Michele G. Sullivan

AT ECCMID 2016

AMSTERDAM – Daptomycin successfully treated infective endocarditis in 90% of patients who developed it after undergoing heart valve replacement, according to a report presented at the annual congress of the European Society of Clinical Microbiology and Infectious Diseases.

Dr. Achyut Guleri, clinical director of laboratory medicine at Blackpool Victoria Hospital, Lancashire, England, said the lipopeptide antibiotic was equally effective against methicillin- and penicillin-resistant Staphylococcus aureus, coagulase-negative staphylococcus, and enterococci.

“This is particularly good to know because sometimes in real life, on the shop floor, you don’t always have a very clear insight into what you’re trying to treat,” said Dr. Guleri. “It’s reassuring to see that the success rate is similar in all these infections.”

He presented a subgroup analysis of patients enrolled in European Cubicin Outcomes Registry and Experience (EUCORE), a retrospective, noninterventional, postmarketing registry. The 4-year study reported real-world clinical experience of daptomycin use for the treatment of Gram-positive infections in patients with infective endocarditis who had undergone heart valve replacement.

Typically, Dr. Guleri said, vancomycin, either alone or with rifampicin, is recommended for the infection. “However, with increasing antibiotic resistance, vancomycin doesn’t inspire much confidence, especially for MRSA infections,” he noted.

Daptomycin is increasingly employed as an alternative treatment. It exhibits rapid bactericidal activity against a wide range of Gram-positive pathogens, including MRSA. It’s approved for the treatment of right-sided infective endocarditis due to S. aureus, at a dose of 6 mg/kg per day. However, higher doses are now recommended by several international guidelines and are often used for hard-to-treat infections, Dr. Guleri said.

EUCORE comprised 6,075 patients from 18 countries who were enrolled from 2006 to 2012. Patients were followed until 2014. Of this group, 610 had infective endocarditis and 198 underwent valve replacement. Most were male (70%); mean age was 58 years. Medical comorbidities were common and included renal disease, sepsis, diabetes, pulmonary disease, gastrointestinal disease, cerebrovascular disease and inflammatory diseases.

Culture results were available for 87%. Of these, 68% were positive. The most common pathogen was S. aureus (37%). Half of these isolates were penicillin resistant and 35% were methicillin resistant. Enterococci were responsible for 14% of the infections, and coagulase-negative staph for 32%. The rest were caused by other pathogens.

Before trying daptomycin, most patients (83%) had already been treated with an antibiotic, which was employed in conjunction with another antibiotic in 77% of cases. The concomitant medications included rifampicin (31%), aminoglycosides (29%) and carbapenems (18%).

The overall clinical cure rate at 2 years was 90%. Daptomycin was equally effective in left- and right-sided disease, and was more effective in penicillin-resistant staph (95%) than methicillin-resistant staph (80%). The cure rate was also good in coagulase-negative staph (81%) and enterococci (75%).

High doses were more effective than low doses. At 4 mg/kg per day, the cure rate was 61%. At 6 mg/kg per day, it was 86%, and at more than 6 mg/kg per day, it was 90%.

Adverse events were rare (3%). Three patients developed increased creatine phosphokinase levels; one patient developed rhabdomyolysis and one developed cholestasis. Agranulocytosis developed in three patients and eosinophilic pneumonia in three. One patient developed a rash. No one discontinued the drug due to a side effect.

Dr. Guleri had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

AT ECCMID 2016

AMSTERDAM – Daptomycin successfully treated infective endocarditis in 90% of patients who developed it after undergoing heart valve replacement, according to a report presented at the annual congress of the European Society of Clinical Microbiology and Infectious Diseases.

Dr. Achyut Guleri, clinical director of laboratory medicine at Blackpool Victoria Hospital, Lancashire, England, said the lipopeptide antibiotic was equally effective against methicillin- and penicillin-resistant Staphylococcus aureus, coagulase-negative staphylococcus, and enterococci.

“This is particularly good to know because sometimes in real life, on the shop floor, you don’t always have a very clear insight into what you’re trying to treat,” said Dr. Guleri. “It’s reassuring to see that the success rate is similar in all these infections.”

He presented a subgroup analysis of patients enrolled in European Cubicin Outcomes Registry and Experience (EUCORE), a retrospective, noninterventional, postmarketing registry. The 4-year study reported real-world clinical experience of daptomycin use for the treatment of Gram-positive infections in patients with infective endocarditis who had undergone heart valve replacement.

Typically, Dr. Guleri said, vancomycin, either alone or with rifampicin, is recommended for the infection. “However, with increasing antibiotic resistance, vancomycin doesn’t inspire much confidence, especially for MRSA infections,” he noted.

Daptomycin is increasingly employed as an alternative treatment. It exhibits rapid bactericidal activity against a wide range of Gram-positive pathogens, including MRSA. It’s approved for the treatment of right-sided infective endocarditis due to S. aureus, at a dose of 6 mg/kg per day. However, higher doses are now recommended by several international guidelines and are often used for hard-to-treat infections, Dr. Guleri said.

EUCORE comprised 6,075 patients from 18 countries who were enrolled from 2006 to 2012. Patients were followed until 2014. Of this group, 610 had infective endocarditis and 198 underwent valve replacement. Most were male (70%); mean age was 58 years. Medical comorbidities were common and included renal disease, sepsis, diabetes, pulmonary disease, gastrointestinal disease, cerebrovascular disease and inflammatory diseases.

Culture results were available for 87%. Of these, 68% were positive. The most common pathogen was S. aureus (37%). Half of these isolates were penicillin resistant and 35% were methicillin resistant. Enterococci were responsible for 14% of the infections, and coagulase-negative staph for 32%. The rest were caused by other pathogens.

Before trying daptomycin, most patients (83%) had already been treated with an antibiotic, which was employed in conjunction with another antibiotic in 77% of cases. The concomitant medications included rifampicin (31%), aminoglycosides (29%) and carbapenems (18%).

The overall clinical cure rate at 2 years was 90%. Daptomycin was equally effective in left- and right-sided disease, and was more effective in penicillin-resistant staph (95%) than methicillin-resistant staph (80%). The cure rate was also good in coagulase-negative staph (81%) and enterococci (75%).

High doses were more effective than low doses. At 4 mg/kg per day, the cure rate was 61%. At 6 mg/kg per day, it was 86%, and at more than 6 mg/kg per day, it was 90%.

Adverse events were rare (3%). Three patients developed increased creatine phosphokinase levels; one patient developed rhabdomyolysis and one developed cholestasis. Agranulocytosis developed in three patients and eosinophilic pneumonia in three. One patient developed a rash. No one discontinued the drug due to a side effect.

Dr. Guleri had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

AT ECCMID 2016

AMSTERDAM – Daptomycin successfully treated infective endocarditis in 90% of patients who developed it after undergoing heart valve replacement, according to a report presented at the annual congress of the European Society of Clinical Microbiology and Infectious Diseases.

Dr. Achyut Guleri, clinical director of laboratory medicine at Blackpool Victoria Hospital, Lancashire, England, said the lipopeptide antibiotic was equally effective against methicillin- and penicillin-resistant Staphylococcus aureus, coagulase-negative staphylococcus, and enterococci.

“This is particularly good to know because sometimes in real life, on the shop floor, you don’t always have a very clear insight into what you’re trying to treat,” said Dr. Guleri. “It’s reassuring to see that the success rate is similar in all these infections.”

He presented a subgroup analysis of patients enrolled in European Cubicin Outcomes Registry and Experience (EUCORE), a retrospective, noninterventional, postmarketing registry. The 4-year study reported real-world clinical experience of daptomycin use for the treatment of Gram-positive infections in patients with infective endocarditis who had undergone heart valve replacement.

Typically, Dr. Guleri said, vancomycin, either alone or with rifampicin, is recommended for the infection. “However, with increasing antibiotic resistance, vancomycin doesn’t inspire much confidence, especially for MRSA infections,” he noted.

Daptomycin is increasingly employed as an alternative treatment. It exhibits rapid bactericidal activity against a wide range of Gram-positive pathogens, including MRSA. It’s approved for the treatment of right-sided infective endocarditis due to S. aureus, at a dose of 6 mg/kg per day. However, higher doses are now recommended by several international guidelines and are often used for hard-to-treat infections, Dr. Guleri said.

EUCORE comprised 6,075 patients from 18 countries who were enrolled from 2006 to 2012. Patients were followed until 2014. Of this group, 610 had infective endocarditis and 198 underwent valve replacement. Most were male (70%); mean age was 58 years. Medical comorbidities were common and included renal disease, sepsis, diabetes, pulmonary disease, gastrointestinal disease, cerebrovascular disease and inflammatory diseases.

Culture results were available for 87%. Of these, 68% were positive. The most common pathogen was S. aureus (37%). Half of these isolates were penicillin resistant and 35% were methicillin resistant. Enterococci were responsible for 14% of the infections, and coagulase-negative staph for 32%. The rest were caused by other pathogens.

Before trying daptomycin, most patients (83%) had already been treated with an antibiotic, which was employed in conjunction with another antibiotic in 77% of cases. The concomitant medications included rifampicin (31%), aminoglycosides (29%) and carbapenems (18%).

The overall clinical cure rate at 2 years was 90%. Daptomycin was equally effective in left- and right-sided disease, and was more effective in penicillin-resistant staph (95%) than methicillin-resistant staph (80%). The cure rate was also good in coagulase-negative staph (81%) and enterococci (75%).

High doses were more effective than low doses. At 4 mg/kg per day, the cure rate was 61%. At 6 mg/kg per day, it was 86%, and at more than 6 mg/kg per day, it was 90%.

Adverse events were rare (3%). Three patients developed increased creatine phosphokinase levels; one patient developed rhabdomyolysis and one developed cholestasis. Agranulocytosis developed in three patients and eosinophilic pneumonia in three. One patient developed a rash. No one discontinued the drug due to a side effect.

Dr. Guleri had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

AMSTERDAM – Neither cycling through a regular schedule of antibiotics on a unit-wide basis, nor randomly mixing them on a patient-level basis reduced the prevalence of antibiotic resistance in eight European intensive care units, a randomized study has determined.

Lead investigator Dr. Pleun Joppe van Duijn of University Medical Center Utrecht (the Netherlands), said he and his colleagues did, however, discover a few common sense findings that seemed to positively affect antibiotic resistance, including compliance with hand hygiene, shorter lengths of stay, staff ratio, and unit occupancy rate. He reported the results of his research at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

Edwin Verin/©Thinkstock

Many ICUs in Europe have one preferred empirical treatment strategy which, Dr. van Duijn said, may create selective pressure for a single resistance type. “An alternative to this is a program of antibiotic rotation,” he noted. “By constantly changing the preferred first-line treatment, selective pressure is constantly changing, which may reduce selection of antibiotic resistance.”

Dr. van Duijn and his colleagues examined this idea in a randomized crossover trial that compared antibiotic cycling and mixing. The protocols employed three antibiotic classes: third- and fourth-generation cephalosporins, piperacillin/tazobactam, and carbapenems. The trial was conducted in eight ICUs in Belgium, Germany, France, Slovenia, and Portugal.

The sites were randomized to two 9-month interventions of cycling or mixing antibiotics, with a 1-month washout period between the two interventions. In cycling protocol, the preferred empiric antibiotic was changed every 6 weeks. In the mixing protocol, every consecutive patient received a different antibiotic. However, treating physicians were allowed to deviate from any protocol for patient safety or to optimize treatment.

The primary endpoint was the monthly prevalence of perineal and/or respiratory carriage of two classes of bacteria:

• Enterobacteriaceae species that were piperacillin/tazobactam–resistant or that showed extended spectrum beta-lactamase production.

• Pseudomonas aeruginosa and Acinetobacter species that were either piperacillin/tazobactam– or carbapenem-resistant.

In all, 8,945 patients were involved, with 4,238 exposed to cycling and 4,707 to mixing. Patients were a mean of 62 years old, with a mean 7-day length of stay. About 4.5% were already colonized with resistant bacteria upon admission. A quarter were on contact isolation; 2% were on both droplet and respiratory isolation.

The overall mortality rate was 11% and did not differ between the cycling and mixing groups (10.9% vs. 11.6%). Antibiotic resistance developed in 22.6% of the cycling group and 21.5% of the mixing group – not a significant difference. Neither protocol significantly reduced over time the amount of antibiotic resistance that was observed in the baseline period.

A multivariate analysis did, however, find a few things associated with resistance prevalence. Women were about 58% less likely to develop a resistant bacterial strain than men. Patients who stayed less than 48 hours had a 38% decreased risk of developing a resistant strain. Good staff compliance with hand hygiene reduced the risk by 12%, and having one-on-one nursing reduced it by 53%.

The study was funded by the European Community’s Seventh Framework Programme. Dr. van Duijn had no financial declarations.

[email protected]

AMSTERDAM – Neither cycling through a regular schedule of antibiotics on a unit-wide basis, nor randomly mixing them on a patient-level basis reduced the prevalence of antibiotic resistance in eight European intensive care units, a randomized study has determined.

Lead investigator Dr. Pleun Joppe van Duijn of University Medical Center Utrecht (the Netherlands), said he and his colleagues did, however, discover a few common sense findings that seemed to positively affect antibiotic resistance, including compliance with hand hygiene, shorter lengths of stay, staff ratio, and unit occupancy rate. He reported the results of his research at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

Edwin Verin/©Thinkstock

Many ICUs in Europe have one preferred empirical treatment strategy which, Dr. van Duijn said, may create selective pressure for a single resistance type. “An alternative to this is a program of antibiotic rotation,” he noted. “By constantly changing the preferred first-line treatment, selective pressure is constantly changing, which may reduce selection of antibiotic resistance.”

Dr. van Duijn and his colleagues examined this idea in a randomized crossover trial that compared antibiotic cycling and mixing. The protocols employed three antibiotic classes: third- and fourth-generation cephalosporins, piperacillin/tazobactam, and carbapenems. The trial was conducted in eight ICUs in Belgium, Germany, France, Slovenia, and Portugal.

The sites were randomized to two 9-month interventions of cycling or mixing antibiotics, with a 1-month washout period between the two interventions. In cycling protocol, the preferred empiric antibiotic was changed every 6 weeks. In the mixing protocol, every consecutive patient received a different antibiotic. However, treating physicians were allowed to deviate from any protocol for patient safety or to optimize treatment.

The primary endpoint was the monthly prevalence of perineal and/or respiratory carriage of two classes of bacteria:

• Enterobacteriaceae species that were piperacillin/tazobactam–resistant or that showed extended spectrum beta-lactamase production.

• Pseudomonas aeruginosa and Acinetobacter species that were either piperacillin/tazobactam– or carbapenem-resistant.

In all, 8,945 patients were involved, with 4,238 exposed to cycling and 4,707 to mixing. Patients were a mean of 62 years old, with a mean 7-day length of stay. About 4.5% were already colonized with resistant bacteria upon admission. A quarter were on contact isolation; 2% were on both droplet and respiratory isolation.

The overall mortality rate was 11% and did not differ between the cycling and mixing groups (10.9% vs. 11.6%). Antibiotic resistance developed in 22.6% of the cycling group and 21.5% of the mixing group – not a significant difference. Neither protocol significantly reduced over time the amount of antibiotic resistance that was observed in the baseline period.

A multivariate analysis did, however, find a few things associated with resistance prevalence. Women were about 58% less likely to develop a resistant bacterial strain than men. Patients who stayed less than 48 hours had a 38% decreased risk of developing a resistant strain. Good staff compliance with hand hygiene reduced the risk by 12%, and having one-on-one nursing reduced it by 53%.

The study was funded by the European Community’s Seventh Framework Programme. Dr. van Duijn had no financial declarations.

[email protected]

AMSTERDAM – Neither cycling through a regular schedule of antibiotics on a unit-wide basis, nor randomly mixing them on a patient-level basis reduced the prevalence of antibiotic resistance in eight European intensive care units, a randomized study has determined.

Lead investigator Dr. Pleun Joppe van Duijn of University Medical Center Utrecht (the Netherlands), said he and his colleagues did, however, discover a few common sense findings that seemed to positively affect antibiotic resistance, including compliance with hand hygiene, shorter lengths of stay, staff ratio, and unit occupancy rate. He reported the results of his research at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

Edwin Verin/©Thinkstock

Many ICUs in Europe have one preferred empirical treatment strategy which, Dr. van Duijn said, may create selective pressure for a single resistance type. “An alternative to this is a program of antibiotic rotation,” he noted. “By constantly changing the preferred first-line treatment, selective pressure is constantly changing, which may reduce selection of antibiotic resistance.”

Dr. van Duijn and his colleagues examined this idea in a randomized crossover trial that compared antibiotic cycling and mixing. The protocols employed three antibiotic classes: third- and fourth-generation cephalosporins, piperacillin/tazobactam, and carbapenems. The trial was conducted in eight ICUs in Belgium, Germany, France, Slovenia, and Portugal.

The sites were randomized to two 9-month interventions of cycling or mixing antibiotics, with a 1-month washout period between the two interventions. In cycling protocol, the preferred empiric antibiotic was changed every 6 weeks. In the mixing protocol, every consecutive patient received a different antibiotic. However, treating physicians were allowed to deviate from any protocol for patient safety or to optimize treatment.

The primary endpoint was the monthly prevalence of perineal and/or respiratory carriage of two classes of bacteria:

• Enterobacteriaceae species that were piperacillin/tazobactam–resistant or that showed extended spectrum beta-lactamase production.

• Pseudomonas aeruginosa and Acinetobacter species that were either piperacillin/tazobactam– or carbapenem-resistant.

In all, 8,945 patients were involved, with 4,238 exposed to cycling and 4,707 to mixing. Patients were a mean of 62 years old, with a mean 7-day length of stay. About 4.5% were already colonized with resistant bacteria upon admission. A quarter were on contact isolation; 2% were on both droplet and respiratory isolation.

The overall mortality rate was 11% and did not differ between the cycling and mixing groups (10.9% vs. 11.6%). Antibiotic resistance developed in 22.6% of the cycling group and 21.5% of the mixing group – not a significant difference. Neither protocol significantly reduced over time the amount of antibiotic resistance that was observed in the baseline period.

A multivariate analysis did, however, find a few things associated with resistance prevalence. Women were about 58% less likely to develop a resistant bacterial strain than men. Patients who stayed less than 48 hours had a 38% decreased risk of developing a resistant strain. Good staff compliance with hand hygiene reduced the risk by 12%, and having one-on-one nursing reduced it by 53%.

The study was funded by the European Community’s Seventh Framework Programme. Dr. van Duijn had no financial declarations.

[email protected]

AMSTERDAM – Infection is a major cause of death among patients waiting for a liver transplant, killing more than half of those who contracted one.

Infection also was the biggest reason that patients with end-stage liver disease withdrew from the transplant waiting list, a 9-year-long study has shown. Patients who developed an infection were six times more likely to withdraw than were those who did not, Dr. Loes Alferink wrote in a poster presented at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

“We need to focus on better prophylactic antibiotic strategies to save lives in patients with end-stage liver disease who are on the waiting list,” said Dr. Alferink of Erasmus Medical Center, Rotterdam, the Netherlands.

She and her colleagues examined the effect of infections on 312 patients who were waiting for a transplant at Erasmus Medical Center from the period of 2006-2013. During that time, a total of 317 infections developed in 144 patients. The infections were fatal in 58% of these patients.

These included spontaneous primary cholangitis (75); spontaneous bacterial peritonitis (61); urogenital (38), respiratory (30), and skin (25) infections; as well as primary bacteremia (22). Also, there were 18 cases of gastroenteritis and 12 cases of Candida esophagitis. The remainder were unspecified infections.

The death rate was highest in primary bacteremia, which killed about 40% of those who developed it. The rate was about 25% in respiratory infections, 20% in spontaneous primary bacteremia, 15% in esophagitis, 10% in gastroenteritis and urinary tract infections, and 10% in patients with multiple site infections.

The pathogens were gram negative (70) and gram positive (37) bacteria; Enterococcus faecium (15) and faecalis (3); yeasts (13); viruses (7); and mold (2). The remainder of the infections yielded a negative culture.

In 24 patients, multiple pathogens were identified. These patients had the highest rate of mortality, with almost half of them dying from their infection; one of the two patients with a mold infection also died. The death rate was 20% in patients with yeast infections, 18% in those with E. faecium, 15% in gram-positive infections, and 10% in gram-negative infections.

A multivariate analysis found several factors that increased the risk of dying from an infection. For every 10 years of increasing age, the risk of infection-related mortality doubled (odds ratio, 2); worse MELD (Model for End-Stage Liver Disease) scores increased the risk by 12%.

Patients with hepatic encephalopathy were 76% more likely to die from an infection, and those with refractory ascites faced a 2.5-fold increased risk. Mechanical ventilation was associated with more than a fivefold increased risk (OR, 5.72).

Patients who developed an infection were almost six times more likely to be withdrawn from the transplant waiting list (hazard ratio, 5.87). The regression analysis for withdrawal identified several factors that significantly increased the risk, including age, MELD score, and serum albumin. The biggest risk factor for withdrawal related to infection was refractory ascites, which more than doubled the risk (HR, 2.2).

Dr. Alferink had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

AMSTERDAM – Infection is a major cause of death among patients waiting for a liver transplant, killing more than half of those who contracted one.

Infection also was the biggest reason that patients with end-stage liver disease withdrew from the transplant waiting list, a 9-year-long study has shown. Patients who developed an infection were six times more likely to withdraw than were those who did not, Dr. Loes Alferink wrote in a poster presented at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

“We need to focus on better prophylactic antibiotic strategies to save lives in patients with end-stage liver disease who are on the waiting list,” said Dr. Alferink of Erasmus Medical Center, Rotterdam, the Netherlands.

She and her colleagues examined the effect of infections on 312 patients who were waiting for a transplant at Erasmus Medical Center from the period of 2006-2013. During that time, a total of 317 infections developed in 144 patients. The infections were fatal in 58% of these patients.

These included spontaneous primary cholangitis (75); spontaneous bacterial peritonitis (61); urogenital (38), respiratory (30), and skin (25) infections; as well as primary bacteremia (22). Also, there were 18 cases of gastroenteritis and 12 cases of Candida esophagitis. The remainder were unspecified infections.

The death rate was highest in primary bacteremia, which killed about 40% of those who developed it. The rate was about 25% in respiratory infections, 20% in spontaneous primary bacteremia, 15% in esophagitis, 10% in gastroenteritis and urinary tract infections, and 10% in patients with multiple site infections.

The pathogens were gram negative (70) and gram positive (37) bacteria; Enterococcus faecium (15) and faecalis (3); yeasts (13); viruses (7); and mold (2). The remainder of the infections yielded a negative culture.

In 24 patients, multiple pathogens were identified. These patients had the highest rate of mortality, with almost half of them dying from their infection; one of the two patients with a mold infection also died. The death rate was 20% in patients with yeast infections, 18% in those with E. faecium, 15% in gram-positive infections, and 10% in gram-negative infections.

A multivariate analysis found several factors that increased the risk of dying from an infection. For every 10 years of increasing age, the risk of infection-related mortality doubled (odds ratio, 2); worse MELD (Model for End-Stage Liver Disease) scores increased the risk by 12%.

Patients with hepatic encephalopathy were 76% more likely to die from an infection, and those with refractory ascites faced a 2.5-fold increased risk. Mechanical ventilation was associated with more than a fivefold increased risk (OR, 5.72).

Patients who developed an infection were almost six times more likely to be withdrawn from the transplant waiting list (hazard ratio, 5.87). The regression analysis for withdrawal identified several factors that significantly increased the risk, including age, MELD score, and serum albumin. The biggest risk factor for withdrawal related to infection was refractory ascites, which more than doubled the risk (HR, 2.2).

Dr. Alferink had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

AMSTERDAM – Infection is a major cause of death among patients waiting for a liver transplant, killing more than half of those who contracted one.

Infection also was the biggest reason that patients with end-stage liver disease withdrew from the transplant waiting list, a 9-year-long study has shown. Patients who developed an infection were six times more likely to withdraw than were those who did not, Dr. Loes Alferink wrote in a poster presented at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

“We need to focus on better prophylactic antibiotic strategies to save lives in patients with end-stage liver disease who are on the waiting list,” said Dr. Alferink of Erasmus Medical Center, Rotterdam, the Netherlands.

She and her colleagues examined the effect of infections on 312 patients who were waiting for a transplant at Erasmus Medical Center from the period of 2006-2013. During that time, a total of 317 infections developed in 144 patients. The infections were fatal in 58% of these patients.

These included spontaneous primary cholangitis (75); spontaneous bacterial peritonitis (61); urogenital (38), respiratory (30), and skin (25) infections; as well as primary bacteremia (22). Also, there were 18 cases of gastroenteritis and 12 cases of Candida esophagitis. The remainder were unspecified infections.

The death rate was highest in primary bacteremia, which killed about 40% of those who developed it. The rate was about 25% in respiratory infections, 20% in spontaneous primary bacteremia, 15% in esophagitis, 10% in gastroenteritis and urinary tract infections, and 10% in patients with multiple site infections.

The pathogens were gram negative (70) and gram positive (37) bacteria; Enterococcus faecium (15) and faecalis (3); yeasts (13); viruses (7); and mold (2). The remainder of the infections yielded a negative culture.

In 24 patients, multiple pathogens were identified. These patients had the highest rate of mortality, with almost half of them dying from their infection; one of the two patients with a mold infection also died. The death rate was 20% in patients with yeast infections, 18% in those with E. faecium, 15% in gram-positive infections, and 10% in gram-negative infections.

A multivariate analysis found several factors that increased the risk of dying from an infection. For every 10 years of increasing age, the risk of infection-related mortality doubled (odds ratio, 2); worse MELD (Model for End-Stage Liver Disease) scores increased the risk by 12%.

Patients with hepatic encephalopathy were 76% more likely to die from an infection, and those with refractory ascites faced a 2.5-fold increased risk. Mechanical ventilation was associated with more than a fivefold increased risk (OR, 5.72).

Patients who developed an infection were almost six times more likely to be withdrawn from the transplant waiting list (hazard ratio, 5.87). The regression analysis for withdrawal identified several factors that significantly increased the risk, including age, MELD score, and serum albumin. The biggest risk factor for withdrawal related to infection was refractory ascites, which more than doubled the risk (HR, 2.2).

Dr. Alferink had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

ORLANDO – The hematologic cancer drug ruxolitinib seems to be associated with cases of aggressive nonmelanoma skin cancer.

After treating a very aggressive squamous cell carcinoma in a 55-year-old man treated with ruxolitinib for polycythemia vera, and hearing firsthand of three other similar cases, Dr. Fiona Zwald is collecting additional data on the association. She intends to publish these cases in a monograph as a warning to dermatologists, hematologists, oncologists, and other physicians who manage patients with hematologic malignancies, she said at the annual meeting of the American College of Mohs Surgery.

The prescribing information for ruxolitinib (Jakafi, Incyte Pharmaceuticals; Jakavi, Novartis) was updated in 2014 to warn that patients taking the drug face an increased risk of nonmelanoma skin cancers. The label also recommends that physicians inspect the skin regularly and urge patients to be alert for and report any new or changing lesions.

Despite the warnings and recommendations, cases are occurring – and some are quite serious, said Dr. Zwald, a Mohs surgeon in Atlanta.

“People should know this is actually happening. If you have experience with this medication, please let us know so we can compile this report. We are trying to assess the number of skin cancers before and after initiating this medication,” she said.

Courtesy Dr. Fiona Zwald

Ruxolitinib is an inhibitor of Janus kinase with a special affinity for the JAK1 and JAK2 subtypes. Like other cytokine-signaling molecules, their function depends on cell context; it may inhibit cell growth in one setting, and, in another, stimulate it. Ruxolitinib was initially approved in 2011 for the treatment of intermediate- and high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis.

In 2014, indications for ruxolitinib were expanded to include treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.

Dr. Zwald’s patient had a 10-year history of polycythemia vera. He was initially well controlled on the standard hydroxyurea treatment. In the meantime, he began working as a caddy at a major U.S. golf club. He developed many facial squamous cell carcinomas that were treated with excision and radiation. A year before he presented to Dr. Zwald, he stopped responding to hydroxyurea and was placed on ruxolitinib.

The patient presented with a 4-cm ulcerated lesion over part of his right temple and to the right helical crus; the lesion had developed over 3 months. Dr. Zwald consulted with the patient’s medical oncologist; treatment with ruxolitinib continued, albeit at a reduced dosage in light of recent events.

She performed Mohs surgery on the patient. It was a challenging case, she said, not the least because adequate anesthesia could not be achieved with local anesthetic. Preoperative staging showed no nodal spread.

“He did, unfortunately demonstrate a large, indurated mass located over one branch of the superficial temporal artery. At the helical crus there was an area of bound-down, fixed tumor. Knowing that I would not be able to fully resect this, I passed him on to the operating room,” Dr. Zwald said. “This tumor was found to extend down to the parotid capsule, but margins were clear.” The surgical defect was successfully repaired with a split-thickness skin graft.

The tumor recurred about 3 months later, and the patient underwent another surgery.

“This time we could not get clear surgical margins, and the tumor was approaching the external auditory meatus. Surgery was abandoned due to fears of complications to that area,” she said.

She presented the case at tumor board, during which she and her colleagues discussed adjuvant radiation. They initially abandoned this idea because he had already had so much radiation to his face. After the second surgery, they decide to proceed with radiation. “The next conversation we have will be whether to add another adjuvant therapy to treatment.”

She sent out the case and requests for feedback to the International Transplant Skin Cancer Collaborative, an 800-member consortium of dermatologists and Mohs surgeons who take care of transplant patients. She received information on three additional cases of aggressive squamous cell carcinoma (SCC) associated with ruxolitinib treatment:

• A patient with myelodysplastic syndrome with aggressive scalp SCC with cutaneous metastases.

• A patient with undifferentiated pleomorphic sarcoma of the scalp, several cutaneous SCCs.

• A patient with a myelodysplastic syndrome with in-transit metastases and explosive cutaneous SCCs. The patient has had the ruxolitinib dose reduced and may be switched to capecitabine.

Dr. Zwald noted that her patient was at risk for aggressive skin cancers for reasons in addition to ruxolitinib treatment.

“He was already immunosuppressed from his malignancy. He was on hydroxyurea, a drug that’s a cumulative phototoxin, and he’s out in the sun playing golf every day, and then was put on ruxolitinib. But the question we face now is how to try and stop this medication so we can get better treatment for him which will, of course, be very difficult.”

To contribute to Dr. Zwald’s case series, please email her at [email protected].

She had no relevant financial disclosures.

[email protected]

On Twitter @Alz_Gal

ORLANDO – The hematologic cancer drug ruxolitinib seems to be associated with cases of aggressive nonmelanoma skin cancer.

After treating a very aggressive squamous cell carcinoma in a 55-year-old man treated with ruxolitinib for polycythemia vera, and hearing firsthand of three other similar cases, Dr. Fiona Zwald is collecting additional data on the association. She intends to publish these cases in a monograph as a warning to dermatologists, hematologists, oncologists, and other physicians who manage patients with hematologic malignancies, she said at the annual meeting of the American College of Mohs Surgery.

The prescribing information for ruxolitinib (Jakafi, Incyte Pharmaceuticals; Jakavi, Novartis) was updated in 2014 to warn that patients taking the drug face an increased risk of nonmelanoma skin cancers. The label also recommends that physicians inspect the skin regularly and urge patients to be alert for and report any new or changing lesions.

Despite the warnings and recommendations, cases are occurring – and some are quite serious, said Dr. Zwald, a Mohs surgeon in Atlanta.

“People should know this is actually happening. If you have experience with this medication, please let us know so we can compile this report. We are trying to assess the number of skin cancers before and after initiating this medication,” she said.

Courtesy Dr. Fiona Zwald

Ruxolitinib is an inhibitor of Janus kinase with a special affinity for the JAK1 and JAK2 subtypes. Like other cytokine-signaling molecules, their function depends on cell context; it may inhibit cell growth in one setting, and, in another, stimulate it. Ruxolitinib was initially approved in 2011 for the treatment of intermediate- and high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis.

In 2014, indications for ruxolitinib were expanded to include treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.

Dr. Zwald’s patient had a 10-year history of polycythemia vera. He was initially well controlled on the standard hydroxyurea treatment. In the meantime, he began working as a caddy at a major U.S. golf club. He developed many facial squamous cell carcinomas that were treated with excision and radiation. A year before he presented to Dr. Zwald, he stopped responding to hydroxyurea and was placed on ruxolitinib.

The patient presented with a 4-cm ulcerated lesion over part of his right temple and to the right helical crus; the lesion had developed over 3 months. Dr. Zwald consulted with the patient’s medical oncologist; treatment with ruxolitinib continued, albeit at a reduced dosage in light of recent events.

She performed Mohs surgery on the patient. It was a challenging case, she said, not the least because adequate anesthesia could not be achieved with local anesthetic. Preoperative staging showed no nodal spread.

“He did, unfortunately demonstrate a large, indurated mass located over one branch of the superficial temporal artery. At the helical crus there was an area of bound-down, fixed tumor. Knowing that I would not be able to fully resect this, I passed him on to the operating room,” Dr. Zwald said. “This tumor was found to extend down to the parotid capsule, but margins were clear.” The surgical defect was successfully repaired with a split-thickness skin graft.

The tumor recurred about 3 months later, and the patient underwent another surgery.

“This time we could not get clear surgical margins, and the tumor was approaching the external auditory meatus. Surgery was abandoned due to fears of complications to that area,” she said.

She presented the case at tumor board, during which she and her colleagues discussed adjuvant radiation. They initially abandoned this idea because he had already had so much radiation to his face. After the second surgery, they decide to proceed with radiation. “The next conversation we have will be whether to add another adjuvant therapy to treatment.”

She sent out the case and requests for feedback to the International Transplant Skin Cancer Collaborative, an 800-member consortium of dermatologists and Mohs surgeons who take care of transplant patients. She received information on three additional cases of aggressive squamous cell carcinoma (SCC) associated with ruxolitinib treatment:

• A patient with myelodysplastic syndrome with aggressive scalp SCC with cutaneous metastases.

• A patient with undifferentiated pleomorphic sarcoma of the scalp, several cutaneous SCCs.

• A patient with a myelodysplastic syndrome with in-transit metastases and explosive cutaneous SCCs. The patient has had the ruxolitinib dose reduced and may be switched to capecitabine.

Dr. Zwald noted that her patient was at risk for aggressive skin cancers for reasons in addition to ruxolitinib treatment.

“He was already immunosuppressed from his malignancy. He was on hydroxyurea, a drug that’s a cumulative phototoxin, and he’s out in the sun playing golf every day, and then was put on ruxolitinib. But the question we face now is how to try and stop this medication so we can get better treatment for him which will, of course, be very difficult.”

To contribute to Dr. Zwald’s case series, please email her at [email protected].

She had no relevant financial disclosures.

[email protected]

On Twitter @Alz_Gal

ORLANDO – The hematologic cancer drug ruxolitinib seems to be associated with cases of aggressive nonmelanoma skin cancer.

After treating a very aggressive squamous cell carcinoma in a 55-year-old man treated with ruxolitinib for polycythemia vera, and hearing firsthand of three other similar cases, Dr. Fiona Zwald is collecting additional data on the association. She intends to publish these cases in a monograph as a warning to dermatologists, hematologists, oncologists, and other physicians who manage patients with hematologic malignancies, she said at the annual meeting of the American College of Mohs Surgery.

The prescribing information for ruxolitinib (Jakafi, Incyte Pharmaceuticals; Jakavi, Novartis) was updated in 2014 to warn that patients taking the drug face an increased risk of nonmelanoma skin cancers. The label also recommends that physicians inspect the skin regularly and urge patients to be alert for and report any new or changing lesions.

Despite the warnings and recommendations, cases are occurring – and some are quite serious, said Dr. Zwald, a Mohs surgeon in Atlanta.

“People should know this is actually happening. If you have experience with this medication, please let us know so we can compile this report. We are trying to assess the number of skin cancers before and after initiating this medication,” she said.

Courtesy Dr. Fiona Zwald

Ruxolitinib is an inhibitor of Janus kinase with a special affinity for the JAK1 and JAK2 subtypes. Like other cytokine-signaling molecules, their function depends on cell context; it may inhibit cell growth in one setting, and, in another, stimulate it. Ruxolitinib was initially approved in 2011 for the treatment of intermediate- and high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis.

In 2014, indications for ruxolitinib were expanded to include treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.

Dr. Zwald’s patient had a 10-year history of polycythemia vera. He was initially well controlled on the standard hydroxyurea treatment. In the meantime, he began working as a caddy at a major U.S. golf club. He developed many facial squamous cell carcinomas that were treated with excision and radiation. A year before he presented to Dr. Zwald, he stopped responding to hydroxyurea and was placed on ruxolitinib.

The patient presented with a 4-cm ulcerated lesion over part of his right temple and to the right helical crus; the lesion had developed over 3 months. Dr. Zwald consulted with the patient’s medical oncologist; treatment with ruxolitinib continued, albeit at a reduced dosage in light of recent events.

She performed Mohs surgery on the patient. It was a challenging case, she said, not the least because adequate anesthesia could not be achieved with local anesthetic. Preoperative staging showed no nodal spread.

“He did, unfortunately demonstrate a large, indurated mass located over one branch of the superficial temporal artery. At the helical crus there was an area of bound-down, fixed tumor. Knowing that I would not be able to fully resect this, I passed him on to the operating room,” Dr. Zwald said. “This tumor was found to extend down to the parotid capsule, but margins were clear.” The surgical defect was successfully repaired with a split-thickness skin graft.

The tumor recurred about 3 months later, and the patient underwent another surgery.

“This time we could not get clear surgical margins, and the tumor was approaching the external auditory meatus. Surgery was abandoned due to fears of complications to that area,” she said.

She presented the case at tumor board, during which she and her colleagues discussed adjuvant radiation. They initially abandoned this idea because he had already had so much radiation to his face. After the second surgery, they decide to proceed with radiation. “The next conversation we have will be whether to add another adjuvant therapy to treatment.”

She sent out the case and requests for feedback to the International Transplant Skin Cancer Collaborative, an 800-member consortium of dermatologists and Mohs surgeons who take care of transplant patients. She received information on three additional cases of aggressive squamous cell carcinoma (SCC) associated with ruxolitinib treatment:

• A patient with myelodysplastic syndrome with aggressive scalp SCC with cutaneous metastases.

• A patient with undifferentiated pleomorphic sarcoma of the scalp, several cutaneous SCCs.

• A patient with a myelodysplastic syndrome with in-transit metastases and explosive cutaneous SCCs. The patient has had the ruxolitinib dose reduced and may be switched to capecitabine.

Dr. Zwald noted that her patient was at risk for aggressive skin cancers for reasons in addition to ruxolitinib treatment.

“He was already immunosuppressed from his malignancy. He was on hydroxyurea, a drug that’s a cumulative phototoxin, and he’s out in the sun playing golf every day, and then was put on ruxolitinib. But the question we face now is how to try and stop this medication so we can get better treatment for him which will, of course, be very difficult.”

To contribute to Dr. Zwald’s case series, please email her at [email protected].

She had no relevant financial disclosures.

[email protected]

On Twitter @Alz_Gal

AMSTERDAM – Intravenous tigecycline was significantly more effective than standard therapy at curing refractory Clostridium difficile infections, according to a case-control study presented at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

Tigecycline effected a 76% clinical cure rate, compared with 53% for the combination regimen of intravenous metronidazole and oral vancomycin, Dr. Baltin Gergely Szabo reported. And despite the fact that those who took tigecycline had more clinically severe disease, no colectomies were required in that group, while two patients in the standard treatment arm did need the procedure.

However, tigecycline didn’t significantly improve relapse rates or mortality, noted Dr. Szabo of the St. Stephan and St. Ladislaus Hospital-Clinic, Budapest, Hungary.

He presented the results of a matched case-control study of 90 patients with severe C. difficile infections, who were treated with either of the protocols. Patients who took tigecycline were more likely to have a recurrent infection (38% vs. 29%). Thus, they were also more likely to have previously been treated with metronidazole (38% vs. 24%) and vancomycin (24% vs. 7%). Prior tigecycline use was very rare in both groups (2% vs. 0%).

Those who took tigecycline were significantly younger as well (72 vs. 78 years), and more often men (56% vs. 30%). They were more likely to be hypertensive, have chronic obstructive pulmonary disease, have cancers, be immunosuppressed, and be chronic users of corticosteroids.

However, the Charlson comorbidity index was similar between the tigecycline and standard therapy groups (4.6 vs. 5). They were also matched for ATLAS scores (mean 7.8 in each group).

Significantly more patients taking tigecycline had acquired their infections during hospitalization (64% vs. 30%). They also had a longer duration of symptoms (17 vs. 10 days).

Imaging showed more severe disease in the tigecycline group with significantly more colonic distension, mural thickening, and ascites. Tigecycline patients had also undergone significantly more colonoscopies and blood cultures.

Tigecycline was given in the hospital for 7-10 days, with a 100-mg loading dose and subsequent 50-mg daily doses. The main duration of therapy was 10 days, but that varied widely, from 2 to 22 days. It was given only as first-line treatment to 15% of patients; the rest received tigecycline as an alternative treatment, often after the combination of metronidazole/vancomycin had failed. No adverse drug reactions occurred in the group.

Clinical cure was achieved in 76% of the tigecycline group and 53% of the standard protocol group – a significant difference. The drug was associated with a decreased rate of complicated disease course (29% vs. 53%) and significantly fewer colectomies (0 vs. 2).

Rates of toxic megacolon were equal (7% each group); ileus was more frequent in the tigecycline group (11% vs. 9%), but this difference was not statistically significant.

However, tigecycline had no impact on either in-hospital or 90-day relapse, or on in-hospital mortality (15 vs. 16 deaths). At 90 days, fewer patients taking the drug had died (17 vs. 21), but that difference was not statistically significant (P = 0.52).

A multivariate analysis identified several characteristics associated with a beneficial response to tigecycline:

• Male sex.

• Being immunosuppressed.

• Chronic steroid treatment.

• Malignancy.

• Longer duration of symptoms.

• Prior C. difficile infections.

• Nosocomial onset.

• Signs of severe infection on imaging.

Dr. Szabo said these characteristics can be used to create a profile of patients who might be good candidates for the drug.

He had no relevant financial declarations.

[email protected]

On Twitter @Alz_Gal

AMSTERDAM – Intravenous tigecycline was significantly more effective than standard therapy at curing refractory Clostridium difficile infections, according to a case-control study presented at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

Tigecycline effected a 76% clinical cure rate, compared with 53% for the combination regimen of intravenous metronidazole and oral vancomycin, Dr. Baltin Gergely Szabo reported. And despite the fact that those who took tigecycline had more clinically severe disease, no colectomies were required in that group, while two patients in the standard treatment arm did need the procedure.

However, tigecycline didn’t significantly improve relapse rates or mortality, noted Dr. Szabo of the St. Stephan and St. Ladislaus Hospital-Clinic, Budapest, Hungary.

He presented the results of a matched case-control study of 90 patients with severe C. difficile infections, who were treated with either of the protocols. Patients who took tigecycline were more likely to have a recurrent infection (38% vs. 29%). Thus, they were also more likely to have previously been treated with metronidazole (38% vs. 24%) and vancomycin (24% vs. 7%). Prior tigecycline use was very rare in both groups (2% vs. 0%).

Those who took tigecycline were significantly younger as well (72 vs. 78 years), and more often men (56% vs. 30%). They were more likely to be hypertensive, have chronic obstructive pulmonary disease, have cancers, be immunosuppressed, and be chronic users of corticosteroids.

However, the Charlson comorbidity index was similar between the tigecycline and standard therapy groups (4.6 vs. 5). They were also matched for ATLAS scores (mean 7.8 in each group).

Significantly more patients taking tigecycline had acquired their infections during hospitalization (64% vs. 30%). They also had a longer duration of symptoms (17 vs. 10 days).

Imaging showed more severe disease in the tigecycline group with significantly more colonic distension, mural thickening, and ascites. Tigecycline patients had also undergone significantly more colonoscopies and blood cultures.

Tigecycline was given in the hospital for 7-10 days, with a 100-mg loading dose and subsequent 50-mg daily doses. The main duration of therapy was 10 days, but that varied widely, from 2 to 22 days. It was given only as first-line treatment to 15% of patients; the rest received tigecycline as an alternative treatment, often after the combination of metronidazole/vancomycin had failed. No adverse drug reactions occurred in the group.

Clinical cure was achieved in 76% of the tigecycline group and 53% of the standard protocol group – a significant difference. The drug was associated with a decreased rate of complicated disease course (29% vs. 53%) and significantly fewer colectomies (0 vs. 2).

Rates of toxic megacolon were equal (7% each group); ileus was more frequent in the tigecycline group (11% vs. 9%), but this difference was not statistically significant.

However, tigecycline had no impact on either in-hospital or 90-day relapse, or on in-hospital mortality (15 vs. 16 deaths). At 90 days, fewer patients taking the drug had died (17 vs. 21), but that difference was not statistically significant (P = 0.52).

A multivariate analysis identified several characteristics associated with a beneficial response to tigecycline:

• Male sex.

• Being immunosuppressed.

• Chronic steroid treatment.

• Malignancy.

• Longer duration of symptoms.

• Prior C. difficile infections.

• Nosocomial onset.

• Signs of severe infection on imaging.

Dr. Szabo said these characteristics can be used to create a profile of patients who might be good candidates for the drug.

He had no relevant financial declarations.

[email protected]

On Twitter @Alz_Gal

AMSTERDAM – Intravenous tigecycline was significantly more effective than standard therapy at curing refractory Clostridium difficile infections, according to a case-control study presented at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

Tigecycline effected a 76% clinical cure rate, compared with 53% for the combination regimen of intravenous metronidazole and oral vancomycin, Dr. Baltin Gergely Szabo reported. And despite the fact that those who took tigecycline had more clinically severe disease, no colectomies were required in that group, while two patients in the standard treatment arm did need the procedure.

However, tigecycline didn’t significantly improve relapse rates or mortality, noted Dr. Szabo of the St. Stephan and St. Ladislaus Hospital-Clinic, Budapest, Hungary.

He presented the results of a matched case-control study of 90 patients with severe C. difficile infections, who were treated with either of the protocols. Patients who took tigecycline were more likely to have a recurrent infection (38% vs. 29%). Thus, they were also more likely to have previously been treated with metronidazole (38% vs. 24%) and vancomycin (24% vs. 7%). Prior tigecycline use was very rare in both groups (2% vs. 0%).

Those who took tigecycline were significantly younger as well (72 vs. 78 years), and more often men (56% vs. 30%). They were more likely to be hypertensive, have chronic obstructive pulmonary disease, have cancers, be immunosuppressed, and be chronic users of corticosteroids.

However, the Charlson comorbidity index was similar between the tigecycline and standard therapy groups (4.6 vs. 5). They were also matched for ATLAS scores (mean 7.8 in each group).

Significantly more patients taking tigecycline had acquired their infections during hospitalization (64% vs. 30%). They also had a longer duration of symptoms (17 vs. 10 days).

Imaging showed more severe disease in the tigecycline group with significantly more colonic distension, mural thickening, and ascites. Tigecycline patients had also undergone significantly more colonoscopies and blood cultures.

Tigecycline was given in the hospital for 7-10 days, with a 100-mg loading dose and subsequent 50-mg daily doses. The main duration of therapy was 10 days, but that varied widely, from 2 to 22 days. It was given only as first-line treatment to 15% of patients; the rest received tigecycline as an alternative treatment, often after the combination of metronidazole/vancomycin had failed. No adverse drug reactions occurred in the group.

Clinical cure was achieved in 76% of the tigecycline group and 53% of the standard protocol group – a significant difference. The drug was associated with a decreased rate of complicated disease course (29% vs. 53%) and significantly fewer colectomies (0 vs. 2).

Rates of toxic megacolon were equal (7% each group); ileus was more frequent in the tigecycline group (11% vs. 9%), but this difference was not statistically significant.

However, tigecycline had no impact on either in-hospital or 90-day relapse, or on in-hospital mortality (15 vs. 16 deaths). At 90 days, fewer patients taking the drug had died (17 vs. 21), but that difference was not statistically significant (P = 0.52).

A multivariate analysis identified several characteristics associated with a beneficial response to tigecycline:

• Male sex.

• Being immunosuppressed.

• Chronic steroid treatment.

• Malignancy.

• Longer duration of symptoms.

• Prior C. difficile infections.

• Nosocomial onset.

• Signs of severe infection on imaging.

Dr. Szabo said these characteristics can be used to create a profile of patients who might be good candidates for the drug.

He had no relevant financial declarations.

[email protected]

On Twitter @Alz_Gal

BETHESDA, MD. – Cerebral vascular dysfunction exerts a significant negative influence on cognition, doubling the risk of dementia in old age and speeding the rate of cognitive decline.

These findings have been confirmed in a number of studies, and their advancement in both research and clinical arenas continues. But studies of the vascular conditions that affect cognition remain largely observational. Intervention trials are few and limited in scope. The dearth of animal models that express compromised cerebral vascular function has made conducting basic studies feel like wheels spinning in the mud.

According to investigators who discussed the problem at the recent Alzheimer’s Disease–Related Dementias 2016 Summit, sponsored by the National Institutes of Health, the situation calls for a targeted push to better understand vascular complications and their impact on cognition and the development of dementias – and a new, 5-year NIH research program aims to do just that.

M²OVE–AD: Molecular Mechanisms of the Vascular Etiology of Alzheimer’s Disease, is a $30 million initiative that brings together more than a dozen research teams. Investigators will employ new molecular profiling technologies and big data analytics to understand how vascular dysfunction influences the development of Alzheimer’s. The teams will collaborate on five different projects, each exploring a different facet of these complex processes, according to Dr. Suzana Petanceska, program director of the neuroscience division at the National Institute on Aging, Bethesda, Md., who shared her thoughts after the meeting.

“The central goal of the consortium is to generate a deeper understanding of the molecular mechanisms linking vascular risk factors, cerebrovascular disease, and Alzheimer’s, and to generate a new big-data resource that will aid the discovery of therapeutic targets for disease treatment and prevention and molecular signatures that can be used as biomarkers for disease risk,” Dr. Petanceska said in an interview.

Following a new trend of sharing Alzheimer’s research data across public and academic domains, data generated by this program will be made rapidly available to the greater research community. “Making these complex biological data sets available and usable by researchers other than the data generators is key to accelerating the pace at which the research community can generate new knowledge and replicate new findings. The M²OVE–AD initiative builds on the open-science approach established by the Accelerating Medicines Partnership – AD Programand Alzheimer’s Disease Neuroimaging Initiative (ADNI). By coordinating the experimental and analytical approaches the research teams will maximize the usability of the data generated on these projects.”

Five complementary projects comprise the consortium:

Integrative Translational Discovery of Vascular Risk Factors in Aging and Dementia

Researchers at the Mayo Clinics in Minnesota and Florida will collaborate with those at the Icahn Institute for Genomics and Multiscale Biology, New York, to explore how molecular networks influence vascular risk in normal aging, as well as in Alzheimer’s and other dementias.

The project’s goal is to understand how gender and the Alzheimer’s disease risk factor gene ApoE4 influence the molecular processes that lead to Alzheimer’s-related cerebral amyloid angiopathy (CAA).

CAA appears to be a key player in the progression of Alzheimer’s disease. The health of small vessels of the brain is important not only in age-related cognitive decline, but also in amyloid clearance. When amyloid collects in these vessels, it may cause a potentially self-sustaining loop of vascular injury and impaired amyloid clearance, which causes more intravascular amyloid deposition, more CAA, and increasing amyloid pathology.

The team intends to use genetic and expression profiling data from human brain and bloods samples, as well as existing molecular, clinical, and pathologic data in hopes of discovering therapeutic targets. The dynamic interaction between gender, apoE4 and aging and its impact on various AD pathologic and clinical traits will be explored in an array of existing and new animal models.

“Integrating the analysis of multidimensional human data with studies in animal models will accelerate the speed with which the findings can be translated to new interventions for treatment and prevention,” Dr. Petanceska said.

Interdisciplinary Research to Understand the Interplay of Diabetes, Cerebrovascular Disease and Alzheimer’s Disease

Type 2 diabetes mellitus and prediabetes metabolic abnormalities affect one-third of U.S. adults and the majority of persons aged 60 years and older. Diabetes is associated with a higher risk of the clinical manifestations of AD, including dementia and mild cognitive impairment. Hispanics in the United States have higher rates of diabetes, putting them at greater risk for developing Alzheimer’s. Investigators at Columbia University and SUNY Downstate Medical Center, both in New York, will examine the complex relationship between diabetes, cerebrovascular disease, and Alzheimer’s in a cohort of 200 middle-aged Hispanic participants, with either normal glucose metabolism, prediabetes, or type 2 diabetes; the subjects will be followed for 5 years with whole-brain magnetic resonance imaging and a variety of cognitive measures. The brain imaging will track AD-like functional and pathologic changes and vascular lesions.

In addition, the team will carry out molecular profiling of plasma samples collected in the same participants to identify metabolic and protein signatures that may predict clinical, pathologic, and physiologic outcomes related to Alzheimer’s and cerebrovascular disease.

In a companion study using mouse models with diabetes and Alzheimer’s pathology traits, the researchers will examine how the interaction between diabetes and Alzheimer’s pathology affects the structure and function of neural circuits important to learning and memory.

“This project is addressing two critical knowledge gaps,” Dr. Petanceska said. “The first is understanding the mechanisms by which dysregulated glucose metabolism impacts the onset and progression of pathologic changes in the course of the preclinical phase of Alzheimer’s disease; the second is understanding the molecular determinants of AD risk in Hispanics, a population with higher prevalence of diabetes and at greater risk for AD.”

The Role of Renin-Angiotensin-Endothelial Pathway in Alzheimer’s Disease

Researchers at Emory University, Atlanta, will focus on understanding the molecular mechanisms by which vascular dysfunction associated with high blood pressure affects the onset and progression of Alzheimer’s.

The research cohort comprises 160 subjects from the Emory Cardiovascular Biobank and Predictive Health Study– 80 with normal cognition and 80 with mild cognitive impairment – who will be followed for 2 years. Molecular data (genomic, epigenetic and metabolomic) combined with clinical data on the same subjects collected over 2 years, will be used to build a molecular network model of the interaction between vascular dysfunction and various Alzheimer’s disease traits.

Parallel studies in a rat model that uniquely exhibits human-like AD neuropathology will help uncover the temporal relationship between vascular dysfunction and AD and examine the potential of the molecular regulators of vascular function, such as the renin-angiotensin system, as therapeutic targets for AD. The goal is to characterize this pathway as a therapeutic target.

Metabolic Signatures Underlying Vascular Risk Factors for Alzheimer’s-Type Dementias

Teams at Duke University, Durham, N.C., and the University of Pennsylvania, Philadelphia, will carry out extensive profiling of plasma samples from 900 ADNI participants and from participants in the Duke University MURDOCK Memory and Cognitive Health Study in search for lipid metabolites that are associated with cardiovascular disease and cognitive change. These lipidomic profiles will be integrated with the vast array of clinical and other molecular data available for these participants to identify molecular signatures that may be used to differentiate among various risk-factor types of AD.

In addition, in a subset of subjects, the team will compare the lipidomic profiles between plasma and cerebrospinal fluid; this will enable the team to test hypotheses about the role of systemic vascular and metabolic factors on cognitive aging and AD.

Cerebral Amyloid Angiopathy and Mechanisms of Brain Amyloid Accumulation

Investigators at Massachusetts General Hospital, Boston, will investigate the molecular underpinnings of CAA and its impact on Alzheimer’s disease. Employing a mouse model and human subjects with CAA, the study will explore this cycle of progressive amyloid deposition and brain injury. The team’s approach combines noninvasive detection and analysis of human CAA, real-time measurement of vascular structure and physiology in living transgenic mouse models, and molecular analysis of gene expression in brain microvessels. Ultimately, the team hopes to identify candidate therapies with which could block it.

“This highly multidisciplinary investigation into how the vascular effects of amyloid at the molecular, single-blood vessel, and whole-brain levels influence the clinical disease promises to deliver new, well-characterized therapeutic targets for disease prevention,” Dr. Petanceska said.

She predicted that the wide-ranging projects of the M²OVE–AD consortium will bring invaluable understanding to an enormously important, but still unexplored, aspect of Alzheimer’s pathology.

“We hope that this large-scale team science effort will generate an in-depth understanding of how vascular and metabolic factors contribute to neurodegenerative changes that result in cognitive decline and dementia and that the data and knowledge generated by this program will be the basis for developing effective interventions for disease treatment and prevention.”

BETHESDA, MD. – Cerebral vascular dysfunction exerts a significant negative influence on cognition, doubling the risk of dementia in old age and speeding the rate of cognitive decline.

These findings have been confirmed in a number of studies, and their advancement in both research and clinical arenas continues. But studies of the vascular conditions that affect cognition remain largely observational. Intervention trials are few and limited in scope. The dearth of animal models that express compromised cerebral vascular function has made conducting basic studies feel like wheels spinning in the mud.

According to investigators who discussed the problem at the recent Alzheimer’s Disease–Related Dementias 2016 Summit, sponsored by the National Institutes of Health, the situation calls for a targeted push to better understand vascular complications and their impact on cognition and the development of dementias – and a new, 5-year NIH research program aims to do just that.

M²OVE–AD: Molecular Mechanisms of the Vascular Etiology of Alzheimer’s Disease, is a $30 million initiative that brings together more than a dozen research teams. Investigators will employ new molecular profiling technologies and big data analytics to understand how vascular dysfunction influences the development of Alzheimer’s. The teams will collaborate on five different projects, each exploring a different facet of these complex processes, according to Dr. Suzana Petanceska, program director of the neuroscience division at the National Institute on Aging, Bethesda, Md., who shared her thoughts after the meeting.

“The central goal of the consortium is to generate a deeper understanding of the molecular mechanisms linking vascular risk factors, cerebrovascular disease, and Alzheimer’s, and to generate a new big-data resource that will aid the discovery of therapeutic targets for disease treatment and prevention and molecular signatures that can be used as biomarkers for disease risk,” Dr. Petanceska said in an interview.

Following a new trend of sharing Alzheimer’s research data across public and academic domains, data generated by this program will be made rapidly available to the greater research community. “Making these complex biological data sets available and usable by researchers other than the data generators is key to accelerating the pace at which the research community can generate new knowledge and replicate new findings. The M²OVE–AD initiative builds on the open-science approach established by the Accelerating Medicines Partnership – AD Programand Alzheimer’s Disease Neuroimaging Initiative (ADNI). By coordinating the experimental and analytical approaches the research teams will maximize the usability of the data generated on these projects.”

Five complementary projects comprise the consortium:

Integrative Translational Discovery of Vascular Risk Factors in Aging and Dementia

Researchers at the Mayo Clinics in Minnesota and Florida will collaborate with those at the Icahn Institute for Genomics and Multiscale Biology, New York, to explore how molecular networks influence vascular risk in normal aging, as well as in Alzheimer’s and other dementias.

The project’s goal is to understand how gender and the Alzheimer’s disease risk factor gene ApoE4 influence the molecular processes that lead to Alzheimer’s-related cerebral amyloid angiopathy (CAA).

CAA appears to be a key player in the progression of Alzheimer’s disease. The health of small vessels of the brain is important not only in age-related cognitive decline, but also in amyloid clearance. When amyloid collects in these vessels, it may cause a potentially self-sustaining loop of vascular injury and impaired amyloid clearance, which causes more intravascular amyloid deposition, more CAA, and increasing amyloid pathology.

The team intends to use genetic and expression profiling data from human brain and bloods samples, as well as existing molecular, clinical, and pathologic data in hopes of discovering therapeutic targets. The dynamic interaction between gender, apoE4 and aging and its impact on various AD pathologic and clinical traits will be explored in an array of existing and new animal models.

“Integrating the analysis of multidimensional human data with studies in animal models will accelerate the speed with which the findings can be translated to new interventions for treatment and prevention,” Dr. Petanceska said.

Interdisciplinary Research to Understand the Interplay of Diabetes, Cerebrovascular Disease and Alzheimer’s Disease

Type 2 diabetes mellitus and prediabetes metabolic abnormalities affect one-third of U.S. adults and the majority of persons aged 60 years and older. Diabetes is associated with a higher risk of the clinical manifestations of AD, including dementia and mild cognitive impairment. Hispanics in the United States have higher rates of diabetes, putting them at greater risk for developing Alzheimer’s. Investigators at Columbia University and SUNY Downstate Medical Center, both in New York, will examine the complex relationship between diabetes, cerebrovascular disease, and Alzheimer’s in a cohort of 200 middle-aged Hispanic participants, with either normal glucose metabolism, prediabetes, or type 2 diabetes; the subjects will be followed for 5 years with whole-brain magnetic resonance imaging and a variety of cognitive measures. The brain imaging will track AD-like functional and pathologic changes and vascular lesions.

In addition, the team will carry out molecular profiling of plasma samples collected in the same participants to identify metabolic and protein signatures that may predict clinical, pathologic, and physiologic outcomes related to Alzheimer’s and cerebrovascular disease.

In a companion study using mouse models with diabetes and Alzheimer’s pathology traits, the researchers will examine how the interaction between diabetes and Alzheimer’s pathology affects the structure and function of neural circuits important to learning and memory.

“This project is addressing two critical knowledge gaps,” Dr. Petanceska said. “The first is understanding the mechanisms by which dysregulated glucose metabolism impacts the onset and progression of pathologic changes in the course of the preclinical phase of Alzheimer’s disease; the second is understanding the molecular determinants of AD risk in Hispanics, a population with higher prevalence of diabetes and at greater risk for AD.”

The Role of Renin-Angiotensin-Endothelial Pathway in Alzheimer’s Disease

Researchers at Emory University, Atlanta, will focus on understanding the molecular mechanisms by which vascular dysfunction associated with high blood pressure affects the onset and progression of Alzheimer’s.

The research cohort comprises 160 subjects from the Emory Cardiovascular Biobank and Predictive Health Study– 80 with normal cognition and 80 with mild cognitive impairment – who will be followed for 2 years. Molecular data (genomic, epigenetic and metabolomic) combined with clinical data on the same subjects collected over 2 years, will be used to build a molecular network model of the interaction between vascular dysfunction and various Alzheimer’s disease traits.

Parallel studies in a rat model that uniquely exhibits human-like AD neuropathology will help uncover the temporal relationship between vascular dysfunction and AD and examine the potential of the molecular regulators of vascular function, such as the renin-angiotensin system, as therapeutic targets for AD. The goal is to characterize this pathway as a therapeutic target.

Metabolic Signatures Underlying Vascular Risk Factors for Alzheimer’s-Type Dementias

Teams at Duke University, Durham, N.C., and the University of Pennsylvania, Philadelphia, will carry out extensive profiling of plasma samples from 900 ADNI participants and from participants in the Duke University MURDOCK Memory and Cognitive Health Study in search for lipid metabolites that are associated with cardiovascular disease and cognitive change. These lipidomic profiles will be integrated with the vast array of clinical and other molecular data available for these participants to identify molecular signatures that may be used to differentiate among various risk-factor types of AD.

In addition, in a subset of subjects, the team will compare the lipidomic profiles between plasma and cerebrospinal fluid; this will enable the team to test hypotheses about the role of systemic vascular and metabolic factors on cognitive aging and AD.

Cerebral Amyloid Angiopathy and Mechanisms of Brain Amyloid Accumulation

Investigators at Massachusetts General Hospital, Boston, will investigate the molecular underpinnings of CAA and its impact on Alzheimer’s disease. Employing a mouse model and human subjects with CAA, the study will explore this cycle of progressive amyloid deposition and brain injury. The team’s approach combines noninvasive detection and analysis of human CAA, real-time measurement of vascular structure and physiology in living transgenic mouse models, and molecular analysis of gene expression in brain microvessels. Ultimately, the team hopes to identify candidate therapies with which could block it.

“This highly multidisciplinary investigation into how the vascular effects of amyloid at the molecular, single-blood vessel, and whole-brain levels influence the clinical disease promises to deliver new, well-characterized therapeutic targets for disease prevention,” Dr. Petanceska said.

She predicted that the wide-ranging projects of the M²OVE–AD consortium will bring invaluable understanding to an enormously important, but still unexplored, aspect of Alzheimer’s pathology.

“We hope that this large-scale team science effort will generate an in-depth understanding of how vascular and metabolic factors contribute to neurodegenerative changes that result in cognitive decline and dementia and that the data and knowledge generated by this program will be the basis for developing effective interventions for disease treatment and prevention.”

BETHESDA, MD. – Cerebral vascular dysfunction exerts a significant negative influence on cognition, doubling the risk of dementia in old age and speeding the rate of cognitive decline.

These findings have been confirmed in a number of studies, and their advancement in both research and clinical arenas continues. But studies of the vascular conditions that affect cognition remain largely observational. Intervention trials are few and limited in scope. The dearth of animal models that express compromised cerebral vascular function has made conducting basic studies feel like wheels spinning in the mud.

According to investigators who discussed the problem at the recent Alzheimer’s Disease–Related Dementias 2016 Summit, sponsored by the National Institutes of Health, the situation calls for a targeted push to better understand vascular complications and their impact on cognition and the development of dementias – and a new, 5-year NIH research program aims to do just that.

M²OVE–AD: Molecular Mechanisms of the Vascular Etiology of Alzheimer’s Disease, is a $30 million initiative that brings together more than a dozen research teams. Investigators will employ new molecular profiling technologies and big data analytics to understand how vascular dysfunction influences the development of Alzheimer’s. The teams will collaborate on five different projects, each exploring a different facet of these complex processes, according to Dr. Suzana Petanceska, program director of the neuroscience division at the National Institute on Aging, Bethesda, Md., who shared her thoughts after the meeting.

“The central goal of the consortium is to generate a deeper understanding of the molecular mechanisms linking vascular risk factors, cerebrovascular disease, and Alzheimer’s, and to generate a new big-data resource that will aid the discovery of therapeutic targets for disease treatment and prevention and molecular signatures that can be used as biomarkers for disease risk,” Dr. Petanceska said in an interview.

Following a new trend of sharing Alzheimer’s research data across public and academic domains, data generated by this program will be made rapidly available to the greater research community. “Making these complex biological data sets available and usable by researchers other than the data generators is key to accelerating the pace at which the research community can generate new knowledge and replicate new findings. The M²OVE–AD initiative builds on the open-science approach established by the Accelerating Medicines Partnership – AD Programand Alzheimer’s Disease Neuroimaging Initiative (ADNI). By coordinating the experimental and analytical approaches the research teams will maximize the usability of the data generated on these projects.”

Five complementary projects comprise the consortium:

Integrative Translational Discovery of Vascular Risk Factors in Aging and Dementia

Researchers at the Mayo Clinics in Minnesota and Florida will collaborate with those at the Icahn Institute for Genomics and Multiscale Biology, New York, to explore how molecular networks influence vascular risk in normal aging, as well as in Alzheimer’s and other dementias.

The project’s goal is to understand how gender and the Alzheimer’s disease risk factor gene ApoE4 influence the molecular processes that lead to Alzheimer’s-related cerebral amyloid angiopathy (CAA).

CAA appears to be a key player in the progression of Alzheimer’s disease. The health of small vessels of the brain is important not only in age-related cognitive decline, but also in amyloid clearance. When amyloid collects in these vessels, it may cause a potentially self-sustaining loop of vascular injury and impaired amyloid clearance, which causes more intravascular amyloid deposition, more CAA, and increasing amyloid pathology.

The team intends to use genetic and expression profiling data from human brain and bloods samples, as well as existing molecular, clinical, and pathologic data in hopes of discovering therapeutic targets. The dynamic interaction between gender, apoE4 and aging and its impact on various AD pathologic and clinical traits will be explored in an array of existing and new animal models.

“Integrating the analysis of multidimensional human data with studies in animal models will accelerate the speed with which the findings can be translated to new interventions for treatment and prevention,” Dr. Petanceska said.

Interdisciplinary Research to Understand the Interplay of Diabetes, Cerebrovascular Disease and Alzheimer’s Disease

Type 2 diabetes mellitus and prediabetes metabolic abnormalities affect one-third of U.S. adults and the majority of persons aged 60 years and older. Diabetes is associated with a higher risk of the clinical manifestations of AD, including dementia and mild cognitive impairment. Hispanics in the United States have higher rates of diabetes, putting them at greater risk for developing Alzheimer’s. Investigators at Columbia University and SUNY Downstate Medical Center, both in New York, will examine the complex relationship between diabetes, cerebrovascular disease, and Alzheimer’s in a cohort of 200 middle-aged Hispanic participants, with either normal glucose metabolism, prediabetes, or type 2 diabetes; the subjects will be followed for 5 years with whole-brain magnetic resonance imaging and a variety of cognitive measures. The brain imaging will track AD-like functional and pathologic changes and vascular lesions.

In addition, the team will carry out molecular profiling of plasma samples collected in the same participants to identify metabolic and protein signatures that may predict clinical, pathologic, and physiologic outcomes related to Alzheimer’s and cerebrovascular disease.

In a companion study using mouse models with diabetes and Alzheimer’s pathology traits, the researchers will examine how the interaction between diabetes and Alzheimer’s pathology affects the structure and function of neural circuits important to learning and memory.

“This project is addressing two critical knowledge gaps,” Dr. Petanceska said. “The first is understanding the mechanisms by which dysregulated glucose metabolism impacts the onset and progression of pathologic changes in the course of the preclinical phase of Alzheimer’s disease; the second is understanding the molecular determinants of AD risk in Hispanics, a population with higher prevalence of diabetes and at greater risk for AD.”

The Role of Renin-Angiotensin-Endothelial Pathway in Alzheimer’s Disease

Researchers at Emory University, Atlanta, will focus on understanding the molecular mechanisms by which vascular dysfunction associated with high blood pressure affects the onset and progression of Alzheimer’s.

The research cohort comprises 160 subjects from the Emory Cardiovascular Biobank and Predictive Health Study– 80 with normal cognition and 80 with mild cognitive impairment – who will be followed for 2 years. Molecular data (genomic, epigenetic and metabolomic) combined with clinical data on the same subjects collected over 2 years, will be used to build a molecular network model of the interaction between vascular dysfunction and various Alzheimer’s disease traits.

Parallel studies in a rat model that uniquely exhibits human-like AD neuropathology will help uncover the temporal relationship between vascular dysfunction and AD and examine the potential of the molecular regulators of vascular function, such as the renin-angiotensin system, as therapeutic targets for AD. The goal is to characterize this pathway as a therapeutic target.

Metabolic Signatures Underlying Vascular Risk Factors for Alzheimer’s-Type Dementias

Teams at Duke University, Durham, N.C., and the University of Pennsylvania, Philadelphia, will carry out extensive profiling of plasma samples from 900 ADNI participants and from participants in the Duke University MURDOCK Memory and Cognitive Health Study in search for lipid metabolites that are associated with cardiovascular disease and cognitive change. These lipidomic profiles will be integrated with the vast array of clinical and other molecular data available for these participants to identify molecular signatures that may be used to differentiate among various risk-factor types of AD.

In addition, in a subset of subjects, the team will compare the lipidomic profiles between plasma and cerebrospinal fluid; this will enable the team to test hypotheses about the role of systemic vascular and metabolic factors on cognitive aging and AD.

Cerebral Amyloid Angiopathy and Mechanisms of Brain Amyloid Accumulation

Investigators at Massachusetts General Hospital, Boston, will investigate the molecular underpinnings of CAA and its impact on Alzheimer’s disease. Employing a mouse model and human subjects with CAA, the study will explore this cycle of progressive amyloid deposition and brain injury. The team’s approach combines noninvasive detection and analysis of human CAA, real-time measurement of vascular structure and physiology in living transgenic mouse models, and molecular analysis of gene expression in brain microvessels. Ultimately, the team hopes to identify candidate therapies with which could block it.

“This highly multidisciplinary investigation into how the vascular effects of amyloid at the molecular, single-blood vessel, and whole-brain levels influence the clinical disease promises to deliver new, well-characterized therapeutic targets for disease prevention,” Dr. Petanceska said.

She predicted that the wide-ranging projects of the M²OVE–AD consortium will bring invaluable understanding to an enormously important, but still unexplored, aspect of Alzheimer’s pathology.

“We hope that this large-scale team science effort will generate an in-depth understanding of how vascular and metabolic factors contribute to neurodegenerative changes that result in cognitive decline and dementia and that the data and knowledge generated by this program will be the basis for developing effective interventions for disease treatment and prevention.”