Interscience Conference on Antimicrobial Agents & Chemotherapy (ICAAC)

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 – Of all the novel cutaneous delivery methods being studied for vaccine administration, noninvasive patchlike systems appear to offer the most advantages, according to Dr. Bruce G. Weniger.

"This is maybe 5 or 10 years off in the future, but this method could be painless upon delivery of antigen on either coated solid microneedles or within dissolving microneedles only to the epidermis, which lacks nerve endings," Dr. Weniger said at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"In theory, it can also be very space efficient for cold chain volume constraints, which is a serious problem as the new prefilled, single-dose packagings for rotavirus vaccine are taking up scarce space in the developing-world vaccine refrigerators. Moreover, such Band-Aid–like delivery systems (called "plasters" in British parlance) are potentially thermostable outside the cold chain. They may be cheaper than needle syringes to dispose of as nonhazardous waste, and in some cases there may be no complex, reusable applicator device to buy, transport, maintain, break, or lose."

Speaking at a later symposium on novel vaccination strategies, Dr. Weniger, an associate editor at the journal Vaccine, and retired former lead for vaccine technology at the Centers for Disease Control and Prevention (CDC), reported that cutaneous vaccination often produced better immune responses than deposition into deeper tissues, thus in some cases permitting dose sparing when vaccine may be scarce or expensive.

He also noted that some new methods of vaccine delivery into or onto the skin – but not patches – share one advantage of the traditional Mantoux method, now used for tuberculosis skin testing and BCG vaccine: the use of existing off-the-shelf vaccines. "The disadvantages of this 100-year-old method are that it’s difficult to do correctly, and local reactions are often more frequent and may be unacceptable if the vaccine contains an irritating adjuvant," he said. "It’s also uncomfortable for the patient."

Newtown, Pa.–based SID Technologies is developing an intradermal injection adapter that attaches to a conventional tuberculin/insulin syringe "to make the Mantoux injection method foolproof," Dr. Weniger said. "Just push it in, and it guides you consistently to the desired bleb or wheal."

The company, which received Small Business Innovation Research (SBIR) funding from the CDC for the technology, is working with West Pharmaceuticals for the developed-world market and with PATH (Program for Appropriate Technology in Health), a Seattle-based nonprofit organization, "to bring this to the developing world for potential cost-saving intradermal administration of expensive rabies and polio vaccines," he said at the meeting, sponsored by the American Society for Microbiology.

The Bioject ID Pen needle-free jet injector, developed by Portland, Ore.–based Bioject Medical Technologies, is anticipated to receive clearance from the Food and Drug Administration (FDA) this year for intradermal delivery. Dr. Weniger described this device as "small, light, powered by metal springs, and featuring single-use autodisabling syringes for 0.05- or 0.1-mL volumes." Studies supported by PATH and the World Health Organization are evaluating its use for delivering rabies and polio vaccines in developing countries.

Another spring-action jet injector product, PharmaJet’s intradermal (ID) model, which also received CDC SBIR contract support, was granted FDA 510(k) clearance in 2011. According to Dr. Weniger, this device, manufactured by Golden Colo.–based PharmaJet, is being used to intradermally administer one of the four candidate dengue vaccines under study in the world. It has been tested in primates, and human trials were launched in 2010. Other clinical trials of the PharmaJet ID are underway in India for delivering rabies and polio vaccines.

The various techniques for cutaneous delivery of vaccines fall into the following categories:

• Mechanical disruption of the stratum corneum. "There are a variety of methods that are used to basically scrape off or abrade that dead layer of skin to allow the vaccine in," explained Dr. Weniger, who is now on the faculty of Chiang Mai University in Thailand. "You can even use cellophane tape applied to the skin and just pull it off a few times. Some researchers have even applied cyanoacrylate superglue and ripped that off, which is probably not painless, he added. There are also microscopic projections which are used to scrape the skin before you apply a drop of vaccine, and you can even use sandpaper friction."

• Coated solid microneedles. This technology involves coating dried vaccines onto microprojections. "When it’s put into the body, within the first few seconds or minutes, the moisture of the body dissolves the vaccine and it begins to be taken up by antigen-processing cells," Dr. Weniger said. "There are but a few human trials to date of which I’m becoming aware."

Fremont, Calif.–based Zosano Pharma created a ZP Patch, which uses an applicator device to push the microneedles into the skin, while St. Paul, Minn.–based 3M is developing a Microstructured Transdermal System. Neither is licensed for vaccine delivery.

In 2011, the Soluvia prefilled microinjection system, manufactured by BD Medical of Franklin Lakes, N.J., was approved in the United States for administering a new Fluzone Intradermal vaccine (Sanofi Pasteur) in adults aged 18-64 years. In 2009, it was licensed in the European Union for administration of the same company’s Intanzaand IDfluinfluenza vaccines. The device features a 30-gauge minineedle staked onto a prefilled glass syringe. "The outer diameter of the needle is 0.305 mm, and it projects 1.5 mm outside of the syringe," Dr. Weniger said. "Sanofi Pasteur purchased exclusive worldwide rights to the technology for all commercially sold vaccines."

Another hollow microneedle system under investigation is the MicronJet, manufactured by NanoPass Technologies of Nes Ziona, Israel. This device features an array of 250-mcg-tall microneedles on a Luer-slip syringe adapter. One human trial found that intradermal delivery of 3 or 6 mcg of influenza hemagglutinin yielded similar hemaglutination inhibition antibody titers as intramuscular delivery of 15 mcg (Vaccine 2009;27:454-9).

• Dissolving microneedles. In this approach pioneered at the Georgia Institute of Technology, the antigen/drug is formulated within a solid dissolvable matrix on a patch using biocompatible and nontoxic components, such as carboxymethylcellulose. "Upon dissolution into the body, all the sharps are gone, so there is less of an issue of expensive sharps waste and the cost of disposing of them," Dr. Weniger said. "Other research groups are pursuing this approach, as well."

Other cutaneous vaccine delivery methods are "a bit more futuristic," he said, including kinetic deposition of propelled microparticles, thermoporation, laser light ablation, iontophoresis, chemical enhancers, and sound waves.

Although some of the novel cutaneous delivery systems he discussed might use off-the-shelf liquid products, "others may require extensive, expensive reformulation efforts," Dr. Weniger cautioned.

"Also, regulatory criteria to license annual influenza vaccines may not be biologically relevant for novel nonparenteral routes/antigens. This means that phase III field-efficacy trials may be required to tease out and validate new immunologic correlates of protection."

Even so, the minimally invasive nature of delivering antigen onto or into the skin "means it’s easier to monitor and treat local adverse reactions," he said. "You can see them. You can put topical steroids or other treatments on them to reduce them, and you can hypothesize fewer unanticipated serious adverse events than we’ve seen with other routes."

Another advantage of the cutaneous route is that it’s less dependent on patient cooperation than other novel routes.

"Think of a squirming, uncooperative child unable to swallow capsules, retain oral doses, activate inhalers, or quietly breathe a vaccine mist for an extended time." Dr. Weniger offered. He added that the cutaneous route provides "a relatively sure and certain delivery, compared with oral and respiratory administration."

Dr. Weniger disclosed that he holds stock in Pfizer.

CHICAGO – Of all the novel cutaneous delivery methods being studied for vaccine administration, noninvasive patchlike systems appear to offer the most advantages, according to Dr. Bruce G. Weniger.

"This is maybe 5 or 10 years off in the future, but this method could be painless upon delivery of antigen on either coated solid microneedles or within dissolving microneedles only to the epidermis, which lacks nerve endings," Dr. Weniger said at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"In theory, it can also be very space efficient for cold chain volume constraints, which is a serious problem as the new prefilled, single-dose packagings for rotavirus vaccine are taking up scarce space in the developing-world vaccine refrigerators. Moreover, such Band-Aid–like delivery systems (called "plasters" in British parlance) are potentially thermostable outside the cold chain. They may be cheaper than needle syringes to dispose of as nonhazardous waste, and in some cases there may be no complex, reusable applicator device to buy, transport, maintain, break, or lose."

Speaking at a later symposium on novel vaccination strategies, Dr. Weniger, an associate editor at the journal Vaccine, and retired former lead for vaccine technology at the Centers for Disease Control and Prevention (CDC), reported that cutaneous vaccination often produced better immune responses than deposition into deeper tissues, thus in some cases permitting dose sparing when vaccine may be scarce or expensive.

He also noted that some new methods of vaccine delivery into or onto the skin – but not patches – share one advantage of the traditional Mantoux method, now used for tuberculosis skin testing and BCG vaccine: the use of existing off-the-shelf vaccines. "The disadvantages of this 100-year-old method are that it’s difficult to do correctly, and local reactions are often more frequent and may be unacceptable if the vaccine contains an irritating adjuvant," he said. "It’s also uncomfortable for the patient."

Newtown, Pa.–based SID Technologies is developing an intradermal injection adapter that attaches to a conventional tuberculin/insulin syringe "to make the Mantoux injection method foolproof," Dr. Weniger said. "Just push it in, and it guides you consistently to the desired bleb or wheal."

The company, which received Small Business Innovation Research (SBIR) funding from the CDC for the technology, is working with West Pharmaceuticals for the developed-world market and with PATH (Program for Appropriate Technology in Health), a Seattle-based nonprofit organization, "to bring this to the developing world for potential cost-saving intradermal administration of expensive rabies and polio vaccines," he said at the meeting, sponsored by the American Society for Microbiology.

The Bioject ID Pen needle-free jet injector, developed by Portland, Ore.–based Bioject Medical Technologies, is anticipated to receive clearance from the Food and Drug Administration (FDA) this year for intradermal delivery. Dr. Weniger described this device as "small, light, powered by metal springs, and featuring single-use autodisabling syringes for 0.05- or 0.1-mL volumes." Studies supported by PATH and the World Health Organization are evaluating its use for delivering rabies and polio vaccines in developing countries.

Another spring-action jet injector product, PharmaJet’s intradermal (ID) model, which also received CDC SBIR contract support, was granted FDA 510(k) clearance in 2011. According to Dr. Weniger, this device, manufactured by Golden Colo.–based PharmaJet, is being used to intradermally administer one of the four candidate dengue vaccines under study in the world. It has been tested in primates, and human trials were launched in 2010. Other clinical trials of the PharmaJet ID are underway in India for delivering rabies and polio vaccines.

The various techniques for cutaneous delivery of vaccines fall into the following categories:

• Mechanical disruption of the stratum corneum. "There are a variety of methods that are used to basically scrape off or abrade that dead layer of skin to allow the vaccine in," explained Dr. Weniger, who is now on the faculty of Chiang Mai University in Thailand. "You can even use cellophane tape applied to the skin and just pull it off a few times. Some researchers have even applied cyanoacrylate superglue and ripped that off, which is probably not painless, he added. There are also microscopic projections which are used to scrape the skin before you apply a drop of vaccine, and you can even use sandpaper friction."

• Coated solid microneedles. This technology involves coating dried vaccines onto microprojections. "When it’s put into the body, within the first few seconds or minutes, the moisture of the body dissolves the vaccine and it begins to be taken up by antigen-processing cells," Dr. Weniger said. "There are but a few human trials to date of which I’m becoming aware."

Fremont, Calif.–based Zosano Pharma created a ZP Patch, which uses an applicator device to push the microneedles into the skin, while St. Paul, Minn.–based 3M is developing a Microstructured Transdermal System. Neither is licensed for vaccine delivery.

In 2011, the Soluvia prefilled microinjection system, manufactured by BD Medical of Franklin Lakes, N.J., was approved in the United States for administering a new Fluzone Intradermal vaccine (Sanofi Pasteur) in adults aged 18-64 years. In 2009, it was licensed in the European Union for administration of the same company’s Intanzaand IDfluinfluenza vaccines. The device features a 30-gauge minineedle staked onto a prefilled glass syringe. "The outer diameter of the needle is 0.305 mm, and it projects 1.5 mm outside of the syringe," Dr. Weniger said. "Sanofi Pasteur purchased exclusive worldwide rights to the technology for all commercially sold vaccines."

Another hollow microneedle system under investigation is the MicronJet, manufactured by NanoPass Technologies of Nes Ziona, Israel. This device features an array of 250-mcg-tall microneedles on a Luer-slip syringe adapter. One human trial found that intradermal delivery of 3 or 6 mcg of influenza hemagglutinin yielded similar hemaglutination inhibition antibody titers as intramuscular delivery of 15 mcg (Vaccine 2009;27:454-9).

• Dissolving microneedles. In this approach pioneered at the Georgia Institute of Technology, the antigen/drug is formulated within a solid dissolvable matrix on a patch using biocompatible and nontoxic components, such as carboxymethylcellulose. "Upon dissolution into the body, all the sharps are gone, so there is less of an issue of expensive sharps waste and the cost of disposing of them," Dr. Weniger said. "Other research groups are pursuing this approach, as well."

Other cutaneous vaccine delivery methods are "a bit more futuristic," he said, including kinetic deposition of propelled microparticles, thermoporation, laser light ablation, iontophoresis, chemical enhancers, and sound waves.

Although some of the novel cutaneous delivery systems he discussed might use off-the-shelf liquid products, "others may require extensive, expensive reformulation efforts," Dr. Weniger cautioned.

"Also, regulatory criteria to license annual influenza vaccines may not be biologically relevant for novel nonparenteral routes/antigens. This means that phase III field-efficacy trials may be required to tease out and validate new immunologic correlates of protection."

Even so, the minimally invasive nature of delivering antigen onto or into the skin "means it’s easier to monitor and treat local adverse reactions," he said. "You can see them. You can put topical steroids or other treatments on them to reduce them, and you can hypothesize fewer unanticipated serious adverse events than we’ve seen with other routes."

Another advantage of the cutaneous route is that it’s less dependent on patient cooperation than other novel routes.

"Think of a squirming, uncooperative child unable to swallow capsules, retain oral doses, activate inhalers, or quietly breathe a vaccine mist for an extended time." Dr. Weniger offered. He added that the cutaneous route provides "a relatively sure and certain delivery, compared with oral and respiratory administration."

Dr. Weniger disclosed that he holds stock in Pfizer.

CHICAGO – Of all the novel cutaneous delivery methods being studied for vaccine administration, noninvasive patchlike systems appear to offer the most advantages, according to Dr. Bruce G. Weniger.

"This is maybe 5 or 10 years off in the future, but this method could be painless upon delivery of antigen on either coated solid microneedles or within dissolving microneedles only to the epidermis, which lacks nerve endings," Dr. Weniger said at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"In theory, it can also be very space efficient for cold chain volume constraints, which is a serious problem as the new prefilled, single-dose packagings for rotavirus vaccine are taking up scarce space in the developing-world vaccine refrigerators. Moreover, such Band-Aid–like delivery systems (called "plasters" in British parlance) are potentially thermostable outside the cold chain. They may be cheaper than needle syringes to dispose of as nonhazardous waste, and in some cases there may be no complex, reusable applicator device to buy, transport, maintain, break, or lose."

Speaking at a later symposium on novel vaccination strategies, Dr. Weniger, an associate editor at the journal Vaccine, and retired former lead for vaccine technology at the Centers for Disease Control and Prevention (CDC), reported that cutaneous vaccination often produced better immune responses than deposition into deeper tissues, thus in some cases permitting dose sparing when vaccine may be scarce or expensive.

He also noted that some new methods of vaccine delivery into or onto the skin – but not patches – share one advantage of the traditional Mantoux method, now used for tuberculosis skin testing and BCG vaccine: the use of existing off-the-shelf vaccines. "The disadvantages of this 100-year-old method are that it’s difficult to do correctly, and local reactions are often more frequent and may be unacceptable if the vaccine contains an irritating adjuvant," he said. "It’s also uncomfortable for the patient."

Newtown, Pa.–based SID Technologies is developing an intradermal injection adapter that attaches to a conventional tuberculin/insulin syringe "to make the Mantoux injection method foolproof," Dr. Weniger said. "Just push it in, and it guides you consistently to the desired bleb or wheal."

The company, which received Small Business Innovation Research (SBIR) funding from the CDC for the technology, is working with West Pharmaceuticals for the developed-world market and with PATH (Program for Appropriate Technology in Health), a Seattle-based nonprofit organization, "to bring this to the developing world for potential cost-saving intradermal administration of expensive rabies and polio vaccines," he said at the meeting, sponsored by the American Society for Microbiology.

The Bioject ID Pen needle-free jet injector, developed by Portland, Ore.–based Bioject Medical Technologies, is anticipated to receive clearance from the Food and Drug Administration (FDA) this year for intradermal delivery. Dr. Weniger described this device as "small, light, powered by metal springs, and featuring single-use autodisabling syringes for 0.05- or 0.1-mL volumes." Studies supported by PATH and the World Health Organization are evaluating its use for delivering rabies and polio vaccines in developing countries.

Another spring-action jet injector product, PharmaJet’s intradermal (ID) model, which also received CDC SBIR contract support, was granted FDA 510(k) clearance in 2011. According to Dr. Weniger, this device, manufactured by Golden Colo.–based PharmaJet, is being used to intradermally administer one of the four candidate dengue vaccines under study in the world. It has been tested in primates, and human trials were launched in 2010. Other clinical trials of the PharmaJet ID are underway in India for delivering rabies and polio vaccines.

The various techniques for cutaneous delivery of vaccines fall into the following categories:

• Mechanical disruption of the stratum corneum. "There are a variety of methods that are used to basically scrape off or abrade that dead layer of skin to allow the vaccine in," explained Dr. Weniger, who is now on the faculty of Chiang Mai University in Thailand. "You can even use cellophane tape applied to the skin and just pull it off a few times. Some researchers have even applied cyanoacrylate superglue and ripped that off, which is probably not painless, he added. There are also microscopic projections which are used to scrape the skin before you apply a drop of vaccine, and you can even use sandpaper friction."

• Coated solid microneedles. This technology involves coating dried vaccines onto microprojections. "When it’s put into the body, within the first few seconds or minutes, the moisture of the body dissolves the vaccine and it begins to be taken up by antigen-processing cells," Dr. Weniger said. "There are but a few human trials to date of which I’m becoming aware."

Fremont, Calif.–based Zosano Pharma created a ZP Patch, which uses an applicator device to push the microneedles into the skin, while St. Paul, Minn.–based 3M is developing a Microstructured Transdermal System. Neither is licensed for vaccine delivery.

In 2011, the Soluvia prefilled microinjection system, manufactured by BD Medical of Franklin Lakes, N.J., was approved in the United States for administering a new Fluzone Intradermal vaccine (Sanofi Pasteur) in adults aged 18-64 years. In 2009, it was licensed in the European Union for administration of the same company’s Intanzaand IDfluinfluenza vaccines. The device features a 30-gauge minineedle staked onto a prefilled glass syringe. "The outer diameter of the needle is 0.305 mm, and it projects 1.5 mm outside of the syringe," Dr. Weniger said. "Sanofi Pasteur purchased exclusive worldwide rights to the technology for all commercially sold vaccines."

Another hollow microneedle system under investigation is the MicronJet, manufactured by NanoPass Technologies of Nes Ziona, Israel. This device features an array of 250-mcg-tall microneedles on a Luer-slip syringe adapter. One human trial found that intradermal delivery of 3 or 6 mcg of influenza hemagglutinin yielded similar hemaglutination inhibition antibody titers as intramuscular delivery of 15 mcg (Vaccine 2009;27:454-9).

• Dissolving microneedles. In this approach pioneered at the Georgia Institute of Technology, the antigen/drug is formulated within a solid dissolvable matrix on a patch using biocompatible and nontoxic components, such as carboxymethylcellulose. "Upon dissolution into the body, all the sharps are gone, so there is less of an issue of expensive sharps waste and the cost of disposing of them," Dr. Weniger said. "Other research groups are pursuing this approach, as well."

Other cutaneous vaccine delivery methods are "a bit more futuristic," he said, including kinetic deposition of propelled microparticles, thermoporation, laser light ablation, iontophoresis, chemical enhancers, and sound waves.

Although some of the novel cutaneous delivery systems he discussed might use off-the-shelf liquid products, "others may require extensive, expensive reformulation efforts," Dr. Weniger cautioned.

"Also, regulatory criteria to license annual influenza vaccines may not be biologically relevant for novel nonparenteral routes/antigens. This means that phase III field-efficacy trials may be required to tease out and validate new immunologic correlates of protection."

Even so, the minimally invasive nature of delivering antigen onto or into the skin "means it’s easier to monitor and treat local adverse reactions," he said. "You can see them. You can put topical steroids or other treatments on them to reduce them, and you can hypothesize fewer unanticipated serious adverse events than we’ve seen with other routes."

Another advantage of the cutaneous route is that it’s less dependent on patient cooperation than other novel routes.

"Think of a squirming, uncooperative child unable to swallow capsules, retain oral doses, activate inhalers, or quietly breathe a vaccine mist for an extended time." Dr. Weniger offered. He added that the cutaneous route provides "a relatively sure and certain delivery, compared with oral and respiratory administration."

Dr. Weniger disclosed that he holds stock in Pfizer.

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.

CHICAGO – Antibiotic de-escalation in ICU patients with nosocomial pneumonia in the intensive care unit produced the same clinical outcome – or better – as maintaining broad-spectrum coverage through the treatment course, a study has shown.

Modifying empiric therapy by continuing with narrower-spectrum antibiotics based on culture and antibiotic susceptibility reports not only limits the emergence of multidrug-resistant pathogens, but also reduces resource utilization for the treatment of hospital-acquired pneumonia, ventilator-assisted pneumonia, and health care–associated pneumonia, Chris Destache, Pharm.D., said at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

The Infectious Diseases Society of America and the American Thoracic Society both advocate early broad-spectrum empiric antibiotics with subsequent streamlining based on the organisms identified and susceptibility patterns in nosocomial pneumonia, but the effect of antibiotic de-escalation on resource utilization, particularly hospital length of stay and cost of hospitalization, has not been examined, Dr. Destache said.

To evaluate the impact of antibiotic de-escalation in the intensive care unit on these resource utilization factors, Dr. Destache of Creighton University in Omaha, Neb., and his colleagues retrospectively studied the charts of patients older than 18 years admitted to the Creighton University Medical Center ICU in 2009 with a presumptive diagnosis of hospital-acquired pneumonia, ventilator-assisted pneumonia, or health care–associated pneumonia, who also had blood or respiratory cultures collected prior to the initiation of antibiotic treatment.

Antibiotic de-escalation was defined as the discontinuation of at least one empiric agent or the change to a narrower-spectrum antibiotic, he said. Patients who received systemic antibacterial, antifungal, or antiviral treatment within 72 hours of their pneumonia diagnosis were excluded from the analysis. The primary study end point was ICU length of stay; secondary end points included total hospital length of stay, in-hospital mortality, and hospitalization costs.

"Culture-negative pneumonias derived the greatest benefit from de-escalation."

Of 378 records identified, 95 patients representing 99 cases of nosocomial pneumonia met the eligibility requirements. "All of the patients had presumptive pneumonia based on [Centers for Disease Control and Prevention] criteria and received broad-spectrum antibiotic therapy based on universal guidelines, and de-escalation was performed in 60 cases," Dr. Destache reported. Universal guidelines call for patients to receive piperacillin-tazobactam, levofloxacin, and vancomycin for at least 24 hours.

Patients in whom the streamlined antibiotic approach was utilized were more likely to be older than those in whom empiric treatment was maintained, with a mean age of 66 years compared with 55.5 years, he said, noting that patients in the de-escalation group were also more likely to have diabetes (38% vs. 18%) and to have cardiovascular disease (38% vs. 15%).

No differences in sequential organ failure assessment scores were observed between the two groups at baseline, although these scores at culture finalization were significantly lower in the de-escalation group, which may have been a factor in the decision to de-escalate, Dr. Destache said.

The ICU length of stay was shorter in the de-escalation group at 9.4 days, compared with 12.8 days in the empiric treatment group, although the difference was not significant. Total length of stay was also shorter, at 15.3 vs. 16.9 days, and hospitalization costs were lower, at $45,640 vs. $60,640, Dr. Destache said at the meeting, sponsored by the American Society for Microbiology. In-hospital mortality was significantly lower in the de-escalation group, at 17% compared with 41%.

Culture was negative in 39 of the de-escalation cases and 18 of the controls, and was positive in 21 of each group, Dr. Destache said. The most common causative pathogens identified in the de-escalation group were methicillin-resistant Staphylococcus aureus (MRSA), followed by methicillin-susceptible S. aureus (MSSA), Pseudomonas aeruginosa, and Streptococcus pneumoniae, he said. In the control group, the most common was MSSA, followed by P. aeruginosa and S. pneumoniae, he said.

In comparing the benefits of antibiotic de-escalation based on culture status, the investigators found that "culture-negative pneumonias derived the greatest benefit from de-escalation," Dr. Destache said. In culture-negative pneumonias, the de-escalation group had an ICU stay of 7.2 days, a total length of stay of 10.4 days, and a mortality of 10%; in the culture-negative control group, ICU stay was 11.9 days, total length of stay was 15.1 days, and mortality was 50%, he said. Culture-positive patients in the de-escalation group stayed in the ICU for 13.6 days and in the hospital for 24.5 days, both of which were statistically similar to the 13.6 days and 18.5 days in the control group; the respective mortality rates were 29% and 33%.

The findings confirm the feasibility and clinical benefit of antimicrobial de-escalation and indicate that the strategy reduces resource utilization, compared with maintaining broad-spectrum coverage, Dr. Destache said. As such, he said, the treatment strategy should be utilized when appropriate as a way to improve antimicrobial stewardship.

Dr. Destache said he had no relevant financial disclosures.

CHICAGO – Antibiotic de-escalation in ICU patients with nosocomial pneumonia in the intensive care unit produced the same clinical outcome – or better – as maintaining broad-spectrum coverage through the treatment course, a study has shown.

Modifying empiric therapy by continuing with narrower-spectrum antibiotics based on culture and antibiotic susceptibility reports not only limits the emergence of multidrug-resistant pathogens, but also reduces resource utilization for the treatment of hospital-acquired pneumonia, ventilator-assisted pneumonia, and health care–associated pneumonia, Chris Destache, Pharm.D., said at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

The Infectious Diseases Society of America and the American Thoracic Society both advocate early broad-spectrum empiric antibiotics with subsequent streamlining based on the organisms identified and susceptibility patterns in nosocomial pneumonia, but the effect of antibiotic de-escalation on resource utilization, particularly hospital length of stay and cost of hospitalization, has not been examined, Dr. Destache said.

To evaluate the impact of antibiotic de-escalation in the intensive care unit on these resource utilization factors, Dr. Destache of Creighton University in Omaha, Neb., and his colleagues retrospectively studied the charts of patients older than 18 years admitted to the Creighton University Medical Center ICU in 2009 with a presumptive diagnosis of hospital-acquired pneumonia, ventilator-assisted pneumonia, or health care–associated pneumonia, who also had blood or respiratory cultures collected prior to the initiation of antibiotic treatment.

Antibiotic de-escalation was defined as the discontinuation of at least one empiric agent or the change to a narrower-spectrum antibiotic, he said. Patients who received systemic antibacterial, antifungal, or antiviral treatment within 72 hours of their pneumonia diagnosis were excluded from the analysis. The primary study end point was ICU length of stay; secondary end points included total hospital length of stay, in-hospital mortality, and hospitalization costs.

"Culture-negative pneumonias derived the greatest benefit from de-escalation."

Of 378 records identified, 95 patients representing 99 cases of nosocomial pneumonia met the eligibility requirements. "All of the patients had presumptive pneumonia based on [Centers for Disease Control and Prevention] criteria and received broad-spectrum antibiotic therapy based on universal guidelines, and de-escalation was performed in 60 cases," Dr. Destache reported. Universal guidelines call for patients to receive piperacillin-tazobactam, levofloxacin, and vancomycin for at least 24 hours.

Patients in whom the streamlined antibiotic approach was utilized were more likely to be older than those in whom empiric treatment was maintained, with a mean age of 66 years compared with 55.5 years, he said, noting that patients in the de-escalation group were also more likely to have diabetes (38% vs. 18%) and to have cardiovascular disease (38% vs. 15%).

No differences in sequential organ failure assessment scores were observed between the two groups at baseline, although these scores at culture finalization were significantly lower in the de-escalation group, which may have been a factor in the decision to de-escalate, Dr. Destache said.

The ICU length of stay was shorter in the de-escalation group at 9.4 days, compared with 12.8 days in the empiric treatment group, although the difference was not significant. Total length of stay was also shorter, at 15.3 vs. 16.9 days, and hospitalization costs were lower, at $45,640 vs. $60,640, Dr. Destache said at the meeting, sponsored by the American Society for Microbiology. In-hospital mortality was significantly lower in the de-escalation group, at 17% compared with 41%.

Culture was negative in 39 of the de-escalation cases and 18 of the controls, and was positive in 21 of each group, Dr. Destache said. The most common causative pathogens identified in the de-escalation group were methicillin-resistant Staphylococcus aureus (MRSA), followed by methicillin-susceptible S. aureus (MSSA), Pseudomonas aeruginosa, and Streptococcus pneumoniae, he said. In the control group, the most common was MSSA, followed by P. aeruginosa and S. pneumoniae, he said.

In comparing the benefits of antibiotic de-escalation based on culture status, the investigators found that "culture-negative pneumonias derived the greatest benefit from de-escalation," Dr. Destache said. In culture-negative pneumonias, the de-escalation group had an ICU stay of 7.2 days, a total length of stay of 10.4 days, and a mortality of 10%; in the culture-negative control group, ICU stay was 11.9 days, total length of stay was 15.1 days, and mortality was 50%, he said. Culture-positive patients in the de-escalation group stayed in the ICU for 13.6 days and in the hospital for 24.5 days, both of which were statistically similar to the 13.6 days and 18.5 days in the control group; the respective mortality rates were 29% and 33%.

The findings confirm the feasibility and clinical benefit of antimicrobial de-escalation and indicate that the strategy reduces resource utilization, compared with maintaining broad-spectrum coverage, Dr. Destache said. As such, he said, the treatment strategy should be utilized when appropriate as a way to improve antimicrobial stewardship.

Dr. Destache said he had no relevant financial disclosures.

CHICAGO – Antibiotic de-escalation in ICU patients with nosocomial pneumonia in the intensive care unit produced the same clinical outcome – or better – as maintaining broad-spectrum coverage through the treatment course, a study has shown.

Modifying empiric therapy by continuing with narrower-spectrum antibiotics based on culture and antibiotic susceptibility reports not only limits the emergence of multidrug-resistant pathogens, but also reduces resource utilization for the treatment of hospital-acquired pneumonia, ventilator-assisted pneumonia, and health care–associated pneumonia, Chris Destache, Pharm.D., said at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

The Infectious Diseases Society of America and the American Thoracic Society both advocate early broad-spectrum empiric antibiotics with subsequent streamlining based on the organisms identified and susceptibility patterns in nosocomial pneumonia, but the effect of antibiotic de-escalation on resource utilization, particularly hospital length of stay and cost of hospitalization, has not been examined, Dr. Destache said.

To evaluate the impact of antibiotic de-escalation in the intensive care unit on these resource utilization factors, Dr. Destache of Creighton University in Omaha, Neb., and his colleagues retrospectively studied the charts of patients older than 18 years admitted to the Creighton University Medical Center ICU in 2009 with a presumptive diagnosis of hospital-acquired pneumonia, ventilator-assisted pneumonia, or health care–associated pneumonia, who also had blood or respiratory cultures collected prior to the initiation of antibiotic treatment.

Antibiotic de-escalation was defined as the discontinuation of at least one empiric agent or the change to a narrower-spectrum antibiotic, he said. Patients who received systemic antibacterial, antifungal, or antiviral treatment within 72 hours of their pneumonia diagnosis were excluded from the analysis. The primary study end point was ICU length of stay; secondary end points included total hospital length of stay, in-hospital mortality, and hospitalization costs.

"Culture-negative pneumonias derived the greatest benefit from de-escalation."

Of 378 records identified, 95 patients representing 99 cases of nosocomial pneumonia met the eligibility requirements. "All of the patients had presumptive pneumonia based on [Centers for Disease Control and Prevention] criteria and received broad-spectrum antibiotic therapy based on universal guidelines, and de-escalation was performed in 60 cases," Dr. Destache reported. Universal guidelines call for patients to receive piperacillin-tazobactam, levofloxacin, and vancomycin for at least 24 hours.

Patients in whom the streamlined antibiotic approach was utilized were more likely to be older than those in whom empiric treatment was maintained, with a mean age of 66 years compared with 55.5 years, he said, noting that patients in the de-escalation group were also more likely to have diabetes (38% vs. 18%) and to have cardiovascular disease (38% vs. 15%).

No differences in sequential organ failure assessment scores were observed between the two groups at baseline, although these scores at culture finalization were significantly lower in the de-escalation group, which may have been a factor in the decision to de-escalate, Dr. Destache said.

The ICU length of stay was shorter in the de-escalation group at 9.4 days, compared with 12.8 days in the empiric treatment group, although the difference was not significant. Total length of stay was also shorter, at 15.3 vs. 16.9 days, and hospitalization costs were lower, at $45,640 vs. $60,640, Dr. Destache said at the meeting, sponsored by the American Society for Microbiology. In-hospital mortality was significantly lower in the de-escalation group, at 17% compared with 41%.

Culture was negative in 39 of the de-escalation cases and 18 of the controls, and was positive in 21 of each group, Dr. Destache said. The most common causative pathogens identified in the de-escalation group were methicillin-resistant Staphylococcus aureus (MRSA), followed by methicillin-susceptible S. aureus (MSSA), Pseudomonas aeruginosa, and Streptococcus pneumoniae, he said. In the control group, the most common was MSSA, followed by P. aeruginosa and S. pneumoniae, he said.

In comparing the benefits of antibiotic de-escalation based on culture status, the investigators found that "culture-negative pneumonias derived the greatest benefit from de-escalation," Dr. Destache said. In culture-negative pneumonias, the de-escalation group had an ICU stay of 7.2 days, a total length of stay of 10.4 days, and a mortality of 10%; in the culture-negative control group, ICU stay was 11.9 days, total length of stay was 15.1 days, and mortality was 50%, he said. Culture-positive patients in the de-escalation group stayed in the ICU for 13.6 days and in the hospital for 24.5 days, both of which were statistically similar to the 13.6 days and 18.5 days in the control group; the respective mortality rates were 29% and 33%.

The findings confirm the feasibility and clinical benefit of antimicrobial de-escalation and indicate that the strategy reduces resource utilization, compared with maintaining broad-spectrum coverage, Dr. Destache said. As such, he said, the treatment strategy should be utilized when appropriate as a way to improve antimicrobial stewardship.

Dr. Destache said he had no relevant financial disclosures.

CHICAGO – An intranasal vaccine reduces norovirus disease and infection in humans, results from a proof-of-concept study suggest.

The findings are important because infections with norovirus, commonly referred to as "cruise ship viruses," cause 96% of all nonbacterial outbreaks of gastroenteritis, Mary K. Estes, Ph.D., said during the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"These viruses are highly contagious and affect all age groups," said Dr. Estes, who directs the Texas Medical Center Digestive Diseases Center in Houston. "They are known to be the leading cause of viral gastroenteritis and outbreaks worldwide, and their impact is increasingly being recognized."

In the United States, she said, norovirus infections causes 12% of severe gastroenteritis cases among children younger than 5 years of age, 64,000 hospitalizations, and 900,000 pediatric clinic visits. "With the significant impact of the new rotavirus vaccines, noroviruses are now emerging as the primary cause of gastroenteritis in hospitalized children," Dr. Estes said. "They are also recognized now to be causing excess deaths in the elderly. In the developing world, they’re estimated to cause about 200,000 deaths each year."

"This is the first demonstration that an intranasally-delivered vaccine can prevent human illness due to an enteric pathogen."

A chief obstacle to developing a vaccine for norovirus includes the lack of an in vitro culture system. "We still can’t grow these viruses yet, although they grow very well in people," Dr. Estes explained. "There is no readily available relevant animal model, and there is antigenic and genetic diversity of noroviruses."

The two main genogroups of noroviruses in humans include genogroup 1, which is comprised of nine clusters (including the Norwalk virus), and genogroup 2, which is comprised of 19 different clusters. "These are the viruses that are most commonly associated with outbreaks," she said. "Ultimately, we probably will at least need a bivalent vaccine to protect against these viruses in the different groups."

Using challenge models in humans, researchers have discovered that norovirus affects secreter positive individuals while nonsecreters, who lack a functioning FUT2 gene, are resistant to norovirus infection.

Dr. Estes presented results from a randomized trial of a baculovirus-expressed norovirus vaccine made by Bozeman (Ligocyte Pharmaceuticals).

The randomized study took place in two stages at four clinical sites. In the first stage, 98 secretor-positive volunteers between the ages of 18 and 50 were given either vaccine or placebo (10 mcg of Norwalk virus-like particles). In stage two, 84 of the volunteers were challenged with the virus to see if infection or disease could be prevented. The primary objective of the study was to evaluate vaccine safety as measured by frequency of viral acute gastroenteritis (AGE). Secondary objectives were to determine efficacy as measured by infection frequency, AGE severity and duration, viral antigen and RNA shedding, vaccine immunogenicity, and vaccine safety.

Study participants were randomized to a two-dose regimen 3 weeks apart: 100 mcg of norovirus virus-like particles or placebo intranasally. They were challenged with 10 human infectious doses at 50% of the challenge virus.

The researchers established three definitions for AGE: greater than 200 g watery diarrhea within 24 hours, vomiting plus any watery diarrhea, and vomiting plus at least one constitutional symptom.

Viral infection was monitored by virus fecal shedding by antigen or real-time polymerase chain reaction testing as well as a rise in antibody levels from pre- to post-challenge.

Dr. Estes reported that the intranasal vaccine was well tolerated, with no vaccine-related severe adverse events or new onset of medically significant conditions. There were two unrelated hospitalizations: one for appendectomy and one for anxiety.

The percentage of subjects with a fourfold or greater rise of total antibodies after the second dose was 62% in vaccine group versus 2% in placebo group, while the percentage with a fourfold or greater rise of IgA antibody after the second dose was 64% in vaccine group versus 2% in the placebo group.

"Noroviruses are now emerging as the primary cause of gastroenteritis in hospitalized children."

In the intent-to-treat analysis, 40% of subjects in the vaccine group had AGE vs. 71% of subjects in the placebo group, for a reduction of 44%. The numbers were similar in the per protocol analysis, which demonstrated that 37% of subjects in the vaccine group had AGE versus 69% in the placebo group, for a reduction of 47%.

In the intent-to-treat analysis, norovirus infection occurred in 65% of the vaccine group versus. 83% of the placebo group, for nonsignificant reduction of 22%.

In the per-protocol analysis, norovirus infection occurred in 61% in the vaccine group versus 82% in the placebo group, for a significant reduction of 26%.

"From this study, we can conclude that the intranasally administered norovirus vaccine was immunogenic in about two-thirds of subjects," Dr. Estes said at the meeting, which was sponsored by the American Society for Microbiology. "The vaccine protected against illness in both analyses and decreased infection per protocol only. Protection in this vaccine study also correlated with histo-blood group antigen blocking titer 50%. This is the first demonstration that an intranasally-delivered vaccine can prevent human illness due to an enteric pathogen."

She pointed out that several questions about the vaccine remain unanswered, including its duration of protection and whether or not immunogenicity can be improved. "We need to evaluate different routes of administration, schedules, dosages, and adjuvants," she added.

Dr. Estes disclosed that she is a consultant for Ligocyte Pharmaceuticals. She has also received royalties from Denka Seiken Diagnostics of Tokyo.

CHICAGO – An intranasal vaccine reduces norovirus disease and infection in humans, results from a proof-of-concept study suggest.

The findings are important because infections with norovirus, commonly referred to as "cruise ship viruses," cause 96% of all nonbacterial outbreaks of gastroenteritis, Mary K. Estes, Ph.D., said during the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"These viruses are highly contagious and affect all age groups," said Dr. Estes, who directs the Texas Medical Center Digestive Diseases Center in Houston. "They are known to be the leading cause of viral gastroenteritis and outbreaks worldwide, and their impact is increasingly being recognized."

In the United States, she said, norovirus infections causes 12% of severe gastroenteritis cases among children younger than 5 years of age, 64,000 hospitalizations, and 900,000 pediatric clinic visits. "With the significant impact of the new rotavirus vaccines, noroviruses are now emerging as the primary cause of gastroenteritis in hospitalized children," Dr. Estes said. "They are also recognized now to be causing excess deaths in the elderly. In the developing world, they’re estimated to cause about 200,000 deaths each year."

"This is the first demonstration that an intranasally-delivered vaccine can prevent human illness due to an enteric pathogen."

A chief obstacle to developing a vaccine for norovirus includes the lack of an in vitro culture system. "We still can’t grow these viruses yet, although they grow very well in people," Dr. Estes explained. "There is no readily available relevant animal model, and there is antigenic and genetic diversity of noroviruses."

The two main genogroups of noroviruses in humans include genogroup 1, which is comprised of nine clusters (including the Norwalk virus), and genogroup 2, which is comprised of 19 different clusters. "These are the viruses that are most commonly associated with outbreaks," she said. "Ultimately, we probably will at least need a bivalent vaccine to protect against these viruses in the different groups."

Using challenge models in humans, researchers have discovered that norovirus affects secreter positive individuals while nonsecreters, who lack a functioning FUT2 gene, are resistant to norovirus infection.

Dr. Estes presented results from a randomized trial of a baculovirus-expressed norovirus vaccine made by Bozeman (Ligocyte Pharmaceuticals).

The randomized study took place in two stages at four clinical sites. In the first stage, 98 secretor-positive volunteers between the ages of 18 and 50 were given either vaccine or placebo (10 mcg of Norwalk virus-like particles). In stage two, 84 of the volunteers were challenged with the virus to see if infection or disease could be prevented. The primary objective of the study was to evaluate vaccine safety as measured by frequency of viral acute gastroenteritis (AGE). Secondary objectives were to determine efficacy as measured by infection frequency, AGE severity and duration, viral antigen and RNA shedding, vaccine immunogenicity, and vaccine safety.

Study participants were randomized to a two-dose regimen 3 weeks apart: 100 mcg of norovirus virus-like particles or placebo intranasally. They were challenged with 10 human infectious doses at 50% of the challenge virus.

The researchers established three definitions for AGE: greater than 200 g watery diarrhea within 24 hours, vomiting plus any watery diarrhea, and vomiting plus at least one constitutional symptom.

Viral infection was monitored by virus fecal shedding by antigen or real-time polymerase chain reaction testing as well as a rise in antibody levels from pre- to post-challenge.

Dr. Estes reported that the intranasal vaccine was well tolerated, with no vaccine-related severe adverse events or new onset of medically significant conditions. There were two unrelated hospitalizations: one for appendectomy and one for anxiety.

The percentage of subjects with a fourfold or greater rise of total antibodies after the second dose was 62% in vaccine group versus 2% in placebo group, while the percentage with a fourfold or greater rise of IgA antibody after the second dose was 64% in vaccine group versus 2% in the placebo group.

"Noroviruses are now emerging as the primary cause of gastroenteritis in hospitalized children."

In the intent-to-treat analysis, 40% of subjects in the vaccine group had AGE vs. 71% of subjects in the placebo group, for a reduction of 44%. The numbers were similar in the per protocol analysis, which demonstrated that 37% of subjects in the vaccine group had AGE versus 69% in the placebo group, for a reduction of 47%.

In the intent-to-treat analysis, norovirus infection occurred in 65% of the vaccine group versus. 83% of the placebo group, for nonsignificant reduction of 22%.

In the per-protocol analysis, norovirus infection occurred in 61% in the vaccine group versus 82% in the placebo group, for a significant reduction of 26%.

"From this study, we can conclude that the intranasally administered norovirus vaccine was immunogenic in about two-thirds of subjects," Dr. Estes said at the meeting, which was sponsored by the American Society for Microbiology. "The vaccine protected against illness in both analyses and decreased infection per protocol only. Protection in this vaccine study also correlated with histo-blood group antigen blocking titer 50%. This is the first demonstration that an intranasally-delivered vaccine can prevent human illness due to an enteric pathogen."

She pointed out that several questions about the vaccine remain unanswered, including its duration of protection and whether or not immunogenicity can be improved. "We need to evaluate different routes of administration, schedules, dosages, and adjuvants," she added.

Dr. Estes disclosed that she is a consultant for Ligocyte Pharmaceuticals. She has also received royalties from Denka Seiken Diagnostics of Tokyo.

CHICAGO – An intranasal vaccine reduces norovirus disease and infection in humans, results from a proof-of-concept study suggest.

The findings are important because infections with norovirus, commonly referred to as "cruise ship viruses," cause 96% of all nonbacterial outbreaks of gastroenteritis, Mary K. Estes, Ph.D., said during the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"These viruses are highly contagious and affect all age groups," said Dr. Estes, who directs the Texas Medical Center Digestive Diseases Center in Houston. "They are known to be the leading cause of viral gastroenteritis and outbreaks worldwide, and their impact is increasingly being recognized."

In the United States, she said, norovirus infections causes 12% of severe gastroenteritis cases among children younger than 5 years of age, 64,000 hospitalizations, and 900,000 pediatric clinic visits. "With the significant impact of the new rotavirus vaccines, noroviruses are now emerging as the primary cause of gastroenteritis in hospitalized children," Dr. Estes said. "They are also recognized now to be causing excess deaths in the elderly. In the developing world, they’re estimated to cause about 200,000 deaths each year."

"This is the first demonstration that an intranasally-delivered vaccine can prevent human illness due to an enteric pathogen."

A chief obstacle to developing a vaccine for norovirus includes the lack of an in vitro culture system. "We still can’t grow these viruses yet, although they grow very well in people," Dr. Estes explained. "There is no readily available relevant animal model, and there is antigenic and genetic diversity of noroviruses."

The two main genogroups of noroviruses in humans include genogroup 1, which is comprised of nine clusters (including the Norwalk virus), and genogroup 2, which is comprised of 19 different clusters. "These are the viruses that are most commonly associated with outbreaks," she said. "Ultimately, we probably will at least need a bivalent vaccine to protect against these viruses in the different groups."

Using challenge models in humans, researchers have discovered that norovirus affects secreter positive individuals while nonsecreters, who lack a functioning FUT2 gene, are resistant to norovirus infection.

Dr. Estes presented results from a randomized trial of a baculovirus-expressed norovirus vaccine made by Bozeman (Ligocyte Pharmaceuticals).

The randomized study took place in two stages at four clinical sites. In the first stage, 98 secretor-positive volunteers between the ages of 18 and 50 were given either vaccine or placebo (10 mcg of Norwalk virus-like particles). In stage two, 84 of the volunteers were challenged with the virus to see if infection or disease could be prevented. The primary objective of the study was to evaluate vaccine safety as measured by frequency of viral acute gastroenteritis (AGE). Secondary objectives were to determine efficacy as measured by infection frequency, AGE severity and duration, viral antigen and RNA shedding, vaccine immunogenicity, and vaccine safety.

Study participants were randomized to a two-dose regimen 3 weeks apart: 100 mcg of norovirus virus-like particles or placebo intranasally. They were challenged with 10 human infectious doses at 50% of the challenge virus.

The researchers established three definitions for AGE: greater than 200 g watery diarrhea within 24 hours, vomiting plus any watery diarrhea, and vomiting plus at least one constitutional symptom.

Viral infection was monitored by virus fecal shedding by antigen or real-time polymerase chain reaction testing as well as a rise in antibody levels from pre- to post-challenge.

Dr. Estes reported that the intranasal vaccine was well tolerated, with no vaccine-related severe adverse events or new onset of medically significant conditions. There were two unrelated hospitalizations: one for appendectomy and one for anxiety.

The percentage of subjects with a fourfold or greater rise of total antibodies after the second dose was 62% in vaccine group versus 2% in placebo group, while the percentage with a fourfold or greater rise of IgA antibody after the second dose was 64% in vaccine group versus 2% in the placebo group.

"Noroviruses are now emerging as the primary cause of gastroenteritis in hospitalized children."

In the intent-to-treat analysis, 40% of subjects in the vaccine group had AGE vs. 71% of subjects in the placebo group, for a reduction of 44%. The numbers were similar in the per protocol analysis, which demonstrated that 37% of subjects in the vaccine group had AGE versus 69% in the placebo group, for a reduction of 47%.

In the intent-to-treat analysis, norovirus infection occurred in 65% of the vaccine group versus. 83% of the placebo group, for nonsignificant reduction of 22%.

In the per-protocol analysis, norovirus infection occurred in 61% in the vaccine group versus 82% in the placebo group, for a significant reduction of 26%.

"From this study, we can conclude that the intranasally administered norovirus vaccine was immunogenic in about two-thirds of subjects," Dr. Estes said at the meeting, which was sponsored by the American Society for Microbiology. "The vaccine protected against illness in both analyses and decreased infection per protocol only. Protection in this vaccine study also correlated with histo-blood group antigen blocking titer 50%. This is the first demonstration that an intranasally-delivered vaccine can prevent human illness due to an enteric pathogen."

She pointed out that several questions about the vaccine remain unanswered, including its duration of protection and whether or not immunogenicity can be improved. "We need to evaluate different routes of administration, schedules, dosages, and adjuvants," she added.

Dr. Estes disclosed that she is a consultant for Ligocyte Pharmaceuticals. She has also received royalties from Denka Seiken Diagnostics of Tokyo.

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 course of Clostridium difficile–associated colitis differs considerably among immunosuppressed patients, compared with those who are immunocompetent, results from a German study suggest.

"Besides the known risk factor of antibiotic therapy, immunosuppression must also be regarded as an independent risk factor" for C. difficile-associated infections, Dr. Christoph Lübbert said during a poster session at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"Immunosuppressive or immmodulatory treatment results in a higher rate of asymptomatic colonization with C. difficile and a minor clinical manifestation (less diarrhea episodes), probably due to the anti-inflammatory effects of steroids in particular. An increasing proportion of symptomatic C. difficile infections, especially in immunosuppressed patients, develops without any history of prior antibiotic treatment."

Between 2005 and 2009, Dr. Lübbert, of the department of medicine at University Hospital, Martin Luther University Halle-Wittenberg, Germany, and his associates evaluated the symptoms and clinical features of 105 inpatients with demonstration of the C. difficile toxin in stool specimens by enzyme immunoassay. Of the 105 patients, 55 were immunosuppressed, which was defined as a neutrophil count of less than 1,000 leukocytes per mL and/or drug immunosuppression by cytostatic agents, glucocorticoids, azathioprine, methotrexate, monoclonal antibodies, and cyclosporin A. The remaining 50 patients in the study were immunocompetent.

Immunosuppressed patients were significantly younger than immunocompetent patients (a mean of 60 vs. 70 years of age, respectively). They were also more likely to be colonized with C. difficile without obvious clinical manifestation of illness (22% vs. 2%), and more likely to relapse (15% vs. 6%).

The researchers also reported that antibiotic use among immunosuppressed patients was 53%, compared with 84% among immunocompetent patients.

"You have to look for C. difficile-associated disease in hospitalized patients on immunosuppressive treatment, even if they don’t take antibiotics," Dr. Lübbert said in an interview at the meeting, which was sponsored by the American Society for Microbiology. "Look for fever, elevated leukocyte count, and for morphologic changes in the intestinal wall. You can have inflammation in the intestine but no significant diarrhea. That is possible."

Dr. Lübbert said that he had no relevant conflicts to disclose.

CHICAGO – The course of Clostridium difficile–associated colitis differs considerably among immunosuppressed patients, compared with those who are immunocompetent, results from a German study suggest.

"Besides the known risk factor of antibiotic therapy, immunosuppression must also be regarded as an independent risk factor" for C. difficile-associated infections, Dr. Christoph Lübbert said during a poster session at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"Immunosuppressive or immmodulatory treatment results in a higher rate of asymptomatic colonization with C. difficile and a minor clinical manifestation (less diarrhea episodes), probably due to the anti-inflammatory effects of steroids in particular. An increasing proportion of symptomatic C. difficile infections, especially in immunosuppressed patients, develops without any history of prior antibiotic treatment."

Between 2005 and 2009, Dr. Lübbert, of the department of medicine at University Hospital, Martin Luther University Halle-Wittenberg, Germany, and his associates evaluated the symptoms and clinical features of 105 inpatients with demonstration of the C. difficile toxin in stool specimens by enzyme immunoassay. Of the 105 patients, 55 were immunosuppressed, which was defined as a neutrophil count of less than 1,000 leukocytes per mL and/or drug immunosuppression by cytostatic agents, glucocorticoids, azathioprine, methotrexate, monoclonal antibodies, and cyclosporin A. The remaining 50 patients in the study were immunocompetent.

Immunosuppressed patients were significantly younger than immunocompetent patients (a mean of 60 vs. 70 years of age, respectively). They were also more likely to be colonized with C. difficile without obvious clinical manifestation of illness (22% vs. 2%), and more likely to relapse (15% vs. 6%).

The researchers also reported that antibiotic use among immunosuppressed patients was 53%, compared with 84% among immunocompetent patients.

"You have to look for C. difficile-associated disease in hospitalized patients on immunosuppressive treatment, even if they don’t take antibiotics," Dr. Lübbert said in an interview at the meeting, which was sponsored by the American Society for Microbiology. "Look for fever, elevated leukocyte count, and for morphologic changes in the intestinal wall. You can have inflammation in the intestine but no significant diarrhea. That is possible."

Dr. Lübbert said that he had no relevant conflicts to disclose.

CHICAGO – The course of Clostridium difficile–associated colitis differs considerably among immunosuppressed patients, compared with those who are immunocompetent, results from a German study suggest.

"Besides the known risk factor of antibiotic therapy, immunosuppression must also be regarded as an independent risk factor" for C. difficile-associated infections, Dr. Christoph Lübbert said during a poster session at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"Immunosuppressive or immmodulatory treatment results in a higher rate of asymptomatic colonization with C. difficile and a minor clinical manifestation (less diarrhea episodes), probably due to the anti-inflammatory effects of steroids in particular. An increasing proportion of symptomatic C. difficile infections, especially in immunosuppressed patients, develops without any history of prior antibiotic treatment."

Between 2005 and 2009, Dr. Lübbert, of the department of medicine at University Hospital, Martin Luther University Halle-Wittenberg, Germany, and his associates evaluated the symptoms and clinical features of 105 inpatients with demonstration of the C. difficile toxin in stool specimens by enzyme immunoassay. Of the 105 patients, 55 were immunosuppressed, which was defined as a neutrophil count of less than 1,000 leukocytes per mL and/or drug immunosuppression by cytostatic agents, glucocorticoids, azathioprine, methotrexate, monoclonal antibodies, and cyclosporin A. The remaining 50 patients in the study were immunocompetent.

Immunosuppressed patients were significantly younger than immunocompetent patients (a mean of 60 vs. 70 years of age, respectively). They were also more likely to be colonized with C. difficile without obvious clinical manifestation of illness (22% vs. 2%), and more likely to relapse (15% vs. 6%).

The researchers also reported that antibiotic use among immunosuppressed patients was 53%, compared with 84% among immunocompetent patients.

"You have to look for C. difficile-associated disease in hospitalized patients on immunosuppressive treatment, even if they don’t take antibiotics," Dr. Lübbert said in an interview at the meeting, which was sponsored by the American Society for Microbiology. "Look for fever, elevated leukocyte count, and for morphologic changes in the intestinal wall. You can have inflammation in the intestine but no significant diarrhea. That is possible."

Dr. Lübbert said that he had no relevant conflicts to disclose.

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.