families from getting antibiotics and potential interventions to improve the rate of children receiving recommended prescriptions.

“Interventions to improve the receipt of antibiotics among children with sickle cell anemia should include enhanced collaboration between healthcare providers, pharmacists, and families,” Dr Reeves said.

“Doctors need to repeatedly discuss the importance of taking antibiotics with families of children with sickle cell anemia. Social factors that may impact receiving filled prescriptions should also be considered, such as the availability of transportation and time to travel to pharmacies to pick up the prescriptions.”

Children’s Research Hospital

Many young children with sickle cell anemia (SCA) may not be taking the recommended antibiotics to prevent invasive pneumococcal disease (IPD), according to research published in Pediatrics.

Results of a previous study indicated that daily treatment with penicillin could reduce the risk of IPD by 84% in young children with SCA.

In the current study, only 18% of young SCA patients received daily penicillin or an equivalent antibiotic as IPD prophylaxis.

“Most children with sickle cell anemia are not getting the antibiotics they should be to adequately protect against potentially deadly infections,” said study author Sarah Reeves, PhD, of the University of Michigan Medical School in Ann Arbor.

“Long-standing recommendations say children with sickle cell anemia should take antibiotics daily for their first 5 years of life. It can be life-saving.”

For this study, Dr Reeves and her colleagues analyzed data on 2821 SCA patients, ages 3 months to 5 years, living in Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas.

The patients were continuously enrolled in the Medicaid program for at least 1 calendar year between 2005 and 2012. The researchers evaluated the receipt of antibiotics through the insurance claims for filled prescriptions.

The team found that, overall, 18% of patients received at least 300 days of antibiotics.

Sixteen percent of patients received at least 300 days of penicillin; 16% received at least 300 days of penicillin or erythromycin; 18% received at least 300 days of penicillin, erythromycin, or amoxicillin; and 22% received at least 300 days of any antibiotic to prevent Streptococcus pneumoniae.

On average, patients received 162 days of penicillin; 164 days of penicillin or erythromycin; 178 days of penicillin, erythromycin, or amoxicillin; and 193 days of any antibiotic to prevent S pneumoniae.

Multivariable analysis suggested that medical visits and a patient’s state of residence were associated with receiving at least 300 days of antibiotics.

The researchers said that each additional SCA-related outpatient visit and well-child visit was associated with incrementally increased odds of receiving at least 300 days of antibiotics. The odds ratio (OR) was 1.01 for SCA-related outpatient visits and 1.08 for well-child visits (P<0.05 for both).

Patients in Florida (OR=0.51, P<0.05), Louisiana (OR=0.57, P<0.05), Michigan (OR=0.60, P<0.05), and South Carolina (OR=0.62, P<0.05) had lower odds of receiving at least 300 days of antibiotics than patients in Illinois (OR=1.00) or Texas (OR=1.01).

The researchers did not investigate why children were not receiving recommended antibiotics, but Dr Reeves identified possible barriers to compliance. She noted that caregiver challenges include picking up prescriptions every 2 weeks from a pharmacy as well as remembering to administer an antibiotic to a young, healthy-appearing child twice a day.

“The types of challenges involved in making sure children get the recommended dose of antibiotics is exacerbated by the substantial burden of care already experienced by families to help control the symptoms of this disease,” Dr Reeves said.

She added that future studies should more deeply explore barriers preventing families from getting antibiotics and potential interventions to improve the rate of children receiving recommended prescriptions.

“Interventions to improve the receipt of antibiotics among children with sickle cell anemia should include enhanced collaboration between healthcare providers, pharmacists, and families,” Dr Reeves said.

“Doctors need to repeatedly discuss the importance of taking antibiotics with families of children with sickle cell anemia. Social factors that may impact receiving filled prescriptions should also be considered, such as the availability of transportation and time to travel to pharmacies to pick up the prescriptions.”

Image from PLOS ONE

Preclinical research suggests that targeting JAK2 can reduce the risk of graft-versus-host disease (GVHD) in transplant recipients.

Researchers found that genetic ablation of JAK2 on donor T cells or inhibition of JAK2 via treatment with pacritinib reduced GVHD in mice without compromising graft-versus-leukemia (GVL) activity.

“An effort to identify selective immune suppression whereby GVHD is reduced and the antitumor activity of the graft is preserved is key to improving the success of blood and marrow transplantation,” said Brian C. Betts, MD, of Moffitt Cancer Center in Tampa, Florida.

Dr Betts and his colleagues conducted this research and recounted their findings in PNAS.

In experiments with mice, the researchers found that donor T cells with JAK2 deletion were less likely than wild-type donor T cells to induce GVHD. However, JAK2 deletion did not impair the GVL effect.

Mice that received JAK2^−/− T cells had longer survival, higher body weights, and less GVHD than control mice.

The researchers said targeting JAK2 may reduce GVHD, in part, by limiting Th1 differentiation and the migratory capacity of alloreactive T cells. However, targeting JAK2 promotes beneficial regulatory-T-cell and Th2 differentiation as well.

The researchers also tested the effects of JAK2 inhibition with pacritinib. Mice received allografts and were treated with pacritinib or vehicle control for 3 weeks.

As before, JAK2 inhibition reduced acute GVHD mortality while preserving the GVL effect.

The team also discovered that pacritinib could protect mice from tissue graft rejection, suggesting the drug could be used to prevent kidney or liver transplant rejection.

Now, the researchers are working on a phase 1/2 trial designed to determine if pacritinib and standard immune suppression can prevent acute GVHD after hematopoietic stem cell transplant (NCT02891603).

Image from PLOS ONE

Preclinical research suggests that targeting JAK2 can reduce the risk of graft-versus-host disease (GVHD) in transplant recipients.

Researchers found that genetic ablation of JAK2 on donor T cells or inhibition of JAK2 via treatment with pacritinib reduced GVHD in mice without compromising graft-versus-leukemia (GVL) activity.

“An effort to identify selective immune suppression whereby GVHD is reduced and the antitumor activity of the graft is preserved is key to improving the success of blood and marrow transplantation,” said Brian C. Betts, MD, of Moffitt Cancer Center in Tampa, Florida.

Dr Betts and his colleagues conducted this research and recounted their findings in PNAS.

In experiments with mice, the researchers found that donor T cells with JAK2 deletion were less likely than wild-type donor T cells to induce GVHD. However, JAK2 deletion did not impair the GVL effect.

Mice that received JAK2^−/− T cells had longer survival, higher body weights, and less GVHD than control mice.

The researchers said targeting JAK2 may reduce GVHD, in part, by limiting Th1 differentiation and the migratory capacity of alloreactive T cells. However, targeting JAK2 promotes beneficial regulatory-T-cell and Th2 differentiation as well.

The researchers also tested the effects of JAK2 inhibition with pacritinib. Mice received allografts and were treated with pacritinib or vehicle control for 3 weeks.

As before, JAK2 inhibition reduced acute GVHD mortality while preserving the GVL effect.

The team also discovered that pacritinib could protect mice from tissue graft rejection, suggesting the drug could be used to prevent kidney or liver transplant rejection.

Now, the researchers are working on a phase 1/2 trial designed to determine if pacritinib and standard immune suppression can prevent acute GVHD after hematopoietic stem cell transplant (NCT02891603).

Image from PLOS ONE

Preclinical research suggests that targeting JAK2 can reduce the risk of graft-versus-host disease (GVHD) in transplant recipients.

Researchers found that genetic ablation of JAK2 on donor T cells or inhibition of JAK2 via treatment with pacritinib reduced GVHD in mice without compromising graft-versus-leukemia (GVL) activity.

“An effort to identify selective immune suppression whereby GVHD is reduced and the antitumor activity of the graft is preserved is key to improving the success of blood and marrow transplantation,” said Brian C. Betts, MD, of Moffitt Cancer Center in Tampa, Florida.

Dr Betts and his colleagues conducted this research and recounted their findings in PNAS.

In experiments with mice, the researchers found that donor T cells with JAK2 deletion were less likely than wild-type donor T cells to induce GVHD. However, JAK2 deletion did not impair the GVL effect.

Mice that received JAK2^−/− T cells had longer survival, higher body weights, and less GVHD than control mice.

The researchers said targeting JAK2 may reduce GVHD, in part, by limiting Th1 differentiation and the migratory capacity of alloreactive T cells. However, targeting JAK2 promotes beneficial regulatory-T-cell and Th2 differentiation as well.

The researchers also tested the effects of JAK2 inhibition with pacritinib. Mice received allografts and were treated with pacritinib or vehicle control for 3 weeks.

As before, JAK2 inhibition reduced acute GVHD mortality while preserving the GVL effect.

The team also discovered that pacritinib could protect mice from tissue graft rejection, suggesting the drug could be used to prevent kidney or liver transplant rejection.

Now, the researchers are working on a phase 1/2 trial designed to determine if pacritinib and standard immune suppression can prevent acute GVHD after hematopoietic stem cell transplant (NCT02891603).

Photo by Bill Branson

A study conducted in Sweden revealed that social benefits can ease financial burdens for parents of children recently diagnosed with cancer.

However, the study also showed that mothers experienced persistently lower income after benefits diminished.

Ayako Hiyoshi, PhD, of Örebro University in Örebro, Sweden, and her colleagues detailed these findings in Cancer.

The researchers gathered information from Swedish national registers and examined the trajectories of parents’ income from different sources.

Parents of children with cancer diagnosed between 2004 and 2009 were identified and matched with parents of children without cancer (reference parents).

In total, 20,091 families were followed from the year before cancer diagnosis to a maximum of 8 years.

The researchers noted that, around the time of a child’s cancer diagnosis, total income (from all sources) was, on average, higher in mothers of children with cancer than in reference mothers.

The ratio of mean total income for mothers of children with cancer, compared to reference mothers, was 1.032 at 1 year prior to the child’s diagnosis and 1.064 the year of diagnosis.

For fathers of children with cancer, total income was slightly lower than reference fathers’ income. The ratios were 0.987 at 1 year prior to diagnosis and 0.995 the year of diagnosis.

The researchers also noted that parents’ income from work was at its lowest around the time of a child’s cancer diagnosis but increased with time.

At cancer diagnosis, the ratio of mean income from work was 0.642 for mothers and 0.858 for fathers. One year later, the ratios were 0.786 and 0.956, respectively. At 3 years, the ratios were 0.876 and 0.986, respectively. At 6 years, the ratios were 0.856 and 1.058, respectively.

The researchers pointed out that sickness and childcare-related benefits, which compensated for income loss, were greater for parents of children with cancer than for reference parents. However, social benefits diminished over time.

One year prior to cancer diagnosis, the ratio of sickness benefits was 3.495 for mothers and 5.213 for fathers. The year of diagnosis, the ratios were 4.785 and 5.795, respectively. At 3 years, the ratios were 1.404 and 1.339, respectively. And at 6 years, the ratios were 0.931 and 1.421, respectively.

One year prior to cancer diagnosis, the ratio of childcare-related benefits was 2.830 for mothers and 3.514 for fathers. The year of diagnosis, the ratios were 4.553 and 4.930, respectively. At 3 years, the ratios were 2.225 and 1.948, respectively. And at 6 years, the ratios were 1.272 and 1.095, respectively.

The decline of social benefits over time meant that cancer mothers’ total income became lower than that of reference mothers, and this difference persisted over the period studied. This was not the case for cancer fathers, however.

The ratio of income from all sources for cancer mothers compared to reference mothers was 1.064 the year of diagnosis, 0.985 at 2 years, 0.966 at 4 years, and 0.934 at 6 years.

The ratio of income from all sources for cancer fathers compared to reference fathers was 0.995 the year of diagnosis, 0.993 at 2 years, 0.998 at 4 years, and 1.029 at 6 years.

“A significant and unexpected finding was that, although income from employment stayed lower for several years for mothers, total income was higher for mothers of children with cancer around the time of the child’s cancer diagnosis when the compensation from social benefits were included,” Dr Hiyoshi said.

“The persistently lower income from employment for mothers of children with cancer compared with mothers of cancer-free children implies potential long-term consequences for the mothers of children with cancer, including their career and future pension in old age.”

Photo by Bill Branson

A study conducted in Sweden revealed that social benefits can ease financial burdens for parents of children recently diagnosed with cancer.

However, the study also showed that mothers experienced persistently lower income after benefits diminished.

Ayako Hiyoshi, PhD, of Örebro University in Örebro, Sweden, and her colleagues detailed these findings in Cancer.

The researchers gathered information from Swedish national registers and examined the trajectories of parents’ income from different sources.

Parents of children with cancer diagnosed between 2004 and 2009 were identified and matched with parents of children without cancer (reference parents).

In total, 20,091 families were followed from the year before cancer diagnosis to a maximum of 8 years.

The researchers noted that, around the time of a child’s cancer diagnosis, total income (from all sources) was, on average, higher in mothers of children with cancer than in reference mothers.

The ratio of mean total income for mothers of children with cancer, compared to reference mothers, was 1.032 at 1 year prior to the child’s diagnosis and 1.064 the year of diagnosis.

For fathers of children with cancer, total income was slightly lower than reference fathers’ income. The ratios were 0.987 at 1 year prior to diagnosis and 0.995 the year of diagnosis.

The researchers also noted that parents’ income from work was at its lowest around the time of a child’s cancer diagnosis but increased with time.

At cancer diagnosis, the ratio of mean income from work was 0.642 for mothers and 0.858 for fathers. One year later, the ratios were 0.786 and 0.956, respectively. At 3 years, the ratios were 0.876 and 0.986, respectively. At 6 years, the ratios were 0.856 and 1.058, respectively.

The researchers pointed out that sickness and childcare-related benefits, which compensated for income loss, were greater for parents of children with cancer than for reference parents. However, social benefits diminished over time.

One year prior to cancer diagnosis, the ratio of sickness benefits was 3.495 for mothers and 5.213 for fathers. The year of diagnosis, the ratios were 4.785 and 5.795, respectively. At 3 years, the ratios were 1.404 and 1.339, respectively. And at 6 years, the ratios were 0.931 and 1.421, respectively.

One year prior to cancer diagnosis, the ratio of childcare-related benefits was 2.830 for mothers and 3.514 for fathers. The year of diagnosis, the ratios were 4.553 and 4.930, respectively. At 3 years, the ratios were 2.225 and 1.948, respectively. And at 6 years, the ratios were 1.272 and 1.095, respectively.

The decline of social benefits over time meant that cancer mothers’ total income became lower than that of reference mothers, and this difference persisted over the period studied. This was not the case for cancer fathers, however.

The ratio of income from all sources for cancer mothers compared to reference mothers was 1.064 the year of diagnosis, 0.985 at 2 years, 0.966 at 4 years, and 0.934 at 6 years.

The ratio of income from all sources for cancer fathers compared to reference fathers was 0.995 the year of diagnosis, 0.993 at 2 years, 0.998 at 4 years, and 1.029 at 6 years.

“A significant and unexpected finding was that, although income from employment stayed lower for several years for mothers, total income was higher for mothers of children with cancer around the time of the child’s cancer diagnosis when the compensation from social benefits were included,” Dr Hiyoshi said.

“The persistently lower income from employment for mothers of children with cancer compared with mothers of cancer-free children implies potential long-term consequences for the mothers of children with cancer, including their career and future pension in old age.”

Photo by Bill Branson

A study conducted in Sweden revealed that social benefits can ease financial burdens for parents of children recently diagnosed with cancer.

However, the study also showed that mothers experienced persistently lower income after benefits diminished.

Ayako Hiyoshi, PhD, of Örebro University in Örebro, Sweden, and her colleagues detailed these findings in Cancer.

The researchers gathered information from Swedish national registers and examined the trajectories of parents’ income from different sources.

Parents of children with cancer diagnosed between 2004 and 2009 were identified and matched with parents of children without cancer (reference parents).

In total, 20,091 families were followed from the year before cancer diagnosis to a maximum of 8 years.

The researchers noted that, around the time of a child’s cancer diagnosis, total income (from all sources) was, on average, higher in mothers of children with cancer than in reference mothers.

The ratio of mean total income for mothers of children with cancer, compared to reference mothers, was 1.032 at 1 year prior to the child’s diagnosis and 1.064 the year of diagnosis.

For fathers of children with cancer, total income was slightly lower than reference fathers’ income. The ratios were 0.987 at 1 year prior to diagnosis and 0.995 the year of diagnosis.

The researchers also noted that parents’ income from work was at its lowest around the time of a child’s cancer diagnosis but increased with time.

At cancer diagnosis, the ratio of mean income from work was 0.642 for mothers and 0.858 for fathers. One year later, the ratios were 0.786 and 0.956, respectively. At 3 years, the ratios were 0.876 and 0.986, respectively. At 6 years, the ratios were 0.856 and 1.058, respectively.

The researchers pointed out that sickness and childcare-related benefits, which compensated for income loss, were greater for parents of children with cancer than for reference parents. However, social benefits diminished over time.

One year prior to cancer diagnosis, the ratio of sickness benefits was 3.495 for mothers and 5.213 for fathers. The year of diagnosis, the ratios were 4.785 and 5.795, respectively. At 3 years, the ratios were 1.404 and 1.339, respectively. And at 6 years, the ratios were 0.931 and 1.421, respectively.

One year prior to cancer diagnosis, the ratio of childcare-related benefits was 2.830 for mothers and 3.514 for fathers. The year of diagnosis, the ratios were 4.553 and 4.930, respectively. At 3 years, the ratios were 2.225 and 1.948, respectively. And at 6 years, the ratios were 1.272 and 1.095, respectively.

The decline of social benefits over time meant that cancer mothers’ total income became lower than that of reference mothers, and this difference persisted over the period studied. This was not the case for cancer fathers, however.

The ratio of income from all sources for cancer mothers compared to reference mothers was 1.064 the year of diagnosis, 0.985 at 2 years, 0.966 at 4 years, and 0.934 at 6 years.

The ratio of income from all sources for cancer fathers compared to reference fathers was 0.995 the year of diagnosis, 0.993 at 2 years, 0.998 at 4 years, and 1.029 at 6 years.

“A significant and unexpected finding was that, although income from employment stayed lower for several years for mothers, total income was higher for mothers of children with cancer around the time of the child’s cancer diagnosis when the compensation from social benefits were included,” Dr Hiyoshi said.

“The persistently lower income from employment for mothers of children with cancer compared with mothers of cancer-free children implies potential long-term consequences for the mothers of children with cancer, including their career and future pension in old age.”

Despite universal agreement that antibiotic overprescribing is a problem, the practice continues to vex us. Antibiotic use—whether appropriate or not—has been linked to rising rates of antimicrobial resistance, disruption of the gut microbiome leading to Clostridium difficile infections (CDI), allergic reactions, and increased health care costs (see Table 1).^1-6 And yet, clinicians continue to overprescribe this class of medication.

A 2016 report from the CDC estimates that at least 30% of antibiotics prescribed in US outpatient settings are unnecessary.⁷ Another report cites a slightly higher figure across a variety of health care settings.⁸ Pair these findings with the fact that there are currently few new drugs in development to target resistant bacteria, and you have the potential for a postantibiotic era in which common infections could become lethal.⁷

In 2003, the CDC launched its “Get Smart: Know When Antibiotics Work” program (now known as “Be Antibiotics Aware”), focused on decreasing inappropriate antibiotic use in the outpatient setting.⁹ In 2015, the White House released the National Action Plan for Combating Antibiotic-Resistant Bacteria, with a goal of decreasing inappropriate outpatient antibiotic use by 50% and inappropriate inpatient use by 20% by 2020.¹⁰ And, on an international level, the World Health Organization (WHO) in 2015 developed a five-year strategic framework for implementing its Global Action Plan on Antimicrobial Resistance.¹¹

Family practitioners are on the front lines of this battle. Here’s what we can do now.

WHEN AND WHERE ARE ANTIBIOTICS MOST OFTEN INAPPROPRIATELY PRESCRIBED?

The diagnosis leading to the most frequent inappropriate prescribing of antibiotics is acute respiratory tract infection (ARTI), which includes bronchitis, otitis media, pharyngitis, sinusitis, tonsillitis, the common cold, and pneumonia. Up to 40% of antibiotic prescriptions for these conditions are unnecessary.^8,12 Bronchitis is the most common ARTI diagnosis associated with inappropriate antibiotic prescriptions, while sinusitis, suppurative otitis media, and pharyngitis are the diagnoses associated with the lion’s share of all (appropriate and inappropriate) antibiotic prescriptions within the ARTI category.^8,9,12,13 Refer to national clinical guidelines, which delineate when antibiotic treatment is appropriate for these conditions.^14-16

With respect to setting, there are conflicting findings as to whether antibiotic prescribing differs in office-based versus emergency department (ED) settings.

• One study found a higher rate of antibiotic prescribing during ED visits than office visits (21% vs 9%), even though, between 2007 and 2009, more antibiotic prescriptions were written for adults in primary care offices than in either outpatient hospital clinics or EDs.¹⁷
• In a cross-sectional study using data from 2005 to 2010 National Ambulatory Medical Care Surveys (NAMCS) and National Hospital Ambulatory Medical Care Surveys (NHAMCS), more than half of patients with uncomplicated acute rhinosinu­sitis received a prescription for antibiotics, but there was no overall difference in antibiotic prescriptions between primary care and ED presentation.¹⁸
• A retrospective analysis found that between 2006 and 2010, outpatient hospital practices (56%) and community-practice offices (60%) prescribed more antibiotics for ARTIs than EDs did (51%).¹²

STICK TO NARROW-SPECTRUM AGENTS WHEN POSSIBLE

Using broad-spectrum antibiotics, such as quinolones or imipenem, firstline, contributes more to the problem of antibiotic resistance than does prescribing narrow-spectrum antibiotics such as amoxicillin, cephalexin, or trimethoprim-sulfamethoxazole.⁷ Yet between 2007 and 2009, broad-spectrum agents were prescribed for 61% of outpatient adult visits in which patients received an antibiotic prescription.¹⁷ Quinolones (25%), macrolides (20%), and aminopenicillins (12%) were most commonly prescribed, and antibiotic prescriptions were most often written for respiratory conditions, such as bronchitis, for which we now know antibiotics are rarely indicated.¹⁷

Between 2006 and 2008, pediatric patients who received antibiotic prescriptions were given broad-spectrum agents 50% of the time, of which macrolides were the class most commonly prescribed.¹³

More recently, researchers examined the frequency with which clinicians prescribe narrow-spectrum, firstline antibiotics for otitis media, sinusitis, and pharyngitis using 2010 to 2011 NAMCS/NHAMCS data. They found that providers used firstline agents recommended by professional guidelines 52% of the time, although it was estimated that they would have been appropriate in 80% of cases; pediatric patients were more likely to receive appropriate firstline antibiotics than adult patients.¹⁹ Macrolides, especially azithromycin, were the most common non-firstline antibiotics prescribed.^19,20 The bottom line is that when antibiotics are indicated for upper respiratory infections (otitis media, sinusitis, and pharyngitis), clinicians should prescribe a narrow-spectrum antibiotic first.

ANTIBIOTIC OVERPRESCIBING AFFECTS THE GUT AND BEYOND

The human intestinal microbiome is composed of a diverse array of bacteria, viruses, and parasites.²¹ The main functions of the gut microbiome include interacting with the immune system and participating in biochemical reactions in the gut, such as absorption of fat-soluble vitamins and the production of vitamin K.

As we know, antibiotics decrease the diversity of gut bacteria, which, in turn, can cause less efficient nutrient extraction, as well as vulnerability to enteric infections.²¹ It is well known, for example, that the bacterial gut microbiome can either inhibit or promote diarrheal illnesses such as those caused by CDI. CDI is now the most common health care-related infection, accounting for about a half-million health care facility infections per year.²² It extends hospital stays an average of almost 10 days and is estimated to cost the health care system $6.3 billion annually.²³

Antibiotics can also eliminate antibiotic-susceptible organisms, allowing resistant organisms to proliferate.⁴ They also promote the transmission of genes for antibiotic resistance between gut bacteria.⁴

Beyond the gut

Less well known is that gut bacteria can promote or inhibit extraintestinal infections.

Gut bacteria and HIV. In early HIV infections, for example, gut populations of Lactobacillus and Bifidobacteria are reduced, and the gut barrier becomes compromised.²⁴ Increasing translocation of bacterial products is associated with HIV disease progression. Preservation of Lactobacillus populations in the gut is associated with markers predictive of better HIV outcomes, including a higher CD4 count, a lower viral load, and less evidence of gut microbial translocation.²⁴ This underscores the importance of maintaining healthy gut flora in patients with HIV, using such steps as avoiding unnecessary antibiotics.

Gut bacteria and stress, depression. Antibiotics directly induce the expression of key genes that affect the stress response.²⁵ While causative studies are lacking, there is a growing body of evidence suggesting that the gut microbiome is involved in two-way communication with the brain and can affect, and be affected by, stress and depression.^21,26-30 Diseases and conditions that seem to have a putative connection to a disordered microbiome (dysbiosis) include depression, anxiety, Crohn disease, type 2 diabetes, and obesity. (For a discussion of the relationship between the gut microbiome and diabetes, see Endocrine Consult: The Gut Microbiome in Type 2 Diabetes.)

Gut bacteria and childhood obesity. Repeated use of broader-spectrum antibiotics in children younger than 24 months of age increases the risk for childhood obesity.^1,6 One theory for the association is that the effects of broad-spectrum antibiotics on the intestinal flora of young children may alter long-term energy homeostasis, resulting in a higher risk for obesity.¹

Gut bacteria and asthma. Studies demonstrate differences in the gut microbiomes of asthmatic and nonasthmatic patients. These differences affect the activities of helper T-cell subsets (Th1 and Th2), which in turn affect the development of immune tolerance.³¹

Although additional studies are needed to confirm these findings, the evidence collected thus far should make us all pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

WHAT CAN WE DO RIGHT NOW?

The issues created by the inappropriate prescribing of antibiotics have been known for decades, and multiple attempts have been made to find solutions and implement change. Although some small successes have occurred, little overall progress has been made in reducing antibiotic prescribing in the general population. A historical review of why clinicians prescribe antibiotics inappropriately and the interventions that have successfully reduced this prescribing may prove valuable as we continue to look for new, effective answers.

Why do we overprescribe antibiotics? A 2015 systematic literature review found that patient demand, pharmaceutical company marketing activities, limited up-to-date information sources, and fear of losing patients are major reasons providers cite for prescribing antibiotics.³²

In a separate study that explored antibiotic prescribing habits for acute bronchitis, clinicians cited “patient demand” as the major reason for prescribing antibiotics. Respondents also reported that “other physicians were responsible for inappropriate antibiotic prescribing.”³³

Strategies that work

Some early intervention programs directed at reducing antibiotic prescribing demonstrated success (see Table 2).^34-36

One example comes from a 1996-1998 study of four primary care practices.³⁴ Researchers evaluated the impact of a multidimensional intervention effort targeted at clinicians and patients and aimed at lowering the use of antimicrobial agents for acute uncomplicated bronchitis in adults. It incorporated multiple elements, including office-based and household patient educational materials and a clinician intervention involving education, practice profiling, and academic detailing. Clinicians in this program reduced their rates of antibiotic prescribing for uncomplicated bronchitis from 74% to 48%.³⁴

Employing EMRs. A more recent study focused on use of electronic medical rec­ords (EMRs) and communications to modify clinician antibiotic prescribing.³⁵ By sending clinicians monthly emails comparing their prescribing patterns to those of peers and “typical top performers,” inappropriate antibiotic prescriptions for ARTIs went from 19.9% to 3.7%.³⁵

In another effort, the same researchers modified providers’ EMRs to detect when potentially inappropriate antibiotics were prescribed. The system then prompted the clinician to provide an “antibiotic justification note,” which remained visible in the patient’s chart. This approach, which encouraged providers to follow prescribing guidelines by capitalizing on their concerns about their reputations, produced a 77% reduction in antibiotic prescribing.³⁵

Focusing on the public. Studies have also examined the effectiveness of educating the public about when antibiotics are not likely to be helpful and of the harms of unnecessary antibiotics.

Studies conducted in Tennessee and Wisconsin that combined prescriber and community education about unnecessary antibiotics for children found that the intervention reduced antibiotic prescribing in both locations by about 19%, compared with about a 9% reduction in the control groups.^36,37

DOES PRESCRIBING ANTIBIOTICS AFFECT PATIENT SATISFACTION?

The results are mixed as to whether prescribing antibiotics affects patient satisfaction. Two studies in the early 2000s found that both patients and parents reported higher satisfaction with clinicians who explained why antibiotics were not indicated versus those who simply prescribed them—and that such explanations do not need to take a lot of time (see Table 3 for patient care tips).^37,38

A more recent study found that higher antibiotic prescribing practices in Britain were associated with modestly higher patient satisfaction ratings.³⁹ The authors of this study noted, however, that reduced antibiotic prescribing may be a proxy for other practice patterns that affected satisfaction ratings.

REDUCING ANTIBIOTIC PRESCRIBING REDUCES RESISTANCE

There is also strong evidence that when clinicians decrease antibiotic prescribing, antimicrobial resistance follows suit. One of the earlier landmark studies to demonstrate this was a Finnish study published in 1997.⁴⁰ The authors found that a reduction of macrolide antibiotic consumption in Finland led to a reduction in streptococci macrolide resistance from 16.5% to 8.6%.⁴⁰

Multiple studies have since demonstrated similar results for both respiratory and urinary tract infections.^41,42 A 2017 meta-analysis of 32 studies found that antibiotic stewardship programs reduced the incidence of infections and colonization with multidrug-resistant Gram-negative bacteria (by 51%), extended-spectrum beta-lactamase–producing Gram-negative bacteria (48%), and methicillin-resistant Staphylococcus aureus (37%). There was also a reduction in the incidence of CDI (32%).⁴³

Despite universal agreement that antibiotic overprescribing is a problem, the practice continues to vex us. Antibiotic use—whether appropriate or not—has been linked to rising rates of antimicrobial resistance, disruption of the gut microbiome leading to Clostridium difficile infections (CDI), allergic reactions, and increased health care costs (see Table 1).^1-6 And yet, clinicians continue to overprescribe this class of medication.

A 2016 report from the CDC estimates that at least 30% of antibiotics prescribed in US outpatient settings are unnecessary.⁷ Another report cites a slightly higher figure across a variety of health care settings.⁸ Pair these findings with the fact that there are currently few new drugs in development to target resistant bacteria, and you have the potential for a postantibiotic era in which common infections could become lethal.⁷

In 2003, the CDC launched its “Get Smart: Know When Antibiotics Work” program (now known as “Be Antibiotics Aware”), focused on decreasing inappropriate antibiotic use in the outpatient setting.⁹ In 2015, the White House released the National Action Plan for Combating Antibiotic-Resistant Bacteria, with a goal of decreasing inappropriate outpatient antibiotic use by 50% and inappropriate inpatient use by 20% by 2020.¹⁰ And, on an international level, the World Health Organization (WHO) in 2015 developed a five-year strategic framework for implementing its Global Action Plan on Antimicrobial Resistance.¹¹

Family practitioners are on the front lines of this battle. Here’s what we can do now.

WHEN AND WHERE ARE ANTIBIOTICS MOST OFTEN INAPPROPRIATELY PRESCRIBED?

The diagnosis leading to the most frequent inappropriate prescribing of antibiotics is acute respiratory tract infection (ARTI), which includes bronchitis, otitis media, pharyngitis, sinusitis, tonsillitis, the common cold, and pneumonia. Up to 40% of antibiotic prescriptions for these conditions are unnecessary.^8,12 Bronchitis is the most common ARTI diagnosis associated with inappropriate antibiotic prescriptions, while sinusitis, suppurative otitis media, and pharyngitis are the diagnoses associated with the lion’s share of all (appropriate and inappropriate) antibiotic prescriptions within the ARTI category.^8,9,12,13 Refer to national clinical guidelines, which delineate when antibiotic treatment is appropriate for these conditions.^14-16

With respect to setting, there are conflicting findings as to whether antibiotic prescribing differs in office-based versus emergency department (ED) settings.

• One study found a higher rate of antibiotic prescribing during ED visits than office visits (21% vs 9%), even though, between 2007 and 2009, more antibiotic prescriptions were written for adults in primary care offices than in either outpatient hospital clinics or EDs.¹⁷
• In a cross-sectional study using data from 2005 to 2010 National Ambulatory Medical Care Surveys (NAMCS) and National Hospital Ambulatory Medical Care Surveys (NHAMCS), more than half of patients with uncomplicated acute rhinosinu­sitis received a prescription for antibiotics, but there was no overall difference in antibiotic prescriptions between primary care and ED presentation.¹⁸
• A retrospective analysis found that between 2006 and 2010, outpatient hospital practices (56%) and community-practice offices (60%) prescribed more antibiotics for ARTIs than EDs did (51%).¹²

STICK TO NARROW-SPECTRUM AGENTS WHEN POSSIBLE

Using broad-spectrum antibiotics, such as quinolones or imipenem, firstline, contributes more to the problem of antibiotic resistance than does prescribing narrow-spectrum antibiotics such as amoxicillin, cephalexin, or trimethoprim-sulfamethoxazole.⁷ Yet between 2007 and 2009, broad-spectrum agents were prescribed for 61% of outpatient adult visits in which patients received an antibiotic prescription.¹⁷ Quinolones (25%), macrolides (20%), and aminopenicillins (12%) were most commonly prescribed, and antibiotic prescriptions were most often written for respiratory conditions, such as bronchitis, for which we now know antibiotics are rarely indicated.¹⁷

Between 2006 and 2008, pediatric patients who received antibiotic prescriptions were given broad-spectrum agents 50% of the time, of which macrolides were the class most commonly prescribed.¹³

More recently, researchers examined the frequency with which clinicians prescribe narrow-spectrum, firstline antibiotics for otitis media, sinusitis, and pharyngitis using 2010 to 2011 NAMCS/NHAMCS data. They found that providers used firstline agents recommended by professional guidelines 52% of the time, although it was estimated that they would have been appropriate in 80% of cases; pediatric patients were more likely to receive appropriate firstline antibiotics than adult patients.¹⁹ Macrolides, especially azithromycin, were the most common non-firstline antibiotics prescribed.^19,20 The bottom line is that when antibiotics are indicated for upper respiratory infections (otitis media, sinusitis, and pharyngitis), clinicians should prescribe a narrow-spectrum antibiotic first.

ANTIBIOTIC OVERPRESCIBING AFFECTS THE GUT AND BEYOND

The human intestinal microbiome is composed of a diverse array of bacteria, viruses, and parasites.²¹ The main functions of the gut microbiome include interacting with the immune system and participating in biochemical reactions in the gut, such as absorption of fat-soluble vitamins and the production of vitamin K.

As we know, antibiotics decrease the diversity of gut bacteria, which, in turn, can cause less efficient nutrient extraction, as well as vulnerability to enteric infections.²¹ It is well known, for example, that the bacterial gut microbiome can either inhibit or promote diarrheal illnesses such as those caused by CDI. CDI is now the most common health care-related infection, accounting for about a half-million health care facility infections per year.²² It extends hospital stays an average of almost 10 days and is estimated to cost the health care system $6.3 billion annually.²³

Antibiotics can also eliminate antibiotic-susceptible organisms, allowing resistant organisms to proliferate.⁴ They also promote the transmission of genes for antibiotic resistance between gut bacteria.⁴

Beyond the gut

Less well known is that gut bacteria can promote or inhibit extraintestinal infections.

Gut bacteria and HIV. In early HIV infections, for example, gut populations of Lactobacillus and Bifidobacteria are reduced, and the gut barrier becomes compromised.²⁴ Increasing translocation of bacterial products is associated with HIV disease progression. Preservation of Lactobacillus populations in the gut is associated with markers predictive of better HIV outcomes, including a higher CD4 count, a lower viral load, and less evidence of gut microbial translocation.²⁴ This underscores the importance of maintaining healthy gut flora in patients with HIV, using such steps as avoiding unnecessary antibiotics.

Gut bacteria and stress, depression. Antibiotics directly induce the expression of key genes that affect the stress response.²⁵ While causative studies are lacking, there is a growing body of evidence suggesting that the gut microbiome is involved in two-way communication with the brain and can affect, and be affected by, stress and depression.^21,26-30 Diseases and conditions that seem to have a putative connection to a disordered microbiome (dysbiosis) include depression, anxiety, Crohn disease, type 2 diabetes, and obesity. (For a discussion of the relationship between the gut microbiome and diabetes, see Endocrine Consult: The Gut Microbiome in Type 2 Diabetes.)

Gut bacteria and childhood obesity. Repeated use of broader-spectrum antibiotics in children younger than 24 months of age increases the risk for childhood obesity.^1,6 One theory for the association is that the effects of broad-spectrum antibiotics on the intestinal flora of young children may alter long-term energy homeostasis, resulting in a higher risk for obesity.¹

Gut bacteria and asthma. Studies demonstrate differences in the gut microbiomes of asthmatic and nonasthmatic patients. These differences affect the activities of helper T-cell subsets (Th1 and Th2), which in turn affect the development of immune tolerance.³¹

Although additional studies are needed to confirm these findings, the evidence collected thus far should make us all pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

WHAT CAN WE DO RIGHT NOW?

The issues created by the inappropriate prescribing of antibiotics have been known for decades, and multiple attempts have been made to find solutions and implement change. Although some small successes have occurred, little overall progress has been made in reducing antibiotic prescribing in the general population. A historical review of why clinicians prescribe antibiotics inappropriately and the interventions that have successfully reduced this prescribing may prove valuable as we continue to look for new, effective answers.

Why do we overprescribe antibiotics? A 2015 systematic literature review found that patient demand, pharmaceutical company marketing activities, limited up-to-date information sources, and fear of losing patients are major reasons providers cite for prescribing antibiotics.³²

In a separate study that explored antibiotic prescribing habits for acute bronchitis, clinicians cited “patient demand” as the major reason for prescribing antibiotics. Respondents also reported that “other physicians were responsible for inappropriate antibiotic prescribing.”³³

Strategies that work

Some early intervention programs directed at reducing antibiotic prescribing demonstrated success (see Table 2).^34-36

One example comes from a 1996-1998 study of four primary care practices.³⁴ Researchers evaluated the impact of a multidimensional intervention effort targeted at clinicians and patients and aimed at lowering the use of antimicrobial agents for acute uncomplicated bronchitis in adults. It incorporated multiple elements, including office-based and household patient educational materials and a clinician intervention involving education, practice profiling, and academic detailing. Clinicians in this program reduced their rates of antibiotic prescribing for uncomplicated bronchitis from 74% to 48%.³⁴

Employing EMRs. A more recent study focused on use of electronic medical rec­ords (EMRs) and communications to modify clinician antibiotic prescribing.³⁵ By sending clinicians monthly emails comparing their prescribing patterns to those of peers and “typical top performers,” inappropriate antibiotic prescriptions for ARTIs went from 19.9% to 3.7%.³⁵

In another effort, the same researchers modified providers’ EMRs to detect when potentially inappropriate antibiotics were prescribed. The system then prompted the clinician to provide an “antibiotic justification note,” which remained visible in the patient’s chart. This approach, which encouraged providers to follow prescribing guidelines by capitalizing on their concerns about their reputations, produced a 77% reduction in antibiotic prescribing.³⁵

Focusing on the public. Studies have also examined the effectiveness of educating the public about when antibiotics are not likely to be helpful and of the harms of unnecessary antibiotics.

Studies conducted in Tennessee and Wisconsin that combined prescriber and community education about unnecessary antibiotics for children found that the intervention reduced antibiotic prescribing in both locations by about 19%, compared with about a 9% reduction in the control groups.^36,37

DOES PRESCRIBING ANTIBIOTICS AFFECT PATIENT SATISFACTION?

The results are mixed as to whether prescribing antibiotics affects patient satisfaction. Two studies in the early 2000s found that both patients and parents reported higher satisfaction with clinicians who explained why antibiotics were not indicated versus those who simply prescribed them—and that such explanations do not need to take a lot of time (see Table 3 for patient care tips).^37,38

A more recent study found that higher antibiotic prescribing practices in Britain were associated with modestly higher patient satisfaction ratings.³⁹ The authors of this study noted, however, that reduced antibiotic prescribing may be a proxy for other practice patterns that affected satisfaction ratings.

REDUCING ANTIBIOTIC PRESCRIBING REDUCES RESISTANCE

There is also strong evidence that when clinicians decrease antibiotic prescribing, antimicrobial resistance follows suit. One of the earlier landmark studies to demonstrate this was a Finnish study published in 1997.⁴⁰ The authors found that a reduction of macrolide antibiotic consumption in Finland led to a reduction in streptococci macrolide resistance from 16.5% to 8.6%.⁴⁰

Multiple studies have since demonstrated similar results for both respiratory and urinary tract infections.^41,42 A 2017 meta-analysis of 32 studies found that antibiotic stewardship programs reduced the incidence of infections and colonization with multidrug-resistant Gram-negative bacteria (by 51%), extended-spectrum beta-lactamase–producing Gram-negative bacteria (48%), and methicillin-resistant Staphylococcus aureus (37%). There was also a reduction in the incidence of CDI (32%).⁴³

Despite universal agreement that antibiotic overprescribing is a problem, the practice continues to vex us. Antibiotic use—whether appropriate or not—has been linked to rising rates of antimicrobial resistance, disruption of the gut microbiome leading to Clostridium difficile infections (CDI), allergic reactions, and increased health care costs (see Table 1).^1-6 And yet, clinicians continue to overprescribe this class of medication.

A 2016 report from the CDC estimates that at least 30% of antibiotics prescribed in US outpatient settings are unnecessary.⁷ Another report cites a slightly higher figure across a variety of health care settings.⁸ Pair these findings with the fact that there are currently few new drugs in development to target resistant bacteria, and you have the potential for a postantibiotic era in which common infections could become lethal.⁷

In 2003, the CDC launched its “Get Smart: Know When Antibiotics Work” program (now known as “Be Antibiotics Aware”), focused on decreasing inappropriate antibiotic use in the outpatient setting.⁹ In 2015, the White House released the National Action Plan for Combating Antibiotic-Resistant Bacteria, with a goal of decreasing inappropriate outpatient antibiotic use by 50% and inappropriate inpatient use by 20% by 2020.¹⁰ And, on an international level, the World Health Organization (WHO) in 2015 developed a five-year strategic framework for implementing its Global Action Plan on Antimicrobial Resistance.¹¹

Family practitioners are on the front lines of this battle. Here’s what we can do now.

WHEN AND WHERE ARE ANTIBIOTICS MOST OFTEN INAPPROPRIATELY PRESCRIBED?

The diagnosis leading to the most frequent inappropriate prescribing of antibiotics is acute respiratory tract infection (ARTI), which includes bronchitis, otitis media, pharyngitis, sinusitis, tonsillitis, the common cold, and pneumonia. Up to 40% of antibiotic prescriptions for these conditions are unnecessary.^8,12 Bronchitis is the most common ARTI diagnosis associated with inappropriate antibiotic prescriptions, while sinusitis, suppurative otitis media, and pharyngitis are the diagnoses associated with the lion’s share of all (appropriate and inappropriate) antibiotic prescriptions within the ARTI category.^8,9,12,13 Refer to national clinical guidelines, which delineate when antibiotic treatment is appropriate for these conditions.^14-16

With respect to setting, there are conflicting findings as to whether antibiotic prescribing differs in office-based versus emergency department (ED) settings.

• One study found a higher rate of antibiotic prescribing during ED visits than office visits (21% vs 9%), even though, between 2007 and 2009, more antibiotic prescriptions were written for adults in primary care offices than in either outpatient hospital clinics or EDs.¹⁷
• In a cross-sectional study using data from 2005 to 2010 National Ambulatory Medical Care Surveys (NAMCS) and National Hospital Ambulatory Medical Care Surveys (NHAMCS), more than half of patients with uncomplicated acute rhinosinu­sitis received a prescription for antibiotics, but there was no overall difference in antibiotic prescriptions between primary care and ED presentation.¹⁸
• A retrospective analysis found that between 2006 and 2010, outpatient hospital practices (56%) and community-practice offices (60%) prescribed more antibiotics for ARTIs than EDs did (51%).¹²

STICK TO NARROW-SPECTRUM AGENTS WHEN POSSIBLE

Using broad-spectrum antibiotics, such as quinolones or imipenem, firstline, contributes more to the problem of antibiotic resistance than does prescribing narrow-spectrum antibiotics such as amoxicillin, cephalexin, or trimethoprim-sulfamethoxazole.⁷ Yet between 2007 and 2009, broad-spectrum agents were prescribed for 61% of outpatient adult visits in which patients received an antibiotic prescription.¹⁷ Quinolones (25%), macrolides (20%), and aminopenicillins (12%) were most commonly prescribed, and antibiotic prescriptions were most often written for respiratory conditions, such as bronchitis, for which we now know antibiotics are rarely indicated.¹⁷

Between 2006 and 2008, pediatric patients who received antibiotic prescriptions were given broad-spectrum agents 50% of the time, of which macrolides were the class most commonly prescribed.¹³

More recently, researchers examined the frequency with which clinicians prescribe narrow-spectrum, firstline antibiotics for otitis media, sinusitis, and pharyngitis using 2010 to 2011 NAMCS/NHAMCS data. They found that providers used firstline agents recommended by professional guidelines 52% of the time, although it was estimated that they would have been appropriate in 80% of cases; pediatric patients were more likely to receive appropriate firstline antibiotics than adult patients.¹⁹ Macrolides, especially azithromycin, were the most common non-firstline antibiotics prescribed.^19,20 The bottom line is that when antibiotics are indicated for upper respiratory infections (otitis media, sinusitis, and pharyngitis), clinicians should prescribe a narrow-spectrum antibiotic first.

ANTIBIOTIC OVERPRESCIBING AFFECTS THE GUT AND BEYOND

The human intestinal microbiome is composed of a diverse array of bacteria, viruses, and parasites.²¹ The main functions of the gut microbiome include interacting with the immune system and participating in biochemical reactions in the gut, such as absorption of fat-soluble vitamins and the production of vitamin K.

As we know, antibiotics decrease the diversity of gut bacteria, which, in turn, can cause less efficient nutrient extraction, as well as vulnerability to enteric infections.²¹ It is well known, for example, that the bacterial gut microbiome can either inhibit or promote diarrheal illnesses such as those caused by CDI. CDI is now the most common health care-related infection, accounting for about a half-million health care facility infections per year.²² It extends hospital stays an average of almost 10 days and is estimated to cost the health care system $6.3 billion annually.²³

Antibiotics can also eliminate antibiotic-susceptible organisms, allowing resistant organisms to proliferate.⁴ They also promote the transmission of genes for antibiotic resistance between gut bacteria.⁴

Beyond the gut

Less well known is that gut bacteria can promote or inhibit extraintestinal infections.

Gut bacteria and HIV. In early HIV infections, for example, gut populations of Lactobacillus and Bifidobacteria are reduced, and the gut barrier becomes compromised.²⁴ Increasing translocation of bacterial products is associated with HIV disease progression. Preservation of Lactobacillus populations in the gut is associated with markers predictive of better HIV outcomes, including a higher CD4 count, a lower viral load, and less evidence of gut microbial translocation.²⁴ This underscores the importance of maintaining healthy gut flora in patients with HIV, using such steps as avoiding unnecessary antibiotics.

Gut bacteria and stress, depression. Antibiotics directly induce the expression of key genes that affect the stress response.²⁵ While causative studies are lacking, there is a growing body of evidence suggesting that the gut microbiome is involved in two-way communication with the brain and can affect, and be affected by, stress and depression.^21,26-30 Diseases and conditions that seem to have a putative connection to a disordered microbiome (dysbiosis) include depression, anxiety, Crohn disease, type 2 diabetes, and obesity. (For a discussion of the relationship between the gut microbiome and diabetes, see Endocrine Consult: The Gut Microbiome in Type 2 Diabetes.)

Gut bacteria and childhood obesity. Repeated use of broader-spectrum antibiotics in children younger than 24 months of age increases the risk for childhood obesity.^1,6 One theory for the association is that the effects of broad-spectrum antibiotics on the intestinal flora of young children may alter long-term energy homeostasis, resulting in a higher risk for obesity.¹

Gut bacteria and asthma. Studies demonstrate differences in the gut microbiomes of asthmatic and nonasthmatic patients. These differences affect the activities of helper T-cell subsets (Th1 and Th2), which in turn affect the development of immune tolerance.³¹

Although additional studies are needed to confirm these findings, the evidence collected thus far should make us all pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

WHAT CAN WE DO RIGHT NOW?

The issues created by the inappropriate prescribing of antibiotics have been known for decades, and multiple attempts have been made to find solutions and implement change. Although some small successes have occurred, little overall progress has been made in reducing antibiotic prescribing in the general population. A historical review of why clinicians prescribe antibiotics inappropriately and the interventions that have successfully reduced this prescribing may prove valuable as we continue to look for new, effective answers.

Why do we overprescribe antibiotics? A 2015 systematic literature review found that patient demand, pharmaceutical company marketing activities, limited up-to-date information sources, and fear of losing patients are major reasons providers cite for prescribing antibiotics.³²

In a separate study that explored antibiotic prescribing habits for acute bronchitis, clinicians cited “patient demand” as the major reason for prescribing antibiotics. Respondents also reported that “other physicians were responsible for inappropriate antibiotic prescribing.”³³

Strategies that work

Some early intervention programs directed at reducing antibiotic prescribing demonstrated success (see Table 2).^34-36

One example comes from a 1996-1998 study of four primary care practices.³⁴ Researchers evaluated the impact of a multidimensional intervention effort targeted at clinicians and patients and aimed at lowering the use of antimicrobial agents for acute uncomplicated bronchitis in adults. It incorporated multiple elements, including office-based and household patient educational materials and a clinician intervention involving education, practice profiling, and academic detailing. Clinicians in this program reduced their rates of antibiotic prescribing for uncomplicated bronchitis from 74% to 48%.³⁴

Employing EMRs. A more recent study focused on use of electronic medical rec­ords (EMRs) and communications to modify clinician antibiotic prescribing.³⁵ By sending clinicians monthly emails comparing their prescribing patterns to those of peers and “typical top performers,” inappropriate antibiotic prescriptions for ARTIs went from 19.9% to 3.7%.³⁵

In another effort, the same researchers modified providers’ EMRs to detect when potentially inappropriate antibiotics were prescribed. The system then prompted the clinician to provide an “antibiotic justification note,” which remained visible in the patient’s chart. This approach, which encouraged providers to follow prescribing guidelines by capitalizing on their concerns about their reputations, produced a 77% reduction in antibiotic prescribing.³⁵

Focusing on the public. Studies have also examined the effectiveness of educating the public about when antibiotics are not likely to be helpful and of the harms of unnecessary antibiotics.

Studies conducted in Tennessee and Wisconsin that combined prescriber and community education about unnecessary antibiotics for children found that the intervention reduced antibiotic prescribing in both locations by about 19%, compared with about a 9% reduction in the control groups.^36,37

DOES PRESCRIBING ANTIBIOTICS AFFECT PATIENT SATISFACTION?

The results are mixed as to whether prescribing antibiotics affects patient satisfaction. Two studies in the early 2000s found that both patients and parents reported higher satisfaction with clinicians who explained why antibiotics were not indicated versus those who simply prescribed them—and that such explanations do not need to take a lot of time (see Table 3 for patient care tips).^37,38

A more recent study found that higher antibiotic prescribing practices in Britain were associated with modestly higher patient satisfaction ratings.³⁹ The authors of this study noted, however, that reduced antibiotic prescribing may be a proxy for other practice patterns that affected satisfaction ratings.

REDUCING ANTIBIOTIC PRESCRIBING REDUCES RESISTANCE

There is also strong evidence that when clinicians decrease antibiotic prescribing, antimicrobial resistance follows suit. One of the earlier landmark studies to demonstrate this was a Finnish study published in 1997.⁴⁰ The authors found that a reduction of macrolide antibiotic consumption in Finland led to a reduction in streptococci macrolide resistance from 16.5% to 8.6%.⁴⁰

Multiple studies have since demonstrated similar results for both respiratory and urinary tract infections.^41,42 A 2017 meta-analysis of 32 studies found that antibiotic stewardship programs reduced the incidence of infections and colonization with multidrug-resistant Gram-negative bacteria (by 51%), extended-spectrum beta-lactamase–producing Gram-negative bacteria (48%), and methicillin-resistant Staphylococcus aureus (37%). There was also a reduction in the incidence of CDI (32%).⁴³

Clinical questions: What are the trends in patient outcome for Staphylococcus aureus bacteremia (SAB)? Does the use of evidence-based care processes decrease mortality in SAB?

Background: SAB is associated with poor clinical outcomes. Prior research has demonstrated that several evidence-based interventions, namely appropriate antibiotics, echocardiography, and infectious disease consults, have been associated with improved outcomes. The use of these interventions in clinical practice and their large-scale impact on SAB mortality is not known.

Clinical questions: What are the trends in patient outcome for Staphylococcus aureus bacteremia (SAB)? Does the use of evidence-based care processes decrease mortality in SAB?

Background: SAB is associated with poor clinical outcomes. Prior research has demonstrated that several evidence-based interventions, namely appropriate antibiotics, echocardiography, and infectious disease consults, have been associated with improved outcomes. The use of these interventions in clinical practice and their large-scale impact on SAB mortality is not known.

Clinical questions: What are the trends in patient outcome for Staphylococcus aureus bacteremia (SAB)? Does the use of evidence-based care processes decrease mortality in SAB?

Background: SAB is associated with poor clinical outcomes. Prior research has demonstrated that several evidence-based interventions, namely appropriate antibiotics, echocardiography, and infectious disease consults, have been associated with improved outcomes. The use of these interventions in clinical practice and their large-scale impact on SAB mortality is not known.

Why are you bothering to read this? What could I offer that could possibly be useful to you? In fact, I was invited to write this column simply because I happened to be at the right conference at the right time. Soon, if not already, you’ll discover I’m actually not that clever. I’m an impostor.

I’ve thought this while staring at the blank page that is to be my article for the month. Reflecting on it, I realize you’ve probably had the same feelings of fraud at one time or another. Impostor syndrome is common. It is the experience of believing you don’t deserve a role or success despite evidence to the contrary. It often occurs at moments of transition, such as when you were accepted into medical school or matched into a competitive specialty. Looking at your peers, watching how your colleagues perform, you feel you just aren’t smart enough to be there; either someone made a mistake or you just got lucky.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

Why are you bothering to read this? What could I offer that could possibly be useful to you? In fact, I was invited to write this column simply because I happened to be at the right conference at the right time. Soon, if not already, you’ll discover I’m actually not that clever. I’m an impostor.

I’ve thought this while staring at the blank page that is to be my article for the month. Reflecting on it, I realize you’ve probably had the same feelings of fraud at one time or another. Impostor syndrome is common. It is the experience of believing you don’t deserve a role or success despite evidence to the contrary. It often occurs at moments of transition, such as when you were accepted into medical school or matched into a competitive specialty. Looking at your peers, watching how your colleagues perform, you feel you just aren’t smart enough to be there; either someone made a mistake or you just got lucky.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

Why are you bothering to read this? What could I offer that could possibly be useful to you? In fact, I was invited to write this column simply because I happened to be at the right conference at the right time. Soon, if not already, you’ll discover I’m actually not that clever. I’m an impostor.

I’ve thought this while staring at the blank page that is to be my article for the month. Reflecting on it, I realize you’ve probably had the same feelings of fraud at one time or another. Impostor syndrome is common. It is the experience of believing you don’t deserve a role or success despite evidence to the contrary. It often occurs at moments of transition, such as when you were accepted into medical school or matched into a competitive specialty. Looking at your peers, watching how your colleagues perform, you feel you just aren’t smart enough to be there; either someone made a mistake or you just got lucky.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

The Diagnosis: Hypopigmented Mycosis Fungoides

The patient was started on clobetasol dipropionate cream 0.05% twice daily, which she did not tolerate due to a burning sensation on application. She then was started on narrowband UVB phototherapy 2 to 3 times weekly, and the hypopigmented areas began to improve. Narrowband UVB phototherapy was discontinued after 7 weeks due to the high cost to the patient, but the hypopigmented patches on the left thigh appeared to remit, and the patient did not return to the clinic for 6 months. She returned when the areas on the left thigh reappeared, along with new areas on the right buttock and right medial upper arm. Serial biopsies of the new patches also revealed a CD8⁺ atypical lymphocytic infiltrate consistent with hypopigmented patch-stage mycosis fungoides (MF). She was started on halobetasol ointment 0.05% twice daily to affected areas, which she tolerated well. Complete blood count and peripheral blood smear were unremarkable, and the patient continued to deny systemic symptoms. Over the next year, the patient's cutaneous findings continued to wax and wane with topical treatment, and she was referred to a regional cancer treatment center for a second opinion from a hematopathologist. Hematopathologic and dermatopathologic review of the case, including hematoxylin and eosin and immunohistochemical staining, was highly consistent with hypopigmented MF (Figures 1-3).

Mycosis fungoides is an uncommon disease characterized by atypical clonal T cells exhibiting epidermotropism. Most commonly, MF is characterized by a CD4⁺ lymphocytic infiltrate. Mycosis fungoides can be difficult to diagnose in its early stages, as it may resemble benign inflammatory conditions (eg, chronic atopic dermatitis, nummular eczema) and often requires biopsy and additional studies, such as immunohistochemistry, to secure a diagnosis. Hypopigmented MF is regarded as a subtype of MF, as it can exhibit different clinical and pathologic characteristics from classical MF. In particular, the lymphocytic phenotype in hypopigmented MF is more likely to be CD8⁺. 

In general, the progression of MF is characterized as stage IA (patches or plaques involving less than 10% body surface area [BSA]), IB (patches or plaques involving ≥10% BSA without lymph node or visceral involvement), IIA (patches or plaques of any percentage of BSA with lymph node involvement), IIB (cutaneous tumors with or without lymph node involvement), III (erythroderma with low blood tumor burden), or IV (erythroderma with high blood tumor burden with or without visceral involvement). Hypopigmented MF generally presents in early patch stage and rarely progresses past stage IB, and thus generally has a favorable prognosis.^1,2 Kim et al³ demonstrated that evolution from patch to plaque stage MF is accompanied by a shift in lymphocytes from the T helper 1 (Th1) to T helper 2 phenotype; therefore the Th1 phenotype, CD8⁺ T cells are associated with lower risk for disease progression. Other investigators also have hypothesized that predominance of Th1 phenotype, CD8⁺ T cells may have an immunoregulatory effect, thus preventing evolution of disease from patch to plaque stage and explaining why hypopigmented MF, with a predominantly CD8⁺ phenotype, confers better prognosis with less chance for disease progression than classical MF.^4,5 The patch- or plaque-stage lesions of classical MF have a predilection for non-sun exposed areas (eg, buttocks, medial thighs, breasts),² whereas hypopigmented MF tends to present with hypopigmented or depigmented lesions mainly distributed on the trunk, arms, and legs. These lesions may become more visible following sun exposure.¹ The size of the hypopigmented lesions can vary, and patients may complain of pruritus with variable intensity.

Hypopigmented MF presents more commonly in younger populations, in contrast to classical MF.^6-8 However, like classical MF, hypopigmented MF appears to more frequently affect individuals with darker Fitzpatrick skin types.^1,9,10 Although it generally is accepted that hypopigmented MF does not favor either sex, some studies suggest that hypopigmented MF has a female predominance.^6,10

Classical MF is characterized by an epidermotropic infiltrate of CD4⁺ T helper cells,¹⁰ whereas CD8⁺ epidermotropism is considered hallmark in hypopigmented MF.^10-12 The other typical histopathologic features of hypopigmented MF generally are identical to those of classical MF, with solitary or small groups of atypical haloed lymphocytes within the basal layer, exocytosis of lymphocytes out of proportion to spongiosis, and papillary dermal fibrosis. Immunohistochemistry generally is helpful in distinguishing between classical MF and hypopigmented MF.

The clinical differential diagnosis for hypopigmented MF includes the early (inflammatory) stage of vitiligo, postinflammatory hypopigmentation, lichen sclerosus, pityriasis alba, and leprosy.

First-line treatment for hypopigmented MF consists of phototherapy/photochemotherapy and topical steroids.^9,13 Narrowband UVB phototherapy has been used with good success in pediatric patients.¹⁴ However, narrowband UVB may not be as effective in darker-skinned individuals; it has been hypothesized that this lack of efficacy could be due to the protective effects of increased melanin in the skin.¹ Other topical therapies may include topical carmustine and topical nitrogen mustard.

The Diagnosis: Hypopigmented Mycosis Fungoides

The patient was started on clobetasol dipropionate cream 0.05% twice daily, which she did not tolerate due to a burning sensation on application. She then was started on narrowband UVB phototherapy 2 to 3 times weekly, and the hypopigmented areas began to improve. Narrowband UVB phototherapy was discontinued after 7 weeks due to the high cost to the patient, but the hypopigmented patches on the left thigh appeared to remit, and the patient did not return to the clinic for 6 months. She returned when the areas on the left thigh reappeared, along with new areas on the right buttock and right medial upper arm. Serial biopsies of the new patches also revealed a CD8⁺ atypical lymphocytic infiltrate consistent with hypopigmented patch-stage mycosis fungoides (MF). She was started on halobetasol ointment 0.05% twice daily to affected areas, which she tolerated well. Complete blood count and peripheral blood smear were unremarkable, and the patient continued to deny systemic symptoms. Over the next year, the patient's cutaneous findings continued to wax and wane with topical treatment, and she was referred to a regional cancer treatment center for a second opinion from a hematopathologist. Hematopathologic and dermatopathologic review of the case, including hematoxylin and eosin and immunohistochemical staining, was highly consistent with hypopigmented MF (Figures 1-3).

Mycosis fungoides is an uncommon disease characterized by atypical clonal T cells exhibiting epidermotropism. Most commonly, MF is characterized by a CD4⁺ lymphocytic infiltrate. Mycosis fungoides can be difficult to diagnose in its early stages, as it may resemble benign inflammatory conditions (eg, chronic atopic dermatitis, nummular eczema) and often requires biopsy and additional studies, such as immunohistochemistry, to secure a diagnosis. Hypopigmented MF is regarded as a subtype of MF, as it can exhibit different clinical and pathologic characteristics from classical MF. In particular, the lymphocytic phenotype in hypopigmented MF is more likely to be CD8⁺. 

In general, the progression of MF is characterized as stage IA (patches or plaques involving less than 10% body surface area [BSA]), IB (patches or plaques involving ≥10% BSA without lymph node or visceral involvement), IIA (patches or plaques of any percentage of BSA with lymph node involvement), IIB (cutaneous tumors with or without lymph node involvement), III (erythroderma with low blood tumor burden), or IV (erythroderma with high blood tumor burden with or without visceral involvement). Hypopigmented MF generally presents in early patch stage and rarely progresses past stage IB, and thus generally has a favorable prognosis.^1,2 Kim et al³ demonstrated that evolution from patch to plaque stage MF is accompanied by a shift in lymphocytes from the T helper 1 (Th1) to T helper 2 phenotype; therefore the Th1 phenotype, CD8⁺ T cells are associated with lower risk for disease progression. Other investigators also have hypothesized that predominance of Th1 phenotype, CD8⁺ T cells may have an immunoregulatory effect, thus preventing evolution of disease from patch to plaque stage and explaining why hypopigmented MF, with a predominantly CD8⁺ phenotype, confers better prognosis with less chance for disease progression than classical MF.^4,5 The patch- or plaque-stage lesions of classical MF have a predilection for non-sun exposed areas (eg, buttocks, medial thighs, breasts),² whereas hypopigmented MF tends to present with hypopigmented or depigmented lesions mainly distributed on the trunk, arms, and legs. These lesions may become more visible following sun exposure.¹ The size of the hypopigmented lesions can vary, and patients may complain of pruritus with variable intensity.

Hypopigmented MF presents more commonly in younger populations, in contrast to classical MF.^6-8 However, like classical MF, hypopigmented MF appears to more frequently affect individuals with darker Fitzpatrick skin types.^1,9,10 Although it generally is accepted that hypopigmented MF does not favor either sex, some studies suggest that hypopigmented MF has a female predominance.^6,10

Classical MF is characterized by an epidermotropic infiltrate of CD4⁺ T helper cells,¹⁰ whereas CD8⁺ epidermotropism is considered hallmark in hypopigmented MF.^10-12 The other typical histopathologic features of hypopigmented MF generally are identical to those of classical MF, with solitary or small groups of atypical haloed lymphocytes within the basal layer, exocytosis of lymphocytes out of proportion to spongiosis, and papillary dermal fibrosis. Immunohistochemistry generally is helpful in distinguishing between classical MF and hypopigmented MF.

The clinical differential diagnosis for hypopigmented MF includes the early (inflammatory) stage of vitiligo, postinflammatory hypopigmentation, lichen sclerosus, pityriasis alba, and leprosy.

First-line treatment for hypopigmented MF consists of phototherapy/photochemotherapy and topical steroids.^9,13 Narrowband UVB phototherapy has been used with good success in pediatric patients.¹⁴ However, narrowband UVB may not be as effective in darker-skinned individuals; it has been hypothesized that this lack of efficacy could be due to the protective effects of increased melanin in the skin.¹ Other topical therapies may include topical carmustine and topical nitrogen mustard.

The Diagnosis: Hypopigmented Mycosis Fungoides

The patient was started on clobetasol dipropionate cream 0.05% twice daily, which she did not tolerate due to a burning sensation on application. She then was started on narrowband UVB phototherapy 2 to 3 times weekly, and the hypopigmented areas began to improve. Narrowband UVB phototherapy was discontinued after 7 weeks due to the high cost to the patient, but the hypopigmented patches on the left thigh appeared to remit, and the patient did not return to the clinic for 6 months. She returned when the areas on the left thigh reappeared, along with new areas on the right buttock and right medial upper arm. Serial biopsies of the new patches also revealed a CD8⁺ atypical lymphocytic infiltrate consistent with hypopigmented patch-stage mycosis fungoides (MF). She was started on halobetasol ointment 0.05% twice daily to affected areas, which she tolerated well. Complete blood count and peripheral blood smear were unremarkable, and the patient continued to deny systemic symptoms. Over the next year, the patient's cutaneous findings continued to wax and wane with topical treatment, and she was referred to a regional cancer treatment center for a second opinion from a hematopathologist. Hematopathologic and dermatopathologic review of the case, including hematoxylin and eosin and immunohistochemical staining, was highly consistent with hypopigmented MF (Figures 1-3).

Mycosis fungoides is an uncommon disease characterized by atypical clonal T cells exhibiting epidermotropism. Most commonly, MF is characterized by a CD4⁺ lymphocytic infiltrate. Mycosis fungoides can be difficult to diagnose in its early stages, as it may resemble benign inflammatory conditions (eg, chronic atopic dermatitis, nummular eczema) and often requires biopsy and additional studies, such as immunohistochemistry, to secure a diagnosis. Hypopigmented MF is regarded as a subtype of MF, as it can exhibit different clinical and pathologic characteristics from classical MF. In particular, the lymphocytic phenotype in hypopigmented MF is more likely to be CD8⁺. 

In general, the progression of MF is characterized as stage IA (patches or plaques involving less than 10% body surface area [BSA]), IB (patches or plaques involving ≥10% BSA without lymph node or visceral involvement), IIA (patches or plaques of any percentage of BSA with lymph node involvement), IIB (cutaneous tumors with or without lymph node involvement), III (erythroderma with low blood tumor burden), or IV (erythroderma with high blood tumor burden with or without visceral involvement). Hypopigmented MF generally presents in early patch stage and rarely progresses past stage IB, and thus generally has a favorable prognosis.^1,2 Kim et al³ demonstrated that evolution from patch to plaque stage MF is accompanied by a shift in lymphocytes from the T helper 1 (Th1) to T helper 2 phenotype; therefore the Th1 phenotype, CD8⁺ T cells are associated with lower risk for disease progression. Other investigators also have hypothesized that predominance of Th1 phenotype, CD8⁺ T cells may have an immunoregulatory effect, thus preventing evolution of disease from patch to plaque stage and explaining why hypopigmented MF, with a predominantly CD8⁺ phenotype, confers better prognosis with less chance for disease progression than classical MF.^4,5 The patch- or plaque-stage lesions of classical MF have a predilection for non-sun exposed areas (eg, buttocks, medial thighs, breasts),² whereas hypopigmented MF tends to present with hypopigmented or depigmented lesions mainly distributed on the trunk, arms, and legs. These lesions may become more visible following sun exposure.¹ The size of the hypopigmented lesions can vary, and patients may complain of pruritus with variable intensity.

Hypopigmented MF presents more commonly in younger populations, in contrast to classical MF.^6-8 However, like classical MF, hypopigmented MF appears to more frequently affect individuals with darker Fitzpatrick skin types.^1,9,10 Although it generally is accepted that hypopigmented MF does not favor either sex, some studies suggest that hypopigmented MF has a female predominance.^6,10

Classical MF is characterized by an epidermotropic infiltrate of CD4⁺ T helper cells,¹⁰ whereas CD8⁺ epidermotropism is considered hallmark in hypopigmented MF.^10-12 The other typical histopathologic features of hypopigmented MF generally are identical to those of classical MF, with solitary or small groups of atypical haloed lymphocytes within the basal layer, exocytosis of lymphocytes out of proportion to spongiosis, and papillary dermal fibrosis. Immunohistochemistry generally is helpful in distinguishing between classical MF and hypopigmented MF.

The clinical differential diagnosis for hypopigmented MF includes the early (inflammatory) stage of vitiligo, postinflammatory hypopigmentation, lichen sclerosus, pityriasis alba, and leprosy.

First-line treatment for hypopigmented MF consists of phototherapy/photochemotherapy and topical steroids.^9,13 Narrowband UVB phototherapy has been used with good success in pediatric patients.¹⁴ However, narrowband UVB may not be as effective in darker-skinned individuals; it has been hypothesized that this lack of efficacy could be due to the protective effects of increased melanin in the skin.¹ Other topical therapies may include topical carmustine and topical nitrogen mustard.

KAUAI, HAWAII – The novel interleukin-17 inhibitor bimekizumab achieved “remarkable” outcomes for moderate to severe plaque psoriasis in the phase 2b BE ABLE study.

And that’s not all: Much the same was true in patients with psoriatic arthritis in the parallel phase 2b BE ACTIVE study and for ankylosing spondylitis in the BE AGILE study. BE ABLE was a double-blind, 12-week, multicenter, five-arm, placebo-controlled, dose-ranging study of 250 psoriasis patients randomized to various doses of subcutaneous bimekizumab or placebo every 4 weeks. The primary outcome – the PASI 90 response rate at 12 weeks, rather than the lower-bar PASI 75 endpoint more typically used in clinical trials – was 79% at the optimal dose. The PASI 100 rate – complete clearance of disease – at 12 weeks was 60%, Craig L. Leonardi, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
 

Bruce Jancin/Frontline Medical News

[email protected]

KAUAI, HAWAII – The novel interleukin-17 inhibitor bimekizumab achieved “remarkable” outcomes for moderate to severe plaque psoriasis in the phase 2b BE ABLE study.

And that’s not all: Much the same was true in patients with psoriatic arthritis in the parallel phase 2b BE ACTIVE study and for ankylosing spondylitis in the BE AGILE study. BE ABLE was a double-blind, 12-week, multicenter, five-arm, placebo-controlled, dose-ranging study of 250 psoriasis patients randomized to various doses of subcutaneous bimekizumab or placebo every 4 weeks. The primary outcome – the PASI 90 response rate at 12 weeks, rather than the lower-bar PASI 75 endpoint more typically used in clinical trials – was 79% at the optimal dose. The PASI 100 rate – complete clearance of disease – at 12 weeks was 60%, Craig L. Leonardi, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
 

Bruce Jancin/Frontline Medical News

[email protected]

KAUAI, HAWAII – The novel interleukin-17 inhibitor bimekizumab achieved “remarkable” outcomes for moderate to severe plaque psoriasis in the phase 2b BE ABLE study.

And that’s not all: Much the same was true in patients with psoriatic arthritis in the parallel phase 2b BE ACTIVE study and for ankylosing spondylitis in the BE AGILE study. BE ABLE was a double-blind, 12-week, multicenter, five-arm, placebo-controlled, dose-ranging study of 250 psoriasis patients randomized to various doses of subcutaneous bimekizumab or placebo every 4 weeks. The primary outcome – the PASI 90 response rate at 12 weeks, rather than the lower-bar PASI 75 endpoint more typically used in clinical trials – was 79% at the optimal dose. The PASI 100 rate – complete clearance of disease – at 12 weeks was 60%, Craig L. Leonardi, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
 

Bruce Jancin/Frontline Medical News

[email protected]

Virtual reality–based cognitive-behavioral therapy could help reduce momentary paranoia and anxiety, and improve social cognition in individuals with psychotic disorders.

Researchers reported the results of a randomized controlled trial of personalized virtual reality-based cognitive-behavioral therapy in 116 patients with a DSM IV–diagnosed psychotic disorder and paranoid ideation in an article published online Feb. 8 in Lancet Psychiatry.

SOURCE: Lancet Psychiatry. 2018 Feb 8. doi: 10.1016/S2215-0366(18)30053-1.

Virtual reality–based cognitive-behavioral therapy could help reduce momentary paranoia and anxiety, and improve social cognition in individuals with psychotic disorders.

Researchers reported the results of a randomized controlled trial of personalized virtual reality-based cognitive-behavioral therapy in 116 patients with a DSM IV–diagnosed psychotic disorder and paranoid ideation in an article published online Feb. 8 in Lancet Psychiatry.

SOURCE: Lancet Psychiatry. 2018 Feb 8. doi: 10.1016/S2215-0366(18)30053-1.

Virtual reality–based cognitive-behavioral therapy could help reduce momentary paranoia and anxiety, and improve social cognition in individuals with psychotic disorders.

Researchers reported the results of a randomized controlled trial of personalized virtual reality-based cognitive-behavioral therapy in 116 patients with a DSM IV–diagnosed psychotic disorder and paranoid ideation in an article published online Feb. 8 in Lancet Psychiatry.

SOURCE: Lancet Psychiatry. 2018 Feb 8. doi: 10.1016/S2215-0366(18)30053-1.

LAS VEGAS – In the clinical opinion of Edward V. Loftus Jr., MD, biologics for inflammatory bowel disease (IBD) patients are best positioned based on age, personal medical history, and the presence of extraintestinal manifestations.

“An algorithmic treatment regimen guided by biomarkers of inflammation in addition to symptoms results in higher rates of endoscopic healing, and is the way to go if you’re trying to change the trajectory of illness,” Dr. Loftus said at the Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

In general, patients who are younger at diagnosis are going to have more severe disease than patients diagnosed older, said Dr. Loftus, professor of medicine at the Mayo Clinic, Rochester, Minn. “For CD [Crohn’s disease], the presence of fistulizing disease, especially internal fistulas, and to a lesser extent perianal fistulas, and then the presence of small-bowel disease or proximal GI disease, are all harbingers of more aggressive disease,” he said. “Multiple studies show that the time interval between diagnosis and development of intestinal complications is shorter in patients with small-bowel disease relative to colonic disease. When you add up those factors, you’re talking about 70% of CD patients, if not more. Most Crohn’s patients are going to be high-risk patients.”

For ulcerative colitis (UC), being male is a risk factor for hospitalization, surgery, and for developing colon cancer. On average, males are twice as likely as females to require surgery, and they’re twice as likely to develop colon cancer. Other predictors in UC for high-risk disease include early need for hospitalization, early need for corticosteroids, and extensive colitis at diagnosis. “You’re thinking about these things because how you’re going to treat these patients is going to differ,” he said.

According to Dr. Loftus, aminosalicylate (5-ASA) drugs are the frontline drugs of choice for low-risk UC patients with mild symptoms. “If they’re having moderate symptoms, you might initially start with a corticosteroid taper,” he noted. “That can be either prednisone or budesonide MMX. In a patient with really active symptoms, they’re going to go to IV steroids or maybe directly to anti-TNF [tumor necrosis factor] therapy.” For low-risk CD patients, consider budesonide taper then observation. “If they don’t flare again, maybe monitor that patient periodically,” he advised. “For high-risk patients, consider biologic therapy with or without thiopurine or methotrexate.”

A recent analysis of Medicare and Medicaid data from 2006 to 2013 found a significantly higher rate of mortality in IBD patients treated with prolonged corticosteroids than that seen in those treated with anti-TNF therapy (Am J Gastroenterol. Jan 16, 2018. doi: 10.1038/ajg2017.479). “That should give you pause,” Dr. Loftus said. “Don’t just put your patient on prednisone because you think it’s the easiest and safest thing to do. It’s not. It’s much more dangerous and has implications [for] the patient’s life expectancy.”

Some data are beginning to emerge about the use of biosimilars in IBD, mostly from Europe. Investigators of one randomized, controlled trial of biosimilar CT-P13 vs. originator infliximab in CD presented at the 2017 Digestive Disease Week meeting; they found in their trial that at week 6 all clinical endpoints were similar between the two agents. “If you’re forced to change your patient to this particular biosimilar, I wouldn’t be too worried about it,” Dr. Loftus said. “Of course, I’m not necessarily going to switch unless my institution or a particular third-party payer mandate it.”

In a published study funded by the Norwegian government, researchers conducted a prospective trial of switching from infliximab to CT-P13 in patients with a variety of conditions (Lancet. 2017;389:2304-16). Overall, the clinical failure rate was the same for both agents. Among CD patients, the researchers observed a nonsignificant trend toward disease worsening among those on the biosimilar, “but there was essentially no difference,” Dr. Loftus said.

He went on to discuss vedolizumab, a monoclonal antibody to alpha₄beta₇ integrin approved in 2014 for patients with moderate to severely active UC or CD. Phase 3 data from GEMINI I in moderate to severe UC found that relevant clinical endpoints were met by week 6 and they persisted at week 52 at both doses (N Engl J Med. 2013;369[8]:699-710). “For CD, the use of vedolizumab is a bit of a mixed picture,” Dr. Loftus said. “In GEMINI II, some of the primary endpoints were met at week 6, but at least one was missed (N Engl J Med. 2013;369[8]:711-21). The same thing was seen in GEMINI III. There’s a sense here that vedolizumab takes a little bit longer to work in CD.”

Integrated safety analyses of the GEMINI trials found no signal for increased rates of serious adverse events, and no cases of progressive multifocal leukoencephalopathy have been reported (J Crohns Colitis. 2017;11[2]:185-90). “The risk factors for serious infections were prior anti-TNF failure and opioid analgesic use in UC patients and younger age, steroid use, and opioid analgesic use in CD patients,” Dr. Loftus said.

In a trial of CD patients failing anti-TNF therapy, researchers observed a robust clinical response with ustekinumab, compared with placebo, at week 6 (N Engl J Med. 2016;375:1946-60). Even greater effects were observed in UNITI-2, a trial of ustekinumab in CD patients who hadn’t failed anti-TNFs.

Dr. Loftus cautioned that elderly and immunocompromised patients face an increased risk for infections when they’re placed on anti-TNF therapy. At the same time, researchers used a French database to determine the risk of lymphoma in IBD patients stratified by medication. For patients unexposed to such therapies, the risk of lymphoma was 1:4,000. For patients on thiopurine monotherapy, the risk was about 1:2,000; it was about 1:2,500 for those on anti-TNF monotherapy and about 1:1,000 for those on combination therapy (JAMA. 2017;318:1679-86). “One of the messages in this study is we can reassure our more risk-averse patients that the absolute risk of lymphoma is very low, even among patients on combination therapy,” he said.

Dr. Loftus called for head-to-head trials comparing the individual biologic agents and shared his recommendations on how to position currently available therapies. “I would say that for the average ‘bread and butter’ Crohn’s patient, anti-TNF therapy is the way to go,” he said. “For perianal fistulizing patients, I’m going to go with anti-TNF therapy, such as infliximab or adalimumab. For a patient with active extraintestinal manifestations, such as spondyloarthropathy, uveitis, and pyoderma, anti-TNF therapy is the way to go. However, with an elderly or immunosuppressed patient, consider vedolizumab or ustekinumab. For patients with a personal history of malignancy, an anti-TNF is very reasonable, but it may be easier to convince them to consider vedolizumab or ustekinumab.”

Recommendations for UC are largely similar, he continued. “However, I think we have enough data from GEMINI I and the integrated safety data with vedolizumab to say that, for the average ‘bread and butter’ UC patient, anti-TNF therapy or vedolizumab are appropriate. For a patient with extraintestinal manifestations I would avoid vedolizumab initially and try anti-TNF therapy. For patients with acute severe colitis, we have the bulk of evidence for efficacy resting with infliximab, so I would go with that. For the elderly or immunosuppressed patient, I would go with vedolizumab. For the person with a history of malignancy, an anti-TNF agent is reasonable, but consider vedolizumab.”

Dr. Loftus disclosed that he has consulted for AbbVie, Takeda Pharmaceutical, Janssen Pharmaceutica, UCB, Pfizer, Amgen, Eli Lilly, Celltrion Healthcare, Napo Pharmaceuticals. He has also received research support from AbbVie, Takeda Pharmaceutical, Janssen Pharmaceutica, UCB, Pfizer, Amgen, Genentech, Seres Pharmaceuticals, MedImmune, Allergan, and Robarts Clinical Trials.

*This story was updated on 3/26.

[email protected]

LAS VEGAS – In the clinical opinion of Edward V. Loftus Jr., MD, biologics for inflammatory bowel disease (IBD) patients are best positioned based on age, personal medical history, and the presence of extraintestinal manifestations.

“An algorithmic treatment regimen guided by biomarkers of inflammation in addition to symptoms results in higher rates of endoscopic healing, and is the way to go if you’re trying to change the trajectory of illness,” Dr. Loftus said at the Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

In general, patients who are younger at diagnosis are going to have more severe disease than patients diagnosed older, said Dr. Loftus, professor of medicine at the Mayo Clinic, Rochester, Minn. “For CD [Crohn’s disease], the presence of fistulizing disease, especially internal fistulas, and to a lesser extent perianal fistulas, and then the presence of small-bowel disease or proximal GI disease, are all harbingers of more aggressive disease,” he said. “Multiple studies show that the time interval between diagnosis and development of intestinal complications is shorter in patients with small-bowel disease relative to colonic disease. When you add up those factors, you’re talking about 70% of CD patients, if not more. Most Crohn’s patients are going to be high-risk patients.”

For ulcerative colitis (UC), being male is a risk factor for hospitalization, surgery, and for developing colon cancer. On average, males are twice as likely as females to require surgery, and they’re twice as likely to develop colon cancer. Other predictors in UC for high-risk disease include early need for hospitalization, early need for corticosteroids, and extensive colitis at diagnosis. “You’re thinking about these things because how you’re going to treat these patients is going to differ,” he said.

According to Dr. Loftus, aminosalicylate (5-ASA) drugs are the frontline drugs of choice for low-risk UC patients with mild symptoms. “If they’re having moderate symptoms, you might initially start with a corticosteroid taper,” he noted. “That can be either prednisone or budesonide MMX. In a patient with really active symptoms, they’re going to go to IV steroids or maybe directly to anti-TNF [tumor necrosis factor] therapy.” For low-risk CD patients, consider budesonide taper then observation. “If they don’t flare again, maybe monitor that patient periodically,” he advised. “For high-risk patients, consider biologic therapy with or without thiopurine or methotrexate.”

A recent analysis of Medicare and Medicaid data from 2006 to 2013 found a significantly higher rate of mortality in IBD patients treated with prolonged corticosteroids than that seen in those treated with anti-TNF therapy (Am J Gastroenterol. Jan 16, 2018. doi: 10.1038/ajg2017.479). “That should give you pause,” Dr. Loftus said. “Don’t just put your patient on prednisone because you think it’s the easiest and safest thing to do. It’s not. It’s much more dangerous and has implications [for] the patient’s life expectancy.”

Some data are beginning to emerge about the use of biosimilars in IBD, mostly from Europe. Investigators of one randomized, controlled trial of biosimilar CT-P13 vs. originator infliximab in CD presented at the 2017 Digestive Disease Week meeting; they found in their trial that at week 6 all clinical endpoints were similar between the two agents. “If you’re forced to change your patient to this particular biosimilar, I wouldn’t be too worried about it,” Dr. Loftus said. “Of course, I’m not necessarily going to switch unless my institution or a particular third-party payer mandate it.”

In a published study funded by the Norwegian government, researchers conducted a prospective trial of switching from infliximab to CT-P13 in patients with a variety of conditions (Lancet. 2017;389:2304-16). Overall, the clinical failure rate was the same for both agents. Among CD patients, the researchers observed a nonsignificant trend toward disease worsening among those on the biosimilar, “but there was essentially no difference,” Dr. Loftus said.

He went on to discuss vedolizumab, a monoclonal antibody to alpha₄beta₇ integrin approved in 2014 for patients with moderate to severely active UC or CD. Phase 3 data from GEMINI I in moderate to severe UC found that relevant clinical endpoints were met by week 6 and they persisted at week 52 at both doses (N Engl J Med. 2013;369[8]:699-710). “For CD, the use of vedolizumab is a bit of a mixed picture,” Dr. Loftus said. “In GEMINI II, some of the primary endpoints were met at week 6, but at least one was missed (N Engl J Med. 2013;369[8]:711-21). The same thing was seen in GEMINI III. There’s a sense here that vedolizumab takes a little bit longer to work in CD.”

Integrated safety analyses of the GEMINI trials found no signal for increased rates of serious adverse events, and no cases of progressive multifocal leukoencephalopathy have been reported (J Crohns Colitis. 2017;11[2]:185-90). “The risk factors for serious infections were prior anti-TNF failure and opioid analgesic use in UC patients and younger age, steroid use, and opioid analgesic use in CD patients,” Dr. Loftus said.

In a trial of CD patients failing anti-TNF therapy, researchers observed a robust clinical response with ustekinumab, compared with placebo, at week 6 (N Engl J Med. 2016;375:1946-60). Even greater effects were observed in UNITI-2, a trial of ustekinumab in CD patients who hadn’t failed anti-TNFs.

Dr. Loftus cautioned that elderly and immunocompromised patients face an increased risk for infections when they’re placed on anti-TNF therapy. At the same time, researchers used a French database to determine the risk of lymphoma in IBD patients stratified by medication. For patients unexposed to such therapies, the risk of lymphoma was 1:4,000. For patients on thiopurine monotherapy, the risk was about 1:2,000; it was about 1:2,500 for those on anti-TNF monotherapy and about 1:1,000 for those on combination therapy (JAMA. 2017;318:1679-86). “One of the messages in this study is we can reassure our more risk-averse patients that the absolute risk of lymphoma is very low, even among patients on combination therapy,” he said.

Dr. Loftus called for head-to-head trials comparing the individual biologic agents and shared his recommendations on how to position currently available therapies. “I would say that for the average ‘bread and butter’ Crohn’s patient, anti-TNF therapy is the way to go,” he said. “For perianal fistulizing patients, I’m going to go with anti-TNF therapy, such as infliximab or adalimumab. For a patient with active extraintestinal manifestations, such as spondyloarthropathy, uveitis, and pyoderma, anti-TNF therapy is the way to go. However, with an elderly or immunosuppressed patient, consider vedolizumab or ustekinumab. For patients with a personal history of malignancy, an anti-TNF is very reasonable, but it may be easier to convince them to consider vedolizumab or ustekinumab.”

Recommendations for UC are largely similar, he continued. “However, I think we have enough data from GEMINI I and the integrated safety data with vedolizumab to say that, for the average ‘bread and butter’ UC patient, anti-TNF therapy or vedolizumab are appropriate. For a patient with extraintestinal manifestations I would avoid vedolizumab initially and try anti-TNF therapy. For patients with acute severe colitis, we have the bulk of evidence for efficacy resting with infliximab, so I would go with that. For the elderly or immunosuppressed patient, I would go with vedolizumab. For the person with a history of malignancy, an anti-TNF agent is reasonable, but consider vedolizumab.”

Dr. Loftus disclosed that he has consulted for AbbVie, Takeda Pharmaceutical, Janssen Pharmaceutica, UCB, Pfizer, Amgen, Eli Lilly, Celltrion Healthcare, Napo Pharmaceuticals. He has also received research support from AbbVie, Takeda Pharmaceutical, Janssen Pharmaceutica, UCB, Pfizer, Amgen, Genentech, Seres Pharmaceuticals, MedImmune, Allergan, and Robarts Clinical Trials.

*This story was updated on 3/26.

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LAS VEGAS – In the clinical opinion of Edward V. Loftus Jr., MD, biologics for inflammatory bowel disease (IBD) patients are best positioned based on age, personal medical history, and the presence of extraintestinal manifestations.

“An algorithmic treatment regimen guided by biomarkers of inflammation in addition to symptoms results in higher rates of endoscopic healing, and is the way to go if you’re trying to change the trajectory of illness,” Dr. Loftus said at the Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

In general, patients who are younger at diagnosis are going to have more severe disease than patients diagnosed older, said Dr. Loftus, professor of medicine at the Mayo Clinic, Rochester, Minn. “For CD [Crohn’s disease], the presence of fistulizing disease, especially internal fistulas, and to a lesser extent perianal fistulas, and then the presence of small-bowel disease or proximal GI disease, are all harbingers of more aggressive disease,” he said. “Multiple studies show that the time interval between diagnosis and development of intestinal complications is shorter in patients with small-bowel disease relative to colonic disease. When you add up those factors, you’re talking about 70% of CD patients, if not more. Most Crohn’s patients are going to be high-risk patients.”

For ulcerative colitis (UC), being male is a risk factor for hospitalization, surgery, and for developing colon cancer. On average, males are twice as likely as females to require surgery, and they’re twice as likely to develop colon cancer. Other predictors in UC for high-risk disease include early need for hospitalization, early need for corticosteroids, and extensive colitis at diagnosis. “You’re thinking about these things because how you’re going to treat these patients is going to differ,” he said.

According to Dr. Loftus, aminosalicylate (5-ASA) drugs are the frontline drugs of choice for low-risk UC patients with mild symptoms. “If they’re having moderate symptoms, you might initially start with a corticosteroid taper,” he noted. “That can be either prednisone or budesonide MMX. In a patient with really active symptoms, they’re going to go to IV steroids or maybe directly to anti-TNF [tumor necrosis factor] therapy.” For low-risk CD patients, consider budesonide taper then observation. “If they don’t flare again, maybe monitor that patient periodically,” he advised. “For high-risk patients, consider biologic therapy with or without thiopurine or methotrexate.”

A recent analysis of Medicare and Medicaid data from 2006 to 2013 found a significantly higher rate of mortality in IBD patients treated with prolonged corticosteroids than that seen in those treated with anti-TNF therapy (Am J Gastroenterol. Jan 16, 2018. doi: 10.1038/ajg2017.479). “That should give you pause,” Dr. Loftus said. “Don’t just put your patient on prednisone because you think it’s the easiest and safest thing to do. It’s not. It’s much more dangerous and has implications [for] the patient’s life expectancy.”

Some data are beginning to emerge about the use of biosimilars in IBD, mostly from Europe. Investigators of one randomized, controlled trial of biosimilar CT-P13 vs. originator infliximab in CD presented at the 2017 Digestive Disease Week meeting; they found in their trial that at week 6 all clinical endpoints were similar between the two agents. “If you’re forced to change your patient to this particular biosimilar, I wouldn’t be too worried about it,” Dr. Loftus said. “Of course, I’m not necessarily going to switch unless my institution or a particular third-party payer mandate it.”

In a published study funded by the Norwegian government, researchers conducted a prospective trial of switching from infliximab to CT-P13 in patients with a variety of conditions (Lancet. 2017;389:2304-16). Overall, the clinical failure rate was the same for both agents. Among CD patients, the researchers observed a nonsignificant trend toward disease worsening among those on the biosimilar, “but there was essentially no difference,” Dr. Loftus said.

He went on to discuss vedolizumab, a monoclonal antibody to alpha₄beta₇ integrin approved in 2014 for patients with moderate to severely active UC or CD. Phase 3 data from GEMINI I in moderate to severe UC found that relevant clinical endpoints were met by week 6 and they persisted at week 52 at both doses (N Engl J Med. 2013;369[8]:699-710). “For CD, the use of vedolizumab is a bit of a mixed picture,” Dr. Loftus said. “In GEMINI II, some of the primary endpoints were met at week 6, but at least one was missed (N Engl J Med. 2013;369[8]:711-21). The same thing was seen in GEMINI III. There’s a sense here that vedolizumab takes a little bit longer to work in CD.”

Integrated safety analyses of the GEMINI trials found no signal for increased rates of serious adverse events, and no cases of progressive multifocal leukoencephalopathy have been reported (J Crohns Colitis. 2017;11[2]:185-90). “The risk factors for serious infections were prior anti-TNF failure and opioid analgesic use in UC patients and younger age, steroid use, and opioid analgesic use in CD patients,” Dr. Loftus said.

In a trial of CD patients failing anti-TNF therapy, researchers observed a robust clinical response with ustekinumab, compared with placebo, at week 6 (N Engl J Med. 2016;375:1946-60). Even greater effects were observed in UNITI-2, a trial of ustekinumab in CD patients who hadn’t failed anti-TNFs.

Dr. Loftus cautioned that elderly and immunocompromised patients face an increased risk for infections when they’re placed on anti-TNF therapy. At the same time, researchers used a French database to determine the risk of lymphoma in IBD patients stratified by medication. For patients unexposed to such therapies, the risk of lymphoma was 1:4,000. For patients on thiopurine monotherapy, the risk was about 1:2,000; it was about 1:2,500 for those on anti-TNF monotherapy and about 1:1,000 for those on combination therapy (JAMA. 2017;318:1679-86). “One of the messages in this study is we can reassure our more risk-averse patients that the absolute risk of lymphoma is very low, even among patients on combination therapy,” he said.

Dr. Loftus called for head-to-head trials comparing the individual biologic agents and shared his recommendations on how to position currently available therapies. “I would say that for the average ‘bread and butter’ Crohn’s patient, anti-TNF therapy is the way to go,” he said. “For perianal fistulizing patients, I’m going to go with anti-TNF therapy, such as infliximab or adalimumab. For a patient with active extraintestinal manifestations, such as spondyloarthropathy, uveitis, and pyoderma, anti-TNF therapy is the way to go. However, with an elderly or immunosuppressed patient, consider vedolizumab or ustekinumab. For patients with a personal history of malignancy, an anti-TNF is very reasonable, but it may be easier to convince them to consider vedolizumab or ustekinumab.”

Recommendations for UC are largely similar, he continued. “However, I think we have enough data from GEMINI I and the integrated safety data with vedolizumab to say that, for the average ‘bread and butter’ UC patient, anti-TNF therapy or vedolizumab are appropriate. For a patient with extraintestinal manifestations I would avoid vedolizumab initially and try anti-TNF therapy. For patients with acute severe colitis, we have the bulk of evidence for efficacy resting with infliximab, so I would go with that. For the elderly or immunosuppressed patient, I would go with vedolizumab. For the person with a history of malignancy, an anti-TNF agent is reasonable, but consider vedolizumab.”

Dr. Loftus disclosed that he has consulted for AbbVie, Takeda Pharmaceutical, Janssen Pharmaceutica, UCB, Pfizer, Amgen, Eli Lilly, Celltrion Healthcare, Napo Pharmaceuticals. He has also received research support from AbbVie, Takeda Pharmaceutical, Janssen Pharmaceutica, UCB, Pfizer, Amgen, Genentech, Seres Pharmaceuticals, MedImmune, Allergan, and Robarts Clinical Trials.

*This story was updated on 3/26.

[email protected]