Miriam E. Tucker

The risk of developing diabetes after a history of gestational diabetes increased over time and reached nearly 20% by 9 years post partum, according to results from a large, population-based study involving Canadian women.

The finding confirms those from the United States and elsewhere regarding the rise in both gestational diabetes and type 2 diabetes, as well as the highly elevated risk for the development of subsequent diabetes among women who have gestational diabetes. “This estimate should be used by clinicians to assist in their counseling of pregnant women and by policy makers to target these women for screening and prevention,” said Dr. Denice S. Feig of the University of Toronto and her associates (CMAJ;2008:179:229-34).

They used data from two sources: a database of hospital discharges for deliveries that occurred in Ontario from April 1, 1995, to March 31, 2002; and a database of all Ontario residents diagnosed with diabetes through March 31, 2004. Of 659,164 women aged 16-49 years without pre-existing diabetes who delivered a baby between 1995 and 2002, a total of 21,823 were diagnosed with gestational diabetes. The overall incidence of gestational diabetes in Ontario rose from 3.2% in 1995 to 3.6% in 2001.

The incidence of having gestational diabetes was higher among women with higher Charlson Comorbidity Index scores (an estimate of the risk of death from comorbid disease), those with lower incomes, and those living in urban areas, compared with rural. Women who had 10 or fewer primary care visits in the 2 years prior to the index delivery were less likely to be diagnosed with gestational diabetes than were women with more than 10 visits (2.7% vs. 3.7%), and those without a usual care provider were less likely to be diagnosed with gestational diabetes than were those who did have one (3.0% vs. 3.4%).

Following delivery, the probability of developing diabetes among the women with gestational diabetes during pregnancy rose rapidly during the first 9 months post partum, and remained more or less constant thereafter over the 9-year follow-up period of the study.

At 9 months, 3.7% of the women had been diagnosed with diabetes. Most of these women probably had pre-existing type 2 diabetes that was only discovered via screening for gestational diabetes. The database doesn't distinguish between type 1 and type 2 diabetes, but most were probably type 2, Dr. Feig and her associates noted.

The probability of developing diabetes among those with a history of gestational diabetes was 5% at the end of 15 months and 13% at 5 years. By the end of the 9-year follow-up, 19% had developed diabetes, compared with just 2% of those without gestational diabetes. The women with gestational diabetes who delivered during 1999-2001 had a higher risk of subsequent diabetes than did those who delivered during 1995-1996. Among the women in the later group, diabetes had developed in 16% by 5 years, whereas it took 9 years for the earlier group to reach a rate of 16%, they said.

Other factors increasing the risk of diabetes following gestational diabetes included Charlson index, greater age, a higher number of primary care visits prepregnancy, and the development of hypertension after delivery. On the other hand, living in a rural area, having a higher income, and having a prior pregnancy within 4 years of the index pregnancy decreased the risk. However, previous gestational diabetes was a more significant predictive factor than all the others were, the investigators said.

In an accompanying editorial, Dr. David Simmons of the Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, England, called the study “timely, allowing renewal of attention to an important condition where we could do better.” Among the areas needing improvement, he said, are increased efforts to prevent progression to diabetes in these women, particularly those who might become pregnant again, and to improve the diagnosis of type 2 diabetes prior to pregnancy.

“Even if there were no primary prevention programs in place, there should be secondary prevention programs to detect diabetes as near to its development as possible. Such programs would allow control of hyperglycemia before a subsequent pregnancy, something clearly of benefit to any future fetus,” he said.

The risk of developing diabetes after a history of gestational diabetes increased over time and reached nearly 20% by 9 years post partum, according to results from a large, population-based study involving Canadian women.

The finding confirms those from the United States and elsewhere regarding the rise in both gestational diabetes and type 2 diabetes, as well as the highly elevated risk for the development of subsequent diabetes among women who have gestational diabetes. “This estimate should be used by clinicians to assist in their counseling of pregnant women and by policy makers to target these women for screening and prevention,” said Dr. Denice S. Feig of the University of Toronto and her associates (CMAJ;2008:179:229-34).

They used data from two sources: a database of hospital discharges for deliveries that occurred in Ontario from April 1, 1995, to March 31, 2002; and a database of all Ontario residents diagnosed with diabetes through March 31, 2004. Of 659,164 women aged 16-49 years without pre-existing diabetes who delivered a baby between 1995 and 2002, a total of 21,823 were diagnosed with gestational diabetes. The overall incidence of gestational diabetes in Ontario rose from 3.2% in 1995 to 3.6% in 2001.

The incidence of having gestational diabetes was higher among women with higher Charlson Comorbidity Index scores (an estimate of the risk of death from comorbid disease), those with lower incomes, and those living in urban areas, compared with rural. Women who had 10 or fewer primary care visits in the 2 years prior to the index delivery were less likely to be diagnosed with gestational diabetes than were women with more than 10 visits (2.7% vs. 3.7%), and those without a usual care provider were less likely to be diagnosed with gestational diabetes than were those who did have one (3.0% vs. 3.4%).

Following delivery, the probability of developing diabetes among the women with gestational diabetes during pregnancy rose rapidly during the first 9 months post partum, and remained more or less constant thereafter over the 9-year follow-up period of the study.

At 9 months, 3.7% of the women had been diagnosed with diabetes. Most of these women probably had pre-existing type 2 diabetes that was only discovered via screening for gestational diabetes. The database doesn't distinguish between type 1 and type 2 diabetes, but most were probably type 2, Dr. Feig and her associates noted.

The probability of developing diabetes among those with a history of gestational diabetes was 5% at the end of 15 months and 13% at 5 years. By the end of the 9-year follow-up, 19% had developed diabetes, compared with just 2% of those without gestational diabetes. The women with gestational diabetes who delivered during 1999-2001 had a higher risk of subsequent diabetes than did those who delivered during 1995-1996. Among the women in the later group, diabetes had developed in 16% by 5 years, whereas it took 9 years for the earlier group to reach a rate of 16%, they said.

Other factors increasing the risk of diabetes following gestational diabetes included Charlson index, greater age, a higher number of primary care visits prepregnancy, and the development of hypertension after delivery. On the other hand, living in a rural area, having a higher income, and having a prior pregnancy within 4 years of the index pregnancy decreased the risk. However, previous gestational diabetes was a more significant predictive factor than all the others were, the investigators said.

In an accompanying editorial, Dr. David Simmons of the Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, England, called the study “timely, allowing renewal of attention to an important condition where we could do better.” Among the areas needing improvement, he said, are increased efforts to prevent progression to diabetes in these women, particularly those who might become pregnant again, and to improve the diagnosis of type 2 diabetes prior to pregnancy.

“Even if there were no primary prevention programs in place, there should be secondary prevention programs to detect diabetes as near to its development as possible. Such programs would allow control of hyperglycemia before a subsequent pregnancy, something clearly of benefit to any future fetus,” he said.

The risk of developing diabetes after a history of gestational diabetes increased over time and reached nearly 20% by 9 years post partum, according to results from a large, population-based study involving Canadian women.

The finding confirms those from the United States and elsewhere regarding the rise in both gestational diabetes and type 2 diabetes, as well as the highly elevated risk for the development of subsequent diabetes among women who have gestational diabetes. “This estimate should be used by clinicians to assist in their counseling of pregnant women and by policy makers to target these women for screening and prevention,” said Dr. Denice S. Feig of the University of Toronto and her associates (CMAJ;2008:179:229-34).

They used data from two sources: a database of hospital discharges for deliveries that occurred in Ontario from April 1, 1995, to March 31, 2002; and a database of all Ontario residents diagnosed with diabetes through March 31, 2004. Of 659,164 women aged 16-49 years without pre-existing diabetes who delivered a baby between 1995 and 2002, a total of 21,823 were diagnosed with gestational diabetes. The overall incidence of gestational diabetes in Ontario rose from 3.2% in 1995 to 3.6% in 2001.

The incidence of having gestational diabetes was higher among women with higher Charlson Comorbidity Index scores (an estimate of the risk of death from comorbid disease), those with lower incomes, and those living in urban areas, compared with rural. Women who had 10 or fewer primary care visits in the 2 years prior to the index delivery were less likely to be diagnosed with gestational diabetes than were women with more than 10 visits (2.7% vs. 3.7%), and those without a usual care provider were less likely to be diagnosed with gestational diabetes than were those who did have one (3.0% vs. 3.4%).

Following delivery, the probability of developing diabetes among the women with gestational diabetes during pregnancy rose rapidly during the first 9 months post partum, and remained more or less constant thereafter over the 9-year follow-up period of the study.

At 9 months, 3.7% of the women had been diagnosed with diabetes. Most of these women probably had pre-existing type 2 diabetes that was only discovered via screening for gestational diabetes. The database doesn't distinguish between type 1 and type 2 diabetes, but most were probably type 2, Dr. Feig and her associates noted.

The probability of developing diabetes among those with a history of gestational diabetes was 5% at the end of 15 months and 13% at 5 years. By the end of the 9-year follow-up, 19% had developed diabetes, compared with just 2% of those without gestational diabetes. The women with gestational diabetes who delivered during 1999-2001 had a higher risk of subsequent diabetes than did those who delivered during 1995-1996. Among the women in the later group, diabetes had developed in 16% by 5 years, whereas it took 9 years for the earlier group to reach a rate of 16%, they said.

Other factors increasing the risk of diabetes following gestational diabetes included Charlson index, greater age, a higher number of primary care visits prepregnancy, and the development of hypertension after delivery. On the other hand, living in a rural area, having a higher income, and having a prior pregnancy within 4 years of the index pregnancy decreased the risk. However, previous gestational diabetes was a more significant predictive factor than all the others were, the investigators said.

In an accompanying editorial, Dr. David Simmons of the Institute of Metabolic Science, Cambridge University Hospitals NHS Foundation Trust, England, called the study “timely, allowing renewal of attention to an important condition where we could do better.” Among the areas needing improvement, he said, are increased efforts to prevent progression to diabetes in these women, particularly those who might become pregnant again, and to improve the diagnosis of type 2 diabetes prior to pregnancy.

“Even if there were no primary prevention programs in place, there should be secondary prevention programs to detect diabetes as near to its development as possible. Such programs would allow control of hyperglycemia before a subsequent pregnancy, something clearly of benefit to any future fetus,” he said.

SAN FRANCISCO — An investigational quick-release formulation of bromocriptine mesylate produced a 42% reduction in a prespecified combined end point of myocardial infarction, stroke, coronary revascularization, or hospitalization for heart failure or angina in a 52-week study of more than 3,000 patients with type 2 diabetes.

The data come from the Cycloset safety trial, a prospective, randomized, double-blind, placebo-controlled study in which quick-release (QR) bromocriptine was given as add-on therapy to patients already taking one or two oral hypoglycemic agents with or without insulin, as well as cardiovascular medications. The beneficial reduction in the prespecified cardiovascular composite end point was seen even among patients with good glycemic control at baseline, Dr. Richard Scranton reported at the annual scientific sessions of the American Diabetes Association.

Cycloset, developed by VeroScience LLC, is a novel quick-release formulation of the dopamine-2 receptor agonist that is given once daily in the morning. The time of administration is critical, because circadian neuroendocrine rhythms in the hypothalamus are key to the regulation of peripheral metabolism, said Dr. Scranton, chief medical officer of VeroScience.

In animals that undergo marked annual cycles of metabolism, seasonal shifts from the obese, insulin-resistant condition to the lean, insulin-sensitive state are driven by shifts in the circadian phase relations of hypothalamic neurotransmitter levels. By mimicking this neurophysiological shift pharmacologically, it is possible to produce a shift in metabolism. Available evidence suggests that bromocriptine-QR acts centrally to reset hypothalamic centers regulating postprandial insulin-mediated glucose and lipid metabolism, thereby reducing postprandial hyperglycemia and hyperlipidemia.

“The time-of-day-dependent impact of dopamine upon circadian hypothalamic regulation of metabolism is a key component to the drug's mechanism of action,” Dr. Scranton explained.

In three previous phase III clinical trials, Cycloset significantly reduced hyperglycemia among obese individuals with type 2 diabetes (Expert Opin. Investig. Drugs 1999;8:1683-707). Based on those data, the Food and Drug Administration issued an “approvable” letter for the agent for the treatment of type 2 diabetes, conditional in part on the completion of a large, placebo-controlled, randomized trial in patients with type 2 diabetes in order to evaluate drug-related adverse events fully. Those data are provided by the current study, Dr. Scranton said.

A total of 3,095 patients from 74 U.S. centers were randomized 2:1 to receive bromocriptine-QR starting at 0.8 mg and titrating up to 4.8 mg, taken once daily in the morning, or placebo. Concomitant diabetes medications were adjusted to maintain ideal glucose control. The final intent-to-treat analysis included 2,054 patients who received bromocriptine-QR and 1,016 who received placebo.

At baseline, the patients had a mean age of about 60 years, mean hemoglobin A1c (HbA1c) of 7.0%, and mean diabetes duration of 8 years. Most were on at least one oral glucose-lowering agent, about a third were on two oral agents, and about 15% were on insulin. They were typical of type 2 patients, with a mean body mass index of 32 kg/m

The treatment and placebo groups were comparable in all baseline characteristics except history of revascularization surgery, in 10% vs. 13%, respectively.

Discontinuations from any cause were 41% with bromocriptine-QR and 26% on placebo. Discontinuations because of adverse events occurred in 24% with bromocriptine-QR, compared with 10.5% on placebo, including four deaths among those receiving bromocriptine-QR and two in the placebo group (0.2% of each group). Nausea, occurring mainly during the initial dose-escalation phase of the study, was the primary reason for both the increased discontinuations and the adverse event reports in the treatment group. For most patients, the nausea was mild to moderate and lasted less than 2 weeks, Dr. Scranton said in a follow-up interview.

In prespecified analyses of glycemic control, subgroups of patients who failed oral diabetes therapies (HbA1c at or above 7.5%) at baseline experienced on average a 0.7 % reduction in HbA1c in favor of bromocriptine-QR, relative to both placebo and to baseline.

The prespecified composite cardiovascular disease (CVD) end point occurred in 1.6% of the bromocriptine-QR group compared with 3.0% of those on placebo. That 42% relative reduction did not change significantly with adjustment for baseline covariables including stroke, coronary revascularization, or center. Analysis of the individual components of the composite suggested benefit for each one, including a 56% relative reduction in myocardial infarction (0.3% vs. 0.8%) and a 63% relative reduction in stroke (0.2% vs. 0.6%). A 55% relative reduction was seen in the combined end point of myocardial infarction, stroke, or CVD death.

SAN FRANCISCO — An investigational quick-release formulation of bromocriptine mesylate produced a 42% reduction in a prespecified combined end point of myocardial infarction, stroke, coronary revascularization, or hospitalization for heart failure or angina in a 52-week study of more than 3,000 patients with type 2 diabetes.

The data come from the Cycloset safety trial, a prospective, randomized, double-blind, placebo-controlled study in which quick-release (QR) bromocriptine was given as add-on therapy to patients already taking one or two oral hypoglycemic agents with or without insulin, as well as cardiovascular medications. The beneficial reduction in the prespecified cardiovascular composite end point was seen even among patients with good glycemic control at baseline, Dr. Richard Scranton reported at the annual scientific sessions of the American Diabetes Association.

Cycloset, developed by VeroScience LLC, is a novel quick-release formulation of the dopamine-2 receptor agonist that is given once daily in the morning. The time of administration is critical, because circadian neuroendocrine rhythms in the hypothalamus are key to the regulation of peripheral metabolism, said Dr. Scranton, chief medical officer of VeroScience.

In animals that undergo marked annual cycles of metabolism, seasonal shifts from the obese, insulin-resistant condition to the lean, insulin-sensitive state are driven by shifts in the circadian phase relations of hypothalamic neurotransmitter levels. By mimicking this neurophysiological shift pharmacologically, it is possible to produce a shift in metabolism. Available evidence suggests that bromocriptine-QR acts centrally to reset hypothalamic centers regulating postprandial insulin-mediated glucose and lipid metabolism, thereby reducing postprandial hyperglycemia and hyperlipidemia.

“The time-of-day-dependent impact of dopamine upon circadian hypothalamic regulation of metabolism is a key component to the drug's mechanism of action,” Dr. Scranton explained.

In three previous phase III clinical trials, Cycloset significantly reduced hyperglycemia among obese individuals with type 2 diabetes (Expert Opin. Investig. Drugs 1999;8:1683-707). Based on those data, the Food and Drug Administration issued an “approvable” letter for the agent for the treatment of type 2 diabetes, conditional in part on the completion of a large, placebo-controlled, randomized trial in patients with type 2 diabetes in order to evaluate drug-related adverse events fully. Those data are provided by the current study, Dr. Scranton said.

A total of 3,095 patients from 74 U.S. centers were randomized 2:1 to receive bromocriptine-QR starting at 0.8 mg and titrating up to 4.8 mg, taken once daily in the morning, or placebo. Concomitant diabetes medications were adjusted to maintain ideal glucose control. The final intent-to-treat analysis included 2,054 patients who received bromocriptine-QR and 1,016 who received placebo.

At baseline, the patients had a mean age of about 60 years, mean hemoglobin A1c (HbA1c) of 7.0%, and mean diabetes duration of 8 years. Most were on at least one oral glucose-lowering agent, about a third were on two oral agents, and about 15% were on insulin. They were typical of type 2 patients, with a mean body mass index of 32 kg/m

The treatment and placebo groups were comparable in all baseline characteristics except history of revascularization surgery, in 10% vs. 13%, respectively.

Discontinuations from any cause were 41% with bromocriptine-QR and 26% on placebo. Discontinuations because of adverse events occurred in 24% with bromocriptine-QR, compared with 10.5% on placebo, including four deaths among those receiving bromocriptine-QR and two in the placebo group (0.2% of each group). Nausea, occurring mainly during the initial dose-escalation phase of the study, was the primary reason for both the increased discontinuations and the adverse event reports in the treatment group. For most patients, the nausea was mild to moderate and lasted less than 2 weeks, Dr. Scranton said in a follow-up interview.

In prespecified analyses of glycemic control, subgroups of patients who failed oral diabetes therapies (HbA1c at or above 7.5%) at baseline experienced on average a 0.7 % reduction in HbA1c in favor of bromocriptine-QR, relative to both placebo and to baseline.

The prespecified composite cardiovascular disease (CVD) end point occurred in 1.6% of the bromocriptine-QR group compared with 3.0% of those on placebo. That 42% relative reduction did not change significantly with adjustment for baseline covariables including stroke, coronary revascularization, or center. Analysis of the individual components of the composite suggested benefit for each one, including a 56% relative reduction in myocardial infarction (0.3% vs. 0.8%) and a 63% relative reduction in stroke (0.2% vs. 0.6%). A 55% relative reduction was seen in the combined end point of myocardial infarction, stroke, or CVD death.

SAN FRANCISCO — An investigational quick-release formulation of bromocriptine mesylate produced a 42% reduction in a prespecified combined end point of myocardial infarction, stroke, coronary revascularization, or hospitalization for heart failure or angina in a 52-week study of more than 3,000 patients with type 2 diabetes.

The data come from the Cycloset safety trial, a prospective, randomized, double-blind, placebo-controlled study in which quick-release (QR) bromocriptine was given as add-on therapy to patients already taking one or two oral hypoglycemic agents with or without insulin, as well as cardiovascular medications. The beneficial reduction in the prespecified cardiovascular composite end point was seen even among patients with good glycemic control at baseline, Dr. Richard Scranton reported at the annual scientific sessions of the American Diabetes Association.

Cycloset, developed by VeroScience LLC, is a novel quick-release formulation of the dopamine-2 receptor agonist that is given once daily in the morning. The time of administration is critical, because circadian neuroendocrine rhythms in the hypothalamus are key to the regulation of peripheral metabolism, said Dr. Scranton, chief medical officer of VeroScience.

In animals that undergo marked annual cycles of metabolism, seasonal shifts from the obese, insulin-resistant condition to the lean, insulin-sensitive state are driven by shifts in the circadian phase relations of hypothalamic neurotransmitter levels. By mimicking this neurophysiological shift pharmacologically, it is possible to produce a shift in metabolism. Available evidence suggests that bromocriptine-QR acts centrally to reset hypothalamic centers regulating postprandial insulin-mediated glucose and lipid metabolism, thereby reducing postprandial hyperglycemia and hyperlipidemia.

“The time-of-day-dependent impact of dopamine upon circadian hypothalamic regulation of metabolism is a key component to the drug's mechanism of action,” Dr. Scranton explained.

In three previous phase III clinical trials, Cycloset significantly reduced hyperglycemia among obese individuals with type 2 diabetes (Expert Opin. Investig. Drugs 1999;8:1683-707). Based on those data, the Food and Drug Administration issued an “approvable” letter for the agent for the treatment of type 2 diabetes, conditional in part on the completion of a large, placebo-controlled, randomized trial in patients with type 2 diabetes in order to evaluate drug-related adverse events fully. Those data are provided by the current study, Dr. Scranton said.

A total of 3,095 patients from 74 U.S. centers were randomized 2:1 to receive bromocriptine-QR starting at 0.8 mg and titrating up to 4.8 mg, taken once daily in the morning, or placebo. Concomitant diabetes medications were adjusted to maintain ideal glucose control. The final intent-to-treat analysis included 2,054 patients who received bromocriptine-QR and 1,016 who received placebo.

At baseline, the patients had a mean age of about 60 years, mean hemoglobin A1c (HbA1c) of 7.0%, and mean diabetes duration of 8 years. Most were on at least one oral glucose-lowering agent, about a third were on two oral agents, and about 15% were on insulin. They were typical of type 2 patients, with a mean body mass index of 32 kg/m

The treatment and placebo groups were comparable in all baseline characteristics except history of revascularization surgery, in 10% vs. 13%, respectively.

Discontinuations from any cause were 41% with bromocriptine-QR and 26% on placebo. Discontinuations because of adverse events occurred in 24% with bromocriptine-QR, compared with 10.5% on placebo, including four deaths among those receiving bromocriptine-QR and two in the placebo group (0.2% of each group). Nausea, occurring mainly during the initial dose-escalation phase of the study, was the primary reason for both the increased discontinuations and the adverse event reports in the treatment group. For most patients, the nausea was mild to moderate and lasted less than 2 weeks, Dr. Scranton said in a follow-up interview.

In prespecified analyses of glycemic control, subgroups of patients who failed oral diabetes therapies (HbA1c at or above 7.5%) at baseline experienced on average a 0.7 % reduction in HbA1c in favor of bromocriptine-QR, relative to both placebo and to baseline.

The prespecified composite cardiovascular disease (CVD) end point occurred in 1.6% of the bromocriptine-QR group compared with 3.0% of those on placebo. That 42% relative reduction did not change significantly with adjustment for baseline covariables including stroke, coronary revascularization, or center. Analysis of the individual components of the composite suggested benefit for each one, including a 56% relative reduction in myocardial infarction (0.3% vs. 0.8%) and a 63% relative reduction in stroke (0.2% vs. 0.6%). A 55% relative reduction was seen in the combined end point of myocardial infarction, stroke, or CVD death.

The Food and Drug Administration will no longer issue “approvable” or “not approvable” letters when a drug application is not approved, but will instead issue a “complete response” letter at the end of the review period, the agency has announced.

The change, effective on Aug. 11 for all drug applications, applies regardless of when the applications were submitted.

“These new regulations will help the FDA adopt a more consistent and neutral way of conveying information to a company when we cannot approve a drug application in its present form,” Dr. Janet Woodcock, director of the agency's Center for Drug Evaluation and Research, said in a written statement.

Currently, when assessing new drug and generic drug applications, the FDA can respond to a sponsor in one of three types of letters: (1) an “approval” letter, meaning the drug has met agency standards for safety and efficacy and can be marketed for sale in the United States; (2) an “approvable” letter, which generally indicates that the drug can probably be approved at a later date provided that the applicant provides certain additional information or makes specified changes (such as to the labeling); or (3) a “not approvable” letter, meaning the application has deficiencies generally requiring the submission of substantial additional data before approval.

A “complete response” letter, which will replace options 2 and 3, will be issued to inform the company that the review period for a drug is complete and that the application is not yet ready for approval, the statement said.

The letter will describe specific deficiencies and, when possible, will outline recommended actions the applicant might take to prepare the application for approval.

The way in which the FDA communicates its decisions to approve an application—option 1—will not change.

The move brings the process for communication about drug licensing applications in line with that of biologics, for which “complete response” letters have been used since 1998. The revision should not affect the overall time it takes the FDA to review new or generic drug applications or biologic license applications, the agency said.

Other changes included in the new FDA rule involve modifications to the schedule for reviewing amendments to licensing applications, classification of responses to a complete response letter, (i.e., resubmissions), timelines for submitting a response to a complete response letter and administrative actions for a failure to respond, and definition of an efficacy supplement.

The Food and Drug Administration will no longer issue “approvable” or “not approvable” letters when a drug application is not approved, but will instead issue a “complete response” letter at the end of the review period, the agency has announced.

The change, effective on Aug. 11 for all drug applications, applies regardless of when the applications were submitted.

“These new regulations will help the FDA adopt a more consistent and neutral way of conveying information to a company when we cannot approve a drug application in its present form,” Dr. Janet Woodcock, director of the agency's Center for Drug Evaluation and Research, said in a written statement.

Currently, when assessing new drug and generic drug applications, the FDA can respond to a sponsor in one of three types of letters: (1) an “approval” letter, meaning the drug has met agency standards for safety and efficacy and can be marketed for sale in the United States; (2) an “approvable” letter, which generally indicates that the drug can probably be approved at a later date provided that the applicant provides certain additional information or makes specified changes (such as to the labeling); or (3) a “not approvable” letter, meaning the application has deficiencies generally requiring the submission of substantial additional data before approval.

A “complete response” letter, which will replace options 2 and 3, will be issued to inform the company that the review period for a drug is complete and that the application is not yet ready for approval, the statement said.

The letter will describe specific deficiencies and, when possible, will outline recommended actions the applicant might take to prepare the application for approval.

The way in which the FDA communicates its decisions to approve an application—option 1—will not change.

The move brings the process for communication about drug licensing applications in line with that of biologics, for which “complete response” letters have been used since 1998. The revision should not affect the overall time it takes the FDA to review new or generic drug applications or biologic license applications, the agency said.

Other changes included in the new FDA rule involve modifications to the schedule for reviewing amendments to licensing applications, classification of responses to a complete response letter, (i.e., resubmissions), timelines for submitting a response to a complete response letter and administrative actions for a failure to respond, and definition of an efficacy supplement.

The Food and Drug Administration will no longer issue “approvable” or “not approvable” letters when a drug application is not approved, but will instead issue a “complete response” letter at the end of the review period, the agency has announced.

The change, effective on Aug. 11 for all drug applications, applies regardless of when the applications were submitted.

“These new regulations will help the FDA adopt a more consistent and neutral way of conveying information to a company when we cannot approve a drug application in its present form,” Dr. Janet Woodcock, director of the agency's Center for Drug Evaluation and Research, said in a written statement.

Currently, when assessing new drug and generic drug applications, the FDA can respond to a sponsor in one of three types of letters: (1) an “approval” letter, meaning the drug has met agency standards for safety and efficacy and can be marketed for sale in the United States; (2) an “approvable” letter, which generally indicates that the drug can probably be approved at a later date provided that the applicant provides certain additional information or makes specified changes (such as to the labeling); or (3) a “not approvable” letter, meaning the application has deficiencies generally requiring the submission of substantial additional data before approval.

A “complete response” letter, which will replace options 2 and 3, will be issued to inform the company that the review period for a drug is complete and that the application is not yet ready for approval, the statement said.

The letter will describe specific deficiencies and, when possible, will outline recommended actions the applicant might take to prepare the application for approval.

The way in which the FDA communicates its decisions to approve an application—option 1—will not change.

The move brings the process for communication about drug licensing applications in line with that of biologics, for which “complete response” letters have been used since 1998. The revision should not affect the overall time it takes the FDA to review new or generic drug applications or biologic license applications, the agency said.

Other changes included in the new FDA rule involve modifications to the schedule for reviewing amendments to licensing applications, classification of responses to a complete response letter, (i.e., resubmissions), timelines for submitting a response to a complete response letter and administrative actions for a failure to respond, and definition of an efficacy supplement.

ATLANTA — Interim guidelines for use of rabies vaccine have been drafted by an ad hoc working group of the Centers for Disease Control and Prevention to address contingency plans in the event that the current “less than ideal” vaccine supply situation becomes an actual shortage.

At the summer meeting of the CDC's Advisory Committee on Immunization Practices (ACIP), CDC Rabies Program chief Charles E. Rupprecht, VMD, characterized the current rabies vaccine supply situation as being in a “yellow” phase, with “green” being the ability to meet all ACIP recommendations for both pre-exposure and postexposure prophylaxis and red being “critical,” where even those in greatest need would not be able to receive the vaccine (MMWR 2008;57[RR03]:1-26).

“Supplies of biologicals used in human rabies prophylaxis are expected to remain less than ideal over the next several years,” he said, adding that the CDC, along with the Food and Drug Administration, the Department of Health and Human Services, and national stakeholders “continue to work together toward productive solutions to mitigate current human rabies supply issues.”

In June 2007, Sanofi Pasteur Inc. began a planned renovation of its Imovax Rabies vaccine production facility in France to maintain compliance with both FDA and French regulatory requirements. The facility is scheduled to be approved and operational by mid- to late 2009. Prior to suspending production at that facility, the company had established an inventory based on historical levels of sales and projected market demand, Sanofi Pasteur's Dr. David Johnson informed the committee.

After the renovations began, Novartis, the only other supplier of rabies vaccine for the United States (RabAvert), experienced manufacturing problems that prevented them from meeting rabies vaccine supply projections. In early 2008, Novartis announced that it would supply RabAvert for postexposure prophylaxis (PEP) use only. Consequently, in May 2008, Sanofi Pasteur was forced to do the same, as the increase in demand for Imovax began outpacing the company's historical levels of supply.

Those developments, combined with a slight increase in rabies cases—a 5% increase in 2007 over the 6,940 cases reported in 2006—have resulted in the current uneasy situation. “It's been a series of unfortunate concomitant events,” Dr. Rupprecht remarked.

A bit of relief is expected in the next few weeks, as Novartis had just received approval for a shipment of a small amount of vaccine prior to the ACIP meeting in late June. The company plans to make a small amount of that supply available for high-priority pre-exposure use, Novartis' Dr. Rajiv De Silva said.

Moreover, Novartis has just broken ground on a new vaccine production facility in Marburg, Germany, which will supply the U.S. market. It is expected to be operational by 2011. In the meantime, “we are working closely with the FDA to implement some interim steps to ensure sufficient production in our existing facility to supply the U.S. market for 2009 and 2010. … Our situation has improved, but we're not out of the woods yet,” Dr. De Silva said.

Aside from restricting the vaccine to PEP, other principles outlined in the draft document include centralization of national-state communications, mandatory consultation with knowledgeable public health officials prior to use of the vaccine, and renewed education and outreach for key medical providers regarding what constitutes a true exposure.

In general, PEP should be postponed until animal control can locate and capture the suspect animal for rabies testing and until diagnostic tests are completed, and should be withheld after bites from animals where adequate surveillance exists and there is no documented terrestrial rabies reservoir. Of course, PEP is always instituted if there is a high suspicion of rabies, based in part on animal species, local epidemiology, and the nature of the exposure. Most states have guidelines for the length of time to survey an area and to start diagnostic testing in high-risk situations, Dr. Rupprecht said in a follow-up interview.

If rabies vaccination must be given, options to lessen use during a shortage situation include administering only one booster dose to people previously vaccinated, dropping the fifth (final) dose of the series in a vaccine-naive individual, using alternative schedules, use of an intradermal route, and consideration of using other biologicals.

In general, in the event of any shortage situation, people traveling abroad would be “deprioritized” for pre-exposure vaccine and educated in “bite avoidance.” Individuals who will be living overseas can obtain vaccination abroad where safe injection practices are used with an approved cell culture vaccine, Dr. Rupprecht said.

When pre-exposure vaccine becomes available, prioritization will involve “first responders” such as animal control workers, diagnosticians, and veterinary staff.

“We are very cautiously optimistic that, as we speak, supplies will begin to improve to the extent that pre-exposure needs for critical first responders are being met. There are plans afoot to meet the needs of secondary groups at risk in mid-August, such as veterinary schools,” Dr. Rupprecht said at the ACIP meeting.

He emphasized that there is no shortage at the moment. “While it may be perceived that there is an alleged shortage, what's being done very strictly now are things that mitigate against the [possibility] of a shortage. There are available supplies such that any folks [who] are truly exposed will be vaccinated and receive rabies immune globulin. We only expect things to improve, based upon information we have at this time.” There is currently no supply limitation with rabies immune globulin, although market changes in plasma collection could create an impact beyond 2009, he said.

ATLANTA — Interim guidelines for use of rabies vaccine have been drafted by an ad hoc working group of the Centers for Disease Control and Prevention to address contingency plans in the event that the current “less than ideal” vaccine supply situation becomes an actual shortage.

At the summer meeting of the CDC's Advisory Committee on Immunization Practices (ACIP), CDC Rabies Program chief Charles E. Rupprecht, VMD, characterized the current rabies vaccine supply situation as being in a “yellow” phase, with “green” being the ability to meet all ACIP recommendations for both pre-exposure and postexposure prophylaxis and red being “critical,” where even those in greatest need would not be able to receive the vaccine (MMWR 2008;57[RR03]:1-26).

“Supplies of biologicals used in human rabies prophylaxis are expected to remain less than ideal over the next several years,” he said, adding that the CDC, along with the Food and Drug Administration, the Department of Health and Human Services, and national stakeholders “continue to work together toward productive solutions to mitigate current human rabies supply issues.”

In June 2007, Sanofi Pasteur Inc. began a planned renovation of its Imovax Rabies vaccine production facility in France to maintain compliance with both FDA and French regulatory requirements. The facility is scheduled to be approved and operational by mid- to late 2009. Prior to suspending production at that facility, the company had established an inventory based on historical levels of sales and projected market demand, Sanofi Pasteur's Dr. David Johnson informed the committee.

After the renovations began, Novartis, the only other supplier of rabies vaccine for the United States (RabAvert), experienced manufacturing problems that prevented them from meeting rabies vaccine supply projections. In early 2008, Novartis announced that it would supply RabAvert for postexposure prophylaxis (PEP) use only. Consequently, in May 2008, Sanofi Pasteur was forced to do the same, as the increase in demand for Imovax began outpacing the company's historical levels of supply.

Those developments, combined with a slight increase in rabies cases—a 5% increase in 2007 over the 6,940 cases reported in 2006—have resulted in the current uneasy situation. “It's been a series of unfortunate concomitant events,” Dr. Rupprecht remarked.

A bit of relief is expected in the next few weeks, as Novartis had just received approval for a shipment of a small amount of vaccine prior to the ACIP meeting in late June. The company plans to make a small amount of that supply available for high-priority pre-exposure use, Novartis' Dr. Rajiv De Silva said.

Moreover, Novartis has just broken ground on a new vaccine production facility in Marburg, Germany, which will supply the U.S. market. It is expected to be operational by 2011. In the meantime, “we are working closely with the FDA to implement some interim steps to ensure sufficient production in our existing facility to supply the U.S. market for 2009 and 2010. … Our situation has improved, but we're not out of the woods yet,” Dr. De Silva said.

Aside from restricting the vaccine to PEP, other principles outlined in the draft document include centralization of national-state communications, mandatory consultation with knowledgeable public health officials prior to use of the vaccine, and renewed education and outreach for key medical providers regarding what constitutes a true exposure.

In general, PEP should be postponed until animal control can locate and capture the suspect animal for rabies testing and until diagnostic tests are completed, and should be withheld after bites from animals where adequate surveillance exists and there is no documented terrestrial rabies reservoir. Of course, PEP is always instituted if there is a high suspicion of rabies, based in part on animal species, local epidemiology, and the nature of the exposure. Most states have guidelines for the length of time to survey an area and to start diagnostic testing in high-risk situations, Dr. Rupprecht said in a follow-up interview.

If rabies vaccination must be given, options to lessen use during a shortage situation include administering only one booster dose to people previously vaccinated, dropping the fifth (final) dose of the series in a vaccine-naive individual, using alternative schedules, use of an intradermal route, and consideration of using other biologicals.

In general, in the event of any shortage situation, people traveling abroad would be “deprioritized” for pre-exposure vaccine and educated in “bite avoidance.” Individuals who will be living overseas can obtain vaccination abroad where safe injection practices are used with an approved cell culture vaccine, Dr. Rupprecht said.

When pre-exposure vaccine becomes available, prioritization will involve “first responders” such as animal control workers, diagnosticians, and veterinary staff.

“We are very cautiously optimistic that, as we speak, supplies will begin to improve to the extent that pre-exposure needs for critical first responders are being met. There are plans afoot to meet the needs of secondary groups at risk in mid-August, such as veterinary schools,” Dr. Rupprecht said at the ACIP meeting.

He emphasized that there is no shortage at the moment. “While it may be perceived that there is an alleged shortage, what's being done very strictly now are things that mitigate against the [possibility] of a shortage. There are available supplies such that any folks [who] are truly exposed will be vaccinated and receive rabies immune globulin. We only expect things to improve, based upon information we have at this time.” There is currently no supply limitation with rabies immune globulin, although market changes in plasma collection could create an impact beyond 2009, he said.

ATLANTA — Interim guidelines for use of rabies vaccine have been drafted by an ad hoc working group of the Centers for Disease Control and Prevention to address contingency plans in the event that the current “less than ideal” vaccine supply situation becomes an actual shortage.

At the summer meeting of the CDC's Advisory Committee on Immunization Practices (ACIP), CDC Rabies Program chief Charles E. Rupprecht, VMD, characterized the current rabies vaccine supply situation as being in a “yellow” phase, with “green” being the ability to meet all ACIP recommendations for both pre-exposure and postexposure prophylaxis and red being “critical,” where even those in greatest need would not be able to receive the vaccine (MMWR 2008;57[RR03]:1-26).

“Supplies of biologicals used in human rabies prophylaxis are expected to remain less than ideal over the next several years,” he said, adding that the CDC, along with the Food and Drug Administration, the Department of Health and Human Services, and national stakeholders “continue to work together toward productive solutions to mitigate current human rabies supply issues.”

In June 2007, Sanofi Pasteur Inc. began a planned renovation of its Imovax Rabies vaccine production facility in France to maintain compliance with both FDA and French regulatory requirements. The facility is scheduled to be approved and operational by mid- to late 2009. Prior to suspending production at that facility, the company had established an inventory based on historical levels of sales and projected market demand, Sanofi Pasteur's Dr. David Johnson informed the committee.

After the renovations began, Novartis, the only other supplier of rabies vaccine for the United States (RabAvert), experienced manufacturing problems that prevented them from meeting rabies vaccine supply projections. In early 2008, Novartis announced that it would supply RabAvert for postexposure prophylaxis (PEP) use only. Consequently, in May 2008, Sanofi Pasteur was forced to do the same, as the increase in demand for Imovax began outpacing the company's historical levels of supply.

Those developments, combined with a slight increase in rabies cases—a 5% increase in 2007 over the 6,940 cases reported in 2006—have resulted in the current uneasy situation. “It's been a series of unfortunate concomitant events,” Dr. Rupprecht remarked.

A bit of relief is expected in the next few weeks, as Novartis had just received approval for a shipment of a small amount of vaccine prior to the ACIP meeting in late June. The company plans to make a small amount of that supply available for high-priority pre-exposure use, Novartis' Dr. Rajiv De Silva said.

Moreover, Novartis has just broken ground on a new vaccine production facility in Marburg, Germany, which will supply the U.S. market. It is expected to be operational by 2011. In the meantime, “we are working closely with the FDA to implement some interim steps to ensure sufficient production in our existing facility to supply the U.S. market for 2009 and 2010. … Our situation has improved, but we're not out of the woods yet,” Dr. De Silva said.

Aside from restricting the vaccine to PEP, other principles outlined in the draft document include centralization of national-state communications, mandatory consultation with knowledgeable public health officials prior to use of the vaccine, and renewed education and outreach for key medical providers regarding what constitutes a true exposure.

In general, PEP should be postponed until animal control can locate and capture the suspect animal for rabies testing and until diagnostic tests are completed, and should be withheld after bites from animals where adequate surveillance exists and there is no documented terrestrial rabies reservoir. Of course, PEP is always instituted if there is a high suspicion of rabies, based in part on animal species, local epidemiology, and the nature of the exposure. Most states have guidelines for the length of time to survey an area and to start diagnostic testing in high-risk situations, Dr. Rupprecht said in a follow-up interview.

If rabies vaccination must be given, options to lessen use during a shortage situation include administering only one booster dose to people previously vaccinated, dropping the fifth (final) dose of the series in a vaccine-naive individual, using alternative schedules, use of an intradermal route, and consideration of using other biologicals.

In general, in the event of any shortage situation, people traveling abroad would be “deprioritized” for pre-exposure vaccine and educated in “bite avoidance.” Individuals who will be living overseas can obtain vaccination abroad where safe injection practices are used with an approved cell culture vaccine, Dr. Rupprecht said.

When pre-exposure vaccine becomes available, prioritization will involve “first responders” such as animal control workers, diagnosticians, and veterinary staff.

“We are very cautiously optimistic that, as we speak, supplies will begin to improve to the extent that pre-exposure needs for critical first responders are being met. There are plans afoot to meet the needs of secondary groups at risk in mid-August, such as veterinary schools,” Dr. Rupprecht said at the ACIP meeting.

He emphasized that there is no shortage at the moment. “While it may be perceived that there is an alleged shortage, what's being done very strictly now are things that mitigate against the [possibility] of a shortage. There are available supplies such that any folks [who] are truly exposed will be vaccinated and receive rabies immune globulin. We only expect things to improve, based upon information we have at this time.” There is currently no supply limitation with rabies immune globulin, although market changes in plasma collection could create an impact beyond 2009, he said.

ATLANTA — Recommendations regarding use of the 23-valent pneumococcal polysaccharide vaccine in high-risk children aged 24–59 months who previously received the 7-valent pneumococcal conjugate vaccine remain to be finalized after discussion of the issues by the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention at its summer meeting.

Current recommendations call for use of 23-valent pneumococcal polysaccharide vaccine (PPV23) at 2 years of age following receipt of the 7-valent pneumococcal conjugate vaccine (PCV7) vaccine series prior to age 2 for children in certain high-risk groups, including those with HIV infection, asplenia, or immunocompromising or chronic conditions. The addition of PPV23 may also be considered among children of Alaska Native or Native American descent. For children aged 10 years or younger, one revaccination should be considered 3–5 years after the previous PPV23 dose.

Although data regarding the safety of PPV23 given after PCV7 are limited, the rationale for the recommendation is to provide additional serotype coverage among children at very high risk (MMWR 2000;49[RR-09]:1–38).

Dr. Pekka Nuorti of the CDC's Respiratory Diseases Branch presented the committee with three possible votes—drafted prior to the meeting by a working group—to clarify language from those recommendations. Of the three issues—use of PPV23 in Alaska Native and American Indian children, the time interval for PPV23 revaccination in high-risk children, and use of the PCV7 in HIV-infected school-age children—the committee ended up voting only on the third item.

That advice, still subject to approval by the CDC, was that providers “may consider” administering two doses of PCV7 followed by PPV23 in HIV-infected children aged 5–17 years on highly active antiretivinal therapy (HAART) who were not previously immunized with PCV7.

The ACIP also agreed with the working group's prior decision not to recommend use of PPV23 in children with asthma who are not on high-dose corticosteroid therapy, despite voting to recommend the vaccine for all adults with asthma. Diagnosis of pediatric asthma is difficult and many children outgrow wheezing, and current rates of invasive pneumococcal disease (IPD) are very low overall in children aged 2 years and older because of both the direct and the indirect impact of routine PCV7 use. Thus, PPV23 is also not recommended even for older adolescents with asthma who did not receive PCV7, Dr. Nuorti said in an interview.

The current American Indian/Alaska Native recommendation was based primarily on expert opinion, and there are few data on use of PPV23 in those populations of children after the PCV7 series. The recommendation also lacks specificity, because not all such groups are at equal risk and the group definitions are not always clear. Moreover, in practice PPV23 typically has not been used among these children except for those with high-risk medical conditions.

Because of concern about potential hyporesponsiveness after PPV23, the working group had prepared a recommendation against routine use of PPV23 in all American Indian/Alaska Native children and to limit its use to only those “living in areas with documented elevated rates of [IPD].” However, several committee members felt this still wasn't clear enough, so the decision was left for the working group to retool.

ATLANTA — Recommendations regarding use of the 23-valent pneumococcal polysaccharide vaccine in high-risk children aged 24–59 months who previously received the 7-valent pneumococcal conjugate vaccine remain to be finalized after discussion of the issues by the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention at its summer meeting.

Current recommendations call for use of 23-valent pneumococcal polysaccharide vaccine (PPV23) at 2 years of age following receipt of the 7-valent pneumococcal conjugate vaccine (PCV7) vaccine series prior to age 2 for children in certain high-risk groups, including those with HIV infection, asplenia, or immunocompromising or chronic conditions. The addition of PPV23 may also be considered among children of Alaska Native or Native American descent. For children aged 10 years or younger, one revaccination should be considered 3–5 years after the previous PPV23 dose.

Although data regarding the safety of PPV23 given after PCV7 are limited, the rationale for the recommendation is to provide additional serotype coverage among children at very high risk (MMWR 2000;49[RR-09]:1–38).

Dr. Pekka Nuorti of the CDC's Respiratory Diseases Branch presented the committee with three possible votes—drafted prior to the meeting by a working group—to clarify language from those recommendations. Of the three issues—use of PPV23 in Alaska Native and American Indian children, the time interval for PPV23 revaccination in high-risk children, and use of the PCV7 in HIV-infected school-age children—the committee ended up voting only on the third item.

That advice, still subject to approval by the CDC, was that providers “may consider” administering two doses of PCV7 followed by PPV23 in HIV-infected children aged 5–17 years on highly active antiretivinal therapy (HAART) who were not previously immunized with PCV7.

The ACIP also agreed with the working group's prior decision not to recommend use of PPV23 in children with asthma who are not on high-dose corticosteroid therapy, despite voting to recommend the vaccine for all adults with asthma. Diagnosis of pediatric asthma is difficult and many children outgrow wheezing, and current rates of invasive pneumococcal disease (IPD) are very low overall in children aged 2 years and older because of both the direct and the indirect impact of routine PCV7 use. Thus, PPV23 is also not recommended even for older adolescents with asthma who did not receive PCV7, Dr. Nuorti said in an interview.

The current American Indian/Alaska Native recommendation was based primarily on expert opinion, and there are few data on use of PPV23 in those populations of children after the PCV7 series. The recommendation also lacks specificity, because not all such groups are at equal risk and the group definitions are not always clear. Moreover, in practice PPV23 typically has not been used among these children except for those with high-risk medical conditions.

Because of concern about potential hyporesponsiveness after PPV23, the working group had prepared a recommendation against routine use of PPV23 in all American Indian/Alaska Native children and to limit its use to only those “living in areas with documented elevated rates of [IPD].” However, several committee members felt this still wasn't clear enough, so the decision was left for the working group to retool.

ATLANTA — Recommendations regarding use of the 23-valent pneumococcal polysaccharide vaccine in high-risk children aged 24–59 months who previously received the 7-valent pneumococcal conjugate vaccine remain to be finalized after discussion of the issues by the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention at its summer meeting.

Current recommendations call for use of 23-valent pneumococcal polysaccharide vaccine (PPV23) at 2 years of age following receipt of the 7-valent pneumococcal conjugate vaccine (PCV7) vaccine series prior to age 2 for children in certain high-risk groups, including those with HIV infection, asplenia, or immunocompromising or chronic conditions. The addition of PPV23 may also be considered among children of Alaska Native or Native American descent. For children aged 10 years or younger, one revaccination should be considered 3–5 years after the previous PPV23 dose.

Although data regarding the safety of PPV23 given after PCV7 are limited, the rationale for the recommendation is to provide additional serotype coverage among children at very high risk (MMWR 2000;49[RR-09]:1–38).

Dr. Pekka Nuorti of the CDC's Respiratory Diseases Branch presented the committee with three possible votes—drafted prior to the meeting by a working group—to clarify language from those recommendations. Of the three issues—use of PPV23 in Alaska Native and American Indian children, the time interval for PPV23 revaccination in high-risk children, and use of the PCV7 in HIV-infected school-age children—the committee ended up voting only on the third item.

That advice, still subject to approval by the CDC, was that providers “may consider” administering two doses of PCV7 followed by PPV23 in HIV-infected children aged 5–17 years on highly active antiretivinal therapy (HAART) who were not previously immunized with PCV7.

The ACIP also agreed with the working group's prior decision not to recommend use of PPV23 in children with asthma who are not on high-dose corticosteroid therapy, despite voting to recommend the vaccine for all adults with asthma. Diagnosis of pediatric asthma is difficult and many children outgrow wheezing, and current rates of invasive pneumococcal disease (IPD) are very low overall in children aged 2 years and older because of both the direct and the indirect impact of routine PCV7 use. Thus, PPV23 is also not recommended even for older adolescents with asthma who did not receive PCV7, Dr. Nuorti said in an interview.

The current American Indian/Alaska Native recommendation was based primarily on expert opinion, and there are few data on use of PPV23 in those populations of children after the PCV7 series. The recommendation also lacks specificity, because not all such groups are at equal risk and the group definitions are not always clear. Moreover, in practice PPV23 typically has not been used among these children except for those with high-risk medical conditions.

Because of concern about potential hyporesponsiveness after PPV23, the working group had prepared a recommendation against routine use of PPV23 in all American Indian/Alaska Native children and to limit its use to only those “living in areas with documented elevated rates of [IPD].” However, several committee members felt this still wasn't clear enough, so the decision was left for the working group to retool.

WASHINGTON — Rates of Clostridium difficile diarrhea have declined in Quebec since the 2003–2004 outbreak of a new highly transmissible and lethal strain, but infectious disease experts do not believe this means that the disease has peaked in North America.

“Personally, I'm a bit pessimistic. I think the property of this specific strain is such that it will persist for a long time,” Dr. Jacques Pepin of the University of Sherbrooke (Que.), said at a press briefing during the jointly held annual Interscience Conference on Antimicrobial Agents and Chemotherapy and the annual meeting of the Infectious Diseases Society of America.

Dr. Dale N. Gerding of Hines Veterans Affairs Hospital, Chicago, agrees. “Have we hit the peak of the epidemic yet? In the United States, I don't think we have.”

The strain is now present in all 50 U.S. states and is largely responsible for the changing epidemiology of C. difficile infection (CDI), noted Dr. L. Clifford McDonald of the Centers for Disease Control and Prevention, who first reported the appearance of the strain in six U.S. states in 2005 (N. Engl. J. Med. 2005;353:2433–41.

Recent studies suggest that the strain is present in 30%–50% of U.S. isolates, but the lack of national surveillance data makes it difficult to monitor. It is estimated that in 2006 more than 500,000 total CDI cases resulted—directly or indirectly—in more than 15,000 deaths. “There is marked geographic variation in rates of cases and deaths. It's [affected] by the age of the population,” Dr. McDonald said in a symposium held during the meeting.

Hospital survey data suggest that the rate of discharges with C. difficile listed as a diagnosis for short-stay patients rose from 30.7/100,000 population in 1996 to 77.3/100,000 in 2006, a slight decline from the 84.8/100,000 seen in 2005. National inpatient survey samples show a similar trend. There appears to be a slight leveling off, but it's far too soon to declare the epidemic over, Dr. McDonald said.

In a prospective study conducted at 12 Quebec hospitals, there were 1,703 CDI patients, with an incidence of 22.5 per 1,000 admissions and an 30-day attributable mortality rate of 6.9% (N. Engl. J. Med. 2005;353:2442–9).

The Quebec outbreak represented the first multihospital epidemic of a new strain of C. difficile. Since the peak years of 2003–2004, the incidence has yet to fall back to what it was before the outbreak. Before the strain arrived, death certificates listed about 100 deaths per year caused by C. difficile. That rose to about 700 deaths per year during the outbreak, and is now about 400. The population of Quebec is about 7 million, so an extrapolation to the United States would equal about 100,000 deaths, Dr. Pepin said.

“The new strain is not going to disappear. The proportion of cases caused by this strain has remained stable. It's possible to reduce the incidence, but I don't think we will ever get back to the incidence levels we had prior to that unless we have a vaccine,” he said.

The current treatments of choice for C. difficile—vancomycin and metronidazole—have been used for 30 years, Dr. Gerding noted. Recent data suggest that metronidazole does not work as well as it used to, particularly in severely ill patients. But concern about the disease has led to increased research into antimicrobial agents as well as unconventional approaches such as toxin binders, monoclonal antibodies, and “biotherapeutic” treatments such as fecal transfusions.

“It's a desperate situation and we need new treatment approaches,” he said.

Improvements in diagnostic testing will also be needed, said Dr. Lance R. Peterson, director of microbiology and infectious disease research at NorthShore University HealthSystem, Evanston, Ill., who also spoke at the symposium.

About 20% of all hospitalized patients have loose stools, most of which are not infected with C. difficile. Current enzyme immunoassays give rapid results, but their sensitivity is only about 70–80%, with a 3–5% false-positive rate. The error rates among the current tests have led to confusion in the literature regarding the epidemiology of the disease. The confusion includes controversy over whether proton pump inhibitors are related to C. difficile and whether some strains may not be related to antimicrobial use.

New molecular diagnostics include real-time polymerase chain reaction (PCR) tests, which can accurately detect 95%–98% of C. difficile infections within 2 hours. At least three companies are developing commercial versions of the test.

“We're starting to have a rapid test that's useful. … This will be imperative to understand the epidemiology of this changing emerging infection going forward,” said Dr. Peterson, who also is professor of pathology and medicine at Northwestern University, Chicago.

The new emphasis on prevention of health care-acquired infections could make a difference, Dr. McDonald noted. The CDC is working with hospitals to prevent outbreaks by revising antimicrobial prescribing practices as well as environmental efforts, such as using gowns and enforcing hand-washing rules. “Data suggest that many more cases of CDI can be prevented than we currently realize. … It seems like it's something that will require a new way of doing business with regard to infection-control measures.”

Dr. Pepin is on the advisory board for Acambis, which is developing a C. difficile vaccine. Dr. Gerding holds patents for the treatment and prevention of CDI licensed to ViroPharma Inc., and is a consultant for and/or holds research grants from several companies. Dr. Peterson has received research funding and/or consulting fees from several companies and the National Institutes of Health. Dr. McDonald reported having nothing to disclose.

WASHINGTON — Rates of Clostridium difficile diarrhea have declined in Quebec since the 2003–2004 outbreak of a new highly transmissible and lethal strain, but infectious disease experts do not believe this means that the disease has peaked in North America.

“Personally, I'm a bit pessimistic. I think the property of this specific strain is such that it will persist for a long time,” Dr. Jacques Pepin of the University of Sherbrooke (Que.), said at a press briefing during the jointly held annual Interscience Conference on Antimicrobial Agents and Chemotherapy and the annual meeting of the Infectious Diseases Society of America.

Dr. Dale N. Gerding of Hines Veterans Affairs Hospital, Chicago, agrees. “Have we hit the peak of the epidemic yet? In the United States, I don't think we have.”

The strain is now present in all 50 U.S. states and is largely responsible for the changing epidemiology of C. difficile infection (CDI), noted Dr. L. Clifford McDonald of the Centers for Disease Control and Prevention, who first reported the appearance of the strain in six U.S. states in 2005 (N. Engl. J. Med. 2005;353:2433–41.

Recent studies suggest that the strain is present in 30%–50% of U.S. isolates, but the lack of national surveillance data makes it difficult to monitor. It is estimated that in 2006 more than 500,000 total CDI cases resulted—directly or indirectly—in more than 15,000 deaths. “There is marked geographic variation in rates of cases and deaths. It's [affected] by the age of the population,” Dr. McDonald said in a symposium held during the meeting.

Hospital survey data suggest that the rate of discharges with C. difficile listed as a diagnosis for short-stay patients rose from 30.7/100,000 population in 1996 to 77.3/100,000 in 2006, a slight decline from the 84.8/100,000 seen in 2005. National inpatient survey samples show a similar trend. There appears to be a slight leveling off, but it's far too soon to declare the epidemic over, Dr. McDonald said.

In a prospective study conducted at 12 Quebec hospitals, there were 1,703 CDI patients, with an incidence of 22.5 per 1,000 admissions and an 30-day attributable mortality rate of 6.9% (N. Engl. J. Med. 2005;353:2442–9).

The Quebec outbreak represented the first multihospital epidemic of a new strain of C. difficile. Since the peak years of 2003–2004, the incidence has yet to fall back to what it was before the outbreak. Before the strain arrived, death certificates listed about 100 deaths per year caused by C. difficile. That rose to about 700 deaths per year during the outbreak, and is now about 400. The population of Quebec is about 7 million, so an extrapolation to the United States would equal about 100,000 deaths, Dr. Pepin said.

“The new strain is not going to disappear. The proportion of cases caused by this strain has remained stable. It's possible to reduce the incidence, but I don't think we will ever get back to the incidence levels we had prior to that unless we have a vaccine,” he said.

The current treatments of choice for C. difficile—vancomycin and metronidazole—have been used for 30 years, Dr. Gerding noted. Recent data suggest that metronidazole does not work as well as it used to, particularly in severely ill patients. But concern about the disease has led to increased research into antimicrobial agents as well as unconventional approaches such as toxin binders, monoclonal antibodies, and “biotherapeutic” treatments such as fecal transfusions.

“It's a desperate situation and we need new treatment approaches,” he said.

Improvements in diagnostic testing will also be needed, said Dr. Lance R. Peterson, director of microbiology and infectious disease research at NorthShore University HealthSystem, Evanston, Ill., who also spoke at the symposium.

About 20% of all hospitalized patients have loose stools, most of which are not infected with C. difficile. Current enzyme immunoassays give rapid results, but their sensitivity is only about 70–80%, with a 3–5% false-positive rate. The error rates among the current tests have led to confusion in the literature regarding the epidemiology of the disease. The confusion includes controversy over whether proton pump inhibitors are related to C. difficile and whether some strains may not be related to antimicrobial use.

New molecular diagnostics include real-time polymerase chain reaction (PCR) tests, which can accurately detect 95%–98% of C. difficile infections within 2 hours. At least three companies are developing commercial versions of the test.

“We're starting to have a rapid test that's useful. … This will be imperative to understand the epidemiology of this changing emerging infection going forward,” said Dr. Peterson, who also is professor of pathology and medicine at Northwestern University, Chicago.

The new emphasis on prevention of health care-acquired infections could make a difference, Dr. McDonald noted. The CDC is working with hospitals to prevent outbreaks by revising antimicrobial prescribing practices as well as environmental efforts, such as using gowns and enforcing hand-washing rules. “Data suggest that many more cases of CDI can be prevented than we currently realize. … It seems like it's something that will require a new way of doing business with regard to infection-control measures.”

Dr. Pepin is on the advisory board for Acambis, which is developing a C. difficile vaccine. Dr. Gerding holds patents for the treatment and prevention of CDI licensed to ViroPharma Inc., and is a consultant for and/or holds research grants from several companies. Dr. Peterson has received research funding and/or consulting fees from several companies and the National Institutes of Health. Dr. McDonald reported having nothing to disclose.

WASHINGTON — Rates of Clostridium difficile diarrhea have declined in Quebec since the 2003–2004 outbreak of a new highly transmissible and lethal strain, but infectious disease experts do not believe this means that the disease has peaked in North America.

“Personally, I'm a bit pessimistic. I think the property of this specific strain is such that it will persist for a long time,” Dr. Jacques Pepin of the University of Sherbrooke (Que.), said at a press briefing during the jointly held annual Interscience Conference on Antimicrobial Agents and Chemotherapy and the annual meeting of the Infectious Diseases Society of America.

Dr. Dale N. Gerding of Hines Veterans Affairs Hospital, Chicago, agrees. “Have we hit the peak of the epidemic yet? In the United States, I don't think we have.”

The strain is now present in all 50 U.S. states and is largely responsible for the changing epidemiology of C. difficile infection (CDI), noted Dr. L. Clifford McDonald of the Centers for Disease Control and Prevention, who first reported the appearance of the strain in six U.S. states in 2005 (N. Engl. J. Med. 2005;353:2433–41.

Recent studies suggest that the strain is present in 30%–50% of U.S. isolates, but the lack of national surveillance data makes it difficult to monitor. It is estimated that in 2006 more than 500,000 total CDI cases resulted—directly or indirectly—in more than 15,000 deaths. “There is marked geographic variation in rates of cases and deaths. It's [affected] by the age of the population,” Dr. McDonald said in a symposium held during the meeting.

Hospital survey data suggest that the rate of discharges with C. difficile listed as a diagnosis for short-stay patients rose from 30.7/100,000 population in 1996 to 77.3/100,000 in 2006, a slight decline from the 84.8/100,000 seen in 2005. National inpatient survey samples show a similar trend. There appears to be a slight leveling off, but it's far too soon to declare the epidemic over, Dr. McDonald said.

In a prospective study conducted at 12 Quebec hospitals, there were 1,703 CDI patients, with an incidence of 22.5 per 1,000 admissions and an 30-day attributable mortality rate of 6.9% (N. Engl. J. Med. 2005;353:2442–9).

The Quebec outbreak represented the first multihospital epidemic of a new strain of C. difficile. Since the peak years of 2003–2004, the incidence has yet to fall back to what it was before the outbreak. Before the strain arrived, death certificates listed about 100 deaths per year caused by C. difficile. That rose to about 700 deaths per year during the outbreak, and is now about 400. The population of Quebec is about 7 million, so an extrapolation to the United States would equal about 100,000 deaths, Dr. Pepin said.

“The new strain is not going to disappear. The proportion of cases caused by this strain has remained stable. It's possible to reduce the incidence, but I don't think we will ever get back to the incidence levels we had prior to that unless we have a vaccine,” he said.

The current treatments of choice for C. difficile—vancomycin and metronidazole—have been used for 30 years, Dr. Gerding noted. Recent data suggest that metronidazole does not work as well as it used to, particularly in severely ill patients. But concern about the disease has led to increased research into antimicrobial agents as well as unconventional approaches such as toxin binders, monoclonal antibodies, and “biotherapeutic” treatments such as fecal transfusions.

“It's a desperate situation and we need new treatment approaches,” he said.

Improvements in diagnostic testing will also be needed, said Dr. Lance R. Peterson, director of microbiology and infectious disease research at NorthShore University HealthSystem, Evanston, Ill., who also spoke at the symposium.

About 20% of all hospitalized patients have loose stools, most of which are not infected with C. difficile. Current enzyme immunoassays give rapid results, but their sensitivity is only about 70–80%, with a 3–5% false-positive rate. The error rates among the current tests have led to confusion in the literature regarding the epidemiology of the disease. The confusion includes controversy over whether proton pump inhibitors are related to C. difficile and whether some strains may not be related to antimicrobial use.

New molecular diagnostics include real-time polymerase chain reaction (PCR) tests, which can accurately detect 95%–98% of C. difficile infections within 2 hours. At least three companies are developing commercial versions of the test.

“We're starting to have a rapid test that's useful. … This will be imperative to understand the epidemiology of this changing emerging infection going forward,” said Dr. Peterson, who also is professor of pathology and medicine at Northwestern University, Chicago.

The new emphasis on prevention of health care-acquired infections could make a difference, Dr. McDonald noted. The CDC is working with hospitals to prevent outbreaks by revising antimicrobial prescribing practices as well as environmental efforts, such as using gowns and enforcing hand-washing rules. “Data suggest that many more cases of CDI can be prevented than we currently realize. … It seems like it's something that will require a new way of doing business with regard to infection-control measures.”

Dr. Pepin is on the advisory board for Acambis, which is developing a C. difficile vaccine. Dr. Gerding holds patents for the treatment and prevention of CDI licensed to ViroPharma Inc., and is a consultant for and/or holds research grants from several companies. Dr. Peterson has received research funding and/or consulting fees from several companies and the National Institutes of Health. Dr. McDonald reported having nothing to disclose.

WASHINGTON — A single-use bacteriophage amplification test kit was able to both accurately identify Staphylococcus aureus and determine whether it was methicillin sensitive or resistant within 5 hours in a study of clinical bacteremia isolates.

The findings suggest that it is possible to slash the diagnostic time for bacteremia—from 2–3 days to 5 hours—and obtain rapid results that will guide treatment and prevent overuse of broad-spectrum antibiotics, Dr. J. Drew Smith said in an interview during his poster presentation at the jointly held annual Interscience Conference on Antimicrobial Agents and Chemotherapy and the annual meeting of the Infectious Diseases Society of America.

The test, made by MicroPhage Inc., uses bacteriophage amplification technology, which detects proteins produced by viruses that are selected to amplify in response to S. aureus. Blood culture samples are mixed in two separate tubes and placed in an incubator for 5 hours. The tubes are removed and six drops of each sample are applied to dipstick-type detectors similar to those used in home pregnancy tests. One tube determines whether or not the sample contains S. aureus; the other determines whether the bacteria are antibiotic resistant or susceptible, said Dr. Smith, director of research and development at MicroPhage.

In a panel of 120 S. aureus clinical isolates and 120 closely related nonpathogenic coagulase-negative staphylococci, the identity test for S. aureus had a sensitivity of 93% and a specificity of 96%. Among the strains identified as S. aureus, methicillin susceptibility was determined with 99% sensitivity and 99% specificity. Only 1.8% of samples were falsely identified as methicillin-resistant S. aureus (MRSA) and no samples were falsely identified as methicillin sensitive (MSSA), Dr. Smith and his associates reported.

Current polymerase chain reaction (PCR) technology allows for rapid detection of MRSA but doesn't accurately determine susceptibility. With the bacteriophage test, a result indicating MSSA allows for the patient to be safely switched from empiric vancomycin to nafcillin or another conventional β-lactam antibiotic, which are more effective against S. aureus than is vancomycin and can reduce mortality by 30%–50% if the organism is susceptible. The PCR test gives too many false positives for MSSA in order to be used for this purpose, Dr. Smith explained in the interview.

Bacteriophage amplification also could be used to screen patients for MRSA carriage. In a separate study presented in another poster, nasal swabs collected from preoperative and ICU patients were streaked on agar plates for MRSA detection. The swabs were transferred to MicroPhage tubes, incubated for 7–24 hours, and read in the same way as was done for the bacteremia test. This time, 32 samples were read at 7 and 24 hours and 77 were read at 12–18 hours and again at 18–24 hours. (More time is needed for nasal swabs than blood cultures because fewer bacteria are present, Dr. Smith explained.)

Sensitivity for detecting MRSA nasal carriage was 33% at 7 hours, 92% at 12–18 hours, and 100% at 18–24 hours. Specificity was 100% at 7 hours and 98% at 12–18 and 18–24 hours. Positive predictive value was 100% at 7 hours and 88% by 18–24 hours; negative predictive value rose from 94% at 7 hours to 100% at 18–24 hours.

Lab personnel were trained to use the test in less than half an hour, and it required no specialized or dedicated equipment. Moreover, “the test is flexible with respect to read times, allowing it to be adapted to a variety of testing and reporting schedules,” the investigators said.

MicroPhage is hoping to market both uses for the technology to community hospitals and to offer the nasal tests to outpatient settings such as nursing homes or surgicenters. Clinical testing will begin in early 2009, and the company hopes to obtain licensure by early 2010, Dr. Smith said.

WASHINGTON — A single-use bacteriophage amplification test kit was able to both accurately identify Staphylococcus aureus and determine whether it was methicillin sensitive or resistant within 5 hours in a study of clinical bacteremia isolates.

The findings suggest that it is possible to slash the diagnostic time for bacteremia—from 2–3 days to 5 hours—and obtain rapid results that will guide treatment and prevent overuse of broad-spectrum antibiotics, Dr. J. Drew Smith said in an interview during his poster presentation at the jointly held annual Interscience Conference on Antimicrobial Agents and Chemotherapy and the annual meeting of the Infectious Diseases Society of America.

The test, made by MicroPhage Inc., uses bacteriophage amplification technology, which detects proteins produced by viruses that are selected to amplify in response to S. aureus. Blood culture samples are mixed in two separate tubes and placed in an incubator for 5 hours. The tubes are removed and six drops of each sample are applied to dipstick-type detectors similar to those used in home pregnancy tests. One tube determines whether or not the sample contains S. aureus; the other determines whether the bacteria are antibiotic resistant or susceptible, said Dr. Smith, director of research and development at MicroPhage.

In a panel of 120 S. aureus clinical isolates and 120 closely related nonpathogenic coagulase-negative staphylococci, the identity test for S. aureus had a sensitivity of 93% and a specificity of 96%. Among the strains identified as S. aureus, methicillin susceptibility was determined with 99% sensitivity and 99% specificity. Only 1.8% of samples were falsely identified as methicillin-resistant S. aureus (MRSA) and no samples were falsely identified as methicillin sensitive (MSSA), Dr. Smith and his associates reported.

Current polymerase chain reaction (PCR) technology allows for rapid detection of MRSA but doesn't accurately determine susceptibility. With the bacteriophage test, a result indicating MSSA allows for the patient to be safely switched from empiric vancomycin to nafcillin or another conventional β-lactam antibiotic, which are more effective against S. aureus than is vancomycin and can reduce mortality by 30%–50% if the organism is susceptible. The PCR test gives too many false positives for MSSA in order to be used for this purpose, Dr. Smith explained in the interview.

Bacteriophage amplification also could be used to screen patients for MRSA carriage. In a separate study presented in another poster, nasal swabs collected from preoperative and ICU patients were streaked on agar plates for MRSA detection. The swabs were transferred to MicroPhage tubes, incubated for 7–24 hours, and read in the same way as was done for the bacteremia test. This time, 32 samples were read at 7 and 24 hours and 77 were read at 12–18 hours and again at 18–24 hours. (More time is needed for nasal swabs than blood cultures because fewer bacteria are present, Dr. Smith explained.)

Sensitivity for detecting MRSA nasal carriage was 33% at 7 hours, 92% at 12–18 hours, and 100% at 18–24 hours. Specificity was 100% at 7 hours and 98% at 12–18 and 18–24 hours. Positive predictive value was 100% at 7 hours and 88% by 18–24 hours; negative predictive value rose from 94% at 7 hours to 100% at 18–24 hours.

Lab personnel were trained to use the test in less than half an hour, and it required no specialized or dedicated equipment. Moreover, “the test is flexible with respect to read times, allowing it to be adapted to a variety of testing and reporting schedules,” the investigators said.

MicroPhage is hoping to market both uses for the technology to community hospitals and to offer the nasal tests to outpatient settings such as nursing homes or surgicenters. Clinical testing will begin in early 2009, and the company hopes to obtain licensure by early 2010, Dr. Smith said.

WASHINGTON — A single-use bacteriophage amplification test kit was able to both accurately identify Staphylococcus aureus and determine whether it was methicillin sensitive or resistant within 5 hours in a study of clinical bacteremia isolates.

The findings suggest that it is possible to slash the diagnostic time for bacteremia—from 2–3 days to 5 hours—and obtain rapid results that will guide treatment and prevent overuse of broad-spectrum antibiotics, Dr. J. Drew Smith said in an interview during his poster presentation at the jointly held annual Interscience Conference on Antimicrobial Agents and Chemotherapy and the annual meeting of the Infectious Diseases Society of America.

The test, made by MicroPhage Inc., uses bacteriophage amplification technology, which detects proteins produced by viruses that are selected to amplify in response to S. aureus. Blood culture samples are mixed in two separate tubes and placed in an incubator for 5 hours. The tubes are removed and six drops of each sample are applied to dipstick-type detectors similar to those used in home pregnancy tests. One tube determines whether or not the sample contains S. aureus; the other determines whether the bacteria are antibiotic resistant or susceptible, said Dr. Smith, director of research and development at MicroPhage.

In a panel of 120 S. aureus clinical isolates and 120 closely related nonpathogenic coagulase-negative staphylococci, the identity test for S. aureus had a sensitivity of 93% and a specificity of 96%. Among the strains identified as S. aureus, methicillin susceptibility was determined with 99% sensitivity and 99% specificity. Only 1.8% of samples were falsely identified as methicillin-resistant S. aureus (MRSA) and no samples were falsely identified as methicillin sensitive (MSSA), Dr. Smith and his associates reported.

Current polymerase chain reaction (PCR) technology allows for rapid detection of MRSA but doesn't accurately determine susceptibility. With the bacteriophage test, a result indicating MSSA allows for the patient to be safely switched from empiric vancomycin to nafcillin or another conventional β-lactam antibiotic, which are more effective against S. aureus than is vancomycin and can reduce mortality by 30%–50% if the organism is susceptible. The PCR test gives too many false positives for MSSA in order to be used for this purpose, Dr. Smith explained in the interview.

Bacteriophage amplification also could be used to screen patients for MRSA carriage. In a separate study presented in another poster, nasal swabs collected from preoperative and ICU patients were streaked on agar plates for MRSA detection. The swabs were transferred to MicroPhage tubes, incubated for 7–24 hours, and read in the same way as was done for the bacteremia test. This time, 32 samples were read at 7 and 24 hours and 77 were read at 12–18 hours and again at 18–24 hours. (More time is needed for nasal swabs than blood cultures because fewer bacteria are present, Dr. Smith explained.)

Sensitivity for detecting MRSA nasal carriage was 33% at 7 hours, 92% at 12–18 hours, and 100% at 18–24 hours. Specificity was 100% at 7 hours and 98% at 12–18 and 18–24 hours. Positive predictive value was 100% at 7 hours and 88% by 18–24 hours; negative predictive value rose from 94% at 7 hours to 100% at 18–24 hours.

Lab personnel were trained to use the test in less than half an hour, and it required no specialized or dedicated equipment. Moreover, “the test is flexible with respect to read times, allowing it to be adapted to a variety of testing and reporting schedules,” the investigators said.

MicroPhage is hoping to market both uses for the technology to community hospitals and to offer the nasal tests to outpatient settings such as nursing homes or surgicenters. Clinical testing will begin in early 2009, and the company hopes to obtain licensure by early 2010, Dr. Smith said.

WASHINGTON — When women develop deep vein thrombosis while on oral contraceptives, the lower left side of the body is more likely to be affected than are the upper extremities or the lower right side, according to the results of a single-center, retrospective chart review.

The findings also suggest that a narrow left common iliac vein may predispose women to thromboses in this location, and that this risk facor could be addressed with endovascular stenting, said Dr. Grace A. Tye, who reported the results at the annual meeting of the Society of Interventional Radiology.

Oral contraceptives are a known risk factor for lower extremity venous thromboembolic events, but there are few published studies on the anatomical distribution of these events in women on OCs.

Among 52 women who were younger than age 45 and were diagnosed with DVT at Stanford (Calif.) University Hospital in 2002–2006, 19 were on OCs at the time of their diagnosis, reported Dr. Tye, a radiology resident at Stanford. All 19 women on OCs had lower extremity DVTs; of these, 16 were in the left lower extremity and 3 were in the right lower extremity, a statistically significant difference.

Cross-sectional imaging was available for 11 of the 19 patients, and the findings indicated a left common iliac diameter (at the point of maximal narrowing) of 3.7 mm, compared with a right common iliac diameter of 13.1 mm, a highly significant difference.

Dr. Tye proposed that the lower left side predominance of the DVTs might be related to May-Thurner Syndrome, also called iliac vein compression syndrome. Named after the two physicians who first described it more than 50 years ago (Angiology 1957;8:419-27), the syndrome describes the small diameter of the left common iliac vein as typically resulting from compression by the right common iliac artery.

Conventional anticoagulation therapy may not address the risk for recurrent DVTs and postthrombotic syndrome in these women, Dr. Tye said. However, they may benefit from endovascular stenting of the left common iliac vein to relieve compression at this location, which may subsequently result in a lower risk for recurrent DVTs and postthrombotic syndrome, she concluded.

WASHINGTON — When women develop deep vein thrombosis while on oral contraceptives, the lower left side of the body is more likely to be affected than are the upper extremities or the lower right side, according to the results of a single-center, retrospective chart review.

The findings also suggest that a narrow left common iliac vein may predispose women to thromboses in this location, and that this risk facor could be addressed with endovascular stenting, said Dr. Grace A. Tye, who reported the results at the annual meeting of the Society of Interventional Radiology.

Oral contraceptives are a known risk factor for lower extremity venous thromboembolic events, but there are few published studies on the anatomical distribution of these events in women on OCs.

Among 52 women who were younger than age 45 and were diagnosed with DVT at Stanford (Calif.) University Hospital in 2002–2006, 19 were on OCs at the time of their diagnosis, reported Dr. Tye, a radiology resident at Stanford. All 19 women on OCs had lower extremity DVTs; of these, 16 were in the left lower extremity and 3 were in the right lower extremity, a statistically significant difference.

Cross-sectional imaging was available for 11 of the 19 patients, and the findings indicated a left common iliac diameter (at the point of maximal narrowing) of 3.7 mm, compared with a right common iliac diameter of 13.1 mm, a highly significant difference.

Dr. Tye proposed that the lower left side predominance of the DVTs might be related to May-Thurner Syndrome, also called iliac vein compression syndrome. Named after the two physicians who first described it more than 50 years ago (Angiology 1957;8:419-27), the syndrome describes the small diameter of the left common iliac vein as typically resulting from compression by the right common iliac artery.

Conventional anticoagulation therapy may not address the risk for recurrent DVTs and postthrombotic syndrome in these women, Dr. Tye said. However, they may benefit from endovascular stenting of the left common iliac vein to relieve compression at this location, which may subsequently result in a lower risk for recurrent DVTs and postthrombotic syndrome, she concluded.

WASHINGTON — When women develop deep vein thrombosis while on oral contraceptives, the lower left side of the body is more likely to be affected than are the upper extremities or the lower right side, according to the results of a single-center, retrospective chart review.

The findings also suggest that a narrow left common iliac vein may predispose women to thromboses in this location, and that this risk facor could be addressed with endovascular stenting, said Dr. Grace A. Tye, who reported the results at the annual meeting of the Society of Interventional Radiology.

Oral contraceptives are a known risk factor for lower extremity venous thromboembolic events, but there are few published studies on the anatomical distribution of these events in women on OCs.

Among 52 women who were younger than age 45 and were diagnosed with DVT at Stanford (Calif.) University Hospital in 2002–2006, 19 were on OCs at the time of their diagnosis, reported Dr. Tye, a radiology resident at Stanford. All 19 women on OCs had lower extremity DVTs; of these, 16 were in the left lower extremity and 3 were in the right lower extremity, a statistically significant difference.

Cross-sectional imaging was available for 11 of the 19 patients, and the findings indicated a left common iliac diameter (at the point of maximal narrowing) of 3.7 mm, compared with a right common iliac diameter of 13.1 mm, a highly significant difference.

Dr. Tye proposed that the lower left side predominance of the DVTs might be related to May-Thurner Syndrome, also called iliac vein compression syndrome. Named after the two physicians who first described it more than 50 years ago (Angiology 1957;8:419-27), the syndrome describes the small diameter of the left common iliac vein as typically resulting from compression by the right common iliac artery.

Conventional anticoagulation therapy may not address the risk for recurrent DVTs and postthrombotic syndrome in these women, Dr. Tye said. However, they may benefit from endovascular stenting of the left common iliac vein to relieve compression at this location, which may subsequently result in a lower risk for recurrent DVTs and postthrombotic syndrome, she concluded.

ATLANTA — The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention voted at its summer meeting to expand the maximum ages at which the recently approved infant rotavirus vaccine Rotarix and the established RotaTeq vaccine can be given to simplify and “harmonize” the routine childhood immunization schedule.

The Advisory Committee on Immunization Practices (ACIP) had just voted to add GlaxoSmithKline's infant rotavirus vaccine Rotarix to the schedule.

Rotarix, which was licensed by the Food and Drug Administration in April this year, represents a second oral vaccine option for immunizing infants against rotavirus. Merck's RotaTeq was recommended for routine use in infants by ACIP in Feb. 2006 (MMWR 2006;55[RR-12]1-13).

The two vaccines are equally efficacious, conferring 85%–98% protection against severe rotavirus diarrheal disease and 72%–87% protection against any rotavirus disease. However, they differ in administration schedules: Rotarix is a two-dose series given at 2 and 4 months of age, and RotaTeq is given in three doses at 2, 4, and 6 months. Thus the committee voted to change the maximum ages at which the vaccines can be given to simplify the schedule.

The ACIP did not express a preference for either vaccine, but it did advise the series be completed with the same product whenever possible. If a child switches providers and the product used previously is not available or unknown, the series should be completed with the available product.

Once adopted by the CDC, the new ACIP rotavirus immunization guidelines also are expected to harmonize with those of the American Academy of Family Physicians (AAFP) and the American Academy of Pediatrics (AAP).

Dr. Douglas Campos-Outcalt, the AAFP liaison to ACIP, also expressed support for the recommendation as well as for the availability of a second rotavirus vaccine option: “I think this will make it easier.” He noted that surveys by the CDC and AAFP have found that family physicians have been slower than have pediatricians to adopt RotaTeq in the 2 years since it was licensed, in part because of concerns about cost-effectiveness.

“Hopefully, now that there are two vaccines that are equally effective and equally safe, they'll start competing on price and the cost-effectiveness ratio will [improve],” said Dr. Campos-Outcalt of the University of Arizona, Phoenix.

Both liaisons for the AAFP and AAP said the boards of their respective academies will consider approval of the guidelines once the CDC finalizes them, a process that could take a period of several months for both groups.

Dr. Margaret M. Cortese of the CDC's Division of Viral Diseases, outlined the specifics of the document drafted by a working group and which ACIP subsequently approved. The first dose of either vaccine should be administered to infants aged 6–14 weeks and should not be initiated in those aged 15 weeks or greater. This effectively adds 2 weeks to the 2006 recommendation for RotaTeq, which had said dose 1 should be given at age 6–12 weeks.

The interval between doses should be 4 weeks or greater, and all doses should be given by age 32 weeks. Committee members debated whether the language of the final document should say “8 months 0 days” instead of “32 weeks.” That decision will be made later by CDC. Either way, this would represent an expansion from the Rotarix clinical trials, which used 24 weeks as the maximum age for dose 2, Dr. Cortese said.

Because the oral applicator of Rotarix contains latex and that of RotaTeq doesn't, any infant with a previous severe anaphylactic reaction to latex should receive Rotateq and not Rotarix. The final language also may include a “precaution” about using Rotarix in children with spina bifida, bladder extrophy, or other conditions that predispose to acquiring latex allergy.

The ACIP also voted to include both vaccines for coverage in the federal Vaccines for Children program, per the new recommendations.

ATLANTA — The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention voted at its summer meeting to expand the maximum ages at which the recently approved infant rotavirus vaccine Rotarix and the established RotaTeq vaccine can be given to simplify and “harmonize” the routine childhood immunization schedule.

The Advisory Committee on Immunization Practices (ACIP) had just voted to add GlaxoSmithKline's infant rotavirus vaccine Rotarix to the schedule.

Rotarix, which was licensed by the Food and Drug Administration in April this year, represents a second oral vaccine option for immunizing infants against rotavirus. Merck's RotaTeq was recommended for routine use in infants by ACIP in Feb. 2006 (MMWR 2006;55[RR-12]1-13).

The two vaccines are equally efficacious, conferring 85%–98% protection against severe rotavirus diarrheal disease and 72%–87% protection against any rotavirus disease. However, they differ in administration schedules: Rotarix is a two-dose series given at 2 and 4 months of age, and RotaTeq is given in three doses at 2, 4, and 6 months. Thus the committee voted to change the maximum ages at which the vaccines can be given to simplify the schedule.

The ACIP did not express a preference for either vaccine, but it did advise the series be completed with the same product whenever possible. If a child switches providers and the product used previously is not available or unknown, the series should be completed with the available product.

Once adopted by the CDC, the new ACIP rotavirus immunization guidelines also are expected to harmonize with those of the American Academy of Family Physicians (AAFP) and the American Academy of Pediatrics (AAP).

Dr. Douglas Campos-Outcalt, the AAFP liaison to ACIP, also expressed support for the recommendation as well as for the availability of a second rotavirus vaccine option: “I think this will make it easier.” He noted that surveys by the CDC and AAFP have found that family physicians have been slower than have pediatricians to adopt RotaTeq in the 2 years since it was licensed, in part because of concerns about cost-effectiveness.

“Hopefully, now that there are two vaccines that are equally effective and equally safe, they'll start competing on price and the cost-effectiveness ratio will [improve],” said Dr. Campos-Outcalt of the University of Arizona, Phoenix.

Both liaisons for the AAFP and AAP said the boards of their respective academies will consider approval of the guidelines once the CDC finalizes them, a process that could take a period of several months for both groups.

Dr. Margaret M. Cortese of the CDC's Division of Viral Diseases, outlined the specifics of the document drafted by a working group and which ACIP subsequently approved. The first dose of either vaccine should be administered to infants aged 6–14 weeks and should not be initiated in those aged 15 weeks or greater. This effectively adds 2 weeks to the 2006 recommendation for RotaTeq, which had said dose 1 should be given at age 6–12 weeks.

The interval between doses should be 4 weeks or greater, and all doses should be given by age 32 weeks. Committee members debated whether the language of the final document should say “8 months 0 days” instead of “32 weeks.” That decision will be made later by CDC. Either way, this would represent an expansion from the Rotarix clinical trials, which used 24 weeks as the maximum age for dose 2, Dr. Cortese said.

Because the oral applicator of Rotarix contains latex and that of RotaTeq doesn't, any infant with a previous severe anaphylactic reaction to latex should receive Rotateq and not Rotarix. The final language also may include a “precaution” about using Rotarix in children with spina bifida, bladder extrophy, or other conditions that predispose to acquiring latex allergy.

The ACIP also voted to include both vaccines for coverage in the federal Vaccines for Children program, per the new recommendations.

ATLANTA — The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention voted at its summer meeting to expand the maximum ages at which the recently approved infant rotavirus vaccine Rotarix and the established RotaTeq vaccine can be given to simplify and “harmonize” the routine childhood immunization schedule.

The Advisory Committee on Immunization Practices (ACIP) had just voted to add GlaxoSmithKline's infant rotavirus vaccine Rotarix to the schedule.

Rotarix, which was licensed by the Food and Drug Administration in April this year, represents a second oral vaccine option for immunizing infants against rotavirus. Merck's RotaTeq was recommended for routine use in infants by ACIP in Feb. 2006 (MMWR 2006;55[RR-12]1-13).

The two vaccines are equally efficacious, conferring 85%–98% protection against severe rotavirus diarrheal disease and 72%–87% protection against any rotavirus disease. However, they differ in administration schedules: Rotarix is a two-dose series given at 2 and 4 months of age, and RotaTeq is given in three doses at 2, 4, and 6 months. Thus the committee voted to change the maximum ages at which the vaccines can be given to simplify the schedule.

The ACIP did not express a preference for either vaccine, but it did advise the series be completed with the same product whenever possible. If a child switches providers and the product used previously is not available or unknown, the series should be completed with the available product.

Once adopted by the CDC, the new ACIP rotavirus immunization guidelines also are expected to harmonize with those of the American Academy of Family Physicians (AAFP) and the American Academy of Pediatrics (AAP).

Dr. Douglas Campos-Outcalt, the AAFP liaison to ACIP, also expressed support for the recommendation as well as for the availability of a second rotavirus vaccine option: “I think this will make it easier.” He noted that surveys by the CDC and AAFP have found that family physicians have been slower than have pediatricians to adopt RotaTeq in the 2 years since it was licensed, in part because of concerns about cost-effectiveness.

“Hopefully, now that there are two vaccines that are equally effective and equally safe, they'll start competing on price and the cost-effectiveness ratio will [improve],” said Dr. Campos-Outcalt of the University of Arizona, Phoenix.

Both liaisons for the AAFP and AAP said the boards of their respective academies will consider approval of the guidelines once the CDC finalizes them, a process that could take a period of several months for both groups.

Dr. Margaret M. Cortese of the CDC's Division of Viral Diseases, outlined the specifics of the document drafted by a working group and which ACIP subsequently approved. The first dose of either vaccine should be administered to infants aged 6–14 weeks and should not be initiated in those aged 15 weeks or greater. This effectively adds 2 weeks to the 2006 recommendation for RotaTeq, which had said dose 1 should be given at age 6–12 weeks.

The interval between doses should be 4 weeks or greater, and all doses should be given by age 32 weeks. Committee members debated whether the language of the final document should say “8 months 0 days” instead of “32 weeks.” That decision will be made later by CDC. Either way, this would represent an expansion from the Rotarix clinical trials, which used 24 weeks as the maximum age for dose 2, Dr. Cortese said.

Because the oral applicator of Rotarix contains latex and that of RotaTeq doesn't, any infant with a previous severe anaphylactic reaction to latex should receive Rotateq and not Rotarix. The final language also may include a “precaution” about using Rotarix in children with spina bifida, bladder extrophy, or other conditions that predispose to acquiring latex allergy.

The ACIP also voted to include both vaccines for coverage in the federal Vaccines for Children program, per the new recommendations.

PITTSBURGH — Hospitals with low adherence to acute MI process measures have higher 30-day mortality rates than do other U.S. hospitals, even after adjustment for differences in patient populations.

Recent studies have shown significant improvements in adherence to acute MI process measures—particularly aspirin and β-blockers and ACE inhibitors for left-ventricular systolic dysfunction—but little is known about the hospitals with consistently poor adherence or the relationship between poor adherence and outcomes.

Dr. Ioana Popescu of the department of internal medicine at the University of Iowa, Iowa City, and associates calculated a composite acute MI compliance score for 2,761 hospitals that reported acute MI process measures for at least 25 acute MI cases a year to the Centers for Medicare and Medicaid Services' Hospital Quality Alliance database in 2004–2006. The number of hospitals—2,761—represents 63% of U.S. hospitals treating acute MI patients.

The hospitals were categorized as low-performing (lowest decile for every study year), high-performing (highest decile), and intermediate-performing (all other), Dr. Popescu reported at the annual meeting of the Society of General Internal Medicine.

Risk-adjusted mortality was calculated as the observed or predicted mortality multiplied by the mean overall population mortality rate, using the records of 208,080 Medicare beneficiaries admitted with acute MI in 2005. The 30-day predicted mortality was estimated using models controlling for patient demographics, comorbidity, and patient clustering within hospitals.

Mean compliance for the five widely reported acute MI process measures was 68% for the 105 low-performing hospitals, 92% for the 2,493 intermediate performers, and 99% for the 163 high-performing hospitals.

Compared with high-performers, low performers were significantly less likely to be teaching hospitals or in an urban location. Low performers were more likely “safety net” hospitals and to be for-profit institutions. The proportion of uncompensated care was significantly greater at low-performing hospitals, whereas staffing ratio, acute MI volume, revascularization, and bed count rates were lower.

Patients at low-performing hospitals were slightly older (80 vs. 79 years), and more likely to be black (9% vs. 4%), female (56% vs. 48%), have lower incomes ($33,739 vs. $46,698), and more comorbidities than those at high-performing institutions.

Mean observed 30-day mortality after acute MI was 26% at the low-performers, 19% at intermediate hospitals, and 15% at the high performers. Even after controlling for differences in patient characteristics, the mean 30-day risk-adjusted mortality rate was significantly greater for low performers, at 19%, versus 16% for the intermediate and 15% for the high performers.

PITTSBURGH — Hospitals with low adherence to acute MI process measures have higher 30-day mortality rates than do other U.S. hospitals, even after adjustment for differences in patient populations.

Recent studies have shown significant improvements in adherence to acute MI process measures—particularly aspirin and β-blockers and ACE inhibitors for left-ventricular systolic dysfunction—but little is known about the hospitals with consistently poor adherence or the relationship between poor adherence and outcomes.

Dr. Ioana Popescu of the department of internal medicine at the University of Iowa, Iowa City, and associates calculated a composite acute MI compliance score for 2,761 hospitals that reported acute MI process measures for at least 25 acute MI cases a year to the Centers for Medicare and Medicaid Services' Hospital Quality Alliance database in 2004–2006. The number of hospitals—2,761—represents 63% of U.S. hospitals treating acute MI patients.

The hospitals were categorized as low-performing (lowest decile for every study year), high-performing (highest decile), and intermediate-performing (all other), Dr. Popescu reported at the annual meeting of the Society of General Internal Medicine.

Risk-adjusted mortality was calculated as the observed or predicted mortality multiplied by the mean overall population mortality rate, using the records of 208,080 Medicare beneficiaries admitted with acute MI in 2005. The 30-day predicted mortality was estimated using models controlling for patient demographics, comorbidity, and patient clustering within hospitals.

Mean compliance for the five widely reported acute MI process measures was 68% for the 105 low-performing hospitals, 92% for the 2,493 intermediate performers, and 99% for the 163 high-performing hospitals.

Compared with high-performers, low performers were significantly less likely to be teaching hospitals or in an urban location. Low performers were more likely “safety net” hospitals and to be for-profit institutions. The proportion of uncompensated care was significantly greater at low-performing hospitals, whereas staffing ratio, acute MI volume, revascularization, and bed count rates were lower.

Patients at low-performing hospitals were slightly older (80 vs. 79 years), and more likely to be black (9% vs. 4%), female (56% vs. 48%), have lower incomes ($33,739 vs. $46,698), and more comorbidities than those at high-performing institutions.

Mean observed 30-day mortality after acute MI was 26% at the low-performers, 19% at intermediate hospitals, and 15% at the high performers. Even after controlling for differences in patient characteristics, the mean 30-day risk-adjusted mortality rate was significantly greater for low performers, at 19%, versus 16% for the intermediate and 15% for the high performers.

PITTSBURGH — Hospitals with low adherence to acute MI process measures have higher 30-day mortality rates than do other U.S. hospitals, even after adjustment for differences in patient populations.

Recent studies have shown significant improvements in adherence to acute MI process measures—particularly aspirin and β-blockers and ACE inhibitors for left-ventricular systolic dysfunction—but little is known about the hospitals with consistently poor adherence or the relationship between poor adherence and outcomes.

Dr. Ioana Popescu of the department of internal medicine at the University of Iowa, Iowa City, and associates calculated a composite acute MI compliance score for 2,761 hospitals that reported acute MI process measures for at least 25 acute MI cases a year to the Centers for Medicare and Medicaid Services' Hospital Quality Alliance database in 2004–2006. The number of hospitals—2,761—represents 63% of U.S. hospitals treating acute MI patients.

The hospitals were categorized as low-performing (lowest decile for every study year), high-performing (highest decile), and intermediate-performing (all other), Dr. Popescu reported at the annual meeting of the Society of General Internal Medicine.

Risk-adjusted mortality was calculated as the observed or predicted mortality multiplied by the mean overall population mortality rate, using the records of 208,080 Medicare beneficiaries admitted with acute MI in 2005. The 30-day predicted mortality was estimated using models controlling for patient demographics, comorbidity, and patient clustering within hospitals.

Mean compliance for the five widely reported acute MI process measures was 68% for the 105 low-performing hospitals, 92% for the 2,493 intermediate performers, and 99% for the 163 high-performing hospitals.

Compared with high-performers, low performers were significantly less likely to be teaching hospitals or in an urban location. Low performers were more likely “safety net” hospitals and to be for-profit institutions. The proportion of uncompensated care was significantly greater at low-performing hospitals, whereas staffing ratio, acute MI volume, revascularization, and bed count rates were lower.

Patients at low-performing hospitals were slightly older (80 vs. 79 years), and more likely to be black (9% vs. 4%), female (56% vs. 48%), have lower incomes ($33,739 vs. $46,698), and more comorbidities than those at high-performing institutions.

Mean observed 30-day mortality after acute MI was 26% at the low-performers, 19% at intermediate hospitals, and 15% at the high performers. Even after controlling for differences in patient characteristics, the mean 30-day risk-adjusted mortality rate was significantly greater for low performers, at 19%, versus 16% for the intermediate and 15% for the high performers.