Susan London

SAN FRANCISCO – Prasugrel can overcome a lack of platelet response to clopidogrel in patients undergoing elective, noncomplicated percutaneous coronary intervention. But the rate of cardiovascular events in this group of clopidogrel nonresponders is low no matter which agent they receive – so low, in fact, that it prompted early closure of a randomized trial comparing the two.

Trial results, reported at Transcatheter Cardiovascular Therapeutics 2011, showed that merely 1 of the 236 patients having 6 months of follow-up experienced a myocardial infarction and none died of cardiovascular causes, with no significant difference between those who continued on clopidogrel and those who switched to prasugrel. Rates of major bleeding were also low and similar.

"Given the low event rate in elective percutaneous coronary intervention [PCI] patients without periprocedural complications, it was not possible to assess the risk-benefit ratio with prasugrel treatment. Therefore, the study was terminated prematurely for futility," lead investigator Dietmar Trenk, Ph.D., explained in a press conference. He presented results on behalf of the TRIGGER-PCI investigators.

Discussant Dr. Matthew J. Price, director of the Cardiac Catheterization Laboratory at the Scripps Clinic in La Jolla, Calif., agreed that the trial population had very low risk to begin with, and not just from a procedural perspective. For example, the patients on average had relatively large stented vessel diameters and received shorter stents.

"Also, this trial shows the challenges of performing a randomized clinical trial looking at individualized antiplatelet therapy, because about one-third of the patients who were identified as having high on-treatment platelet reactivity withdrew from the study because they did not want to participate," he commented. "So I think this shows that doing these trials, it’s very hard not to get selection bias for the lowest-risk patients, and that’s a challenge that we will have going forward in designing these randomized clinical trials."

"I do think it’s consistent [across trials] that in these low-risk patients, who have low-risk clinical scenarios and low [anatomical risk], the event rates are incredibly low, and although the hazard associated with on-treatment [platelet] reactivity may be substantial, ...the absolute event rates in these very low risk patients may mean that changing therapy may not provide net clinical benefit," Dr. Price maintained.

Patients were eligible for the trial, which was sponsored by Eli Lilly and Daiichi Sankyo Co., if they underwent successful PCI with implantation of drug-eluting stents, did not have any major complications, and did not receive any glycoprotein IIb/IIIa inhibitors, according to Dr. Trenk, who is a professor at the Herz-Zentrum Bad Krozingen (Germany).

All had received standard-of-care clopidogrel in the periprocedural period and were found to be clopidogrel nonresponders because they had a result of more than 208 platelet reactive units on the VerifyNow P2Y12 assay (Accumetrics) on the day after the procedure.

The patients were randomized in nearly equal numbers to either continue clopidogrel (Plavix; 75-mg daily maintenance dose) or switch to prasugrel (Effient; a one-time 60-mg loading dose and a 10-mg daily maintenance dose), with matching placebos.

When the trial was stopped, 423 patients had been enrolled and had data for clinical outcomes, Dr. Trenk reported at the meeting, which was sponsored by the Cardiovascular Research Foundation.

Analyses showed that the patients who switched to prasugrel indeed had lower platelet reactivity than did their counterparts who stayed on clopidogrel, both at 90 days (P less than .001) and at 176 days (P less than .001).

"Platelet reactivity in patients randomized to clopidogrel remained fairly constant, with a high rate of more than 70% of patients being hyporesponsive to the drug," Dr. Trenk pointed out. On the other hand, "prasugrel consistently decreased platelet reactivity, and only 5% of patients remained hyporesponsive at 3 months’ follow-up and at 6 months’ follow-up."

Despite this difference in platelet reactivity, the prasugrel and clopidogrel groups had similarly low 6-month rates of the primary composite efficacy end point of cardiovascular death and MI (0% and 0.5%), and secondary end points such as rehospitalization for cardiac ischemic events (0.9% and 1.9%), urgent target vessel revascularization (0.9% and 0.5%), and stroke (0% and 0.5%). There were no cases of definite or probably stent thrombosis.

Additionally, the prasugrel and clopidogrel groups had similarly low rates of the key safety end point of non–CABG-related TIMI (Thrombolysis in Myocardial Infarction) major bleeding (1.4% and 0.5%).

Dr. Trenk reported that he receives honoraria and advisory board fees from Daiichi-Sankyo, Eli Lilly, AstraZeneca, and Sanofi-Aventis. Dr. Price reported that he receives grant or research support from Bristol-Myers Squibb and Sanofi-Aventis, and that he is a consultant to, receives honoraria from, or is a speaker for Abiomed, AstraZeneca, Boston Scientific, Medtronic, Terumo Medical, Bristol-Myers Squibb, Daiichi-Sankyo/Eli Lilly, Sanofi-Aventis, and W.L. Gore & Associates.

SAN FRANCISCO – Prasugrel can overcome a lack of platelet response to clopidogrel in patients undergoing elective, noncomplicated percutaneous coronary intervention. But the rate of cardiovascular events in this group of clopidogrel nonresponders is low no matter which agent they receive – so low, in fact, that it prompted early closure of a randomized trial comparing the two.

Trial results, reported at Transcatheter Cardiovascular Therapeutics 2011, showed that merely 1 of the 236 patients having 6 months of follow-up experienced a myocardial infarction and none died of cardiovascular causes, with no significant difference between those who continued on clopidogrel and those who switched to prasugrel. Rates of major bleeding were also low and similar.

"Given the low event rate in elective percutaneous coronary intervention [PCI] patients without periprocedural complications, it was not possible to assess the risk-benefit ratio with prasugrel treatment. Therefore, the study was terminated prematurely for futility," lead investigator Dietmar Trenk, Ph.D., explained in a press conference. He presented results on behalf of the TRIGGER-PCI investigators.

Discussant Dr. Matthew J. Price, director of the Cardiac Catheterization Laboratory at the Scripps Clinic in La Jolla, Calif., agreed that the trial population had very low risk to begin with, and not just from a procedural perspective. For example, the patients on average had relatively large stented vessel diameters and received shorter stents.

"Also, this trial shows the challenges of performing a randomized clinical trial looking at individualized antiplatelet therapy, because about one-third of the patients who were identified as having high on-treatment platelet reactivity withdrew from the study because they did not want to participate," he commented. "So I think this shows that doing these trials, it’s very hard not to get selection bias for the lowest-risk patients, and that’s a challenge that we will have going forward in designing these randomized clinical trials."

"I do think it’s consistent [across trials] that in these low-risk patients, who have low-risk clinical scenarios and low [anatomical risk], the event rates are incredibly low, and although the hazard associated with on-treatment [platelet] reactivity may be substantial, ...the absolute event rates in these very low risk patients may mean that changing therapy may not provide net clinical benefit," Dr. Price maintained.

Patients were eligible for the trial, which was sponsored by Eli Lilly and Daiichi Sankyo Co., if they underwent successful PCI with implantation of drug-eluting stents, did not have any major complications, and did not receive any glycoprotein IIb/IIIa inhibitors, according to Dr. Trenk, who is a professor at the Herz-Zentrum Bad Krozingen (Germany).

All had received standard-of-care clopidogrel in the periprocedural period and were found to be clopidogrel nonresponders because they had a result of more than 208 platelet reactive units on the VerifyNow P2Y12 assay (Accumetrics) on the day after the procedure.

The patients were randomized in nearly equal numbers to either continue clopidogrel (Plavix; 75-mg daily maintenance dose) or switch to prasugrel (Effient; a one-time 60-mg loading dose and a 10-mg daily maintenance dose), with matching placebos.

When the trial was stopped, 423 patients had been enrolled and had data for clinical outcomes, Dr. Trenk reported at the meeting, which was sponsored by the Cardiovascular Research Foundation.

Analyses showed that the patients who switched to prasugrel indeed had lower platelet reactivity than did their counterparts who stayed on clopidogrel, both at 90 days (P less than .001) and at 176 days (P less than .001).

"Platelet reactivity in patients randomized to clopidogrel remained fairly constant, with a high rate of more than 70% of patients being hyporesponsive to the drug," Dr. Trenk pointed out. On the other hand, "prasugrel consistently decreased platelet reactivity, and only 5% of patients remained hyporesponsive at 3 months’ follow-up and at 6 months’ follow-up."

Despite this difference in platelet reactivity, the prasugrel and clopidogrel groups had similarly low 6-month rates of the primary composite efficacy end point of cardiovascular death and MI (0% and 0.5%), and secondary end points such as rehospitalization for cardiac ischemic events (0.9% and 1.9%), urgent target vessel revascularization (0.9% and 0.5%), and stroke (0% and 0.5%). There were no cases of definite or probably stent thrombosis.

Additionally, the prasugrel and clopidogrel groups had similarly low rates of the key safety end point of non–CABG-related TIMI (Thrombolysis in Myocardial Infarction) major bleeding (1.4% and 0.5%).

Dr. Trenk reported that he receives honoraria and advisory board fees from Daiichi-Sankyo, Eli Lilly, AstraZeneca, and Sanofi-Aventis. Dr. Price reported that he receives grant or research support from Bristol-Myers Squibb and Sanofi-Aventis, and that he is a consultant to, receives honoraria from, or is a speaker for Abiomed, AstraZeneca, Boston Scientific, Medtronic, Terumo Medical, Bristol-Myers Squibb, Daiichi-Sankyo/Eli Lilly, Sanofi-Aventis, and W.L. Gore & Associates.

SAN FRANCISCO – Prasugrel can overcome a lack of platelet response to clopidogrel in patients undergoing elective, noncomplicated percutaneous coronary intervention. But the rate of cardiovascular events in this group of clopidogrel nonresponders is low no matter which agent they receive – so low, in fact, that it prompted early closure of a randomized trial comparing the two.

Trial results, reported at Transcatheter Cardiovascular Therapeutics 2011, showed that merely 1 of the 236 patients having 6 months of follow-up experienced a myocardial infarction and none died of cardiovascular causes, with no significant difference between those who continued on clopidogrel and those who switched to prasugrel. Rates of major bleeding were also low and similar.

"Given the low event rate in elective percutaneous coronary intervention [PCI] patients without periprocedural complications, it was not possible to assess the risk-benefit ratio with prasugrel treatment. Therefore, the study was terminated prematurely for futility," lead investigator Dietmar Trenk, Ph.D., explained in a press conference. He presented results on behalf of the TRIGGER-PCI investigators.

Discussant Dr. Matthew J. Price, director of the Cardiac Catheterization Laboratory at the Scripps Clinic in La Jolla, Calif., agreed that the trial population had very low risk to begin with, and not just from a procedural perspective. For example, the patients on average had relatively large stented vessel diameters and received shorter stents.

"Also, this trial shows the challenges of performing a randomized clinical trial looking at individualized antiplatelet therapy, because about one-third of the patients who were identified as having high on-treatment platelet reactivity withdrew from the study because they did not want to participate," he commented. "So I think this shows that doing these trials, it’s very hard not to get selection bias for the lowest-risk patients, and that’s a challenge that we will have going forward in designing these randomized clinical trials."

"I do think it’s consistent [across trials] that in these low-risk patients, who have low-risk clinical scenarios and low [anatomical risk], the event rates are incredibly low, and although the hazard associated with on-treatment [platelet] reactivity may be substantial, ...the absolute event rates in these very low risk patients may mean that changing therapy may not provide net clinical benefit," Dr. Price maintained.

Patients were eligible for the trial, which was sponsored by Eli Lilly and Daiichi Sankyo Co., if they underwent successful PCI with implantation of drug-eluting stents, did not have any major complications, and did not receive any glycoprotein IIb/IIIa inhibitors, according to Dr. Trenk, who is a professor at the Herz-Zentrum Bad Krozingen (Germany).

All had received standard-of-care clopidogrel in the periprocedural period and were found to be clopidogrel nonresponders because they had a result of more than 208 platelet reactive units on the VerifyNow P2Y12 assay (Accumetrics) on the day after the procedure.

The patients were randomized in nearly equal numbers to either continue clopidogrel (Plavix; 75-mg daily maintenance dose) or switch to prasugrel (Effient; a one-time 60-mg loading dose and a 10-mg daily maintenance dose), with matching placebos.

When the trial was stopped, 423 patients had been enrolled and had data for clinical outcomes, Dr. Trenk reported at the meeting, which was sponsored by the Cardiovascular Research Foundation.

Analyses showed that the patients who switched to prasugrel indeed had lower platelet reactivity than did their counterparts who stayed on clopidogrel, both at 90 days (P less than .001) and at 176 days (P less than .001).

"Platelet reactivity in patients randomized to clopidogrel remained fairly constant, with a high rate of more than 70% of patients being hyporesponsive to the drug," Dr. Trenk pointed out. On the other hand, "prasugrel consistently decreased platelet reactivity, and only 5% of patients remained hyporesponsive at 3 months’ follow-up and at 6 months’ follow-up."

Despite this difference in platelet reactivity, the prasugrel and clopidogrel groups had similarly low 6-month rates of the primary composite efficacy end point of cardiovascular death and MI (0% and 0.5%), and secondary end points such as rehospitalization for cardiac ischemic events (0.9% and 1.9%), urgent target vessel revascularization (0.9% and 0.5%), and stroke (0% and 0.5%). There were no cases of definite or probably stent thrombosis.

Additionally, the prasugrel and clopidogrel groups had similarly low rates of the key safety end point of non–CABG-related TIMI (Thrombolysis in Myocardial Infarction) major bleeding (1.4% and 0.5%).

Dr. Trenk reported that he receives honoraria and advisory board fees from Daiichi-Sankyo, Eli Lilly, AstraZeneca, and Sanofi-Aventis. Dr. Price reported that he receives grant or research support from Bristol-Myers Squibb and Sanofi-Aventis, and that he is a consultant to, receives honoraria from, or is a speaker for Abiomed, AstraZeneca, Boston Scientific, Medtronic, Terumo Medical, Bristol-Myers Squibb, Daiichi-Sankyo/Eli Lilly, Sanofi-Aventis, and W.L. Gore & Associates.

SAN FRANCISCO – Using a rapid point-of-care test to identify patients likely to be poor metabolizers of clopidogrel and tailoring their antiplatelet therapy accordingly improves the biologic effectiveness of that therapy, concludes a trial reported at the annual Transcatheter Cardiovascular Therapeutics meeting.

Investigators conducted the open-label, randomized trial in 200 patients undergoing percutaneous coronary intervention with stenting, using a point-of-care test for the *2 allele of the CYP2C19 gene. The allele confers a loss of function of the CYP2C19 enzyme and thus reduced hepatic metabolic activation of clopidogrel and an increased risk of adverse cardiovascular events in this setting. Testing was performed by nurses at the bedside using buccal swabs and yielded results in about 1 hour.

Findings of the RAPID GENE (Reassessment of Antiplatelet Therapy Using an Individualized Strategy Based on Genetic Evaluation) trial showed that nearly a third of patients having the *2 allele had impaired platelet activity a week later if they had simply been given standard clopidogrel therapy. This compared with none of their counterparts who were instead given prasugrel, an agent that overcomes the problem of poor metabolism, on the basis of their point-of-care test results.

"What RAPID GENE has shown is that point-of-care genetic testing after stenting performed at the bedside by clinical nurses permits accurate identification of the *2 carrier status and facilitates a rapid, tailored approach to antiplatelet therapy," according to lead investigator Dr. Derek Y.F. So.

The findings are clinically important, given that up to one-fourth of the more than 2 million patients undergoing coronary stenting each year may have genetic variants increasing their risk of clopidogrel failure, he noted. "RAPID GENE is essentially a proof of concept that rapid genetic testing and adherence with tailored therapy is now feasible," he said at the meeting, which is sponsored by the Cardiovascular Research Foundation. "The other reason this is important is that this will be applicable to all other areas of medicine as well."

However, added Dr. So, a cardiologist at the University of Ottawa Heart Institute, such testing remains more of a research tool at present. "I do think that it’s premature right now to say that this is going to be routinely implemented in hospitals. But ... this is going to be a game-changer in the sense that it allows us to design other prospective studies to evaluate this on a more detailed basis," he elaborated.

And this genetic information is merely one piece of a complex puzzle, he noted. "I don’t think using genetics alone is going to allow us to select out all the patients, but it’s going to be a combination of genetics in association with clinical risk factors, in association with platelet function. And I think that [*2 allelic information] will be a potential risk factor that will be incorporated in any future model."

Discussant Dr. Paul A. Gurbel, director of the Sinai Center for Thrombosis Research in Baltimore, expressed reservations about the trial, noting that a previous genome-wide associated study suggested that only 12.5% of the variability in platelet reactivity on clopidogrel can be attributed to the *2 allele, suggesting many genetic influences on the response to this drug. "So I have to say, this is a bit surprising – for any thienopyridine actually, there are so many influences on the response to thienopyridine therapies – to see absolutely no high platelet activity on prasugrel therapy in the *2 carriers," he said.

Furthermore, other studies in patients undergoing PCI suggest that the rate of high platelet reactivity on prasugrel is not zero. "So this [trial’s result] is discordant with data that’s already out there in the literature," Dr. Gurbel maintained.

He also sounded a note of caution about making decisions about clopidogrel therapy based solely on this allele. "There are many patients on clopidogrel who are *2 carriers who respond very nicely to the drug. So [by making] your decision based on *2, a lot of patients who would have responded nicely to clopidogrel are given another agent," he said.

In the trial, patients were randomized in balanced fashion to either standard therapy or genetically tailored therapy.

All patients in the former group received clopidogrel (Plavix) 75 mg daily. All patients in the latter group were started on clopidogrel but had point-of-care genotyping at the time of PCI to determine their *2 carrier status (Spartan RX, Spartan Bioscience); those found to carry the *2 allele were immediately switched to prasugrel 10 mg daily, whereas those found to be noncarriers continued on clopidogrel.

Platelet reactivity was assessed 1 week later with the VerifyNow P2Y12 assay (Accumetrics), and patients were defined as having high reactivity if their result exceeded 234 platelet reactive units. Additionally, *2 carrier status was assessed among patients in the standard therapy group at that time.

Trial results showed that *2 carriers were significantly less likely to have high platelet reactivity at 1 week if they received point-of-care testing plus prasugrel therapy than if they received standard clopidogrel therapy (0% vs. 30.4%).

Additional analyses showed that relative to the conventional laboratory genetic test, the rapid point-of-care test had 100% sensitivity and 99.4% specificity for identifying *2 carriers.

"There was no difference in clinical events between the two arms," Dr. So reported; however "there was a numerical increase in bleeding among patients on the rapid genotyping arm, compared to the standard therapy arm."

He acknowledged the numerous genetic influences on clopidogrel response and their interaction, and noted that the rapid point-of-care testing device is being improved in this regard. "There is a second study now of the three-SNP [single-nucleotide polymorphism] device, so we will be able to look at multiple SNPs at the same time in the future," he said.

Dr. So reported that he receives grant or research support from Spartan and is a consultant to, speaker for, or receives honoraria from Daiichi-Sankyo/Eli Lilly. Dr. Gurbel reported that he is a consultant to, speaker for, or receives honoraria from Merck/Schering Plough, Portola Pharmaceuticals, Bayer/Pozen, AstraZeneca, and Daiichi-Sankyo/Eli Lilly.

SAN FRANCISCO – Using a rapid point-of-care test to identify patients likely to be poor metabolizers of clopidogrel and tailoring their antiplatelet therapy accordingly improves the biologic effectiveness of that therapy, concludes a trial reported at the annual Transcatheter Cardiovascular Therapeutics meeting.

Investigators conducted the open-label, randomized trial in 200 patients undergoing percutaneous coronary intervention with stenting, using a point-of-care test for the *2 allele of the CYP2C19 gene. The allele confers a loss of function of the CYP2C19 enzyme and thus reduced hepatic metabolic activation of clopidogrel and an increased risk of adverse cardiovascular events in this setting. Testing was performed by nurses at the bedside using buccal swabs and yielded results in about 1 hour.

Findings of the RAPID GENE (Reassessment of Antiplatelet Therapy Using an Individualized Strategy Based on Genetic Evaluation) trial showed that nearly a third of patients having the *2 allele had impaired platelet activity a week later if they had simply been given standard clopidogrel therapy. This compared with none of their counterparts who were instead given prasugrel, an agent that overcomes the problem of poor metabolism, on the basis of their point-of-care test results.

"What RAPID GENE has shown is that point-of-care genetic testing after stenting performed at the bedside by clinical nurses permits accurate identification of the *2 carrier status and facilitates a rapid, tailored approach to antiplatelet therapy," according to lead investigator Dr. Derek Y.F. So.

The findings are clinically important, given that up to one-fourth of the more than 2 million patients undergoing coronary stenting each year may have genetic variants increasing their risk of clopidogrel failure, he noted. "RAPID GENE is essentially a proof of concept that rapid genetic testing and adherence with tailored therapy is now feasible," he said at the meeting, which is sponsored by the Cardiovascular Research Foundation. "The other reason this is important is that this will be applicable to all other areas of medicine as well."

However, added Dr. So, a cardiologist at the University of Ottawa Heart Institute, such testing remains more of a research tool at present. "I do think that it’s premature right now to say that this is going to be routinely implemented in hospitals. But ... this is going to be a game-changer in the sense that it allows us to design other prospective studies to evaluate this on a more detailed basis," he elaborated.

And this genetic information is merely one piece of a complex puzzle, he noted. "I don’t think using genetics alone is going to allow us to select out all the patients, but it’s going to be a combination of genetics in association with clinical risk factors, in association with platelet function. And I think that [*2 allelic information] will be a potential risk factor that will be incorporated in any future model."

Discussant Dr. Paul A. Gurbel, director of the Sinai Center for Thrombosis Research in Baltimore, expressed reservations about the trial, noting that a previous genome-wide associated study suggested that only 12.5% of the variability in platelet reactivity on clopidogrel can be attributed to the *2 allele, suggesting many genetic influences on the response to this drug. "So I have to say, this is a bit surprising – for any thienopyridine actually, there are so many influences on the response to thienopyridine therapies – to see absolutely no high platelet activity on prasugrel therapy in the *2 carriers," he said.

Furthermore, other studies in patients undergoing PCI suggest that the rate of high platelet reactivity on prasugrel is not zero. "So this [trial’s result] is discordant with data that’s already out there in the literature," Dr. Gurbel maintained.

He also sounded a note of caution about making decisions about clopidogrel therapy based solely on this allele. "There are many patients on clopidogrel who are *2 carriers who respond very nicely to the drug. So [by making] your decision based on *2, a lot of patients who would have responded nicely to clopidogrel are given another agent," he said.

In the trial, patients were randomized in balanced fashion to either standard therapy or genetically tailored therapy.

All patients in the former group received clopidogrel (Plavix) 75 mg daily. All patients in the latter group were started on clopidogrel but had point-of-care genotyping at the time of PCI to determine their *2 carrier status (Spartan RX, Spartan Bioscience); those found to carry the *2 allele were immediately switched to prasugrel 10 mg daily, whereas those found to be noncarriers continued on clopidogrel.

Platelet reactivity was assessed 1 week later with the VerifyNow P2Y12 assay (Accumetrics), and patients were defined as having high reactivity if their result exceeded 234 platelet reactive units. Additionally, *2 carrier status was assessed among patients in the standard therapy group at that time.

Trial results showed that *2 carriers were significantly less likely to have high platelet reactivity at 1 week if they received point-of-care testing plus prasugrel therapy than if they received standard clopidogrel therapy (0% vs. 30.4%).

Additional analyses showed that relative to the conventional laboratory genetic test, the rapid point-of-care test had 100% sensitivity and 99.4% specificity for identifying *2 carriers.

"There was no difference in clinical events between the two arms," Dr. So reported; however "there was a numerical increase in bleeding among patients on the rapid genotyping arm, compared to the standard therapy arm."

He acknowledged the numerous genetic influences on clopidogrel response and their interaction, and noted that the rapid point-of-care testing device is being improved in this regard. "There is a second study now of the three-SNP [single-nucleotide polymorphism] device, so we will be able to look at multiple SNPs at the same time in the future," he said.

Dr. So reported that he receives grant or research support from Spartan and is a consultant to, speaker for, or receives honoraria from Daiichi-Sankyo/Eli Lilly. Dr. Gurbel reported that he is a consultant to, speaker for, or receives honoraria from Merck/Schering Plough, Portola Pharmaceuticals, Bayer/Pozen, AstraZeneca, and Daiichi-Sankyo/Eli Lilly.

SAN FRANCISCO – Using a rapid point-of-care test to identify patients likely to be poor metabolizers of clopidogrel and tailoring their antiplatelet therapy accordingly improves the biologic effectiveness of that therapy, concludes a trial reported at the annual Transcatheter Cardiovascular Therapeutics meeting.

Investigators conducted the open-label, randomized trial in 200 patients undergoing percutaneous coronary intervention with stenting, using a point-of-care test for the *2 allele of the CYP2C19 gene. The allele confers a loss of function of the CYP2C19 enzyme and thus reduced hepatic metabolic activation of clopidogrel and an increased risk of adverse cardiovascular events in this setting. Testing was performed by nurses at the bedside using buccal swabs and yielded results in about 1 hour.

Findings of the RAPID GENE (Reassessment of Antiplatelet Therapy Using an Individualized Strategy Based on Genetic Evaluation) trial showed that nearly a third of patients having the *2 allele had impaired platelet activity a week later if they had simply been given standard clopidogrel therapy. This compared with none of their counterparts who were instead given prasugrel, an agent that overcomes the problem of poor metabolism, on the basis of their point-of-care test results.

"What RAPID GENE has shown is that point-of-care genetic testing after stenting performed at the bedside by clinical nurses permits accurate identification of the *2 carrier status and facilitates a rapid, tailored approach to antiplatelet therapy," according to lead investigator Dr. Derek Y.F. So.

The findings are clinically important, given that up to one-fourth of the more than 2 million patients undergoing coronary stenting each year may have genetic variants increasing their risk of clopidogrel failure, he noted. "RAPID GENE is essentially a proof of concept that rapid genetic testing and adherence with tailored therapy is now feasible," he said at the meeting, which is sponsored by the Cardiovascular Research Foundation. "The other reason this is important is that this will be applicable to all other areas of medicine as well."

However, added Dr. So, a cardiologist at the University of Ottawa Heart Institute, such testing remains more of a research tool at present. "I do think that it’s premature right now to say that this is going to be routinely implemented in hospitals. But ... this is going to be a game-changer in the sense that it allows us to design other prospective studies to evaluate this on a more detailed basis," he elaborated.

And this genetic information is merely one piece of a complex puzzle, he noted. "I don’t think using genetics alone is going to allow us to select out all the patients, but it’s going to be a combination of genetics in association with clinical risk factors, in association with platelet function. And I think that [*2 allelic information] will be a potential risk factor that will be incorporated in any future model."

Discussant Dr. Paul A. Gurbel, director of the Sinai Center for Thrombosis Research in Baltimore, expressed reservations about the trial, noting that a previous genome-wide associated study suggested that only 12.5% of the variability in platelet reactivity on clopidogrel can be attributed to the *2 allele, suggesting many genetic influences on the response to this drug. "So I have to say, this is a bit surprising – for any thienopyridine actually, there are so many influences on the response to thienopyridine therapies – to see absolutely no high platelet activity on prasugrel therapy in the *2 carriers," he said.

Furthermore, other studies in patients undergoing PCI suggest that the rate of high platelet reactivity on prasugrel is not zero. "So this [trial’s result] is discordant with data that’s already out there in the literature," Dr. Gurbel maintained.

He also sounded a note of caution about making decisions about clopidogrel therapy based solely on this allele. "There are many patients on clopidogrel who are *2 carriers who respond very nicely to the drug. So [by making] your decision based on *2, a lot of patients who would have responded nicely to clopidogrel are given another agent," he said.

In the trial, patients were randomized in balanced fashion to either standard therapy or genetically tailored therapy.

All patients in the former group received clopidogrel (Plavix) 75 mg daily. All patients in the latter group were started on clopidogrel but had point-of-care genotyping at the time of PCI to determine their *2 carrier status (Spartan RX, Spartan Bioscience); those found to carry the *2 allele were immediately switched to prasugrel 10 mg daily, whereas those found to be noncarriers continued on clopidogrel.

Platelet reactivity was assessed 1 week later with the VerifyNow P2Y12 assay (Accumetrics), and patients were defined as having high reactivity if their result exceeded 234 platelet reactive units. Additionally, *2 carrier status was assessed among patients in the standard therapy group at that time.

Trial results showed that *2 carriers were significantly less likely to have high platelet reactivity at 1 week if they received point-of-care testing plus prasugrel therapy than if they received standard clopidogrel therapy (0% vs. 30.4%).

Additional analyses showed that relative to the conventional laboratory genetic test, the rapid point-of-care test had 100% sensitivity and 99.4% specificity for identifying *2 carriers.

"There was no difference in clinical events between the two arms," Dr. So reported; however "there was a numerical increase in bleeding among patients on the rapid genotyping arm, compared to the standard therapy arm."

He acknowledged the numerous genetic influences on clopidogrel response and their interaction, and noted that the rapid point-of-care testing device is being improved in this regard. "There is a second study now of the three-SNP [single-nucleotide polymorphism] device, so we will be able to look at multiple SNPs at the same time in the future," he said.

Dr. So reported that he receives grant or research support from Spartan and is a consultant to, speaker for, or receives honoraria from Daiichi-Sankyo/Eli Lilly. Dr. Gurbel reported that he is a consultant to, speaker for, or receives honoraria from Merck/Schering Plough, Portola Pharmaceuticals, Bayer/Pozen, AstraZeneca, and Daiichi-Sankyo/Eli Lilly.

CHICAGO – The prognosis for infections caused by Enterobacteriaceae that harbor Klebsiella pneumoniae carbapenemase (KPC) may not be as poor as some statistics have suggested, according to a small study of patients with bloodstream infections due to these resistant pathogens.

The 30-day mortality rate in the study of 39 patients was 13% – or roughly half to a third of that seen in previous studies – researchers reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy. Moreover, 41% of the patients did not even receive an antibiotic active against KPC-positive pathogens.

"Maybe in other studies reporting such high mortality rates, it’s just that patients at baseline are very sick, and it’s not necessarily attributed to having the KPC."

"There has been a really high mortality associated with this type of infection," lead investigator Elizabeth B. Hirsch, Pharm.D., of Northeastern University in Boston, commented in an interview. "Some people are reporting from 30% to 50% mortality with this type of infection, so we were a little bit surprised at that [13% rate]."

The study also found that a greater severity of illness, as assessed by Acute Physiology and Chronic Health Evaluation (APACHE) II scores, independently predicted death in this population, which may in part explain the disparate findings, she speculated. "Maybe in other studies reporting such high mortality rates, it’s just that patients at baseline are very sick, and it’s not necessarily attributed to having the KPC."

The investigators studied 39 patients with bloodstream infections due to KPC-harboring Enterobacteriaceae treated between May 2009 and December 2010. Study results were reported in a poster session at the meeting, which was sponsored by the American Society for Microbiology.

The patients were 62 years old, on average; 54% were male and 36% were white. They had been hospitalized for a mean of 27 days, and their mean APACHE II score was 12.4.

The most common source of the bacteremia was abdominal (39%), followed by urinary (26%) and pulmonary (15%). In terms of the specific pathogen, 61.5% of patients had Klebsiella species, 36% had Escherichia coli, and 2.5% had Enterobacter aerogenes.

Overall, 13% of the patients died in the 30 days after diagnosis. In a multivariate analysis, patients with an APACHE II score of 17 or higher were more likely to die (odds ratio, 45.4; P = .013), whereas the risk of death fell with advancing age (OR, 0.9; P = .038).

"Surprisingly, a lot of these patients didn’t even receive any therapy that was active against the KPC, but they cleared their bloodstream infection [anyway]," noted Dr. Hirsch.

Specifically, 16 patients did not receive any KPC-active therapy. In this subset, the most common source of bacteremia was urinary (44%) and the 30-day mortality rate was the same as that in the cohort overall (13%).

Given the high prevalence of a urinary source of infection in this group, "if they are receiving carbapenems, which we know the KPC can hydrolyze, maybe they are getting high enough concentrations of the drug in the urine, which I guess is sort of clearing the main source of infection," she said.

Molecular analyses in the overall cohort identified 14 unique clones among the Klebsiella isolates and 7 unique clones among the E. coli isolates.

"Since we found a lower rate of mortality [than previously reported], we are kind of wondering what the virulence is associated with these isolates," Dr. Hirsch concluded. "So that’s the next step – we are going to do some analyses of the isolates to see really how virulent they are."

Dr. Hirsch reported having no conflicts of interest related to the study.

CHICAGO – The prognosis for infections caused by Enterobacteriaceae that harbor Klebsiella pneumoniae carbapenemase (KPC) may not be as poor as some statistics have suggested, according to a small study of patients with bloodstream infections due to these resistant pathogens.

The 30-day mortality rate in the study of 39 patients was 13% – or roughly half to a third of that seen in previous studies – researchers reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy. Moreover, 41% of the patients did not even receive an antibiotic active against KPC-positive pathogens.

"Maybe in other studies reporting such high mortality rates, it’s just that patients at baseline are very sick, and it’s not necessarily attributed to having the KPC."

"There has been a really high mortality associated with this type of infection," lead investigator Elizabeth B. Hirsch, Pharm.D., of Northeastern University in Boston, commented in an interview. "Some people are reporting from 30% to 50% mortality with this type of infection, so we were a little bit surprised at that [13% rate]."

The study also found that a greater severity of illness, as assessed by Acute Physiology and Chronic Health Evaluation (APACHE) II scores, independently predicted death in this population, which may in part explain the disparate findings, she speculated. "Maybe in other studies reporting such high mortality rates, it’s just that patients at baseline are very sick, and it’s not necessarily attributed to having the KPC."

The investigators studied 39 patients with bloodstream infections due to KPC-harboring Enterobacteriaceae treated between May 2009 and December 2010. Study results were reported in a poster session at the meeting, which was sponsored by the American Society for Microbiology.

The patients were 62 years old, on average; 54% were male and 36% were white. They had been hospitalized for a mean of 27 days, and their mean APACHE II score was 12.4.

The most common source of the bacteremia was abdominal (39%), followed by urinary (26%) and pulmonary (15%). In terms of the specific pathogen, 61.5% of patients had Klebsiella species, 36% had Escherichia coli, and 2.5% had Enterobacter aerogenes.

Overall, 13% of the patients died in the 30 days after diagnosis. In a multivariate analysis, patients with an APACHE II score of 17 or higher were more likely to die (odds ratio, 45.4; P = .013), whereas the risk of death fell with advancing age (OR, 0.9; P = .038).

"Surprisingly, a lot of these patients didn’t even receive any therapy that was active against the KPC, but they cleared their bloodstream infection [anyway]," noted Dr. Hirsch.

Specifically, 16 patients did not receive any KPC-active therapy. In this subset, the most common source of bacteremia was urinary (44%) and the 30-day mortality rate was the same as that in the cohort overall (13%).

Given the high prevalence of a urinary source of infection in this group, "if they are receiving carbapenems, which we know the KPC can hydrolyze, maybe they are getting high enough concentrations of the drug in the urine, which I guess is sort of clearing the main source of infection," she said.

Molecular analyses in the overall cohort identified 14 unique clones among the Klebsiella isolates and 7 unique clones among the E. coli isolates.

"Since we found a lower rate of mortality [than previously reported], we are kind of wondering what the virulence is associated with these isolates," Dr. Hirsch concluded. "So that’s the next step – we are going to do some analyses of the isolates to see really how virulent they are."

Dr. Hirsch reported having no conflicts of interest related to the study.

CHICAGO – The prognosis for infections caused by Enterobacteriaceae that harbor Klebsiella pneumoniae carbapenemase (KPC) may not be as poor as some statistics have suggested, according to a small study of patients with bloodstream infections due to these resistant pathogens.

The 30-day mortality rate in the study of 39 patients was 13% – or roughly half to a third of that seen in previous studies – researchers reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy. Moreover, 41% of the patients did not even receive an antibiotic active against KPC-positive pathogens.

"Maybe in other studies reporting such high mortality rates, it’s just that patients at baseline are very sick, and it’s not necessarily attributed to having the KPC."

"There has been a really high mortality associated with this type of infection," lead investigator Elizabeth B. Hirsch, Pharm.D., of Northeastern University in Boston, commented in an interview. "Some people are reporting from 30% to 50% mortality with this type of infection, so we were a little bit surprised at that [13% rate]."

The study also found that a greater severity of illness, as assessed by Acute Physiology and Chronic Health Evaluation (APACHE) II scores, independently predicted death in this population, which may in part explain the disparate findings, she speculated. "Maybe in other studies reporting such high mortality rates, it’s just that patients at baseline are very sick, and it’s not necessarily attributed to having the KPC."

The investigators studied 39 patients with bloodstream infections due to KPC-harboring Enterobacteriaceae treated between May 2009 and December 2010. Study results were reported in a poster session at the meeting, which was sponsored by the American Society for Microbiology.

The patients were 62 years old, on average; 54% were male and 36% were white. They had been hospitalized for a mean of 27 days, and their mean APACHE II score was 12.4.

The most common source of the bacteremia was abdominal (39%), followed by urinary (26%) and pulmonary (15%). In terms of the specific pathogen, 61.5% of patients had Klebsiella species, 36% had Escherichia coli, and 2.5% had Enterobacter aerogenes.

Overall, 13% of the patients died in the 30 days after diagnosis. In a multivariate analysis, patients with an APACHE II score of 17 or higher were more likely to die (odds ratio, 45.4; P = .013), whereas the risk of death fell with advancing age (OR, 0.9; P = .038).

"Surprisingly, a lot of these patients didn’t even receive any therapy that was active against the KPC, but they cleared their bloodstream infection [anyway]," noted Dr. Hirsch.

Specifically, 16 patients did not receive any KPC-active therapy. In this subset, the most common source of bacteremia was urinary (44%) and the 30-day mortality rate was the same as that in the cohort overall (13%).

Given the high prevalence of a urinary source of infection in this group, "if they are receiving carbapenems, which we know the KPC can hydrolyze, maybe they are getting high enough concentrations of the drug in the urine, which I guess is sort of clearing the main source of infection," she said.

Molecular analyses in the overall cohort identified 14 unique clones among the Klebsiella isolates and 7 unique clones among the E. coli isolates.

"Since we found a lower rate of mortality [than previously reported], we are kind of wondering what the virulence is associated with these isolates," Dr. Hirsch concluded. "So that’s the next step – we are going to do some analyses of the isolates to see really how virulent they are."

Dr. Hirsch reported having no conflicts of interest related to the study.

CHICAGO – Daptomycin works as well at clearing diabetic skin and soft tissue infections in real-world clinical practice as it does in clinical trials, according to a retrospective analysis of data from a large European registry.

The rate of clinical success, meaning cure or improvement of the infection, was 86% among nearly 300 patients with diabetic ulcers or foot infections.

By comparison, in a newly completed phase III study of daptomycin, success rates were in the upper 80% range, said Uwe Trostmann, Ph.D., an employee of Novartis Pharma AG in Basel, Switzerland, who presented the registry analysis results at the annual meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy.

In everyday clinical settings, the rate of adverse events possibly related to daptomycin was 1.4%. Only a single patient experienced an increase in levels of creatine phosphokinase (CPK), a known possible adverse effect of the antibiotic.

These are "real-world data. This is not a clinical trial," he stressed. "This is very important information for the clinicians," because it helps them understand what outcomes they can anticipate in their own inpatient and outpatient settings.

Daptomycin has some advantages over vancomycin, which is the current mainstay antibiotic for such infections but also increases the risk of renal complications, Dr. Trostmann said.

The investigators analyzed data from the European Cubicin Outcomes Registry and Experience (EU-CORE), an ongoing, retrospective, noninterventional registry that captures information on patients treated with daptomycin (Cubicin) in routine clinical practice. For the registry, clinicians fill out case report forms after a patient’s treatment has been completed, to avoid any bias.

Of 3,621 patients enrolled between 2006 and 2010, the investigators specifically assessed outcomes among the 277 with diabetic ulcer or foot infections.

On average, these patients were 66 years old. The majority were male (70%) and white (94%). Nearly all (97%) had additional comorbidities, most commonly cardiovascular disease. By setting, the largest share came from the community (43%) followed by the hospital (40%).

Overall, 81% of the patients had a diabetic foot infection, while 19% had a diabetic ulcer infection, Dr. Trostmann reported at the conference, which was sponsored by the American Society for Microbiology. Some had secondary infections as well, such as osteomyelitis (4%) and bacteremia (3%).

Among patients with culture results, the most common pathogen was Staphylococcus aureus (seen in 54%), which was methicillin resistant in more than two-thirds of cases. Thirty-nine percent of patients had received previous antibiotic therapy, usually a fluoroquinolone or penicillin.

Sixty percent received daptomycin in combination with another antibiotic, most often a fluoroquinolone or carbapenem. In addition, 61% of patients had tissue debridement and 15% had bone debridement as part of their treatment.

Daptomycin was started at 4 mg/kg in 55% of patients and at 6 mg/kg in 17%. The median duration of daptomycin therapy was 6 days for outpatients, 12 days for general inpatients, and 2 days for intensive care unit patients.

The overall success rate was 86% (the infection was cured in 31% of patients and improved in 55%). The rate was similar among patients who also had secondary skin and soft-tissue infections (85%), osteomyelitis (91%), and bacteremia (89%). It was lower among patients who also had a urinary tract infection or pyelonephritis (50%); only two patients were in this group.

Overall, 1.4% of patients had adverse events possibly related to the drug. A single patient (0.4% of those studied) had an increase in CPK level.

Daptomycin is manufactured/marketed by Cubist Pharmaceuticals in the United States and by Novartis in Europe.

CHICAGO – Daptomycin works as well at clearing diabetic skin and soft tissue infections in real-world clinical practice as it does in clinical trials, according to a retrospective analysis of data from a large European registry.

The rate of clinical success, meaning cure or improvement of the infection, was 86% among nearly 300 patients with diabetic ulcers or foot infections.

By comparison, in a newly completed phase III study of daptomycin, success rates were in the upper 80% range, said Uwe Trostmann, Ph.D., an employee of Novartis Pharma AG in Basel, Switzerland, who presented the registry analysis results at the annual meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy.

In everyday clinical settings, the rate of adverse events possibly related to daptomycin was 1.4%. Only a single patient experienced an increase in levels of creatine phosphokinase (CPK), a known possible adverse effect of the antibiotic.

These are "real-world data. This is not a clinical trial," he stressed. "This is very important information for the clinicians," because it helps them understand what outcomes they can anticipate in their own inpatient and outpatient settings.

Daptomycin has some advantages over vancomycin, which is the current mainstay antibiotic for such infections but also increases the risk of renal complications, Dr. Trostmann said.

The investigators analyzed data from the European Cubicin Outcomes Registry and Experience (EU-CORE), an ongoing, retrospective, noninterventional registry that captures information on patients treated with daptomycin (Cubicin) in routine clinical practice. For the registry, clinicians fill out case report forms after a patient’s treatment has been completed, to avoid any bias.

Of 3,621 patients enrolled between 2006 and 2010, the investigators specifically assessed outcomes among the 277 with diabetic ulcer or foot infections.

On average, these patients were 66 years old. The majority were male (70%) and white (94%). Nearly all (97%) had additional comorbidities, most commonly cardiovascular disease. By setting, the largest share came from the community (43%) followed by the hospital (40%).

Overall, 81% of the patients had a diabetic foot infection, while 19% had a diabetic ulcer infection, Dr. Trostmann reported at the conference, which was sponsored by the American Society for Microbiology. Some had secondary infections as well, such as osteomyelitis (4%) and bacteremia (3%).

Among patients with culture results, the most common pathogen was Staphylococcus aureus (seen in 54%), which was methicillin resistant in more than two-thirds of cases. Thirty-nine percent of patients had received previous antibiotic therapy, usually a fluoroquinolone or penicillin.

Sixty percent received daptomycin in combination with another antibiotic, most often a fluoroquinolone or carbapenem. In addition, 61% of patients had tissue debridement and 15% had bone debridement as part of their treatment.

Daptomycin was started at 4 mg/kg in 55% of patients and at 6 mg/kg in 17%. The median duration of daptomycin therapy was 6 days for outpatients, 12 days for general inpatients, and 2 days for intensive care unit patients.

The overall success rate was 86% (the infection was cured in 31% of patients and improved in 55%). The rate was similar among patients who also had secondary skin and soft-tissue infections (85%), osteomyelitis (91%), and bacteremia (89%). It was lower among patients who also had a urinary tract infection or pyelonephritis (50%); only two patients were in this group.

Overall, 1.4% of patients had adverse events possibly related to the drug. A single patient (0.4% of those studied) had an increase in CPK level.

Daptomycin is manufactured/marketed by Cubist Pharmaceuticals in the United States and by Novartis in Europe.

CHICAGO – Daptomycin works as well at clearing diabetic skin and soft tissue infections in real-world clinical practice as it does in clinical trials, according to a retrospective analysis of data from a large European registry.

The rate of clinical success, meaning cure or improvement of the infection, was 86% among nearly 300 patients with diabetic ulcers or foot infections.

By comparison, in a newly completed phase III study of daptomycin, success rates were in the upper 80% range, said Uwe Trostmann, Ph.D., an employee of Novartis Pharma AG in Basel, Switzerland, who presented the registry analysis results at the annual meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy.

In everyday clinical settings, the rate of adverse events possibly related to daptomycin was 1.4%. Only a single patient experienced an increase in levels of creatine phosphokinase (CPK), a known possible adverse effect of the antibiotic.

These are "real-world data. This is not a clinical trial," he stressed. "This is very important information for the clinicians," because it helps them understand what outcomes they can anticipate in their own inpatient and outpatient settings.

Daptomycin has some advantages over vancomycin, which is the current mainstay antibiotic for such infections but also increases the risk of renal complications, Dr. Trostmann said.

The investigators analyzed data from the European Cubicin Outcomes Registry and Experience (EU-CORE), an ongoing, retrospective, noninterventional registry that captures information on patients treated with daptomycin (Cubicin) in routine clinical practice. For the registry, clinicians fill out case report forms after a patient’s treatment has been completed, to avoid any bias.

Of 3,621 patients enrolled between 2006 and 2010, the investigators specifically assessed outcomes among the 277 with diabetic ulcer or foot infections.

On average, these patients were 66 years old. The majority were male (70%) and white (94%). Nearly all (97%) had additional comorbidities, most commonly cardiovascular disease. By setting, the largest share came from the community (43%) followed by the hospital (40%).

Overall, 81% of the patients had a diabetic foot infection, while 19% had a diabetic ulcer infection, Dr. Trostmann reported at the conference, which was sponsored by the American Society for Microbiology. Some had secondary infections as well, such as osteomyelitis (4%) and bacteremia (3%).

Among patients with culture results, the most common pathogen was Staphylococcus aureus (seen in 54%), which was methicillin resistant in more than two-thirds of cases. Thirty-nine percent of patients had received previous antibiotic therapy, usually a fluoroquinolone or penicillin.

Sixty percent received daptomycin in combination with another antibiotic, most often a fluoroquinolone or carbapenem. In addition, 61% of patients had tissue debridement and 15% had bone debridement as part of their treatment.

Daptomycin was started at 4 mg/kg in 55% of patients and at 6 mg/kg in 17%. The median duration of daptomycin therapy was 6 days for outpatients, 12 days for general inpatients, and 2 days for intensive care unit patients.

The overall success rate was 86% (the infection was cured in 31% of patients and improved in 55%). The rate was similar among patients who also had secondary skin and soft-tissue infections (85%), osteomyelitis (91%), and bacteremia (89%). It was lower among patients who also had a urinary tract infection or pyelonephritis (50%); only two patients were in this group.

Overall, 1.4% of patients had adverse events possibly related to the drug. A single patient (0.4% of those studied) had an increase in CPK level.

Daptomycin is manufactured/marketed by Cubist Pharmaceuticals in the United States and by Novartis in Europe.

Certain hospitalized adult patients with community-acquired pneumonia (CAP) may require closer monitoring and perhaps intervention because they are at increased risk for acute cardiac events, research suggests.

Eight percent of patients in a prospective cohort study of 3,921 such patients had an acute cardiac event, investigators found. A history of heart disease, hypoalbuminemia, older age, and several other factors conferred an increase in the odds of such events, and a prediction score incorporating these factors had an area under the receiver operating characteristic curve of 0.74.

It may be possible to apply this new information to improve patient outcomes, according to Dr. Carolina Garcia-Vidal, of Bellvitge University Hospital in Barcelona, who presented her research team’s data at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"The first thing is you have to recognize which patients are at high risk. And then in that population, maybe you have to do some extra things," she explained in an interview. "Maybe you have to follow [the patient] closer, maybe you have to follow in a special way, such as with a cardiac monitor."

Increased cardiac stress, hypoxemia, and inflammation may all contribute to cardiac events in patients with CAP, Dr. Garcia-Vidal noted. Regarding the last, "if you are able to relate these events with a proinflammatory effect, maybe you can do something to modulate this inflammatory [state]. I think that’s the future."

The investigators prospectively studied 3,921 adult inpatients treated in the hospital between 1995 and 2010 who had CAP and did not have severe immunosuppression.

Overall, 8% experienced at least one acute cardiac event (myocardial infarction, new or worsening arrhythmia, and/or new or worsening congestive heart failure) during their hospital stay, according to results reported in a poster session at the conference, which was sponsored by the American Society for Microbiology.

"These patients have a mortality that is very high," Dr. Garcia-Vidal pointed out. In fact, they were about three times more likely to die within 30 days than their event-free counterparts (19% vs. 6%).

In a multivariate analysis, patients had significantly higher odds of acute cardiac events if they were older than 65 years or had heart disease, kidney disease, tachycardia, hypotension, hypoalbuminemia, multilobar pneumonia, or pneumococcal pneumonia, with odds ratios ranging from 1.37 to 3.03.

The factors were combined to create a 9-point score, which had an area under the receiver operating characteristic curve of 0.74 for predicting acute cardiac events. The rate of such events was 19% among patients falling into a high-risk group, defined as having a score of 3 or higher.

The investigators plan to validate the model in another patient population, according to Dr. Garcia-Vidal, whose team reported having no relevant conflicts of interest.

Certain hospitalized adult patients with community-acquired pneumonia (CAP) may require closer monitoring and perhaps intervention because they are at increased risk for acute cardiac events, research suggests.

Eight percent of patients in a prospective cohort study of 3,921 such patients had an acute cardiac event, investigators found. A history of heart disease, hypoalbuminemia, older age, and several other factors conferred an increase in the odds of such events, and a prediction score incorporating these factors had an area under the receiver operating characteristic curve of 0.74.

It may be possible to apply this new information to improve patient outcomes, according to Dr. Carolina Garcia-Vidal, of Bellvitge University Hospital in Barcelona, who presented her research team’s data at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"The first thing is you have to recognize which patients are at high risk. And then in that population, maybe you have to do some extra things," she explained in an interview. "Maybe you have to follow [the patient] closer, maybe you have to follow in a special way, such as with a cardiac monitor."

Increased cardiac stress, hypoxemia, and inflammation may all contribute to cardiac events in patients with CAP, Dr. Garcia-Vidal noted. Regarding the last, "if you are able to relate these events with a proinflammatory effect, maybe you can do something to modulate this inflammatory [state]. I think that’s the future."

The investigators prospectively studied 3,921 adult inpatients treated in the hospital between 1995 and 2010 who had CAP and did not have severe immunosuppression.

Overall, 8% experienced at least one acute cardiac event (myocardial infarction, new or worsening arrhythmia, and/or new or worsening congestive heart failure) during their hospital stay, according to results reported in a poster session at the conference, which was sponsored by the American Society for Microbiology.

"These patients have a mortality that is very high," Dr. Garcia-Vidal pointed out. In fact, they were about three times more likely to die within 30 days than their event-free counterparts (19% vs. 6%).

In a multivariate analysis, patients had significantly higher odds of acute cardiac events if they were older than 65 years or had heart disease, kidney disease, tachycardia, hypotension, hypoalbuminemia, multilobar pneumonia, or pneumococcal pneumonia, with odds ratios ranging from 1.37 to 3.03.

The factors were combined to create a 9-point score, which had an area under the receiver operating characteristic curve of 0.74 for predicting acute cardiac events. The rate of such events was 19% among patients falling into a high-risk group, defined as having a score of 3 or higher.

The investigators plan to validate the model in another patient population, according to Dr. Garcia-Vidal, whose team reported having no relevant conflicts of interest.

Certain hospitalized adult patients with community-acquired pneumonia (CAP) may require closer monitoring and perhaps intervention because they are at increased risk for acute cardiac events, research suggests.

Eight percent of patients in a prospective cohort study of 3,921 such patients had an acute cardiac event, investigators found. A history of heart disease, hypoalbuminemia, older age, and several other factors conferred an increase in the odds of such events, and a prediction score incorporating these factors had an area under the receiver operating characteristic curve of 0.74.

It may be possible to apply this new information to improve patient outcomes, according to Dr. Carolina Garcia-Vidal, of Bellvitge University Hospital in Barcelona, who presented her research team’s data at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"The first thing is you have to recognize which patients are at high risk. And then in that population, maybe you have to do some extra things," she explained in an interview. "Maybe you have to follow [the patient] closer, maybe you have to follow in a special way, such as with a cardiac monitor."

Increased cardiac stress, hypoxemia, and inflammation may all contribute to cardiac events in patients with CAP, Dr. Garcia-Vidal noted. Regarding the last, "if you are able to relate these events with a proinflammatory effect, maybe you can do something to modulate this inflammatory [state]. I think that’s the future."

The investigators prospectively studied 3,921 adult inpatients treated in the hospital between 1995 and 2010 who had CAP and did not have severe immunosuppression.

Overall, 8% experienced at least one acute cardiac event (myocardial infarction, new or worsening arrhythmia, and/or new or worsening congestive heart failure) during their hospital stay, according to results reported in a poster session at the conference, which was sponsored by the American Society for Microbiology.

"These patients have a mortality that is very high," Dr. Garcia-Vidal pointed out. In fact, they were about three times more likely to die within 30 days than their event-free counterparts (19% vs. 6%).

In a multivariate analysis, patients had significantly higher odds of acute cardiac events if they were older than 65 years or had heart disease, kidney disease, tachycardia, hypotension, hypoalbuminemia, multilobar pneumonia, or pneumococcal pneumonia, with odds ratios ranging from 1.37 to 3.03.

The factors were combined to create a 9-point score, which had an area under the receiver operating characteristic curve of 0.74 for predicting acute cardiac events. The rate of such events was 19% among patients falling into a high-risk group, defined as having a score of 3 or higher.

The investigators plan to validate the model in another patient population, according to Dr. Garcia-Vidal, whose team reported having no relevant conflicts of interest.

CHICAGO – In obese patients, the antibiotic telavancin may offer an alternative to vancomycin for treating complicated skin and skin structure infections, according to a post hoc analysis.

In the analysis of two phase III trials, Christine M. Slover, Pharm.D., and colleagues, found that obese patients had nearly identical rates of clinical cure of their skin and skin structure infections (SSSI) whether treated with telavancin or vancomycin (72% vs. 73%). However, those in the telavancin group were more likely to have serious adverse events (11% vs. 3%).

The cure rates and adverse event rates with telavancin were generally similar to those seen in nonobese patients from the same trials, said Dr. Slover, a senior project manager at Astellas Pharma Global Development, in Deerfield, Ill.

"If you have a patient who has a complicated skin infection for whom other agents that are available might not be an option, telavancin is something you can consider, even in obese patients," Dr. Slover commented in an interview at the annual meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy.

"Telavancin is a once-a-day drug, and there is no therapeutic drug monitoring required," she added. In contrast, vancomycin is given at least twice a day and drug levels must be checked. "Cost wise, vancomycin has been available for 50 years and is generic and costs pennies a day; telavancin is a branded drug, so it does cost more because of that."

In addition, severely obese patients were 31% less likely than other obese patients and nonobese patients to achieve clinical cure of their SSSI, no matter which antibiotic they received. Such patients "have a lot of peripheral vascular disease, so it’s much harder to get the antibiotic to the sites of infection," Dr. Slover commented at the conference, which was sponsored by the American Society for Microbiology.

"If you have a patient who has a complicated skin infection for whom other agents might not be an option, telavancin is something you can consider."

The researchers analyzed data from the Assessment of Telavancin in Complicated Skin and Skin Structure Infections (ATLAS) trials, which were identical randomized, double-blind trials conducted among 1,867 adults with complicated SSSIs due to suspected or confirmed gram-positive pathogens (Clin. Infect. Dis. 2008;46:1683-93).

Patients were randomized 1:1 to treatment with telavancin (10 mg/kg IV every 24 hours) or vancomycin (1 g IV every 12 hours) for 7 to 14 days.

"For SSSIs, over the last several years, there has been an increase in methicillin-resistant Staphylococcus aureus and a need for drugs that either are better than what’s already out there or more convenient than what’s already out there," Dr. Slover commented, giving some background. Telavancin (brand name Vibativ, manufactured by Astellas) was approved by the U.S. Food and Drug Administration about 2 years ago for the treatment of gram-positive complicated SSSIs in adults.

In the new analysis, she and her colleagues focused on the one-fifth of trial patients who were obese, having a body mass index of 35 kg/m² or greater. Most of this subset (86%) were younger than 65 years. Their leading diagnoses were cellulitis (51%) and abscess (33%). Substantial proportions had diabetes (42%), hypertension, (56%), and peripheral vascular disease (11%).

"Essentially, there was no difference in clinical cure rate between the two [treatment] groups," she reported: the rate was 72% with telavancin and 73% with vancomycin. (The corresponding rates in nonobese patients were 78% and 75%).

The rate of adverse events was 88% with telavancin and 76% with vancomycin (77% and 71% in nonobese patients), and the rate of serious adverse events was 11% with telavancin and 3% with vancomycin (7% and 5% in nonobese patients). Renal events were the leading type of serious adverse events with telavancin among obese patients.

In a multivariate analysis involving all patients in the trials, patients were less likely to have a clinical cure of their SSSI if they had bacteremia at baseline (odds ratio, 0.37), had congestive heart failure (0.43), were aged 65 years or older (0.74), or had a body mass index of at least 40 (0.69). Treatment group (telavancin vs. vancomycin) did not significantly predict this outcome.

In a second multivariate analysis, patients were more likely to have renal adverse events if they had hypertension at baseline (OR, 4.73), had poor renal function at baseline (4.66), were in the telavancin group (3.60), had at least two comorbidities versus none (3.14), or had cellulitis, an ulcer, or a burn (2.44). Patients were less likely to have such events if they were white (0.36) or had a body mass index between 25 and 30, compared with one of less than 18.5 (0.09).

Dr. Slover is an employee of Astellas Pharma Global Development. The trials were supported jointly by Astellas Pharma Global Development and Theravance.

CHICAGO – In obese patients, the antibiotic telavancin may offer an alternative to vancomycin for treating complicated skin and skin structure infections, according to a post hoc analysis.

In the analysis of two phase III trials, Christine M. Slover, Pharm.D., and colleagues, found that obese patients had nearly identical rates of clinical cure of their skin and skin structure infections (SSSI) whether treated with telavancin or vancomycin (72% vs. 73%). However, those in the telavancin group were more likely to have serious adverse events (11% vs. 3%).

The cure rates and adverse event rates with telavancin were generally similar to those seen in nonobese patients from the same trials, said Dr. Slover, a senior project manager at Astellas Pharma Global Development, in Deerfield, Ill.

"If you have a patient who has a complicated skin infection for whom other agents that are available might not be an option, telavancin is something you can consider, even in obese patients," Dr. Slover commented in an interview at the annual meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy.

"Telavancin is a once-a-day drug, and there is no therapeutic drug monitoring required," she added. In contrast, vancomycin is given at least twice a day and drug levels must be checked. "Cost wise, vancomycin has been available for 50 years and is generic and costs pennies a day; telavancin is a branded drug, so it does cost more because of that."

In addition, severely obese patients were 31% less likely than other obese patients and nonobese patients to achieve clinical cure of their SSSI, no matter which antibiotic they received. Such patients "have a lot of peripheral vascular disease, so it’s much harder to get the antibiotic to the sites of infection," Dr. Slover commented at the conference, which was sponsored by the American Society for Microbiology.

"If you have a patient who has a complicated skin infection for whom other agents might not be an option, telavancin is something you can consider."

The researchers analyzed data from the Assessment of Telavancin in Complicated Skin and Skin Structure Infections (ATLAS) trials, which were identical randomized, double-blind trials conducted among 1,867 adults with complicated SSSIs due to suspected or confirmed gram-positive pathogens (Clin. Infect. Dis. 2008;46:1683-93).

Patients were randomized 1:1 to treatment with telavancin (10 mg/kg IV every 24 hours) or vancomycin (1 g IV every 12 hours) for 7 to 14 days.

"For SSSIs, over the last several years, there has been an increase in methicillin-resistant Staphylococcus aureus and a need for drugs that either are better than what’s already out there or more convenient than what’s already out there," Dr. Slover commented, giving some background. Telavancin (brand name Vibativ, manufactured by Astellas) was approved by the U.S. Food and Drug Administration about 2 years ago for the treatment of gram-positive complicated SSSIs in adults.

In the new analysis, she and her colleagues focused on the one-fifth of trial patients who were obese, having a body mass index of 35 kg/m² or greater. Most of this subset (86%) were younger than 65 years. Their leading diagnoses were cellulitis (51%) and abscess (33%). Substantial proportions had diabetes (42%), hypertension, (56%), and peripheral vascular disease (11%).

"Essentially, there was no difference in clinical cure rate between the two [treatment] groups," she reported: the rate was 72% with telavancin and 73% with vancomycin. (The corresponding rates in nonobese patients were 78% and 75%).

The rate of adverse events was 88% with telavancin and 76% with vancomycin (77% and 71% in nonobese patients), and the rate of serious adverse events was 11% with telavancin and 3% with vancomycin (7% and 5% in nonobese patients). Renal events were the leading type of serious adverse events with telavancin among obese patients.

In a multivariate analysis involving all patients in the trials, patients were less likely to have a clinical cure of their SSSI if they had bacteremia at baseline (odds ratio, 0.37), had congestive heart failure (0.43), were aged 65 years or older (0.74), or had a body mass index of at least 40 (0.69). Treatment group (telavancin vs. vancomycin) did not significantly predict this outcome.

In a second multivariate analysis, patients were more likely to have renal adverse events if they had hypertension at baseline (OR, 4.73), had poor renal function at baseline (4.66), were in the telavancin group (3.60), had at least two comorbidities versus none (3.14), or had cellulitis, an ulcer, or a burn (2.44). Patients were less likely to have such events if they were white (0.36) or had a body mass index between 25 and 30, compared with one of less than 18.5 (0.09).

Dr. Slover is an employee of Astellas Pharma Global Development. The trials were supported jointly by Astellas Pharma Global Development and Theravance.

CHICAGO – In obese patients, the antibiotic telavancin may offer an alternative to vancomycin for treating complicated skin and skin structure infections, according to a post hoc analysis.

In the analysis of two phase III trials, Christine M. Slover, Pharm.D., and colleagues, found that obese patients had nearly identical rates of clinical cure of their skin and skin structure infections (SSSI) whether treated with telavancin or vancomycin (72% vs. 73%). However, those in the telavancin group were more likely to have serious adverse events (11% vs. 3%).

The cure rates and adverse event rates with telavancin were generally similar to those seen in nonobese patients from the same trials, said Dr. Slover, a senior project manager at Astellas Pharma Global Development, in Deerfield, Ill.

"If you have a patient who has a complicated skin infection for whom other agents that are available might not be an option, telavancin is something you can consider, even in obese patients," Dr. Slover commented in an interview at the annual meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy.

"Telavancin is a once-a-day drug, and there is no therapeutic drug monitoring required," she added. In contrast, vancomycin is given at least twice a day and drug levels must be checked. "Cost wise, vancomycin has been available for 50 years and is generic and costs pennies a day; telavancin is a branded drug, so it does cost more because of that."

In addition, severely obese patients were 31% less likely than other obese patients and nonobese patients to achieve clinical cure of their SSSI, no matter which antibiotic they received. Such patients "have a lot of peripheral vascular disease, so it’s much harder to get the antibiotic to the sites of infection," Dr. Slover commented at the conference, which was sponsored by the American Society for Microbiology.

"If you have a patient who has a complicated skin infection for whom other agents might not be an option, telavancin is something you can consider."

The researchers analyzed data from the Assessment of Telavancin in Complicated Skin and Skin Structure Infections (ATLAS) trials, which were identical randomized, double-blind trials conducted among 1,867 adults with complicated SSSIs due to suspected or confirmed gram-positive pathogens (Clin. Infect. Dis. 2008;46:1683-93).

Patients were randomized 1:1 to treatment with telavancin (10 mg/kg IV every 24 hours) or vancomycin (1 g IV every 12 hours) for 7 to 14 days.

"For SSSIs, over the last several years, there has been an increase in methicillin-resistant Staphylococcus aureus and a need for drugs that either are better than what’s already out there or more convenient than what’s already out there," Dr. Slover commented, giving some background. Telavancin (brand name Vibativ, manufactured by Astellas) was approved by the U.S. Food and Drug Administration about 2 years ago for the treatment of gram-positive complicated SSSIs in adults.

In the new analysis, she and her colleagues focused on the one-fifth of trial patients who were obese, having a body mass index of 35 kg/m² or greater. Most of this subset (86%) were younger than 65 years. Their leading diagnoses were cellulitis (51%) and abscess (33%). Substantial proportions had diabetes (42%), hypertension, (56%), and peripheral vascular disease (11%).

"Essentially, there was no difference in clinical cure rate between the two [treatment] groups," she reported: the rate was 72% with telavancin and 73% with vancomycin. (The corresponding rates in nonobese patients were 78% and 75%).

The rate of adverse events was 88% with telavancin and 76% with vancomycin (77% and 71% in nonobese patients), and the rate of serious adverse events was 11% with telavancin and 3% with vancomycin (7% and 5% in nonobese patients). Renal events were the leading type of serious adverse events with telavancin among obese patients.

In a multivariate analysis involving all patients in the trials, patients were less likely to have a clinical cure of their SSSI if they had bacteremia at baseline (odds ratio, 0.37), had congestive heart failure (0.43), were aged 65 years or older (0.74), or had a body mass index of at least 40 (0.69). Treatment group (telavancin vs. vancomycin) did not significantly predict this outcome.

In a second multivariate analysis, patients were more likely to have renal adverse events if they had hypertension at baseline (OR, 4.73), had poor renal function at baseline (4.66), were in the telavancin group (3.60), had at least two comorbidities versus none (3.14), or had cellulitis, an ulcer, or a burn (2.44). Patients were less likely to have such events if they were white (0.36) or had a body mass index between 25 and 30, compared with one of less than 18.5 (0.09).

Dr. Slover is an employee of Astellas Pharma Global Development. The trials were supported jointly by Astellas Pharma Global Development and Theravance.

CHICAGO – The rate of hospitalizations for bacterial infective endocarditis has risen sharply in the United States, mainly driven by cases caused by Staphylococcus aureus, investigators reported at the Interscience Conference on Antimicrobial Agents and Chemotherapy.

In a nationwide population-based study, a group led by Jerome J. Federspiel, an MD-PhD student at the University of North Carolina at Chapel Hill, assessed trends in and characteristics of such hospitalizations during a recent 10-year period (1999-2008).

Study results, based on nearly 84,000 hospitalizations for bacterial endocarditis, showed that the annual rate increased by 46%, although most of that increase occurred before 2006.

Rates of endocarditis hospitalizations for most causative pathogens remained fairly stable during the study period, but rates of hospitalizations for S. aureus endocarditis roughly doubled. Moreover, patients with S. aureus endocarditis had poorer clinical outcomes.

"Infective endocarditis–related hospitalization increased between 1999 and 2008, and this increase appears driven by Staph aureus–related hospitalizations," Mr. Federspiel commented. "Staph aureus–related admissions are associated with substantially higher mortality as well as greater service use, whether measured by length of stay or inpatient charges."

For the study, the investigators analyzed data from the Nationwide Inpatient Sample, using diagnostic codes to identify hospitalizations for bacterial infective endocarditis. Analyses were based on 83,700 hospitalizations for which patient disposition was known, representing an estimated 409,665 such hospitalizations nationwide.

Study results, based on nearly 84,000 hospitalizations for bacterial endocarditis, showed that the annual rate increased by 46%, although most of that increase occurred before 2006.

The hospitalized patients had a mean age of 62 years, the majority were male (59%), and 57% had Medicare insurance. On average, their length of stay was 15 days and their total inpatient charges were $97,630. A total of 13% died during hospitalization and 31% were discharged to long- or intermediate-term care facilities.

Trends showed an increase in the overall rate of hospitalizations from bacterial endocarditis over time, from 11.4 to 16.6 discharges/100,000 population-years between 1999 and 2008 (P less than .0001). Most of the increase occurred in the first 7 years.

The investigators were able to determine the pathogen for 56% of the hospitalizations, said Mr. Federspiel. Within this subset, the rates of hospitalization for endocarditis remained essentially stable during the study period when the disease was caused by coagulase-negative staphylococci; streptococci/enterococci; and multiple or other pathogens. In contrast, the hospitalization rate for S. aureus endocarditis roughly doubled, with most of the increase again occurring in the first 7 years.

"The number of unidentified cases was roughly parallel to the number of total cases," he noted. "Based on this evidence, we do not believe that the observed trends are the result of improved organism coding."

Analysis of the specific roles of methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) was not possible, as coding for these pathogens was a fairly recent development in the study period. And origin of infection could not be determined.

"I think the issue of community-acquired vs. nosocomial infective endocarditis is a really important one," but getting a better handle on this issue will require additional information from other types of studies, said Mr. Federspiel.

In analyses limited to hospitalizations in 2002-2008 (when comorbidity data were available), patients with endocarditis caused by S. aureus were younger and more likely to abuse drugs than were patients with endocarditis due to coagulase-negative staphylococci or streptococci/enterococci.

But whether the rates of S. aureus endocarditis reflected increased intravenous drug use is unknown, according to Mr. Federspiel. "We didn’t specifically look at the rate of IV [intravenous] drug use over time, and what we show is simply drug use; there is no specific code for IV drug use in the United States," he explained.

The patients with S. aureus endocarditis also had longer lengths of stay and higher inpatient charges. And they were more likely to die: After adjustment, their rate of in-hospital mortality was 16.1%, compared with 10.5% for their counterparts with streptococcus/enterococcus endocarditis and 10.2% for their counterparts with coagulase-negative staphylococcus endocarditis (P less than .0001).

The study was limited by its reliance on administrative data, Mr. Federspiel acknowledged. "We don’t have the kind of rich clinical data you would need" to assess etiology in greater detail. "This is simply a complementary approach, in concert with our existing work in multicenter and geographically defined cohort studies, to understand infectious endocarditis epidemiology."

"We believe our results underscore the need to continue efforts to prevent endocarditis and to improve its treatment," he concluded at the conference, which was sponsored by the American Society for Microbiology.

Mr. Federspiel reported that he had no relevant conflicts of interest.

CHICAGO – The rate of hospitalizations for bacterial infective endocarditis has risen sharply in the United States, mainly driven by cases caused by Staphylococcus aureus, investigators reported at the Interscience Conference on Antimicrobial Agents and Chemotherapy.

In a nationwide population-based study, a group led by Jerome J. Federspiel, an MD-PhD student at the University of North Carolina at Chapel Hill, assessed trends in and characteristics of such hospitalizations during a recent 10-year period (1999-2008).

Study results, based on nearly 84,000 hospitalizations for bacterial endocarditis, showed that the annual rate increased by 46%, although most of that increase occurred before 2006.

Rates of endocarditis hospitalizations for most causative pathogens remained fairly stable during the study period, but rates of hospitalizations for S. aureus endocarditis roughly doubled. Moreover, patients with S. aureus endocarditis had poorer clinical outcomes.

"Infective endocarditis–related hospitalization increased between 1999 and 2008, and this increase appears driven by Staph aureus–related hospitalizations," Mr. Federspiel commented. "Staph aureus–related admissions are associated with substantially higher mortality as well as greater service use, whether measured by length of stay or inpatient charges."

For the study, the investigators analyzed data from the Nationwide Inpatient Sample, using diagnostic codes to identify hospitalizations for bacterial infective endocarditis. Analyses were based on 83,700 hospitalizations for which patient disposition was known, representing an estimated 409,665 such hospitalizations nationwide.

Study results, based on nearly 84,000 hospitalizations for bacterial endocarditis, showed that the annual rate increased by 46%, although most of that increase occurred before 2006.

The hospitalized patients had a mean age of 62 years, the majority were male (59%), and 57% had Medicare insurance. On average, their length of stay was 15 days and their total inpatient charges were $97,630. A total of 13% died during hospitalization and 31% were discharged to long- or intermediate-term care facilities.

Trends showed an increase in the overall rate of hospitalizations from bacterial endocarditis over time, from 11.4 to 16.6 discharges/100,000 population-years between 1999 and 2008 (P less than .0001). Most of the increase occurred in the first 7 years.

The investigators were able to determine the pathogen for 56% of the hospitalizations, said Mr. Federspiel. Within this subset, the rates of hospitalization for endocarditis remained essentially stable during the study period when the disease was caused by coagulase-negative staphylococci; streptococci/enterococci; and multiple or other pathogens. In contrast, the hospitalization rate for S. aureus endocarditis roughly doubled, with most of the increase again occurring in the first 7 years.

"The number of unidentified cases was roughly parallel to the number of total cases," he noted. "Based on this evidence, we do not believe that the observed trends are the result of improved organism coding."

Analysis of the specific roles of methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) was not possible, as coding for these pathogens was a fairly recent development in the study period. And origin of infection could not be determined.

"I think the issue of community-acquired vs. nosocomial infective endocarditis is a really important one," but getting a better handle on this issue will require additional information from other types of studies, said Mr. Federspiel.

In analyses limited to hospitalizations in 2002-2008 (when comorbidity data were available), patients with endocarditis caused by S. aureus were younger and more likely to abuse drugs than were patients with endocarditis due to coagulase-negative staphylococci or streptococci/enterococci.

But whether the rates of S. aureus endocarditis reflected increased intravenous drug use is unknown, according to Mr. Federspiel. "We didn’t specifically look at the rate of IV [intravenous] drug use over time, and what we show is simply drug use; there is no specific code for IV drug use in the United States," he explained.

The patients with S. aureus endocarditis also had longer lengths of stay and higher inpatient charges. And they were more likely to die: After adjustment, their rate of in-hospital mortality was 16.1%, compared with 10.5% for their counterparts with streptococcus/enterococcus endocarditis and 10.2% for their counterparts with coagulase-negative staphylococcus endocarditis (P less than .0001).

The study was limited by its reliance on administrative data, Mr. Federspiel acknowledged. "We don’t have the kind of rich clinical data you would need" to assess etiology in greater detail. "This is simply a complementary approach, in concert with our existing work in multicenter and geographically defined cohort studies, to understand infectious endocarditis epidemiology."

"We believe our results underscore the need to continue efforts to prevent endocarditis and to improve its treatment," he concluded at the conference, which was sponsored by the American Society for Microbiology.

Mr. Federspiel reported that he had no relevant conflicts of interest.

CHICAGO – The rate of hospitalizations for bacterial infective endocarditis has risen sharply in the United States, mainly driven by cases caused by Staphylococcus aureus, investigators reported at the Interscience Conference on Antimicrobial Agents and Chemotherapy.

In a nationwide population-based study, a group led by Jerome J. Federspiel, an MD-PhD student at the University of North Carolina at Chapel Hill, assessed trends in and characteristics of such hospitalizations during a recent 10-year period (1999-2008).

Study results, based on nearly 84,000 hospitalizations for bacterial endocarditis, showed that the annual rate increased by 46%, although most of that increase occurred before 2006.

Rates of endocarditis hospitalizations for most causative pathogens remained fairly stable during the study period, but rates of hospitalizations for S. aureus endocarditis roughly doubled. Moreover, patients with S. aureus endocarditis had poorer clinical outcomes.

"Infective endocarditis–related hospitalization increased between 1999 and 2008, and this increase appears driven by Staph aureus–related hospitalizations," Mr. Federspiel commented. "Staph aureus–related admissions are associated with substantially higher mortality as well as greater service use, whether measured by length of stay or inpatient charges."

For the study, the investigators analyzed data from the Nationwide Inpatient Sample, using diagnostic codes to identify hospitalizations for bacterial infective endocarditis. Analyses were based on 83,700 hospitalizations for which patient disposition was known, representing an estimated 409,665 such hospitalizations nationwide.

Study results, based on nearly 84,000 hospitalizations for bacterial endocarditis, showed that the annual rate increased by 46%, although most of that increase occurred before 2006.

The hospitalized patients had a mean age of 62 years, the majority were male (59%), and 57% had Medicare insurance. On average, their length of stay was 15 days and their total inpatient charges were $97,630. A total of 13% died during hospitalization and 31% were discharged to long- or intermediate-term care facilities.

Trends showed an increase in the overall rate of hospitalizations from bacterial endocarditis over time, from 11.4 to 16.6 discharges/100,000 population-years between 1999 and 2008 (P less than .0001). Most of the increase occurred in the first 7 years.

The investigators were able to determine the pathogen for 56% of the hospitalizations, said Mr. Federspiel. Within this subset, the rates of hospitalization for endocarditis remained essentially stable during the study period when the disease was caused by coagulase-negative staphylococci; streptococci/enterococci; and multiple or other pathogens. In contrast, the hospitalization rate for S. aureus endocarditis roughly doubled, with most of the increase again occurring in the first 7 years.

"The number of unidentified cases was roughly parallel to the number of total cases," he noted. "Based on this evidence, we do not believe that the observed trends are the result of improved organism coding."

Analysis of the specific roles of methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) was not possible, as coding for these pathogens was a fairly recent development in the study period. And origin of infection could not be determined.

"I think the issue of community-acquired vs. nosocomial infective endocarditis is a really important one," but getting a better handle on this issue will require additional information from other types of studies, said Mr. Federspiel.

In analyses limited to hospitalizations in 2002-2008 (when comorbidity data were available), patients with endocarditis caused by S. aureus were younger and more likely to abuse drugs than were patients with endocarditis due to coagulase-negative staphylococci or streptococci/enterococci.

But whether the rates of S. aureus endocarditis reflected increased intravenous drug use is unknown, according to Mr. Federspiel. "We didn’t specifically look at the rate of IV [intravenous] drug use over time, and what we show is simply drug use; there is no specific code for IV drug use in the United States," he explained.

The patients with S. aureus endocarditis also had longer lengths of stay and higher inpatient charges. And they were more likely to die: After adjustment, their rate of in-hospital mortality was 16.1%, compared with 10.5% for their counterparts with streptococcus/enterococcus endocarditis and 10.2% for their counterparts with coagulase-negative staphylococcus endocarditis (P less than .0001).

The study was limited by its reliance on administrative data, Mr. Federspiel acknowledged. "We don’t have the kind of rich clinical data you would need" to assess etiology in greater detail. "This is simply a complementary approach, in concert with our existing work in multicenter and geographically defined cohort studies, to understand infectious endocarditis epidemiology."

"We believe our results underscore the need to continue efforts to prevent endocarditis and to improve its treatment," he concluded at the conference, which was sponsored by the American Society for Microbiology.

Mr. Federspiel reported that he had no relevant conflicts of interest.

CHICAGO – A new bedside score based on easy-to-assess clinical factors, such as the presence of diabetes and admission to the intensive care unit, may help reduce delays in appropriate antibiotic therapy for bloodstream infections caused by carbapenem-resistant Enterobacteriaceae.

Researchers developed the score using data from patients who had bloodstream infections due to Enterobacteriaceae that produced extended-spectrum beta-lactamase (ESBL). In 9% of the patients, the pathogen was resistant to carbapenem.

Study results, reported in a poster session at the Interscience Conference on Antimicrobial Agents and Chemotherapy, showed that the combination of five simple clinical factors yielded a carbapenem-resistant Enterobacteriaceae (CRE) score having an area under the receiver operating characteristic curve of 0.81, which indicates that the scoring tool would be good for identifying carbapenem-resistant infections.

"We have been trying ... to predict whether [patients] should empirically stick with the carbapenem or use colistin."

The model is being expanded and validated, according to lead investigator Emily T. Martin, Ph.D., an assistant professor in the department of pharmacy practice at Wayne State University, Detroit. The hope is that in its final form, the model will help rapidly determine which patients with ESBL-producing Enterobacteriaceae infections can receive a carbapenem (the usual empiric therapy) and which need an alternate antibiotic. Some patients suspected of having ESBL-producing Enterobacteriaceae could have infections that are resistant to carbapenems, but we don’t know whether that’s true until the lab results come back, which can take up to 5 days," she explained in an interview.

Polymyxins are effective against carbapenem-resistant infections, but they are not appropriate for widespread empiric use because of concerns about nephrotoxicity and the emergence of resistance.

"At Detroit Medical Center, there’s been sort of movement toward using colistin (polymyxin E) if physicians are suspecting that the patient might have a carbapenem-resistant infection, but there is really no data" to guide the practice, she said. "So we have been trying to develop a model using characteristics of the patients to try to predict whether they should empirically stick with the carbapenem or use colistin."

Dr. Martin and her colleagues reviewed the charts of 182 patients admitted to the medical center between 2007 and 2010 who had bloodstream infections due to ESBL-producing Enterobacteriaceae and severe sepsis, septic shock, or multiorgan failure. In 16 patients, the pathogen was resistant to carbapenem.

A multiple regression model was used to incorporate five factors into a score having a maximum possible value of 51 points: neurologic disease (14 points), dependent functional status (7 points), diabetes mellitus (12 points), ICU admission at the time of infection (11 points), and antibiotic exposure in the past 3 months (7 points).

Using a cutoff of 32 points or higher to define high risk, the CRE score had a sensitivity of 81%, a specificity of 70%, a positive predictive value of 21%, and a negative predictive value of 97% for CRE infections, according to results reported at the conference, which was sponsored by the American Society for Microbiology.

The CRE score "has a really high negative predictive value, so basically, using these factors, we’re able to pretty well rule out that [an infection] is going to be requiring colistin," commented Dr. Martin. "But we are not able to identify which patients are the best candidates for colistin so far."

As for the future? "We are trying to get more data so we can improve the model, and then try to look at data from other hospitals too to try to make this as broad a model as possible," she said.

Dr. Martin reported that she had no relevant conflicts of interest.

CHICAGO – A new bedside score based on easy-to-assess clinical factors, such as the presence of diabetes and admission to the intensive care unit, may help reduce delays in appropriate antibiotic therapy for bloodstream infections caused by carbapenem-resistant Enterobacteriaceae.

Researchers developed the score using data from patients who had bloodstream infections due to Enterobacteriaceae that produced extended-spectrum beta-lactamase (ESBL). In 9% of the patients, the pathogen was resistant to carbapenem.

Study results, reported in a poster session at the Interscience Conference on Antimicrobial Agents and Chemotherapy, showed that the combination of five simple clinical factors yielded a carbapenem-resistant Enterobacteriaceae (CRE) score having an area under the receiver operating characteristic curve of 0.81, which indicates that the scoring tool would be good for identifying carbapenem-resistant infections.

"We have been trying ... to predict whether [patients] should empirically stick with the carbapenem or use colistin."

The model is being expanded and validated, according to lead investigator Emily T. Martin, Ph.D., an assistant professor in the department of pharmacy practice at Wayne State University, Detroit. The hope is that in its final form, the model will help rapidly determine which patients with ESBL-producing Enterobacteriaceae infections can receive a carbapenem (the usual empiric therapy) and which need an alternate antibiotic. Some patients suspected of having ESBL-producing Enterobacteriaceae could have infections that are resistant to carbapenems, but we don’t know whether that’s true until the lab results come back, which can take up to 5 days," she explained in an interview.

Polymyxins are effective against carbapenem-resistant infections, but they are not appropriate for widespread empiric use because of concerns about nephrotoxicity and the emergence of resistance.

"At Detroit Medical Center, there’s been sort of movement toward using colistin (polymyxin E) if physicians are suspecting that the patient might have a carbapenem-resistant infection, but there is really no data" to guide the practice, she said. "So we have been trying to develop a model using characteristics of the patients to try to predict whether they should empirically stick with the carbapenem or use colistin."

Dr. Martin and her colleagues reviewed the charts of 182 patients admitted to the medical center between 2007 and 2010 who had bloodstream infections due to ESBL-producing Enterobacteriaceae and severe sepsis, septic shock, or multiorgan failure. In 16 patients, the pathogen was resistant to carbapenem.

A multiple regression model was used to incorporate five factors into a score having a maximum possible value of 51 points: neurologic disease (14 points), dependent functional status (7 points), diabetes mellitus (12 points), ICU admission at the time of infection (11 points), and antibiotic exposure in the past 3 months (7 points).

Using a cutoff of 32 points or higher to define high risk, the CRE score had a sensitivity of 81%, a specificity of 70%, a positive predictive value of 21%, and a negative predictive value of 97% for CRE infections, according to results reported at the conference, which was sponsored by the American Society for Microbiology.

The CRE score "has a really high negative predictive value, so basically, using these factors, we’re able to pretty well rule out that [an infection] is going to be requiring colistin," commented Dr. Martin. "But we are not able to identify which patients are the best candidates for colistin so far."

As for the future? "We are trying to get more data so we can improve the model, and then try to look at data from other hospitals too to try to make this as broad a model as possible," she said.

Dr. Martin reported that she had no relevant conflicts of interest.

CHICAGO – A new bedside score based on easy-to-assess clinical factors, such as the presence of diabetes and admission to the intensive care unit, may help reduce delays in appropriate antibiotic therapy for bloodstream infections caused by carbapenem-resistant Enterobacteriaceae.

Researchers developed the score using data from patients who had bloodstream infections due to Enterobacteriaceae that produced extended-spectrum beta-lactamase (ESBL). In 9% of the patients, the pathogen was resistant to carbapenem.

Study results, reported in a poster session at the Interscience Conference on Antimicrobial Agents and Chemotherapy, showed that the combination of five simple clinical factors yielded a carbapenem-resistant Enterobacteriaceae (CRE) score having an area under the receiver operating characteristic curve of 0.81, which indicates that the scoring tool would be good for identifying carbapenem-resistant infections.

"We have been trying ... to predict whether [patients] should empirically stick with the carbapenem or use colistin."

The model is being expanded and validated, according to lead investigator Emily T. Martin, Ph.D., an assistant professor in the department of pharmacy practice at Wayne State University, Detroit. The hope is that in its final form, the model will help rapidly determine which patients with ESBL-producing Enterobacteriaceae infections can receive a carbapenem (the usual empiric therapy) and which need an alternate antibiotic. Some patients suspected of having ESBL-producing Enterobacteriaceae could have infections that are resistant to carbapenems, but we don’t know whether that’s true until the lab results come back, which can take up to 5 days," she explained in an interview.

Polymyxins are effective against carbapenem-resistant infections, but they are not appropriate for widespread empiric use because of concerns about nephrotoxicity and the emergence of resistance.

"At Detroit Medical Center, there’s been sort of movement toward using colistin (polymyxin E) if physicians are suspecting that the patient might have a carbapenem-resistant infection, but there is really no data" to guide the practice, she said. "So we have been trying to develop a model using characteristics of the patients to try to predict whether they should empirically stick with the carbapenem or use colistin."

Dr. Martin and her colleagues reviewed the charts of 182 patients admitted to the medical center between 2007 and 2010 who had bloodstream infections due to ESBL-producing Enterobacteriaceae and severe sepsis, septic shock, or multiorgan failure. In 16 patients, the pathogen was resistant to carbapenem.

A multiple regression model was used to incorporate five factors into a score having a maximum possible value of 51 points: neurologic disease (14 points), dependent functional status (7 points), diabetes mellitus (12 points), ICU admission at the time of infection (11 points), and antibiotic exposure in the past 3 months (7 points).

Using a cutoff of 32 points or higher to define high risk, the CRE score had a sensitivity of 81%, a specificity of 70%, a positive predictive value of 21%, and a negative predictive value of 97% for CRE infections, according to results reported at the conference, which was sponsored by the American Society for Microbiology.

The CRE score "has a really high negative predictive value, so basically, using these factors, we’re able to pretty well rule out that [an infection] is going to be requiring colistin," commented Dr. Martin. "But we are not able to identify which patients are the best candidates for colistin so far."

As for the future? "We are trying to get more data so we can improve the model, and then try to look at data from other hospitals too to try to make this as broad a model as possible," she said.

Dr. Martin reported that she had no relevant conflicts of interest.