User login
In newborns, concentrated urine helps rule out UTI
SEATTLE – according to investigators at the University of Texas Health Science Center, Houston.
The researchers found that urine testing negative for nitrites with a specific gravity above 1.015 in children up to 2 months old had a sensitivity of 53% for ruling out UTIs, but that urine with a specific gravity below that mark had a sensitivity of just 14%. The finding “should be taken into account when interpreting nitrite results ... in this high-risk population,” they concluded.
Bacteria in the bladder convert nitrates to nitrites, so positive results are pretty much pathognomonic for UTIs, with a specificity of nearly 100%, according to the researchers.
Negative results, however, don’t reliably rule out infection, and are even less reliable in infants because they urinate frequently, which means they usually flush out bacteria before they have enough time to make the conversion, which takes several hours, they said.
The lead investigator Raymond Parlar-Chun, MD, an assistant professor of pediatrics at the University of Texas McGovern Medical School in Houston, said he had a hunch that negative results might be more reliable when newborns urinate less frequently and have more concentrated urine.
He and his team reviewed data collected on 413 infants up to 2 months old who were admitted for fever workup and treated for UTIs both in the hospital and after discharge. Nitrite results were stratified by urine concentration. A specific gravity of 1.015 was used as the cutoff between concentrated and dilute urine, which was “midway between the parameters reported” in every urinalysis, Dr. Parlar-Chun said.
Although the sensitivity of concentrated urine was only 53%, “it’s a stark difference from” the 14% in dilute urine, he said.“You should take a look at specific gravity to interpret nitrites. If urine is concentrated, you have [more confidence] that you don’t have a UTI if you’re negative. It’s better than taking [nitrites] at face value.”
The subjects were 31 days old, on average, and 62% were boys; 112 had a specific gravity above 1.015, and 301 below.
There was no external funding, and Dr. Parlar-Chun didn’t have any disclosures.
SEATTLE – according to investigators at the University of Texas Health Science Center, Houston.
The researchers found that urine testing negative for nitrites with a specific gravity above 1.015 in children up to 2 months old had a sensitivity of 53% for ruling out UTIs, but that urine with a specific gravity below that mark had a sensitivity of just 14%. The finding “should be taken into account when interpreting nitrite results ... in this high-risk population,” they concluded.
Bacteria in the bladder convert nitrates to nitrites, so positive results are pretty much pathognomonic for UTIs, with a specificity of nearly 100%, according to the researchers.
Negative results, however, don’t reliably rule out infection, and are even less reliable in infants because they urinate frequently, which means they usually flush out bacteria before they have enough time to make the conversion, which takes several hours, they said.
The lead investigator Raymond Parlar-Chun, MD, an assistant professor of pediatrics at the University of Texas McGovern Medical School in Houston, said he had a hunch that negative results might be more reliable when newborns urinate less frequently and have more concentrated urine.
He and his team reviewed data collected on 413 infants up to 2 months old who were admitted for fever workup and treated for UTIs both in the hospital and after discharge. Nitrite results were stratified by urine concentration. A specific gravity of 1.015 was used as the cutoff between concentrated and dilute urine, which was “midway between the parameters reported” in every urinalysis, Dr. Parlar-Chun said.
Although the sensitivity of concentrated urine was only 53%, “it’s a stark difference from” the 14% in dilute urine, he said.“You should take a look at specific gravity to interpret nitrites. If urine is concentrated, you have [more confidence] that you don’t have a UTI if you’re negative. It’s better than taking [nitrites] at face value.”
The subjects were 31 days old, on average, and 62% were boys; 112 had a specific gravity above 1.015, and 301 below.
There was no external funding, and Dr. Parlar-Chun didn’t have any disclosures.
SEATTLE – according to investigators at the University of Texas Health Science Center, Houston.
The researchers found that urine testing negative for nitrites with a specific gravity above 1.015 in children up to 2 months old had a sensitivity of 53% for ruling out UTIs, but that urine with a specific gravity below that mark had a sensitivity of just 14%. The finding “should be taken into account when interpreting nitrite results ... in this high-risk population,” they concluded.
Bacteria in the bladder convert nitrates to nitrites, so positive results are pretty much pathognomonic for UTIs, with a specificity of nearly 100%, according to the researchers.
Negative results, however, don’t reliably rule out infection, and are even less reliable in infants because they urinate frequently, which means they usually flush out bacteria before they have enough time to make the conversion, which takes several hours, they said.
The lead investigator Raymond Parlar-Chun, MD, an assistant professor of pediatrics at the University of Texas McGovern Medical School in Houston, said he had a hunch that negative results might be more reliable when newborns urinate less frequently and have more concentrated urine.
He and his team reviewed data collected on 413 infants up to 2 months old who were admitted for fever workup and treated for UTIs both in the hospital and after discharge. Nitrite results were stratified by urine concentration. A specific gravity of 1.015 was used as the cutoff between concentrated and dilute urine, which was “midway between the parameters reported” in every urinalysis, Dr. Parlar-Chun said.
Although the sensitivity of concentrated urine was only 53%, “it’s a stark difference from” the 14% in dilute urine, he said.“You should take a look at specific gravity to interpret nitrites. If urine is concentrated, you have [more confidence] that you don’t have a UTI if you’re negative. It’s better than taking [nitrites] at face value.”
The subjects were 31 days old, on average, and 62% were boys; 112 had a specific gravity above 1.015, and 301 below.
There was no external funding, and Dr. Parlar-Chun didn’t have any disclosures.
REPORTING FROM PHM 2019
FDA panel backs Descovy as HIV PrEP for men and transgender women who have sex with men
The Food and Drug Administration’s Antimicrobial Drugs Advisory Committee backed the fixed dose combination of emtricitabine and tenofovir alafenamide (TAF; Descovy, Gilead) for pre-exposure prophylaxis (PrEP) against HIV for men and transgender women who have sex with men.
In a discussion after a 16-2 vote, committee members cited analysis by the study’s sponsor and the FDA showing efficacy and a generally good safety profile in the DISCOVER trial, the single new clinical trial conducted to support TAF’s use for pre-exposure prophylaxis (PrEP).
However, this trial included no cisgender women; the sponsor asked for approval based primarily on extrapolation from the DISCOVER results and previous results with tenofovir disoproxil fumarate (TDF) in cisgender women. Both formulations of tenofovir are prodrugs and converted to tenofovir diphosphate intracellularly in peripheral blood mononuclear cells, though many aspects of their pharmacokinetics differ.
The committee voted 10-8 against the proposition that these data supported an indication of TAF for PrEP in cisgender women, in a narrowly worded question from the FDA.
Many members who voted on either side of the question had strongly worded reservations about the lack of data for cisgender women. Said committee chair Lindsey R. Baden, MD, director of the infectious disease service at Dana-Farber Cancer Institute, Boston, who voted against the indication for cisgender women, “We’ve failed women. To be at this point and not have the data to guide decision-making is a shame on all of us.”
Ighovwerha Ofotokun, MD, who voted yes, concurred: “I agree it is a terrible failure that the agency, as well as the sponsor, would come to this committee with a lack of data on women.” But for Dr. Ofotokun, a professor of infectious diseases at Emory University, Atlanta, not including cisgender women in the approval was a distasteful proposition. “Creating a two-tier prevention and treatment hierarchy would not be helpful. We should remind ourselves that there are more women living with HIV in the world than there are men, and the risk of new HIV infection is higher among women than among men, if you look at this globally,” he said.
“I find it disrespectful and an issue of research equity. Women deserve the same quality of data about the safety and efficacy of the drugs they are exposed to that men get and that is not the situation we find ourselves in at the moment,” said Dawn K. Smith, MD, MPH, a lead scientist at the Centers for Disease Control and Prevention (CDC), Atlanta, who voted against approval for cisgender women.
Michael Green, MD, MPH, professor of pediatrics, surgery and clinical and translational science at the University of Pittsburgh, echoed the frustration of many committee members when he said, “I voted yes, almost abstained, then almost voted no.” He, along with all who voted yes, emphasized the importance of mandatory postmarketing studies in cisgender women to ensure efficacy data are obtained.
Transgender women made up only about 1% of the DISCOVER population, a fact that also gave many committee members pause.
If TAF is approved, labeling and package materials should be clear that the data support only noninferiority, not superiority, compared with TDF, said several advisory committee members who voted for approval for men and transgender women who have sex with men. “My expectation of this approval is that it should be marketed responsibly from the perspective of not creating these disparities and having Truvada be a drug for poor people and Descovy be a drug for rich people,” said Demetre Dasklalakis, MD, assistant commissioner of the Bureau of HIV/AIDS Prevention and Control at the city of New York’s Department of Health and Hygiene, and of the Icahn School of Medicine at Mount Sinai, N.Y. Truvada is slated to be offered as a generic drug in 2020, according to a Securities and Exchange Commission filing by Gilead Sciences.
The CDC reported earlier in 2019 that rates of new HIV infections have plateaued in recent years. Uptake of PrEP has been particularly low among at-risk members of minority populations, in rural areas, and in the South, according to a CDC report.
The DISCOVER trial is a 96-week ongoing trial to test TAF’s noninferiority to a fixed-drug combination of emcitrabine and tenofovir dimethyl fumarate (TDF; Truvada, Gilead) for PrEP. Both drugs are already approved to treat HIV infection, and TDF is approved for PrEP. Non-inferiority was preestablished at a rate ratio of HIV incidence of 1.62 (TAF:TDF) between the two study arms.
DISCOVER has enrolled 5,387 men and transgender women who have sex with men and are deemed at high risk for HIV, and found an incidence rate ratio of 0.47, with the upper bound of the confidence interval at 1.15. Since this figure was less than the prespecified noninferiority margin, both Gilead presenters and the FDA agreed, TAF’s noninferiority for efficacy was established.
Characteristics were similar between patients in the TAF arm (N = 2,694) and the TDF arm (N = 2,693). About 60% of patients in each arm reported having receptive anal sex with at least two partners in the previous 12 weeks, and recent rectal gonorrhea, syphilis, and chlamydia rates were 9-13% at baseline. Two thirds of participants reported recreational drug use, and about one in four reported binge drinking.
Sexual behavior and sexually transmitted infection rates continued generally unchanged from baseline during the study period.
The median age was 34 years, and most participants (84%) were white. Black participants made up 9% of the study population, and about 25% were of Hispanic or Latin ethnic origin.
Known decreases in bone mineral density occur with TDF; these were not seen with TAF, and bone mineral density increased while on TAF for the DISCOVER population aged 19-25 years.
Renal biomarkers of concern with TDF included two proteins linked with proximal tubule dysfunction, as well as estimated glomerular filtration rate. According to the sponsor’s analysis, eGFR fell by 2.3 mL/min for the TAF group, compared with a 1.8 mL/min rise while on TDF (P less than .001). Changes of similar statistical significance were seen for proximal tubular proteinuria. Also, improvements were seen in renal measures for the subset of patients enrolled who were on TDF PrEP at baseline but switched to TAF, in a prespecified subgroup analysis.
However, patients who were on TDF had a significant decrease in total cholesterol and both low- and high-density lipoprotein cholesterol compared with those on TAF, who had minimal changes or slight increases in lipids (P less than .001 for all). Triglycerides rose for those on TAF and remained unchanged for those on TDF (P = .002).
The PrEP indication sought by Gilead includes adults and adolescents, defined as those who weigh more than 35 kg. A nonvoting question put before the committee asked whether the totality of tenofovir data supported an indication of TAF for cisgender men who have insertive vaginal sex; though this extrapolation didn’t give the committee as much pause as the request for approval in cisgender women, they cited similar concerns and noted that cervicovaginal mucosa are different in many ways from rectal mucosa.
The study included no cisgender women, for a host of reasons cited by the sponsor and the FDA. These included high nonadherence rates among this population, relatively lower HIV infection rates among cisgender women in the United States, and mixed efficacy results in previous tenofovir clinical trials; the latter point made establishing a noninferiority margin problematic, according to the FDA.
For Dr. Baden, “The optics of approval for population A but not for population B are problematic.” Speaking to both the sponsor and the FDA, he said, “Everyone agrees there needs to be actual data. Please do the study as quickly as possible.” What’s needed is the collective will to make it happen, he added: “I don’t accept that it’s too big, too hard, too difficult.”
The FDA usually follows the recommendations of its advisory committees.
This article was updated 8/8/19.
The Food and Drug Administration’s Antimicrobial Drugs Advisory Committee backed the fixed dose combination of emtricitabine and tenofovir alafenamide (TAF; Descovy, Gilead) for pre-exposure prophylaxis (PrEP) against HIV for men and transgender women who have sex with men.
In a discussion after a 16-2 vote, committee members cited analysis by the study’s sponsor and the FDA showing efficacy and a generally good safety profile in the DISCOVER trial, the single new clinical trial conducted to support TAF’s use for pre-exposure prophylaxis (PrEP).
However, this trial included no cisgender women; the sponsor asked for approval based primarily on extrapolation from the DISCOVER results and previous results with tenofovir disoproxil fumarate (TDF) in cisgender women. Both formulations of tenofovir are prodrugs and converted to tenofovir diphosphate intracellularly in peripheral blood mononuclear cells, though many aspects of their pharmacokinetics differ.
The committee voted 10-8 against the proposition that these data supported an indication of TAF for PrEP in cisgender women, in a narrowly worded question from the FDA.
Many members who voted on either side of the question had strongly worded reservations about the lack of data for cisgender women. Said committee chair Lindsey R. Baden, MD, director of the infectious disease service at Dana-Farber Cancer Institute, Boston, who voted against the indication for cisgender women, “We’ve failed women. To be at this point and not have the data to guide decision-making is a shame on all of us.”
Ighovwerha Ofotokun, MD, who voted yes, concurred: “I agree it is a terrible failure that the agency, as well as the sponsor, would come to this committee with a lack of data on women.” But for Dr. Ofotokun, a professor of infectious diseases at Emory University, Atlanta, not including cisgender women in the approval was a distasteful proposition. “Creating a two-tier prevention and treatment hierarchy would not be helpful. We should remind ourselves that there are more women living with HIV in the world than there are men, and the risk of new HIV infection is higher among women than among men, if you look at this globally,” he said.
“I find it disrespectful and an issue of research equity. Women deserve the same quality of data about the safety and efficacy of the drugs they are exposed to that men get and that is not the situation we find ourselves in at the moment,” said Dawn K. Smith, MD, MPH, a lead scientist at the Centers for Disease Control and Prevention (CDC), Atlanta, who voted against approval for cisgender women.
Michael Green, MD, MPH, professor of pediatrics, surgery and clinical and translational science at the University of Pittsburgh, echoed the frustration of many committee members when he said, “I voted yes, almost abstained, then almost voted no.” He, along with all who voted yes, emphasized the importance of mandatory postmarketing studies in cisgender women to ensure efficacy data are obtained.
Transgender women made up only about 1% of the DISCOVER population, a fact that also gave many committee members pause.
If TAF is approved, labeling and package materials should be clear that the data support only noninferiority, not superiority, compared with TDF, said several advisory committee members who voted for approval for men and transgender women who have sex with men. “My expectation of this approval is that it should be marketed responsibly from the perspective of not creating these disparities and having Truvada be a drug for poor people and Descovy be a drug for rich people,” said Demetre Dasklalakis, MD, assistant commissioner of the Bureau of HIV/AIDS Prevention and Control at the city of New York’s Department of Health and Hygiene, and of the Icahn School of Medicine at Mount Sinai, N.Y. Truvada is slated to be offered as a generic drug in 2020, according to a Securities and Exchange Commission filing by Gilead Sciences.
The CDC reported earlier in 2019 that rates of new HIV infections have plateaued in recent years. Uptake of PrEP has been particularly low among at-risk members of minority populations, in rural areas, and in the South, according to a CDC report.
The DISCOVER trial is a 96-week ongoing trial to test TAF’s noninferiority to a fixed-drug combination of emcitrabine and tenofovir dimethyl fumarate (TDF; Truvada, Gilead) for PrEP. Both drugs are already approved to treat HIV infection, and TDF is approved for PrEP. Non-inferiority was preestablished at a rate ratio of HIV incidence of 1.62 (TAF:TDF) between the two study arms.
DISCOVER has enrolled 5,387 men and transgender women who have sex with men and are deemed at high risk for HIV, and found an incidence rate ratio of 0.47, with the upper bound of the confidence interval at 1.15. Since this figure was less than the prespecified noninferiority margin, both Gilead presenters and the FDA agreed, TAF’s noninferiority for efficacy was established.
Characteristics were similar between patients in the TAF arm (N = 2,694) and the TDF arm (N = 2,693). About 60% of patients in each arm reported having receptive anal sex with at least two partners in the previous 12 weeks, and recent rectal gonorrhea, syphilis, and chlamydia rates were 9-13% at baseline. Two thirds of participants reported recreational drug use, and about one in four reported binge drinking.
Sexual behavior and sexually transmitted infection rates continued generally unchanged from baseline during the study period.
The median age was 34 years, and most participants (84%) were white. Black participants made up 9% of the study population, and about 25% were of Hispanic or Latin ethnic origin.
Known decreases in bone mineral density occur with TDF; these were not seen with TAF, and bone mineral density increased while on TAF for the DISCOVER population aged 19-25 years.
Renal biomarkers of concern with TDF included two proteins linked with proximal tubule dysfunction, as well as estimated glomerular filtration rate. According to the sponsor’s analysis, eGFR fell by 2.3 mL/min for the TAF group, compared with a 1.8 mL/min rise while on TDF (P less than .001). Changes of similar statistical significance were seen for proximal tubular proteinuria. Also, improvements were seen in renal measures for the subset of patients enrolled who were on TDF PrEP at baseline but switched to TAF, in a prespecified subgroup analysis.
However, patients who were on TDF had a significant decrease in total cholesterol and both low- and high-density lipoprotein cholesterol compared with those on TAF, who had minimal changes or slight increases in lipids (P less than .001 for all). Triglycerides rose for those on TAF and remained unchanged for those on TDF (P = .002).
The PrEP indication sought by Gilead includes adults and adolescents, defined as those who weigh more than 35 kg. A nonvoting question put before the committee asked whether the totality of tenofovir data supported an indication of TAF for cisgender men who have insertive vaginal sex; though this extrapolation didn’t give the committee as much pause as the request for approval in cisgender women, they cited similar concerns and noted that cervicovaginal mucosa are different in many ways from rectal mucosa.
The study included no cisgender women, for a host of reasons cited by the sponsor and the FDA. These included high nonadherence rates among this population, relatively lower HIV infection rates among cisgender women in the United States, and mixed efficacy results in previous tenofovir clinical trials; the latter point made establishing a noninferiority margin problematic, according to the FDA.
For Dr. Baden, “The optics of approval for population A but not for population B are problematic.” Speaking to both the sponsor and the FDA, he said, “Everyone agrees there needs to be actual data. Please do the study as quickly as possible.” What’s needed is the collective will to make it happen, he added: “I don’t accept that it’s too big, too hard, too difficult.”
The FDA usually follows the recommendations of its advisory committees.
This article was updated 8/8/19.
The Food and Drug Administration’s Antimicrobial Drugs Advisory Committee backed the fixed dose combination of emtricitabine and tenofovir alafenamide (TAF; Descovy, Gilead) for pre-exposure prophylaxis (PrEP) against HIV for men and transgender women who have sex with men.
In a discussion after a 16-2 vote, committee members cited analysis by the study’s sponsor and the FDA showing efficacy and a generally good safety profile in the DISCOVER trial, the single new clinical trial conducted to support TAF’s use for pre-exposure prophylaxis (PrEP).
However, this trial included no cisgender women; the sponsor asked for approval based primarily on extrapolation from the DISCOVER results and previous results with tenofovir disoproxil fumarate (TDF) in cisgender women. Both formulations of tenofovir are prodrugs and converted to tenofovir diphosphate intracellularly in peripheral blood mononuclear cells, though many aspects of their pharmacokinetics differ.
The committee voted 10-8 against the proposition that these data supported an indication of TAF for PrEP in cisgender women, in a narrowly worded question from the FDA.
Many members who voted on either side of the question had strongly worded reservations about the lack of data for cisgender women. Said committee chair Lindsey R. Baden, MD, director of the infectious disease service at Dana-Farber Cancer Institute, Boston, who voted against the indication for cisgender women, “We’ve failed women. To be at this point and not have the data to guide decision-making is a shame on all of us.”
Ighovwerha Ofotokun, MD, who voted yes, concurred: “I agree it is a terrible failure that the agency, as well as the sponsor, would come to this committee with a lack of data on women.” But for Dr. Ofotokun, a professor of infectious diseases at Emory University, Atlanta, not including cisgender women in the approval was a distasteful proposition. “Creating a two-tier prevention and treatment hierarchy would not be helpful. We should remind ourselves that there are more women living with HIV in the world than there are men, and the risk of new HIV infection is higher among women than among men, if you look at this globally,” he said.
“I find it disrespectful and an issue of research equity. Women deserve the same quality of data about the safety and efficacy of the drugs they are exposed to that men get and that is not the situation we find ourselves in at the moment,” said Dawn K. Smith, MD, MPH, a lead scientist at the Centers for Disease Control and Prevention (CDC), Atlanta, who voted against approval for cisgender women.
Michael Green, MD, MPH, professor of pediatrics, surgery and clinical and translational science at the University of Pittsburgh, echoed the frustration of many committee members when he said, “I voted yes, almost abstained, then almost voted no.” He, along with all who voted yes, emphasized the importance of mandatory postmarketing studies in cisgender women to ensure efficacy data are obtained.
Transgender women made up only about 1% of the DISCOVER population, a fact that also gave many committee members pause.
If TAF is approved, labeling and package materials should be clear that the data support only noninferiority, not superiority, compared with TDF, said several advisory committee members who voted for approval for men and transgender women who have sex with men. “My expectation of this approval is that it should be marketed responsibly from the perspective of not creating these disparities and having Truvada be a drug for poor people and Descovy be a drug for rich people,” said Demetre Dasklalakis, MD, assistant commissioner of the Bureau of HIV/AIDS Prevention and Control at the city of New York’s Department of Health and Hygiene, and of the Icahn School of Medicine at Mount Sinai, N.Y. Truvada is slated to be offered as a generic drug in 2020, according to a Securities and Exchange Commission filing by Gilead Sciences.
The CDC reported earlier in 2019 that rates of new HIV infections have plateaued in recent years. Uptake of PrEP has been particularly low among at-risk members of minority populations, in rural areas, and in the South, according to a CDC report.
The DISCOVER trial is a 96-week ongoing trial to test TAF’s noninferiority to a fixed-drug combination of emcitrabine and tenofovir dimethyl fumarate (TDF; Truvada, Gilead) for PrEP. Both drugs are already approved to treat HIV infection, and TDF is approved for PrEP. Non-inferiority was preestablished at a rate ratio of HIV incidence of 1.62 (TAF:TDF) between the two study arms.
DISCOVER has enrolled 5,387 men and transgender women who have sex with men and are deemed at high risk for HIV, and found an incidence rate ratio of 0.47, with the upper bound of the confidence interval at 1.15. Since this figure was less than the prespecified noninferiority margin, both Gilead presenters and the FDA agreed, TAF’s noninferiority for efficacy was established.
Characteristics were similar between patients in the TAF arm (N = 2,694) and the TDF arm (N = 2,693). About 60% of patients in each arm reported having receptive anal sex with at least two partners in the previous 12 weeks, and recent rectal gonorrhea, syphilis, and chlamydia rates were 9-13% at baseline. Two thirds of participants reported recreational drug use, and about one in four reported binge drinking.
Sexual behavior and sexually transmitted infection rates continued generally unchanged from baseline during the study period.
The median age was 34 years, and most participants (84%) were white. Black participants made up 9% of the study population, and about 25% were of Hispanic or Latin ethnic origin.
Known decreases in bone mineral density occur with TDF; these were not seen with TAF, and bone mineral density increased while on TAF for the DISCOVER population aged 19-25 years.
Renal biomarkers of concern with TDF included two proteins linked with proximal tubule dysfunction, as well as estimated glomerular filtration rate. According to the sponsor’s analysis, eGFR fell by 2.3 mL/min for the TAF group, compared with a 1.8 mL/min rise while on TDF (P less than .001). Changes of similar statistical significance were seen for proximal tubular proteinuria. Also, improvements were seen in renal measures for the subset of patients enrolled who were on TDF PrEP at baseline but switched to TAF, in a prespecified subgroup analysis.
However, patients who were on TDF had a significant decrease in total cholesterol and both low- and high-density lipoprotein cholesterol compared with those on TAF, who had minimal changes or slight increases in lipids (P less than .001 for all). Triglycerides rose for those on TAF and remained unchanged for those on TDF (P = .002).
The PrEP indication sought by Gilead includes adults and adolescents, defined as those who weigh more than 35 kg. A nonvoting question put before the committee asked whether the totality of tenofovir data supported an indication of TAF for cisgender men who have insertive vaginal sex; though this extrapolation didn’t give the committee as much pause as the request for approval in cisgender women, they cited similar concerns and noted that cervicovaginal mucosa are different in many ways from rectal mucosa.
The study included no cisgender women, for a host of reasons cited by the sponsor and the FDA. These included high nonadherence rates among this population, relatively lower HIV infection rates among cisgender women in the United States, and mixed efficacy results in previous tenofovir clinical trials; the latter point made establishing a noninferiority margin problematic, according to the FDA.
For Dr. Baden, “The optics of approval for population A but not for population B are problematic.” Speaking to both the sponsor and the FDA, he said, “Everyone agrees there needs to be actual data. Please do the study as quickly as possible.” What’s needed is the collective will to make it happen, he added: “I don’t accept that it’s too big, too hard, too difficult.”
The FDA usually follows the recommendations of its advisory committees.
This article was updated 8/8/19.
FROM AN FDA ADVISORY COMMITTEE MEETING
New RSV vaccine immunogenicity improved with protein engineering
Development of an effective respiratory syncytial virus (RSV) vaccine is feasible using a new technology that can contribute to development of other vaccines as well, according to results of a proof-of-concept study in Science.
The new method of protein engineering preserves the RSV antigen protein’s prefusion structure, including the epitope, thereby inducing antibodies that better “match,” and neutralize, the actual pathogen.
“Protein-based RSV vaccines have had a particularly complicated history, especially those in which the primary immunogen has been the fusion (F) glycoprotein, which exists in two major conformational states: prefusion (pre-F) and postfusion (post-F),” lead author Michelle Crank, MD, of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., and her colleagues explained in the paper.
Since the failure of the whole-inactivated RSV vaccine in the 1960s, researchers have focused on F subunit vaccine candidates, but these contain only post-F or “structurally undefined” F protein.
“Although the products are immunogenic, a substantial proportion of antibodies elicited are non- or poorly neutralizing, and field trials have shown no or minimal efficacy,” the authors wrote.
But now researchers have an “atomic-level understanding of F conformational states, antigenic sites, and the specificity of the human B cell repertoire and serum antibody response to infection.” Having developed a way to engineer proteins to retain the F protein’s prefusion conformation, the researchers developed the DS-Cav1 vaccine with an F protein from RSV subtype A.
In their phase 1, randomized, open-label clinical trial, the researchers tested the safety, tolerability and immunogenicity of DS-Cav1. The trial involved 90 healthy adults, aged 18-50, who had no abnormal findings in clinical lab tests, their medical history, or a physical exam.
The participants received two intramuscular doses, 12 weeks apart, of either 50 mcg, 150 mcg or 500 mcg of the vaccine. In each of these dosage groups, half the participants received a vaccine with 0.5 mcg of alum as an adjuvant, and half received a vaccine without any adjuvants. Each of the six randomized dosage-adjuvant groups had 15 participants.
The investigators report on safety and immunogenicity through 28 days after the first vaccine dose among the first 40 participants enrolled, each randomly assigned into four groups of 10 for the 50 mcg and 150 mcg doses with and without the adjuvant. Their primary immunogenicity endpoint was neutralizing activity from the vaccine.
Neutralizing activity with RSV A was seven times higher with 50 mcg and 12-15 times higher with 150 mcg at week 4 than at baseline (P less than .001).
“These increases in neutralizing activity were higher than those previously reported for F protein subunit vaccines and exceeded the threefold increase in neutralization reported after experimental human challenge with RSV,” the authors noted. Neutralization levels remained 5-10 times higher than baseline at week 12 (P less than .001).
Even with RSV B, neutralizing activity from DS-Cav1 was 4-6 times greater with 50 mcg and 9 times greater with 150 mcg, both with and without alum (P less than .001).
“The boost in neutralizing activity to subtype B after a single immunization with a subtype A–based F vaccine reflected the high conservation of F between subtypes and suggested that multiple prior infections by both RSV A and B subtypes establishes a broad preexisting B-cell repertoire,” the authors wrote.
The adjuvant had no clinically significant effect on immunogenicity, and no serious adverse events occurred in the groups.
The findings reveal that DS-Cav1 induces antibodies far more functionally effective than seen in previous RSV vaccines while opening the door to using similar techniques with other vaccines, the authors wrote. “We are now entering an era of vaccinology in which new technologies provide avenues to define the structural basis of antigenicity and to rapidly isolate and characterize human monoclonal antibodies,” the researchers wrote, marking “a step toward a future of precision vaccines.”
The research was funded by the National Institutes of Health and the Bill & Melinda Gates Foundation. Several of the study authors are inventors on patents for stabilizing the RSV F protein.
Development of an effective respiratory syncytial virus (RSV) vaccine is feasible using a new technology that can contribute to development of other vaccines as well, according to results of a proof-of-concept study in Science.
The new method of protein engineering preserves the RSV antigen protein’s prefusion structure, including the epitope, thereby inducing antibodies that better “match,” and neutralize, the actual pathogen.
“Protein-based RSV vaccines have had a particularly complicated history, especially those in which the primary immunogen has been the fusion (F) glycoprotein, which exists in two major conformational states: prefusion (pre-F) and postfusion (post-F),” lead author Michelle Crank, MD, of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., and her colleagues explained in the paper.
Since the failure of the whole-inactivated RSV vaccine in the 1960s, researchers have focused on F subunit vaccine candidates, but these contain only post-F or “structurally undefined” F protein.
“Although the products are immunogenic, a substantial proportion of antibodies elicited are non- or poorly neutralizing, and field trials have shown no or minimal efficacy,” the authors wrote.
But now researchers have an “atomic-level understanding of F conformational states, antigenic sites, and the specificity of the human B cell repertoire and serum antibody response to infection.” Having developed a way to engineer proteins to retain the F protein’s prefusion conformation, the researchers developed the DS-Cav1 vaccine with an F protein from RSV subtype A.
In their phase 1, randomized, open-label clinical trial, the researchers tested the safety, tolerability and immunogenicity of DS-Cav1. The trial involved 90 healthy adults, aged 18-50, who had no abnormal findings in clinical lab tests, their medical history, or a physical exam.
The participants received two intramuscular doses, 12 weeks apart, of either 50 mcg, 150 mcg or 500 mcg of the vaccine. In each of these dosage groups, half the participants received a vaccine with 0.5 mcg of alum as an adjuvant, and half received a vaccine without any adjuvants. Each of the six randomized dosage-adjuvant groups had 15 participants.
The investigators report on safety and immunogenicity through 28 days after the first vaccine dose among the first 40 participants enrolled, each randomly assigned into four groups of 10 for the 50 mcg and 150 mcg doses with and without the adjuvant. Their primary immunogenicity endpoint was neutralizing activity from the vaccine.
Neutralizing activity with RSV A was seven times higher with 50 mcg and 12-15 times higher with 150 mcg at week 4 than at baseline (P less than .001).
“These increases in neutralizing activity were higher than those previously reported for F protein subunit vaccines and exceeded the threefold increase in neutralization reported after experimental human challenge with RSV,” the authors noted. Neutralization levels remained 5-10 times higher than baseline at week 12 (P less than .001).
Even with RSV B, neutralizing activity from DS-Cav1 was 4-6 times greater with 50 mcg and 9 times greater with 150 mcg, both with and without alum (P less than .001).
“The boost in neutralizing activity to subtype B after a single immunization with a subtype A–based F vaccine reflected the high conservation of F between subtypes and suggested that multiple prior infections by both RSV A and B subtypes establishes a broad preexisting B-cell repertoire,” the authors wrote.
The adjuvant had no clinically significant effect on immunogenicity, and no serious adverse events occurred in the groups.
The findings reveal that DS-Cav1 induces antibodies far more functionally effective than seen in previous RSV vaccines while opening the door to using similar techniques with other vaccines, the authors wrote. “We are now entering an era of vaccinology in which new technologies provide avenues to define the structural basis of antigenicity and to rapidly isolate and characterize human monoclonal antibodies,” the researchers wrote, marking “a step toward a future of precision vaccines.”
The research was funded by the National Institutes of Health and the Bill & Melinda Gates Foundation. Several of the study authors are inventors on patents for stabilizing the RSV F protein.
Development of an effective respiratory syncytial virus (RSV) vaccine is feasible using a new technology that can contribute to development of other vaccines as well, according to results of a proof-of-concept study in Science.
The new method of protein engineering preserves the RSV antigen protein’s prefusion structure, including the epitope, thereby inducing antibodies that better “match,” and neutralize, the actual pathogen.
“Protein-based RSV vaccines have had a particularly complicated history, especially those in which the primary immunogen has been the fusion (F) glycoprotein, which exists in two major conformational states: prefusion (pre-F) and postfusion (post-F),” lead author Michelle Crank, MD, of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., and her colleagues explained in the paper.
Since the failure of the whole-inactivated RSV vaccine in the 1960s, researchers have focused on F subunit vaccine candidates, but these contain only post-F or “structurally undefined” F protein.
“Although the products are immunogenic, a substantial proportion of antibodies elicited are non- or poorly neutralizing, and field trials have shown no or minimal efficacy,” the authors wrote.
But now researchers have an “atomic-level understanding of F conformational states, antigenic sites, and the specificity of the human B cell repertoire and serum antibody response to infection.” Having developed a way to engineer proteins to retain the F protein’s prefusion conformation, the researchers developed the DS-Cav1 vaccine with an F protein from RSV subtype A.
In their phase 1, randomized, open-label clinical trial, the researchers tested the safety, tolerability and immunogenicity of DS-Cav1. The trial involved 90 healthy adults, aged 18-50, who had no abnormal findings in clinical lab tests, their medical history, or a physical exam.
The participants received two intramuscular doses, 12 weeks apart, of either 50 mcg, 150 mcg or 500 mcg of the vaccine. In each of these dosage groups, half the participants received a vaccine with 0.5 mcg of alum as an adjuvant, and half received a vaccine without any adjuvants. Each of the six randomized dosage-adjuvant groups had 15 participants.
The investigators report on safety and immunogenicity through 28 days after the first vaccine dose among the first 40 participants enrolled, each randomly assigned into four groups of 10 for the 50 mcg and 150 mcg doses with and without the adjuvant. Their primary immunogenicity endpoint was neutralizing activity from the vaccine.
Neutralizing activity with RSV A was seven times higher with 50 mcg and 12-15 times higher with 150 mcg at week 4 than at baseline (P less than .001).
“These increases in neutralizing activity were higher than those previously reported for F protein subunit vaccines and exceeded the threefold increase in neutralization reported after experimental human challenge with RSV,” the authors noted. Neutralization levels remained 5-10 times higher than baseline at week 12 (P less than .001).
Even with RSV B, neutralizing activity from DS-Cav1 was 4-6 times greater with 50 mcg and 9 times greater with 150 mcg, both with and without alum (P less than .001).
“The boost in neutralizing activity to subtype B after a single immunization with a subtype A–based F vaccine reflected the high conservation of F between subtypes and suggested that multiple prior infections by both RSV A and B subtypes establishes a broad preexisting B-cell repertoire,” the authors wrote.
The adjuvant had no clinically significant effect on immunogenicity, and no serious adverse events occurred in the groups.
The findings reveal that DS-Cav1 induces antibodies far more functionally effective than seen in previous RSV vaccines while opening the door to using similar techniques with other vaccines, the authors wrote. “We are now entering an era of vaccinology in which new technologies provide avenues to define the structural basis of antigenicity and to rapidly isolate and characterize human monoclonal antibodies,” the researchers wrote, marking “a step toward a future of precision vaccines.”
The research was funded by the National Institutes of Health and the Bill & Melinda Gates Foundation. Several of the study authors are inventors on patents for stabilizing the RSV F protein.
FROM SCIENCE
Key clinical point:
Major finding: Epitope-neutralizing activity is 5-10 times greater 12 weeks after baseline with a 50 mcg or 150 mcg with and without alum adjuvant.
Study details: The findings are based on a prespecified interim analysis of 90 healthy adult participants in a phase 1, randomized, trial of DS-Cav1.
Disclosures: The research was funded by the National Institutes of Health and the Bill & Melinda Gates Foundation. Several authors are inventors on patents for stabilizing the RSV F protein.
Source: Crank MC et al. Science. 2019;365(6452):505-9.
Hospital slashes S. aureus vancomycin resistance
LJUBLJANA, SLOVENIA – , Johannes Huebner, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.
He presented a retrospective analysis of S. aureus isolates obtained from 540 patients at the Dr. von Hauner Children’s Hospital, Munich, from 2002 to 2017. All were either newly identified methicillin-resistant S. aureus (MRSA) or specimens from bacteremic children with invasive MRSA or methicillin-sensitive S. aureus (MSSA). The strains were tested for vancomycin resistance and minimum inhibitory concentration (MIC). The results from the 200 isolates obtained from 2002 to 2009 were then compared to the 340 specimens from 2010 to 2017, when antibiotic stewardship programs rose to the fore at the pediatric hospital.
All samples proved to be vancomycin sensitive. The further good news was there was absolutely no evidence of the worrisome vancomycin MIC creep that has been described at some centers. On the contrary, the MIC was significantly lower in the later samples, at 0.99 mcg/mL, compared with 1.11 mcg/mL in the earlier period. Moreover, the prevalence of heterogeneous glycopeptide-intermediate S. aureus (hGISA) – a phenotype that has been associated with increased rates of treatment failure – improved from 25% in the earlier period to 6% during the later period, reported Dr. Huebner, head of the division of pediatric infectious diseases at the children’s hospital, part of the University of Munich.
Vancomycin MICs weren’t significantly different between the MRSA and MSSA samples.
Based upon this favorable institutional experience, vancomycin remains the first-line treatment for suspected severe gram-positive cocci infections as well as proven infections involving MRSA at Dr. von Hauner Children’s Hospital.
These vancomycin MIC and hGISA data underscore the importance of periodically monitoring local S. aureus antimicrobial susceptibilities, which, as in this case, can differ from the broader global trends. The vancomycin MIC creep issue hadn’t been studied previously in German hospitals, according to Dr. Huebner.
He and his coworkers have published details of the elements of pediatric antibiotic stewardship programs they have found to be most effective (Infection. 2017 Aug;45[4]:493-504) as well as a systematic review of studies on the favorable economic impact of such programs (J Hosp Infect. 2019 Aug;102[4]:369-376).
Dr. Huebner reported having no financial conflicts regarding his study, which was conducted free of commercial support.
LJUBLJANA, SLOVENIA – , Johannes Huebner, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.
He presented a retrospective analysis of S. aureus isolates obtained from 540 patients at the Dr. von Hauner Children’s Hospital, Munich, from 2002 to 2017. All were either newly identified methicillin-resistant S. aureus (MRSA) or specimens from bacteremic children with invasive MRSA or methicillin-sensitive S. aureus (MSSA). The strains were tested for vancomycin resistance and minimum inhibitory concentration (MIC). The results from the 200 isolates obtained from 2002 to 2009 were then compared to the 340 specimens from 2010 to 2017, when antibiotic stewardship programs rose to the fore at the pediatric hospital.
All samples proved to be vancomycin sensitive. The further good news was there was absolutely no evidence of the worrisome vancomycin MIC creep that has been described at some centers. On the contrary, the MIC was significantly lower in the later samples, at 0.99 mcg/mL, compared with 1.11 mcg/mL in the earlier period. Moreover, the prevalence of heterogeneous glycopeptide-intermediate S. aureus (hGISA) – a phenotype that has been associated with increased rates of treatment failure – improved from 25% in the earlier period to 6% during the later period, reported Dr. Huebner, head of the division of pediatric infectious diseases at the children’s hospital, part of the University of Munich.
Vancomycin MICs weren’t significantly different between the MRSA and MSSA samples.
Based upon this favorable institutional experience, vancomycin remains the first-line treatment for suspected severe gram-positive cocci infections as well as proven infections involving MRSA at Dr. von Hauner Children’s Hospital.
These vancomycin MIC and hGISA data underscore the importance of periodically monitoring local S. aureus antimicrobial susceptibilities, which, as in this case, can differ from the broader global trends. The vancomycin MIC creep issue hadn’t been studied previously in German hospitals, according to Dr. Huebner.
He and his coworkers have published details of the elements of pediatric antibiotic stewardship programs they have found to be most effective (Infection. 2017 Aug;45[4]:493-504) as well as a systematic review of studies on the favorable economic impact of such programs (J Hosp Infect. 2019 Aug;102[4]:369-376).
Dr. Huebner reported having no financial conflicts regarding his study, which was conducted free of commercial support.
LJUBLJANA, SLOVENIA – , Johannes Huebner, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.
He presented a retrospective analysis of S. aureus isolates obtained from 540 patients at the Dr. von Hauner Children’s Hospital, Munich, from 2002 to 2017. All were either newly identified methicillin-resistant S. aureus (MRSA) or specimens from bacteremic children with invasive MRSA or methicillin-sensitive S. aureus (MSSA). The strains were tested for vancomycin resistance and minimum inhibitory concentration (MIC). The results from the 200 isolates obtained from 2002 to 2009 were then compared to the 340 specimens from 2010 to 2017, when antibiotic stewardship programs rose to the fore at the pediatric hospital.
All samples proved to be vancomycin sensitive. The further good news was there was absolutely no evidence of the worrisome vancomycin MIC creep that has been described at some centers. On the contrary, the MIC was significantly lower in the later samples, at 0.99 mcg/mL, compared with 1.11 mcg/mL in the earlier period. Moreover, the prevalence of heterogeneous glycopeptide-intermediate S. aureus (hGISA) – a phenotype that has been associated with increased rates of treatment failure – improved from 25% in the earlier period to 6% during the later period, reported Dr. Huebner, head of the division of pediatric infectious diseases at the children’s hospital, part of the University of Munich.
Vancomycin MICs weren’t significantly different between the MRSA and MSSA samples.
Based upon this favorable institutional experience, vancomycin remains the first-line treatment for suspected severe gram-positive cocci infections as well as proven infections involving MRSA at Dr. von Hauner Children’s Hospital.
These vancomycin MIC and hGISA data underscore the importance of periodically monitoring local S. aureus antimicrobial susceptibilities, which, as in this case, can differ from the broader global trends. The vancomycin MIC creep issue hadn’t been studied previously in German hospitals, according to Dr. Huebner.
He and his coworkers have published details of the elements of pediatric antibiotic stewardship programs they have found to be most effective (Infection. 2017 Aug;45[4]:493-504) as well as a systematic review of studies on the favorable economic impact of such programs (J Hosp Infect. 2019 Aug;102[4]:369-376).
Dr. Huebner reported having no financial conflicts regarding his study, which was conducted free of commercial support.
REPORTING FROM ESPID 2019
Key clinical point: Staphylococcus aureus vancomycin MIC creep is reversible through dedicated antimicrobial stewardship.
Major finding: The prevalence of hGISA in MRSA and MSSA specimens improved from 25% during 2002-2009 to 6% during 2010-2017 at one German tertiary children’s hospital.
Study details: This was a retrospective single-center analysis of vancomycin resistance trends over time in 540 S. aureus specimens gathered in 2002-2017.
Disclosures: The presenter reported having no financial conflicts regarding this study, which was conducted free of commercial support.
mRNA technology for respiratory vaccines impresses
LJUBLJANA, SLOVENIA – Encouraging safety and immunogenicity results reported from phase 1 studies of the first mRNA vaccines against the potentially pandemic H10N8 avian influenza and H7N9 influenza viruses suggest a bright future for what appears to be a breakthrough technology in vaccine development.
“We have developed an mRNA platform that has the potential to be quite applicable to the vaccine space. It’s an agile platform with the potential for relatively rapid development of vaccine antigen without the use of dedicated facilities, or growth in eggs, or insects, or mammalian cells,” Lori Panther, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.
“We now have a platform that is relatively plug and play. If one has the mRNA sequence that you’re after to produce the protein that you’re after, it is a relatively repetitive process somewhat irrespective of the goal of the protein that you’re going to manufacture. We’re introducing an mRNA into our cellular machinery – the destination is the cellular ribosome – where it hopefully is able to be translated with fidelity into the target protein. Essentially it’s like the biological equivalent of a software hack for our own cells,” explained Dr. Panther, who is director of clinical development for infectious diseases at Moderna, in Cambridge, Mass.
Indeed, Moderna has numerous ongoing or recently completed phase 1 clinical trials of mRNA vaccines developed to protect against a raft of viral infections: respiratory syncytial virus, cytomegalovirus (NCT03382405), zika, chikungunya (NCT03829384), human metapneumovirus, and parainfluenza virus 3, as well as the aforementioned H10N8 and H7N9 influenza viruses. And an mRNA varicella zoster virus vaccine is in preclinical studies.
The mRNA vaccines closely mimic native viral infections, eliciting both B- and T-cell responses.
Moreover, the company also has ongoing phase 1 studies of mRNA-based cancer vaccines – therapies targeting solid tumors and lymphomas – as well as mRNA-directed increased production of relaxin as a treatment for heart failure and of vascular endothelial growth factor to treat myocardial ischemia.
“For the purposes of my company, the desired protein at this juncture could be an antibody, it could be a tumor antigen, it could be an enzyme that will replace an enzyme that’s lacking in somebody with an inborn error of metabolism. Or it could be a vaccine antigen target,” Dr. Panther said.
In addition to highlighting the results of the two phase 1 proof-of-concept studies of mRNA vaccines targeting the feared H10N8 and H7N9 influenza viruses, she presented interim results of an ongoing 1-year study of an mRNA vaccine that contains two antigens simultaneously targeting human metapneumovirus (hMPV) and parainfluenza virus 3 (PIV3).
“The rationale behind this study is that, taken together, these are two viruses that are responsible for a fair bit of disease burden in terms of lower respiratory tract infections and hospitalizations in children [younger] than 12 months of age, which will be the target population,” the infectious disease specialist noted.
The early positive results of the mRNA influenza vaccine studies were of particular interest to her audience of pediatric infectious disease specialists. Since the first human H7N9 infections were reported in China in 2013, five outbreaks have occurred involving more than 1,500 documented infections, resulting in more than 600 deaths. And ever since the virulent H10N8 avian influenza virus popped up on the radar in 2013, infectious disease physicians the world over have been waiting for the other shoe to drop.
There is obvious appeal to a novel, precise, and rapidly scalable technology such as that promised by intracellular delivery of mRNA in order to ramp up high-volume production of effective vaccines in the face of a looming pandemic threat. Elsewhere at the meeting, it was noted that, during the H1N1 pandemic of 2009, it took 6 months for the first vaccine doses to become available using current antiquated egg-based production methods. Another 2 months elapsed before the necessary millions of doses were produced.
The details of the two phase 1 studies of the mRNA vaccines against H7N9 and H10N8 influenza have recently been published (Vaccine. 2019 May 31;37[25]:3326-34). The vaccines, delivered in the conventional manner via injection into the deltoid muscle, were well tolerated, with the most common adverse events being the familiar ones: injection site pain, erythema, headache, fatigue, and myalgia. The immune response was robust and durable.
In response to an audience question, Dr. Panther said the mRNA vaccines are amenable to development as intranasal formulations.
The ongoing 12-month, phase 1, dose-ranging study of the mRNA hMPV/PIV3 virus vaccine includes 124 healthy adults at three U.S. sites who received two vaccinations on days 1 and 28. One month after a single vaccination, hMPV neutralizing antibody titers were 6.2-6.4 times those in the placebo arm; PIV3 neutralization titers were increased 3.3-fold. The second injection didn’t further boost antibody titers, suggesting that, at least in this study population of preexposed adults, a single vaccination is sufficient.
The use of mRNA technology has been a long time in coming. Dr. Panther explained why: “It’s a big trick to take an mRNA that by its own nature is a pretty fragile molecule and to get it past the degrading enzymes, like RNAses, that are out to chew it up immediately, and then to sneak it across the cellular membrane and into the cytoplasm, all the while avoiding the innate immune responses that exist solely to recognize RNA that looks foreign and chew it up.”
Moderna has accomplished this using a proprietary lipid nanoparticle delivery system.
“Essentially it’s a lipid shield that surrounds the mRNAs and ushers them past those enzymes and past the innate immune response that would otherwise destroy them,” according to Dr. Panther.
She and her colleagues believe they may eventually be able to change the nucleotide sequence of their manufactured mRNAs in order to expand the immunogenicity epitope and achieve a stronger immune response than would result from natural infection.
LJUBLJANA, SLOVENIA – Encouraging safety and immunogenicity results reported from phase 1 studies of the first mRNA vaccines against the potentially pandemic H10N8 avian influenza and H7N9 influenza viruses suggest a bright future for what appears to be a breakthrough technology in vaccine development.
“We have developed an mRNA platform that has the potential to be quite applicable to the vaccine space. It’s an agile platform with the potential for relatively rapid development of vaccine antigen without the use of dedicated facilities, or growth in eggs, or insects, or mammalian cells,” Lori Panther, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.
“We now have a platform that is relatively plug and play. If one has the mRNA sequence that you’re after to produce the protein that you’re after, it is a relatively repetitive process somewhat irrespective of the goal of the protein that you’re going to manufacture. We’re introducing an mRNA into our cellular machinery – the destination is the cellular ribosome – where it hopefully is able to be translated with fidelity into the target protein. Essentially it’s like the biological equivalent of a software hack for our own cells,” explained Dr. Panther, who is director of clinical development for infectious diseases at Moderna, in Cambridge, Mass.
Indeed, Moderna has numerous ongoing or recently completed phase 1 clinical trials of mRNA vaccines developed to protect against a raft of viral infections: respiratory syncytial virus, cytomegalovirus (NCT03382405), zika, chikungunya (NCT03829384), human metapneumovirus, and parainfluenza virus 3, as well as the aforementioned H10N8 and H7N9 influenza viruses. And an mRNA varicella zoster virus vaccine is in preclinical studies.
The mRNA vaccines closely mimic native viral infections, eliciting both B- and T-cell responses.
Moreover, the company also has ongoing phase 1 studies of mRNA-based cancer vaccines – therapies targeting solid tumors and lymphomas – as well as mRNA-directed increased production of relaxin as a treatment for heart failure and of vascular endothelial growth factor to treat myocardial ischemia.
“For the purposes of my company, the desired protein at this juncture could be an antibody, it could be a tumor antigen, it could be an enzyme that will replace an enzyme that’s lacking in somebody with an inborn error of metabolism. Or it could be a vaccine antigen target,” Dr. Panther said.
In addition to highlighting the results of the two phase 1 proof-of-concept studies of mRNA vaccines targeting the feared H10N8 and H7N9 influenza viruses, she presented interim results of an ongoing 1-year study of an mRNA vaccine that contains two antigens simultaneously targeting human metapneumovirus (hMPV) and parainfluenza virus 3 (PIV3).
“The rationale behind this study is that, taken together, these are two viruses that are responsible for a fair bit of disease burden in terms of lower respiratory tract infections and hospitalizations in children [younger] than 12 months of age, which will be the target population,” the infectious disease specialist noted.
The early positive results of the mRNA influenza vaccine studies were of particular interest to her audience of pediatric infectious disease specialists. Since the first human H7N9 infections were reported in China in 2013, five outbreaks have occurred involving more than 1,500 documented infections, resulting in more than 600 deaths. And ever since the virulent H10N8 avian influenza virus popped up on the radar in 2013, infectious disease physicians the world over have been waiting for the other shoe to drop.
There is obvious appeal to a novel, precise, and rapidly scalable technology such as that promised by intracellular delivery of mRNA in order to ramp up high-volume production of effective vaccines in the face of a looming pandemic threat. Elsewhere at the meeting, it was noted that, during the H1N1 pandemic of 2009, it took 6 months for the first vaccine doses to become available using current antiquated egg-based production methods. Another 2 months elapsed before the necessary millions of doses were produced.
The details of the two phase 1 studies of the mRNA vaccines against H7N9 and H10N8 influenza have recently been published (Vaccine. 2019 May 31;37[25]:3326-34). The vaccines, delivered in the conventional manner via injection into the deltoid muscle, were well tolerated, with the most common adverse events being the familiar ones: injection site pain, erythema, headache, fatigue, and myalgia. The immune response was robust and durable.
In response to an audience question, Dr. Panther said the mRNA vaccines are amenable to development as intranasal formulations.
The ongoing 12-month, phase 1, dose-ranging study of the mRNA hMPV/PIV3 virus vaccine includes 124 healthy adults at three U.S. sites who received two vaccinations on days 1 and 28. One month after a single vaccination, hMPV neutralizing antibody titers were 6.2-6.4 times those in the placebo arm; PIV3 neutralization titers were increased 3.3-fold. The second injection didn’t further boost antibody titers, suggesting that, at least in this study population of preexposed adults, a single vaccination is sufficient.
The use of mRNA technology has been a long time in coming. Dr. Panther explained why: “It’s a big trick to take an mRNA that by its own nature is a pretty fragile molecule and to get it past the degrading enzymes, like RNAses, that are out to chew it up immediately, and then to sneak it across the cellular membrane and into the cytoplasm, all the while avoiding the innate immune responses that exist solely to recognize RNA that looks foreign and chew it up.”
Moderna has accomplished this using a proprietary lipid nanoparticle delivery system.
“Essentially it’s a lipid shield that surrounds the mRNAs and ushers them past those enzymes and past the innate immune response that would otherwise destroy them,” according to Dr. Panther.
She and her colleagues believe they may eventually be able to change the nucleotide sequence of their manufactured mRNAs in order to expand the immunogenicity epitope and achieve a stronger immune response than would result from natural infection.
LJUBLJANA, SLOVENIA – Encouraging safety and immunogenicity results reported from phase 1 studies of the first mRNA vaccines against the potentially pandemic H10N8 avian influenza and H7N9 influenza viruses suggest a bright future for what appears to be a breakthrough technology in vaccine development.
“We have developed an mRNA platform that has the potential to be quite applicable to the vaccine space. It’s an agile platform with the potential for relatively rapid development of vaccine antigen without the use of dedicated facilities, or growth in eggs, or insects, or mammalian cells,” Lori Panther, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.
“We now have a platform that is relatively plug and play. If one has the mRNA sequence that you’re after to produce the protein that you’re after, it is a relatively repetitive process somewhat irrespective of the goal of the protein that you’re going to manufacture. We’re introducing an mRNA into our cellular machinery – the destination is the cellular ribosome – where it hopefully is able to be translated with fidelity into the target protein. Essentially it’s like the biological equivalent of a software hack for our own cells,” explained Dr. Panther, who is director of clinical development for infectious diseases at Moderna, in Cambridge, Mass.
Indeed, Moderna has numerous ongoing or recently completed phase 1 clinical trials of mRNA vaccines developed to protect against a raft of viral infections: respiratory syncytial virus, cytomegalovirus (NCT03382405), zika, chikungunya (NCT03829384), human metapneumovirus, and parainfluenza virus 3, as well as the aforementioned H10N8 and H7N9 influenza viruses. And an mRNA varicella zoster virus vaccine is in preclinical studies.
The mRNA vaccines closely mimic native viral infections, eliciting both B- and T-cell responses.
Moreover, the company also has ongoing phase 1 studies of mRNA-based cancer vaccines – therapies targeting solid tumors and lymphomas – as well as mRNA-directed increased production of relaxin as a treatment for heart failure and of vascular endothelial growth factor to treat myocardial ischemia.
“For the purposes of my company, the desired protein at this juncture could be an antibody, it could be a tumor antigen, it could be an enzyme that will replace an enzyme that’s lacking in somebody with an inborn error of metabolism. Or it could be a vaccine antigen target,” Dr. Panther said.
In addition to highlighting the results of the two phase 1 proof-of-concept studies of mRNA vaccines targeting the feared H10N8 and H7N9 influenza viruses, she presented interim results of an ongoing 1-year study of an mRNA vaccine that contains two antigens simultaneously targeting human metapneumovirus (hMPV) and parainfluenza virus 3 (PIV3).
“The rationale behind this study is that, taken together, these are two viruses that are responsible for a fair bit of disease burden in terms of lower respiratory tract infections and hospitalizations in children [younger] than 12 months of age, which will be the target population,” the infectious disease specialist noted.
The early positive results of the mRNA influenza vaccine studies were of particular interest to her audience of pediatric infectious disease specialists. Since the first human H7N9 infections were reported in China in 2013, five outbreaks have occurred involving more than 1,500 documented infections, resulting in more than 600 deaths. And ever since the virulent H10N8 avian influenza virus popped up on the radar in 2013, infectious disease physicians the world over have been waiting for the other shoe to drop.
There is obvious appeal to a novel, precise, and rapidly scalable technology such as that promised by intracellular delivery of mRNA in order to ramp up high-volume production of effective vaccines in the face of a looming pandemic threat. Elsewhere at the meeting, it was noted that, during the H1N1 pandemic of 2009, it took 6 months for the first vaccine doses to become available using current antiquated egg-based production methods. Another 2 months elapsed before the necessary millions of doses were produced.
The details of the two phase 1 studies of the mRNA vaccines against H7N9 and H10N8 influenza have recently been published (Vaccine. 2019 May 31;37[25]:3326-34). The vaccines, delivered in the conventional manner via injection into the deltoid muscle, were well tolerated, with the most common adverse events being the familiar ones: injection site pain, erythema, headache, fatigue, and myalgia. The immune response was robust and durable.
In response to an audience question, Dr. Panther said the mRNA vaccines are amenable to development as intranasal formulations.
The ongoing 12-month, phase 1, dose-ranging study of the mRNA hMPV/PIV3 virus vaccine includes 124 healthy adults at three U.S. sites who received two vaccinations on days 1 and 28. One month after a single vaccination, hMPV neutralizing antibody titers were 6.2-6.4 times those in the placebo arm; PIV3 neutralization titers were increased 3.3-fold. The second injection didn’t further boost antibody titers, suggesting that, at least in this study population of preexposed adults, a single vaccination is sufficient.
The use of mRNA technology has been a long time in coming. Dr. Panther explained why: “It’s a big trick to take an mRNA that by its own nature is a pretty fragile molecule and to get it past the degrading enzymes, like RNAses, that are out to chew it up immediately, and then to sneak it across the cellular membrane and into the cytoplasm, all the while avoiding the innate immune responses that exist solely to recognize RNA that looks foreign and chew it up.”
Moderna has accomplished this using a proprietary lipid nanoparticle delivery system.
“Essentially it’s a lipid shield that surrounds the mRNAs and ushers them past those enzymes and past the innate immune response that would otherwise destroy them,” according to Dr. Panther.
She and her colleagues believe they may eventually be able to change the nucleotide sequence of their manufactured mRNAs in order to expand the immunogenicity epitope and achieve a stronger immune response than would result from natural infection.
REPORTING FROM ESPID 2019
HCV-infected people who inject drugs also have substantial alcohol use
Curing hepatitis C virus (HCV) infection without addressing the high rate of alcohol use disorder in many patients may undermine the benefits of treatment to long-term liver health, according to the results of a large cohort study.
Because excess alcohol use is known to accelerate liver disease progression, researchers Risha Irvin, MD, and her colleagues from Johns Hopkins University, Baltimore, examined the prevalence of alcohol use in HCV-infected people who inject drugs (PWID). Their study examined the prevalence and associated correlates of alcohol use (Addictive Behaviors 2019;96:56-61).
They followed a large cohort of 1,623 HCV-antibody positive PWID from 2005 to 2013 from the AIDS Linked to the Intravenous Experience (ALIVE) study. They characterized alcohol use with the Alcohol Use Disorders Identification Test (AUDIT-C) questionnaire. Multivariable logistic regression with generalized estimated equations was used to examine sociodemographic, clinical, and substance use correlates of alcohol use.
At baseline, the median age was 47 years, 67% were men, 81% were black, and 34% were HIV positive. The majority (60%) reported injection drug use in the prior 6 months, while 46% reported noninjection cocaine or heroin, 31% reported street-acquired prescription drugs, and 22% reported marijuana use in the same time period. According to the AUDIT-C results, 41% of the patients reported no alcohol use, 21% reported moderate alcohol use, and 38% reported heavy alcohol use at their baseline visit.
The factors that were significantly associated with heavy alcohol use included male sex, black race, income of $5,000 or less, a Center for Epidemiologic Studies Depression Scale (range 0-60) score of 23 or greater, being homeless, being incarcerated, marijuana use, use of street-acquired prescription drugs, noninjection cocaine/heroin, injection drug use, and cigarette smoking. In a model that included the composite summary variable for substance use intensity, one drug type (adjusted odds ratio, 1.92), two drug types (AOR, 2.93), and three drug types (AOR, 3.65) were significantly associated with heavy alcohol use.
“While clinicians are undoubtedly concerned about any level of alcohol use in the setting of HCV infection due to the acceleration of liver fibrosis, there is particular concern for individuals with heavy alcohol use and their increased risk for cirrhosis and liver failure even after HCV cure. Without intervention, alcohol use will persist after HCV is cured with the potential to undermine the benefit of HCV cure. Therefore, our data point to the need to invest in and develop programs that effectively address alcohol use and co-occurring substance use in this population of PWID with HCV,” the researchers concluded.
The study was supported by the U.S. National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, and the National Institute on Alcohol Abuse and Alcoholism. The authors declared that they had no conflicts.
SOURCE: Irvin R et al. Addictive Behaviors. 2019;96:56-61.
Curing hepatitis C virus (HCV) infection without addressing the high rate of alcohol use disorder in many patients may undermine the benefits of treatment to long-term liver health, according to the results of a large cohort study.
Because excess alcohol use is known to accelerate liver disease progression, researchers Risha Irvin, MD, and her colleagues from Johns Hopkins University, Baltimore, examined the prevalence of alcohol use in HCV-infected people who inject drugs (PWID). Their study examined the prevalence and associated correlates of alcohol use (Addictive Behaviors 2019;96:56-61).
They followed a large cohort of 1,623 HCV-antibody positive PWID from 2005 to 2013 from the AIDS Linked to the Intravenous Experience (ALIVE) study. They characterized alcohol use with the Alcohol Use Disorders Identification Test (AUDIT-C) questionnaire. Multivariable logistic regression with generalized estimated equations was used to examine sociodemographic, clinical, and substance use correlates of alcohol use.
At baseline, the median age was 47 years, 67% were men, 81% were black, and 34% were HIV positive. The majority (60%) reported injection drug use in the prior 6 months, while 46% reported noninjection cocaine or heroin, 31% reported street-acquired prescription drugs, and 22% reported marijuana use in the same time period. According to the AUDIT-C results, 41% of the patients reported no alcohol use, 21% reported moderate alcohol use, and 38% reported heavy alcohol use at their baseline visit.
The factors that were significantly associated with heavy alcohol use included male sex, black race, income of $5,000 or less, a Center for Epidemiologic Studies Depression Scale (range 0-60) score of 23 or greater, being homeless, being incarcerated, marijuana use, use of street-acquired prescription drugs, noninjection cocaine/heroin, injection drug use, and cigarette smoking. In a model that included the composite summary variable for substance use intensity, one drug type (adjusted odds ratio, 1.92), two drug types (AOR, 2.93), and three drug types (AOR, 3.65) were significantly associated with heavy alcohol use.
“While clinicians are undoubtedly concerned about any level of alcohol use in the setting of HCV infection due to the acceleration of liver fibrosis, there is particular concern for individuals with heavy alcohol use and their increased risk for cirrhosis and liver failure even after HCV cure. Without intervention, alcohol use will persist after HCV is cured with the potential to undermine the benefit of HCV cure. Therefore, our data point to the need to invest in and develop programs that effectively address alcohol use and co-occurring substance use in this population of PWID with HCV,” the researchers concluded.
The study was supported by the U.S. National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, and the National Institute on Alcohol Abuse and Alcoholism. The authors declared that they had no conflicts.
SOURCE: Irvin R et al. Addictive Behaviors. 2019;96:56-61.
Curing hepatitis C virus (HCV) infection without addressing the high rate of alcohol use disorder in many patients may undermine the benefits of treatment to long-term liver health, according to the results of a large cohort study.
Because excess alcohol use is known to accelerate liver disease progression, researchers Risha Irvin, MD, and her colleagues from Johns Hopkins University, Baltimore, examined the prevalence of alcohol use in HCV-infected people who inject drugs (PWID). Their study examined the prevalence and associated correlates of alcohol use (Addictive Behaviors 2019;96:56-61).
They followed a large cohort of 1,623 HCV-antibody positive PWID from 2005 to 2013 from the AIDS Linked to the Intravenous Experience (ALIVE) study. They characterized alcohol use with the Alcohol Use Disorders Identification Test (AUDIT-C) questionnaire. Multivariable logistic regression with generalized estimated equations was used to examine sociodemographic, clinical, and substance use correlates of alcohol use.
At baseline, the median age was 47 years, 67% were men, 81% were black, and 34% were HIV positive. The majority (60%) reported injection drug use in the prior 6 months, while 46% reported noninjection cocaine or heroin, 31% reported street-acquired prescription drugs, and 22% reported marijuana use in the same time period. According to the AUDIT-C results, 41% of the patients reported no alcohol use, 21% reported moderate alcohol use, and 38% reported heavy alcohol use at their baseline visit.
The factors that were significantly associated with heavy alcohol use included male sex, black race, income of $5,000 or less, a Center for Epidemiologic Studies Depression Scale (range 0-60) score of 23 or greater, being homeless, being incarcerated, marijuana use, use of street-acquired prescription drugs, noninjection cocaine/heroin, injection drug use, and cigarette smoking. In a model that included the composite summary variable for substance use intensity, one drug type (adjusted odds ratio, 1.92), two drug types (AOR, 2.93), and three drug types (AOR, 3.65) were significantly associated with heavy alcohol use.
“While clinicians are undoubtedly concerned about any level of alcohol use in the setting of HCV infection due to the acceleration of liver fibrosis, there is particular concern for individuals with heavy alcohol use and their increased risk for cirrhosis and liver failure even after HCV cure. Without intervention, alcohol use will persist after HCV is cured with the potential to undermine the benefit of HCV cure. Therefore, our data point to the need to invest in and develop programs that effectively address alcohol use and co-occurring substance use in this population of PWID with HCV,” the researchers concluded.
The study was supported by the U.S. National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, and the National Institute on Alcohol Abuse and Alcoholism. The authors declared that they had no conflicts.
SOURCE: Irvin R et al. Addictive Behaviors. 2019;96:56-61.
FROM ADDICTIVE BEHAVIORS
Too many blood cultures ordered for pediatric SSTIs
SEATTLE – Blood cultures were ordered for over half of pediatric skin infection encounters across 38 children’s hospitals, with rates varying from about 20% to 80% between hospitals, according to a review of almost 50,000 encounters in the Pediatric Health Information System database.
It was a surprising finding, because current guidelines from the Infectious Diseases Society of America do not recommend blood cultures as part of the routine evaluation of uncomplicated pediatric skin and soft-tissue infections (SSTIs), meaning infections in children who are otherwise healthy without neutropenia or other complicating factors.
Just 0.6% of the cultures were positive in the review, and it’s likely some of those were caused by contamination. After adjustment for demographics, complex chronic conditions, and severity of illness, culture draws were associated with a 20% increase in hospital length of stay (LOS), hospital costs, and 30-day readmission rates.
“Our data provide more evidence that [routine] blood cultures for children with SSTI represents low-value practice and should be avoided,” said lead investigator John Stephens, MD, a pediatrics professor and hospitalist at the University of North Carolina at Chapel Hill.
Dr. Stephens became curious about how common the practice was across hospitals after he and a friend penned an article about the issue for the Journal of Hospital Medicine’s “Things We Do for No Reason” series. The single-center studies they reviewed showed similarly high rates of both testing and negative cultures (J Hosp Med. 2018 Jul;13[7]:496-9).
Dr. Stephens and his team queried the Pediatric Health Information System database for encounters in children aged 2 months to 18 years with the diagnostic code 383, “cellulitis and other skin infections,” from 2012 to 2017, during which time “there really wasn’t a change” in IDSA guidance, he noted. Transfers, encounters with ICU care, and immunocompromised children were excluded.
Hospital admissions were included in the review if they had an additional code for erysipelas, cellulitis, impetigo, or other localized skin infection. The rate of positive cultures was inferred from subsequent codes for bacteremia or septicemia.
Across 49,291 encounters, the median rate of blood culture for skin infection was 51.6%, with tremendous variation between hospitals. With blood cultures, the hospital LOS was about 1.9 days, the hospital cost was $4,030, and the 30-day readmission rate was 1.3%. Without cultures, LOS was 1.6 days, the cost was $3,291, and the readmission rate was 1%.
Although infrequent, it’s likely that positive cultures triggered additional work-up, time in the hospital, and other measures, which might help account for the increase in LOS and costs.
As for why blood testing was so common, especially in some hospitals, “I think it’s just institutional culture. No amount of clinical variation in patient population could explain” a 20%-80% “variation across hospitals. It’s really just ingrained habits,” Dr. Stephens said at Pediatric Hospital Medicine.
“The rate of positive blood culture was really low, and the association was for higher cost and utilization. I think this really reinforces the IDSA guidelines. We need to focus on quality improvement efforts to do this better,” he said, noting that he hopes to do so at his own institution.
“I’d also like to know more on the positives. In the single center studies, we know more than half of them are contaminants. Often, there’s more contamination than true positives,” he said at the meeting sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
Instead of routine blood culture, Dr. Stephens recommended in his article to send pus for a Gram stain and culture and sensitivity, while noting that blood cultures remain reasonable for complicated infections, immunocompromised patients, and neonates.
There was no external funding, and Dr. Stephens didn’t report any disclosures.
SEATTLE – Blood cultures were ordered for over half of pediatric skin infection encounters across 38 children’s hospitals, with rates varying from about 20% to 80% between hospitals, according to a review of almost 50,000 encounters in the Pediatric Health Information System database.
It was a surprising finding, because current guidelines from the Infectious Diseases Society of America do not recommend blood cultures as part of the routine evaluation of uncomplicated pediatric skin and soft-tissue infections (SSTIs), meaning infections in children who are otherwise healthy without neutropenia or other complicating factors.
Just 0.6% of the cultures were positive in the review, and it’s likely some of those were caused by contamination. After adjustment for demographics, complex chronic conditions, and severity of illness, culture draws were associated with a 20% increase in hospital length of stay (LOS), hospital costs, and 30-day readmission rates.
“Our data provide more evidence that [routine] blood cultures for children with SSTI represents low-value practice and should be avoided,” said lead investigator John Stephens, MD, a pediatrics professor and hospitalist at the University of North Carolina at Chapel Hill.
Dr. Stephens became curious about how common the practice was across hospitals after he and a friend penned an article about the issue for the Journal of Hospital Medicine’s “Things We Do for No Reason” series. The single-center studies they reviewed showed similarly high rates of both testing and negative cultures (J Hosp Med. 2018 Jul;13[7]:496-9).
Dr. Stephens and his team queried the Pediatric Health Information System database for encounters in children aged 2 months to 18 years with the diagnostic code 383, “cellulitis and other skin infections,” from 2012 to 2017, during which time “there really wasn’t a change” in IDSA guidance, he noted. Transfers, encounters with ICU care, and immunocompromised children were excluded.
Hospital admissions were included in the review if they had an additional code for erysipelas, cellulitis, impetigo, or other localized skin infection. The rate of positive cultures was inferred from subsequent codes for bacteremia or septicemia.
Across 49,291 encounters, the median rate of blood culture for skin infection was 51.6%, with tremendous variation between hospitals. With blood cultures, the hospital LOS was about 1.9 days, the hospital cost was $4,030, and the 30-day readmission rate was 1.3%. Without cultures, LOS was 1.6 days, the cost was $3,291, and the readmission rate was 1%.
Although infrequent, it’s likely that positive cultures triggered additional work-up, time in the hospital, and other measures, which might help account for the increase in LOS and costs.
As for why blood testing was so common, especially in some hospitals, “I think it’s just institutional culture. No amount of clinical variation in patient population could explain” a 20%-80% “variation across hospitals. It’s really just ingrained habits,” Dr. Stephens said at Pediatric Hospital Medicine.
“The rate of positive blood culture was really low, and the association was for higher cost and utilization. I think this really reinforces the IDSA guidelines. We need to focus on quality improvement efforts to do this better,” he said, noting that he hopes to do so at his own institution.
“I’d also like to know more on the positives. In the single center studies, we know more than half of them are contaminants. Often, there’s more contamination than true positives,” he said at the meeting sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
Instead of routine blood culture, Dr. Stephens recommended in his article to send pus for a Gram stain and culture and sensitivity, while noting that blood cultures remain reasonable for complicated infections, immunocompromised patients, and neonates.
There was no external funding, and Dr. Stephens didn’t report any disclosures.
SEATTLE – Blood cultures were ordered for over half of pediatric skin infection encounters across 38 children’s hospitals, with rates varying from about 20% to 80% between hospitals, according to a review of almost 50,000 encounters in the Pediatric Health Information System database.
It was a surprising finding, because current guidelines from the Infectious Diseases Society of America do not recommend blood cultures as part of the routine evaluation of uncomplicated pediatric skin and soft-tissue infections (SSTIs), meaning infections in children who are otherwise healthy without neutropenia or other complicating factors.
Just 0.6% of the cultures were positive in the review, and it’s likely some of those were caused by contamination. After adjustment for demographics, complex chronic conditions, and severity of illness, culture draws were associated with a 20% increase in hospital length of stay (LOS), hospital costs, and 30-day readmission rates.
“Our data provide more evidence that [routine] blood cultures for children with SSTI represents low-value practice and should be avoided,” said lead investigator John Stephens, MD, a pediatrics professor and hospitalist at the University of North Carolina at Chapel Hill.
Dr. Stephens became curious about how common the practice was across hospitals after he and a friend penned an article about the issue for the Journal of Hospital Medicine’s “Things We Do for No Reason” series. The single-center studies they reviewed showed similarly high rates of both testing and negative cultures (J Hosp Med. 2018 Jul;13[7]:496-9).
Dr. Stephens and his team queried the Pediatric Health Information System database for encounters in children aged 2 months to 18 years with the diagnostic code 383, “cellulitis and other skin infections,” from 2012 to 2017, during which time “there really wasn’t a change” in IDSA guidance, he noted. Transfers, encounters with ICU care, and immunocompromised children were excluded.
Hospital admissions were included in the review if they had an additional code for erysipelas, cellulitis, impetigo, or other localized skin infection. The rate of positive cultures was inferred from subsequent codes for bacteremia or septicemia.
Across 49,291 encounters, the median rate of blood culture for skin infection was 51.6%, with tremendous variation between hospitals. With blood cultures, the hospital LOS was about 1.9 days, the hospital cost was $4,030, and the 30-day readmission rate was 1.3%. Without cultures, LOS was 1.6 days, the cost was $3,291, and the readmission rate was 1%.
Although infrequent, it’s likely that positive cultures triggered additional work-up, time in the hospital, and other measures, which might help account for the increase in LOS and costs.
As for why blood testing was so common, especially in some hospitals, “I think it’s just institutional culture. No amount of clinical variation in patient population could explain” a 20%-80% “variation across hospitals. It’s really just ingrained habits,” Dr. Stephens said at Pediatric Hospital Medicine.
“The rate of positive blood culture was really low, and the association was for higher cost and utilization. I think this really reinforces the IDSA guidelines. We need to focus on quality improvement efforts to do this better,” he said, noting that he hopes to do so at his own institution.
“I’d also like to know more on the positives. In the single center studies, we know more than half of them are contaminants. Often, there’s more contamination than true positives,” he said at the meeting sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
Instead of routine blood culture, Dr. Stephens recommended in his article to send pus for a Gram stain and culture and sensitivity, while noting that blood cultures remain reasonable for complicated infections, immunocompromised patients, and neonates.
There was no external funding, and Dr. Stephens didn’t report any disclosures.
REPORTING FROM PHM 2019
DRC Ebola epidemic continues unabated despite international response
, “currently the outbreak continues at the same pace, so we don’t see evidence of slowing,” according to Henry Walke, MD, director of the Division of Preparedness and Emerging Infections and Incident Manager, 2018 CDC Ebola Response, Centers for Disease Control and Prevention.
He added that new cases of Ebola have been seen in Goma, which is outside the initial outbreak area. Goma is the largest city in the eastern part of the DRC and a major trading port.
Dr. Walke made his remarks in a telephone media briefing Aug. 1 by the U. S. Department of Health and Human Services outlining the current state of the U.S. response to the outbreak.
He described the efforts of the CDC to provide support to the DRC both from Atlanta and in the field. These efforts included support for vaccination activities in DRC’s North Kivu and Ituri provinces for the population and for at-risk health-care workers in the DRC and neighboring countries. In addition, the United States is involved in the testing of experimental therapeutics and vaccines in the DRC in an effort to aid in this and future outbreaks.
“There are no cases of Ebola in the United States,” said Dr. Walke, and the CDC believes the risk to the United States from the outbreak is low. He cited the limited number of travelers from DRC. “There [are] about 16,000 from the DRC to the U.S. on an annual basis, and only about 100 from Goma itself. There aren’t direct flights and we have at the Goma airport both entry and exit screening.”
According to a World Health Organization report, this Ebola outbreak is the second deadliest on record and has killed 1,750 people out of around 2,518 confirmed cases as of July 23.
Efforts to control the epidemic are severely hampered by civil unrest in the area, public mistrust of the government and health care workers, and a comparative lack of international aid compared to previous Ebola outbreaks.
, “currently the outbreak continues at the same pace, so we don’t see evidence of slowing,” according to Henry Walke, MD, director of the Division of Preparedness and Emerging Infections and Incident Manager, 2018 CDC Ebola Response, Centers for Disease Control and Prevention.
He added that new cases of Ebola have been seen in Goma, which is outside the initial outbreak area. Goma is the largest city in the eastern part of the DRC and a major trading port.
Dr. Walke made his remarks in a telephone media briefing Aug. 1 by the U. S. Department of Health and Human Services outlining the current state of the U.S. response to the outbreak.
He described the efforts of the CDC to provide support to the DRC both from Atlanta and in the field. These efforts included support for vaccination activities in DRC’s North Kivu and Ituri provinces for the population and for at-risk health-care workers in the DRC and neighboring countries. In addition, the United States is involved in the testing of experimental therapeutics and vaccines in the DRC in an effort to aid in this and future outbreaks.
“There are no cases of Ebola in the United States,” said Dr. Walke, and the CDC believes the risk to the United States from the outbreak is low. He cited the limited number of travelers from DRC. “There [are] about 16,000 from the DRC to the U.S. on an annual basis, and only about 100 from Goma itself. There aren’t direct flights and we have at the Goma airport both entry and exit screening.”
According to a World Health Organization report, this Ebola outbreak is the second deadliest on record and has killed 1,750 people out of around 2,518 confirmed cases as of July 23.
Efforts to control the epidemic are severely hampered by civil unrest in the area, public mistrust of the government and health care workers, and a comparative lack of international aid compared to previous Ebola outbreaks.
, “currently the outbreak continues at the same pace, so we don’t see evidence of slowing,” according to Henry Walke, MD, director of the Division of Preparedness and Emerging Infections and Incident Manager, 2018 CDC Ebola Response, Centers for Disease Control and Prevention.
He added that new cases of Ebola have been seen in Goma, which is outside the initial outbreak area. Goma is the largest city in the eastern part of the DRC and a major trading port.
Dr. Walke made his remarks in a telephone media briefing Aug. 1 by the U. S. Department of Health and Human Services outlining the current state of the U.S. response to the outbreak.
He described the efforts of the CDC to provide support to the DRC both from Atlanta and in the field. These efforts included support for vaccination activities in DRC’s North Kivu and Ituri provinces for the population and for at-risk health-care workers in the DRC and neighboring countries. In addition, the United States is involved in the testing of experimental therapeutics and vaccines in the DRC in an effort to aid in this and future outbreaks.
“There are no cases of Ebola in the United States,” said Dr. Walke, and the CDC believes the risk to the United States from the outbreak is low. He cited the limited number of travelers from DRC. “There [are] about 16,000 from the DRC to the U.S. on an annual basis, and only about 100 from Goma itself. There aren’t direct flights and we have at the Goma airport both entry and exit screening.”
According to a World Health Organization report, this Ebola outbreak is the second deadliest on record and has killed 1,750 people out of around 2,518 confirmed cases as of July 23.
Efforts to control the epidemic are severely hampered by civil unrest in the area, public mistrust of the government and health care workers, and a comparative lack of international aid compared to previous Ebola outbreaks.
REPORTING FROM A MEDIA BRIEFING BY HHS
Decreasing Treatment of Asymptomatic Bacteriuria: An Interprofessional Approach to Antibiotic Stewardship
From the Mayo Clinic, Rochester, MN.
Abstract
- Objective: Asymptomatic bacteriuria (ASB) denotes asymptomatic carriage of bacteria within the urinary tract and does not require treatment in most patient populations. Unnecessary antimicrobial treatment has several consequences, including promotion of antimicrobial resistance, potential for medication adverse effects, and risk for Clostridiodes difficile infection. The aim of this quality improvement effort was to decrease both the unnecessary ordering of urine culture studies and unnecessary treatment of ASB.
- Methods: This is a single-center study of patients who received care on 3 internal medicine units at a large, academic medical center. We sought to determine the impact of information technology and educational interventions to decrease both inappropriate urine culture ordering and treatment of ASB. Data from included patients were collected over 3 1-month time periods: baseline, post-information technology intervention, and post-educational intervention.
- Results: There was a reduction in the percentage of patients who received antibiotics for ASB in the post-education intervention period as compared to baseline (35% vs 42%). The proportion of total urine cultures ordered by internal medicine clinicians did not change after an information technology intervention to redesign the computerized physician order entry screen for urine cultures.
- Conclusion: Educational interventions are effective ways to reduce rates of inappropriate treatment of ASB in patients admitted to internal medicine services.
Keywords: asymptomatic bacteriuria, UTI, information technology, education, quality.
Asymptomatic bacteriuria (ASB) is a common condition in which bacteria are recovered from a urine culture (UC) in patients without symptoms suggestive of urinary tract infection (UTI), with no pathologic consequences to most patients who are not treated.1,2 Patients with ASB do not exhibit symptoms of a UTI such as dysuria, increased frequency of urination, increased urgency, suprapubic tenderness, or costovertebral pain. Treatment with antibiotics is not indicated for most patients with ASB.1,3 According to the Infectious Diseases Society of America (IDSA), screening for bacteriuria and treatment for positive results is only indicated during pregnancy and prior to urologic procedures with anticipated breach of the mucosal lining.1
An estimated 20% to 52% of patients in hospital settings receive inappropriate treatment with antibiotics for ASB.4 Unnecessary prescribing of antibiotics has several negative consequences, including increased rates of antibiotic resistance, Clostridioides difficile infection, and medication adverse events, as well as increased health care costs.2,5 Antimicrobial stewardship programs to improve judicious use of antimicrobials are paramount to reducing these consequences, and their importance is heightened with recent requirements for antimicrobial stewardship put forth by The Joint Commission and the Centers for Medicare & Medicaid Services.6,7
A previous review of UC and antimicrobial use in patients for purposes of quality improvement at our institution over a 2-month period showed that of 59 patients with positive UCs, 47 patients (80%) did not have documented symptoms of a UTI. Of these 47 patients with ASB, 29 (61.7%) received antimicrobial treatment unnecessarily (unpublished data). We convened a group of clinicians and nonclinicians representing the areas of infectious disease, pharmacy, microbiology, statistics, and hospital internal medicine (IM) to examine the unnecessary treatment of ASB in our institution. Our objective was to address 2 antimicrobial stewardship issues: inappropriate UC ordering and unnecessary use of antibiotics to treat ASB. Our aim was to reduce the inappropriate ordering of UCs and to reduce treatment of ASB.
Methods
Setting
The study was conducted on 3 IM nursing units with a total of 83 beds at a large tertiary care academic medical center in the midwestern United States, and was approved by the organization’s Institutional Review Board.
Participants
We included all non-pregnant patients aged 18 years or older who received care from an IM primary service. These patients were admitted directly to an IM team through the emergency department (ED) or transferred to an IM team after an initial stay in the intensive care unit.
Data Source
Microbiology laboratory reports generated from the electronic health record were used to identify all patients with a collected UC sample who received care from an IM service prior to discharge. Urine samples were collected by midstream catch or catheterization. Data on urine Gram stain and urine dipstick were not included. Henceforth, the phrase “urine culture order” indicates that a UC was both ordered and performed. Data reports were generated for the month of August 2016 to determine the baseline number of UCs ordered. Charts of patients with positive UCs were reviewed to determine if antibiotics were started for the positive UC and whether the patient had signs or symptoms consistent with a UTI. If antibiotics were started in the absence of signs or symptoms to support a UTI, the patient was determined to have been unnecessarily treated for ASB. Reports were then generated for the month after each intervention was implemented, with the same chart review undertaken for positive UCs. Bacteriuria was defined in our study as the presence of microbial growth greater than 10,000 CFU/mL in UC.
Interventions
Initial analysis by our study group determined that lack of electronic clinical decision support (CDS) at the point of care and provider knowledge gaps in interpreting positive UCs were the 2 main contributors to unnecessary UC orders and unnecessary treatment of positive UCs, respectively. We reviewed the work of other groups who reported interventions to decrease treatment of ASB, ranging from educational presentations to pocket cards and treatment algorithms.8-13 We hypothesized that there would be a decrease in UC orders with CDS embedded in the computerized order entry screen, and that we would decrease unnecessary treatment of positive UCs by educating clinicians on indications for appropriate antibiotic prescribing in the setting of a positive UC.
Information technology intervention. The first intervention implemented involved redesign of the UC ordering screen in the computerized physician order entry (CPOE) system. This intervention went live hospital-wide, including the IM floors, intensive care units, and all other areas except the ED, on February 1, 2017 (Figure 1). The ordering screen required the prescriber to select from a list of appropriate indications for ordering a UC, including urine frequency, urgency, or dysuria; unexplained suprapubic or flank pain; fever in patients without another recognized cause; screening obtained prior to urologic procedure; or screening during pregnancy. An additional message advised prescribers to avoid ordering the culture if the patient had malodorous or cloudy urine, pyuria without urinary symptoms, or had an alternative cause of fever. Before we implemented the information technology (IT) intervention, there had been no specific point-of-care guidance on UC ordering.
Educational intervention. The second intervention, driven by clinical pharmacists, involved active and passive education of prescribers specifically designed to address unnecessary treatment of ASB. The IT intervention with CDS for UC ordering remained live. Presentations designed by the study group summarizing the appropriate indications for ordering a UC, distinguishing ASB from UTI, and discouraging treatment of ASB were delivered via a variety of routes by clinical pharmacists to nurses, nurse practitioners, physician assistants, pharmacists, medical residents, and staff physicians providing care to patients on the 3 IM units over a 1-month period in March 2017. The presentations contained the same basic content, but the information was delivered to target each specific audience group.
Medical residents received a 10-minute live presentation during a conference. Nurse practitioners, physician assistants, and staff physicians received a presentation via email, and highlights of the presentation were delivered by clinical pharmacists at their respective monthly group meetings. A handout was presented to nursing staff at nursing huddles, and presentation slides were distributed by email. Educational posters were posted in the medical resident workrooms, nursing breakrooms, and staff bathrooms on the units.
Outcome Measurements
The endpoints of interest were the percentage of patients with positive UCs unnecessarily treated for ASB before and after each intervention and the number of UCs ordered at baseline and after implementation of each intervention. Counterbalance measures assessed included the incidence of UTI, pyelonephritis, or urosepsis within 7 days of positive UC for patients who did not receive antibiotic treatment for ASB.
Results
Data from a total of 270 cultures were examined from IM nursing units. A total of 117 UCs were ordered during the baseline period before interventions were implemented. For a period of 1 month following activation of the IT intervention, 73 UCs were ordered. For a period of 1 month following the educational interventions, 80 UCs were ordered. Of these, 61 (52%) UCs were positive at baseline, 37 (51%) after the IT intervention, and 41 (51%) after the educational intervention. Patient characteristics were similar between the 3 groups (Table); 64.7% of patients were female in their early to mid-seventies. The majority of UCs were ordered by providers in the ED in all 3 periods examined (51%-70%). The percentage of patients who received antibiotics prior to UC for another indication (including bacteriuria) in the baseline, post-IT intervention, and post-education intervention groups were 30%, 27%, and 45%, respectively.
The study outcomes are summarized in Figure 2. Among patients with positive cultures, there was not a reduction in inappropriate treatment of ASB compared to baseline after the IT intervention (48% vs 42%). Following the education intervention, there was a reduction in unnecessary ASB treatment as compared both to baseline (35% vs 42%) and to post-IT intervention (35% vs 48%). There was no difference between the 3 study periods in the percentage of total UCs ordered by IM clinicians. The counterbalance measure showed that 1 patient who did not receive antibiotics within 7 days of a positive UC developed pyelonephritis, UTI, or sepsis due to a UTI in each intervention group.
Discussion
The results of this study demonstrate the role of multimodal interventions in antimicrobial stewardship and add to the growing body of evidence supporting the work of antimicrobial stewardship programs. Our multidisciplinary study group and multipronged intervention follow recent guideline recommendations for antimicrobial stewardship program interventions against unnecessary treatment of ASB.14 Initial analysis by our study group determined lack of CDS at the point of care and provider knowledge gaps in interpreting positive UCs as the 2 main contributors to unnecessary UC orders and unnecessary treatment of positive UCs in our local practice culture. The IT component of our intervention was intended to provide CDS for ordering UCs, and the education component focused on informing clinicians’ treatment decisions for positive UCs.
It has been suggested that the type of stewardship intervention that is most effective fits the specific needs and resources of an institution.14,15 And although the IDSA does not recommend education as a stand-alone intervention,16 we found it to be an effective intervention for our clinicians in our work environment. However, since the CPOE guidance was in place during the educational study periods, it is possible that the effect was due to a combination of these 2 approaches. Our pre-intervention ASB treatment rates were consistent with a recent meta-analysis in which the rate of inappropriate treatment of ASB was 45%.17 This meta-analysis found educational and organizational interventions led to a mean absolute risk reduction of 33%. After the education intervention, we saw a 7% decrease in unnecessary treatment of ASB compared to baseline, and a 13% decrease compared to the month just prior to the educational intervention.
Lessons learned from our work included how clear review of local processes can inform quality improvement interventions. For instance, we initially hypothesized that IM clinicians would benefit from point-of-care CDS guidance, but such guidance used alone without educational interventions was not supported by the results. We also determined that the majority of UCs from patients on general medicine units were ordered by ED providers. This revealed an opportunity to implement similar interventions in the ED, as this was the initial point of contact for many of these patients.
As with any clinical intervention, the anticipated benefits should be weighed against potential harm. Using counterbalance measures, we found there was minimal risk in the occurrence of UTI, pyelonephritis, or sepsis if clinicians avoided treating ASB. This finding is consistent with IDSA guideline recommendations and other studies that suggest that withholding treatment for asymptomatic bacteriuria does not lead to worse outcomes.1
This study has several limitations. Data were obtained through review of the electronic health record and therefore documentation may be incomplete. Also, antimicrobials for empiric coverage or treatment for other infections (eg, pneumonia, sepsis) may have confounded our results, as empirical antimicrobials were given to 27% to 45% of patients prior to UC. This was a quality improvement project carried out over defined time intervals, and thus our sample size was limited and not adequately powered to show statistical significance. Additionally, given the bundling of interventions, it is difficult to determine the impact of each intervention independently. Although CDS for UC ordering may not have influenced ordering, it is possible that the IT intervention raised awareness of ASB and influenced treatment practices.
Conclusion
Our work supports the principles of antibiotic stewardship as brought forth by IDSA.16 This work was the effort of a multidisciplinary team, which aligns with recommendations by Daniel and colleagues, published after our study had ended, for reducing overtreatment of ASB.14 Additionally, our study results provided valuable information for our institution. Although improvements in management of ASB were modest, the success of provider education and identification of other work areas and clinicians to target for future intervention were helpful in consideration of further studies. This work will also aid us in developing an expected effect size for future studies. We plan to provide ongoing education for IM providers as well as education in the ED to target providers who make first contact with patients admitted to inpatient services. In addition, the CPOE UC ordering screen message will continue to be used hospital-wide and will be expanded to the ED ordering system. Our interventions, experiences, and challenges may be used by other institutions to design effective antimicrobial stewardship interventions directed towards reducing rates of inappropriate ASB treatment.
Corresponding author: Prasanna P. Narayanan, PharmD, 200 First Street SW, Rochester, MN 55905; [email protected].
Financial disclosures: None.
1. Nicolle LE, Gupta K, Bradley SF, et al. Clinical practice guideline for the management of asymptomatic bacteriuria: 2019 update by the Infectious Diseases Society of America. Clin Infect Dis. 2019;68:e83–75.
2. Trautner BW, Grigoryan L, Petersen NJ, et al. Effectiveness of an antimicrobial stewardship approach for urinary catheter-associated asymptomatic bacteriuria. JAMA Intern Med. 2015;175:1120-1127.
3. Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control. 2008;36:309-332.
4. Trautner BW. Asymptomatic bacteriuria: when the treatment is worse than the disease. Nat Rev Urol. 2011;9:85-93.
5. Costelloe C, Metcalfe C, Lovering A, et al. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. BMJ. 2010;340:c2096.
6. The Joint Commission. Prepublication Requirements: New antimicrobial stewardship standard. Jun 22, 2016. www.jointcommission.org/assets/1/6/HAP-CAH_Antimicrobial_Prepub.pdf. Accessed January 24, 2019.
7. Federal Register. Medicare and Medicaid Programs; Hospital and Critical Access Hospital (CAH) Changes to Promote Innovation, Flexibility, and Improvement in Patient Care.Centers for Medicare & Medicaid Services. June 16, 2016. CMS-3295-P
8. Hartley SE, Kuhn L, Valley S, et al. Evaluating a hospitalist-based intervention to decrease unnecessary antimicrobial use in patients with asymptomatic bacteriuria. Infect Control Hosp Epidemiol. 2016;37:1044-1051.
9. Pavese P, Saurel N, Labarere J, et al. Does an educational session with an infectious diseases physician reduce the use of inappropriate antibiotic therapy for inpatients with positive urine culture results? A controlled before-and-after study. Infect Control Hosp Epidemiol. 2009;30:596-599.
10. Kelley D, Aaronson P, Poon E, et al. Evaluation of an antimicrobial stewardship approach to minimize overuse of antibiotics in patients with asymptomatic bacteriuria. Infect Control Hosp Epidemiol. 2014;35:193-195.
11. Chowdhury F, Sarkar K, Branche A, et al. Preventing the inappropriate treatment of asymptomatic bacteriuria at a community teaching hospital. J Community Hosp Intern Med Perspect. 2012;2.
12. Bonnal C, Baune B, Mion M, et al. Bacteriuria in a geriatric hospital: impact of an antibiotic improvement program. J Am Med Dir Assoc. 2008;9:605-609.
13. Linares LA, Thornton DJ, Strymish J, et al. Electronic memorandum decreases unnecessary antimicrobial use for asymptomatic bacteriuria and culture-negative pyuria. Infect Control Hosp Epidemiol. 2011;32:644-648.
14. Daniel M, Keller S, Mozafarihashjin M, et al. An implementation guide to reducing overtreatment of asymptomatic bacteriuria. JAMA Intern Med. 2018;178:271-276.
15. Redwood R, Knobloch MJ, Pellegrini DC, et al. Reducing unnecessary culturing: a systems approach to evaluating urine culture ordering and collection practices among nurses in two acute care settings. Antimicrob Resist Infect Control. 2018;7:4.
16. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62:e51–e7.
17. Flokas ME, Andreatos N, Alevizakos M, et al. Inappropriate management of asymptomatic patients with positive urine cultures: a systematic review and meta-analysis. Open Forum Infect Dis. 2017;4:1-10.
From the Mayo Clinic, Rochester, MN.
Abstract
- Objective: Asymptomatic bacteriuria (ASB) denotes asymptomatic carriage of bacteria within the urinary tract and does not require treatment in most patient populations. Unnecessary antimicrobial treatment has several consequences, including promotion of antimicrobial resistance, potential for medication adverse effects, and risk for Clostridiodes difficile infection. The aim of this quality improvement effort was to decrease both the unnecessary ordering of urine culture studies and unnecessary treatment of ASB.
- Methods: This is a single-center study of patients who received care on 3 internal medicine units at a large, academic medical center. We sought to determine the impact of information technology and educational interventions to decrease both inappropriate urine culture ordering and treatment of ASB. Data from included patients were collected over 3 1-month time periods: baseline, post-information technology intervention, and post-educational intervention.
- Results: There was a reduction in the percentage of patients who received antibiotics for ASB in the post-education intervention period as compared to baseline (35% vs 42%). The proportion of total urine cultures ordered by internal medicine clinicians did not change after an information technology intervention to redesign the computerized physician order entry screen for urine cultures.
- Conclusion: Educational interventions are effective ways to reduce rates of inappropriate treatment of ASB in patients admitted to internal medicine services.
Keywords: asymptomatic bacteriuria, UTI, information technology, education, quality.
Asymptomatic bacteriuria (ASB) is a common condition in which bacteria are recovered from a urine culture (UC) in patients without symptoms suggestive of urinary tract infection (UTI), with no pathologic consequences to most patients who are not treated.1,2 Patients with ASB do not exhibit symptoms of a UTI such as dysuria, increased frequency of urination, increased urgency, suprapubic tenderness, or costovertebral pain. Treatment with antibiotics is not indicated for most patients with ASB.1,3 According to the Infectious Diseases Society of America (IDSA), screening for bacteriuria and treatment for positive results is only indicated during pregnancy and prior to urologic procedures with anticipated breach of the mucosal lining.1
An estimated 20% to 52% of patients in hospital settings receive inappropriate treatment with antibiotics for ASB.4 Unnecessary prescribing of antibiotics has several negative consequences, including increased rates of antibiotic resistance, Clostridioides difficile infection, and medication adverse events, as well as increased health care costs.2,5 Antimicrobial stewardship programs to improve judicious use of antimicrobials are paramount to reducing these consequences, and their importance is heightened with recent requirements for antimicrobial stewardship put forth by The Joint Commission and the Centers for Medicare & Medicaid Services.6,7
A previous review of UC and antimicrobial use in patients for purposes of quality improvement at our institution over a 2-month period showed that of 59 patients with positive UCs, 47 patients (80%) did not have documented symptoms of a UTI. Of these 47 patients with ASB, 29 (61.7%) received antimicrobial treatment unnecessarily (unpublished data). We convened a group of clinicians and nonclinicians representing the areas of infectious disease, pharmacy, microbiology, statistics, and hospital internal medicine (IM) to examine the unnecessary treatment of ASB in our institution. Our objective was to address 2 antimicrobial stewardship issues: inappropriate UC ordering and unnecessary use of antibiotics to treat ASB. Our aim was to reduce the inappropriate ordering of UCs and to reduce treatment of ASB.
Methods
Setting
The study was conducted on 3 IM nursing units with a total of 83 beds at a large tertiary care academic medical center in the midwestern United States, and was approved by the organization’s Institutional Review Board.
Participants
We included all non-pregnant patients aged 18 years or older who received care from an IM primary service. These patients were admitted directly to an IM team through the emergency department (ED) or transferred to an IM team after an initial stay in the intensive care unit.
Data Source
Microbiology laboratory reports generated from the electronic health record were used to identify all patients with a collected UC sample who received care from an IM service prior to discharge. Urine samples were collected by midstream catch or catheterization. Data on urine Gram stain and urine dipstick were not included. Henceforth, the phrase “urine culture order” indicates that a UC was both ordered and performed. Data reports were generated for the month of August 2016 to determine the baseline number of UCs ordered. Charts of patients with positive UCs were reviewed to determine if antibiotics were started for the positive UC and whether the patient had signs or symptoms consistent with a UTI. If antibiotics were started in the absence of signs or symptoms to support a UTI, the patient was determined to have been unnecessarily treated for ASB. Reports were then generated for the month after each intervention was implemented, with the same chart review undertaken for positive UCs. Bacteriuria was defined in our study as the presence of microbial growth greater than 10,000 CFU/mL in UC.
Interventions
Initial analysis by our study group determined that lack of electronic clinical decision support (CDS) at the point of care and provider knowledge gaps in interpreting positive UCs were the 2 main contributors to unnecessary UC orders and unnecessary treatment of positive UCs, respectively. We reviewed the work of other groups who reported interventions to decrease treatment of ASB, ranging from educational presentations to pocket cards and treatment algorithms.8-13 We hypothesized that there would be a decrease in UC orders with CDS embedded in the computerized order entry screen, and that we would decrease unnecessary treatment of positive UCs by educating clinicians on indications for appropriate antibiotic prescribing in the setting of a positive UC.
Information technology intervention. The first intervention implemented involved redesign of the UC ordering screen in the computerized physician order entry (CPOE) system. This intervention went live hospital-wide, including the IM floors, intensive care units, and all other areas except the ED, on February 1, 2017 (Figure 1). The ordering screen required the prescriber to select from a list of appropriate indications for ordering a UC, including urine frequency, urgency, or dysuria; unexplained suprapubic or flank pain; fever in patients without another recognized cause; screening obtained prior to urologic procedure; or screening during pregnancy. An additional message advised prescribers to avoid ordering the culture if the patient had malodorous or cloudy urine, pyuria without urinary symptoms, or had an alternative cause of fever. Before we implemented the information technology (IT) intervention, there had been no specific point-of-care guidance on UC ordering.
Educational intervention. The second intervention, driven by clinical pharmacists, involved active and passive education of prescribers specifically designed to address unnecessary treatment of ASB. The IT intervention with CDS for UC ordering remained live. Presentations designed by the study group summarizing the appropriate indications for ordering a UC, distinguishing ASB from UTI, and discouraging treatment of ASB were delivered via a variety of routes by clinical pharmacists to nurses, nurse practitioners, physician assistants, pharmacists, medical residents, and staff physicians providing care to patients on the 3 IM units over a 1-month period in March 2017. The presentations contained the same basic content, but the information was delivered to target each specific audience group.
Medical residents received a 10-minute live presentation during a conference. Nurse practitioners, physician assistants, and staff physicians received a presentation via email, and highlights of the presentation were delivered by clinical pharmacists at their respective monthly group meetings. A handout was presented to nursing staff at nursing huddles, and presentation slides were distributed by email. Educational posters were posted in the medical resident workrooms, nursing breakrooms, and staff bathrooms on the units.
Outcome Measurements
The endpoints of interest were the percentage of patients with positive UCs unnecessarily treated for ASB before and after each intervention and the number of UCs ordered at baseline and after implementation of each intervention. Counterbalance measures assessed included the incidence of UTI, pyelonephritis, or urosepsis within 7 days of positive UC for patients who did not receive antibiotic treatment for ASB.
Results
Data from a total of 270 cultures were examined from IM nursing units. A total of 117 UCs were ordered during the baseline period before interventions were implemented. For a period of 1 month following activation of the IT intervention, 73 UCs were ordered. For a period of 1 month following the educational interventions, 80 UCs were ordered. Of these, 61 (52%) UCs were positive at baseline, 37 (51%) after the IT intervention, and 41 (51%) after the educational intervention. Patient characteristics were similar between the 3 groups (Table); 64.7% of patients were female in their early to mid-seventies. The majority of UCs were ordered by providers in the ED in all 3 periods examined (51%-70%). The percentage of patients who received antibiotics prior to UC for another indication (including bacteriuria) in the baseline, post-IT intervention, and post-education intervention groups were 30%, 27%, and 45%, respectively.
The study outcomes are summarized in Figure 2. Among patients with positive cultures, there was not a reduction in inappropriate treatment of ASB compared to baseline after the IT intervention (48% vs 42%). Following the education intervention, there was a reduction in unnecessary ASB treatment as compared both to baseline (35% vs 42%) and to post-IT intervention (35% vs 48%). There was no difference between the 3 study periods in the percentage of total UCs ordered by IM clinicians. The counterbalance measure showed that 1 patient who did not receive antibiotics within 7 days of a positive UC developed pyelonephritis, UTI, or sepsis due to a UTI in each intervention group.
Discussion
The results of this study demonstrate the role of multimodal interventions in antimicrobial stewardship and add to the growing body of evidence supporting the work of antimicrobial stewardship programs. Our multidisciplinary study group and multipronged intervention follow recent guideline recommendations for antimicrobial stewardship program interventions against unnecessary treatment of ASB.14 Initial analysis by our study group determined lack of CDS at the point of care and provider knowledge gaps in interpreting positive UCs as the 2 main contributors to unnecessary UC orders and unnecessary treatment of positive UCs in our local practice culture. The IT component of our intervention was intended to provide CDS for ordering UCs, and the education component focused on informing clinicians’ treatment decisions for positive UCs.
It has been suggested that the type of stewardship intervention that is most effective fits the specific needs and resources of an institution.14,15 And although the IDSA does not recommend education as a stand-alone intervention,16 we found it to be an effective intervention for our clinicians in our work environment. However, since the CPOE guidance was in place during the educational study periods, it is possible that the effect was due to a combination of these 2 approaches. Our pre-intervention ASB treatment rates were consistent with a recent meta-analysis in which the rate of inappropriate treatment of ASB was 45%.17 This meta-analysis found educational and organizational interventions led to a mean absolute risk reduction of 33%. After the education intervention, we saw a 7% decrease in unnecessary treatment of ASB compared to baseline, and a 13% decrease compared to the month just prior to the educational intervention.
Lessons learned from our work included how clear review of local processes can inform quality improvement interventions. For instance, we initially hypothesized that IM clinicians would benefit from point-of-care CDS guidance, but such guidance used alone without educational interventions was not supported by the results. We also determined that the majority of UCs from patients on general medicine units were ordered by ED providers. This revealed an opportunity to implement similar interventions in the ED, as this was the initial point of contact for many of these patients.
As with any clinical intervention, the anticipated benefits should be weighed against potential harm. Using counterbalance measures, we found there was minimal risk in the occurrence of UTI, pyelonephritis, or sepsis if clinicians avoided treating ASB. This finding is consistent with IDSA guideline recommendations and other studies that suggest that withholding treatment for asymptomatic bacteriuria does not lead to worse outcomes.1
This study has several limitations. Data were obtained through review of the electronic health record and therefore documentation may be incomplete. Also, antimicrobials for empiric coverage or treatment for other infections (eg, pneumonia, sepsis) may have confounded our results, as empirical antimicrobials were given to 27% to 45% of patients prior to UC. This was a quality improvement project carried out over defined time intervals, and thus our sample size was limited and not adequately powered to show statistical significance. Additionally, given the bundling of interventions, it is difficult to determine the impact of each intervention independently. Although CDS for UC ordering may not have influenced ordering, it is possible that the IT intervention raised awareness of ASB and influenced treatment practices.
Conclusion
Our work supports the principles of antibiotic stewardship as brought forth by IDSA.16 This work was the effort of a multidisciplinary team, which aligns with recommendations by Daniel and colleagues, published after our study had ended, for reducing overtreatment of ASB.14 Additionally, our study results provided valuable information for our institution. Although improvements in management of ASB were modest, the success of provider education and identification of other work areas and clinicians to target for future intervention were helpful in consideration of further studies. This work will also aid us in developing an expected effect size for future studies. We plan to provide ongoing education for IM providers as well as education in the ED to target providers who make first contact with patients admitted to inpatient services. In addition, the CPOE UC ordering screen message will continue to be used hospital-wide and will be expanded to the ED ordering system. Our interventions, experiences, and challenges may be used by other institutions to design effective antimicrobial stewardship interventions directed towards reducing rates of inappropriate ASB treatment.
Corresponding author: Prasanna P. Narayanan, PharmD, 200 First Street SW, Rochester, MN 55905; [email protected].
Financial disclosures: None.
From the Mayo Clinic, Rochester, MN.
Abstract
- Objective: Asymptomatic bacteriuria (ASB) denotes asymptomatic carriage of bacteria within the urinary tract and does not require treatment in most patient populations. Unnecessary antimicrobial treatment has several consequences, including promotion of antimicrobial resistance, potential for medication adverse effects, and risk for Clostridiodes difficile infection. The aim of this quality improvement effort was to decrease both the unnecessary ordering of urine culture studies and unnecessary treatment of ASB.
- Methods: This is a single-center study of patients who received care on 3 internal medicine units at a large, academic medical center. We sought to determine the impact of information technology and educational interventions to decrease both inappropriate urine culture ordering and treatment of ASB. Data from included patients were collected over 3 1-month time periods: baseline, post-information technology intervention, and post-educational intervention.
- Results: There was a reduction in the percentage of patients who received antibiotics for ASB in the post-education intervention period as compared to baseline (35% vs 42%). The proportion of total urine cultures ordered by internal medicine clinicians did not change after an information technology intervention to redesign the computerized physician order entry screen for urine cultures.
- Conclusion: Educational interventions are effective ways to reduce rates of inappropriate treatment of ASB in patients admitted to internal medicine services.
Keywords: asymptomatic bacteriuria, UTI, information technology, education, quality.
Asymptomatic bacteriuria (ASB) is a common condition in which bacteria are recovered from a urine culture (UC) in patients without symptoms suggestive of urinary tract infection (UTI), with no pathologic consequences to most patients who are not treated.1,2 Patients with ASB do not exhibit symptoms of a UTI such as dysuria, increased frequency of urination, increased urgency, suprapubic tenderness, or costovertebral pain. Treatment with antibiotics is not indicated for most patients with ASB.1,3 According to the Infectious Diseases Society of America (IDSA), screening for bacteriuria and treatment for positive results is only indicated during pregnancy and prior to urologic procedures with anticipated breach of the mucosal lining.1
An estimated 20% to 52% of patients in hospital settings receive inappropriate treatment with antibiotics for ASB.4 Unnecessary prescribing of antibiotics has several negative consequences, including increased rates of antibiotic resistance, Clostridioides difficile infection, and medication adverse events, as well as increased health care costs.2,5 Antimicrobial stewardship programs to improve judicious use of antimicrobials are paramount to reducing these consequences, and their importance is heightened with recent requirements for antimicrobial stewardship put forth by The Joint Commission and the Centers for Medicare & Medicaid Services.6,7
A previous review of UC and antimicrobial use in patients for purposes of quality improvement at our institution over a 2-month period showed that of 59 patients with positive UCs, 47 patients (80%) did not have documented symptoms of a UTI. Of these 47 patients with ASB, 29 (61.7%) received antimicrobial treatment unnecessarily (unpublished data). We convened a group of clinicians and nonclinicians representing the areas of infectious disease, pharmacy, microbiology, statistics, and hospital internal medicine (IM) to examine the unnecessary treatment of ASB in our institution. Our objective was to address 2 antimicrobial stewardship issues: inappropriate UC ordering and unnecessary use of antibiotics to treat ASB. Our aim was to reduce the inappropriate ordering of UCs and to reduce treatment of ASB.
Methods
Setting
The study was conducted on 3 IM nursing units with a total of 83 beds at a large tertiary care academic medical center in the midwestern United States, and was approved by the organization’s Institutional Review Board.
Participants
We included all non-pregnant patients aged 18 years or older who received care from an IM primary service. These patients were admitted directly to an IM team through the emergency department (ED) or transferred to an IM team after an initial stay in the intensive care unit.
Data Source
Microbiology laboratory reports generated from the electronic health record were used to identify all patients with a collected UC sample who received care from an IM service prior to discharge. Urine samples were collected by midstream catch or catheterization. Data on urine Gram stain and urine dipstick were not included. Henceforth, the phrase “urine culture order” indicates that a UC was both ordered and performed. Data reports were generated for the month of August 2016 to determine the baseline number of UCs ordered. Charts of patients with positive UCs were reviewed to determine if antibiotics were started for the positive UC and whether the patient had signs or symptoms consistent with a UTI. If antibiotics were started in the absence of signs or symptoms to support a UTI, the patient was determined to have been unnecessarily treated for ASB. Reports were then generated for the month after each intervention was implemented, with the same chart review undertaken for positive UCs. Bacteriuria was defined in our study as the presence of microbial growth greater than 10,000 CFU/mL in UC.
Interventions
Initial analysis by our study group determined that lack of electronic clinical decision support (CDS) at the point of care and provider knowledge gaps in interpreting positive UCs were the 2 main contributors to unnecessary UC orders and unnecessary treatment of positive UCs, respectively. We reviewed the work of other groups who reported interventions to decrease treatment of ASB, ranging from educational presentations to pocket cards and treatment algorithms.8-13 We hypothesized that there would be a decrease in UC orders with CDS embedded in the computerized order entry screen, and that we would decrease unnecessary treatment of positive UCs by educating clinicians on indications for appropriate antibiotic prescribing in the setting of a positive UC.
Information technology intervention. The first intervention implemented involved redesign of the UC ordering screen in the computerized physician order entry (CPOE) system. This intervention went live hospital-wide, including the IM floors, intensive care units, and all other areas except the ED, on February 1, 2017 (Figure 1). The ordering screen required the prescriber to select from a list of appropriate indications for ordering a UC, including urine frequency, urgency, or dysuria; unexplained suprapubic or flank pain; fever in patients without another recognized cause; screening obtained prior to urologic procedure; or screening during pregnancy. An additional message advised prescribers to avoid ordering the culture if the patient had malodorous or cloudy urine, pyuria without urinary symptoms, or had an alternative cause of fever. Before we implemented the information technology (IT) intervention, there had been no specific point-of-care guidance on UC ordering.
Educational intervention. The second intervention, driven by clinical pharmacists, involved active and passive education of prescribers specifically designed to address unnecessary treatment of ASB. The IT intervention with CDS for UC ordering remained live. Presentations designed by the study group summarizing the appropriate indications for ordering a UC, distinguishing ASB from UTI, and discouraging treatment of ASB were delivered via a variety of routes by clinical pharmacists to nurses, nurse practitioners, physician assistants, pharmacists, medical residents, and staff physicians providing care to patients on the 3 IM units over a 1-month period in March 2017. The presentations contained the same basic content, but the information was delivered to target each specific audience group.
Medical residents received a 10-minute live presentation during a conference. Nurse practitioners, physician assistants, and staff physicians received a presentation via email, and highlights of the presentation were delivered by clinical pharmacists at their respective monthly group meetings. A handout was presented to nursing staff at nursing huddles, and presentation slides were distributed by email. Educational posters were posted in the medical resident workrooms, nursing breakrooms, and staff bathrooms on the units.
Outcome Measurements
The endpoints of interest were the percentage of patients with positive UCs unnecessarily treated for ASB before and after each intervention and the number of UCs ordered at baseline and after implementation of each intervention. Counterbalance measures assessed included the incidence of UTI, pyelonephritis, or urosepsis within 7 days of positive UC for patients who did not receive antibiotic treatment for ASB.
Results
Data from a total of 270 cultures were examined from IM nursing units. A total of 117 UCs were ordered during the baseline period before interventions were implemented. For a period of 1 month following activation of the IT intervention, 73 UCs were ordered. For a period of 1 month following the educational interventions, 80 UCs were ordered. Of these, 61 (52%) UCs were positive at baseline, 37 (51%) after the IT intervention, and 41 (51%) after the educational intervention. Patient characteristics were similar between the 3 groups (Table); 64.7% of patients were female in their early to mid-seventies. The majority of UCs were ordered by providers in the ED in all 3 periods examined (51%-70%). The percentage of patients who received antibiotics prior to UC for another indication (including bacteriuria) in the baseline, post-IT intervention, and post-education intervention groups were 30%, 27%, and 45%, respectively.
The study outcomes are summarized in Figure 2. Among patients with positive cultures, there was not a reduction in inappropriate treatment of ASB compared to baseline after the IT intervention (48% vs 42%). Following the education intervention, there was a reduction in unnecessary ASB treatment as compared both to baseline (35% vs 42%) and to post-IT intervention (35% vs 48%). There was no difference between the 3 study periods in the percentage of total UCs ordered by IM clinicians. The counterbalance measure showed that 1 patient who did not receive antibiotics within 7 days of a positive UC developed pyelonephritis, UTI, or sepsis due to a UTI in each intervention group.
Discussion
The results of this study demonstrate the role of multimodal interventions in antimicrobial stewardship and add to the growing body of evidence supporting the work of antimicrobial stewardship programs. Our multidisciplinary study group and multipronged intervention follow recent guideline recommendations for antimicrobial stewardship program interventions against unnecessary treatment of ASB.14 Initial analysis by our study group determined lack of CDS at the point of care and provider knowledge gaps in interpreting positive UCs as the 2 main contributors to unnecessary UC orders and unnecessary treatment of positive UCs in our local practice culture. The IT component of our intervention was intended to provide CDS for ordering UCs, and the education component focused on informing clinicians’ treatment decisions for positive UCs.
It has been suggested that the type of stewardship intervention that is most effective fits the specific needs and resources of an institution.14,15 And although the IDSA does not recommend education as a stand-alone intervention,16 we found it to be an effective intervention for our clinicians in our work environment. However, since the CPOE guidance was in place during the educational study periods, it is possible that the effect was due to a combination of these 2 approaches. Our pre-intervention ASB treatment rates were consistent with a recent meta-analysis in which the rate of inappropriate treatment of ASB was 45%.17 This meta-analysis found educational and organizational interventions led to a mean absolute risk reduction of 33%. After the education intervention, we saw a 7% decrease in unnecessary treatment of ASB compared to baseline, and a 13% decrease compared to the month just prior to the educational intervention.
Lessons learned from our work included how clear review of local processes can inform quality improvement interventions. For instance, we initially hypothesized that IM clinicians would benefit from point-of-care CDS guidance, but such guidance used alone without educational interventions was not supported by the results. We also determined that the majority of UCs from patients on general medicine units were ordered by ED providers. This revealed an opportunity to implement similar interventions in the ED, as this was the initial point of contact for many of these patients.
As with any clinical intervention, the anticipated benefits should be weighed against potential harm. Using counterbalance measures, we found there was minimal risk in the occurrence of UTI, pyelonephritis, or sepsis if clinicians avoided treating ASB. This finding is consistent with IDSA guideline recommendations and other studies that suggest that withholding treatment for asymptomatic bacteriuria does not lead to worse outcomes.1
This study has several limitations. Data were obtained through review of the electronic health record and therefore documentation may be incomplete. Also, antimicrobials for empiric coverage or treatment for other infections (eg, pneumonia, sepsis) may have confounded our results, as empirical antimicrobials were given to 27% to 45% of patients prior to UC. This was a quality improvement project carried out over defined time intervals, and thus our sample size was limited and not adequately powered to show statistical significance. Additionally, given the bundling of interventions, it is difficult to determine the impact of each intervention independently. Although CDS for UC ordering may not have influenced ordering, it is possible that the IT intervention raised awareness of ASB and influenced treatment practices.
Conclusion
Our work supports the principles of antibiotic stewardship as brought forth by IDSA.16 This work was the effort of a multidisciplinary team, which aligns with recommendations by Daniel and colleagues, published after our study had ended, for reducing overtreatment of ASB.14 Additionally, our study results provided valuable information for our institution. Although improvements in management of ASB were modest, the success of provider education and identification of other work areas and clinicians to target for future intervention were helpful in consideration of further studies. This work will also aid us in developing an expected effect size for future studies. We plan to provide ongoing education for IM providers as well as education in the ED to target providers who make first contact with patients admitted to inpatient services. In addition, the CPOE UC ordering screen message will continue to be used hospital-wide and will be expanded to the ED ordering system. Our interventions, experiences, and challenges may be used by other institutions to design effective antimicrobial stewardship interventions directed towards reducing rates of inappropriate ASB treatment.
Corresponding author: Prasanna P. Narayanan, PharmD, 200 First Street SW, Rochester, MN 55905; [email protected].
Financial disclosures: None.
1. Nicolle LE, Gupta K, Bradley SF, et al. Clinical practice guideline for the management of asymptomatic bacteriuria: 2019 update by the Infectious Diseases Society of America. Clin Infect Dis. 2019;68:e83–75.
2. Trautner BW, Grigoryan L, Petersen NJ, et al. Effectiveness of an antimicrobial stewardship approach for urinary catheter-associated asymptomatic bacteriuria. JAMA Intern Med. 2015;175:1120-1127.
3. Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control. 2008;36:309-332.
4. Trautner BW. Asymptomatic bacteriuria: when the treatment is worse than the disease. Nat Rev Urol. 2011;9:85-93.
5. Costelloe C, Metcalfe C, Lovering A, et al. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. BMJ. 2010;340:c2096.
6. The Joint Commission. Prepublication Requirements: New antimicrobial stewardship standard. Jun 22, 2016. www.jointcommission.org/assets/1/6/HAP-CAH_Antimicrobial_Prepub.pdf. Accessed January 24, 2019.
7. Federal Register. Medicare and Medicaid Programs; Hospital and Critical Access Hospital (CAH) Changes to Promote Innovation, Flexibility, and Improvement in Patient Care.Centers for Medicare & Medicaid Services. June 16, 2016. CMS-3295-P
8. Hartley SE, Kuhn L, Valley S, et al. Evaluating a hospitalist-based intervention to decrease unnecessary antimicrobial use in patients with asymptomatic bacteriuria. Infect Control Hosp Epidemiol. 2016;37:1044-1051.
9. Pavese P, Saurel N, Labarere J, et al. Does an educational session with an infectious diseases physician reduce the use of inappropriate antibiotic therapy for inpatients with positive urine culture results? A controlled before-and-after study. Infect Control Hosp Epidemiol. 2009;30:596-599.
10. Kelley D, Aaronson P, Poon E, et al. Evaluation of an antimicrobial stewardship approach to minimize overuse of antibiotics in patients with asymptomatic bacteriuria. Infect Control Hosp Epidemiol. 2014;35:193-195.
11. Chowdhury F, Sarkar K, Branche A, et al. Preventing the inappropriate treatment of asymptomatic bacteriuria at a community teaching hospital. J Community Hosp Intern Med Perspect. 2012;2.
12. Bonnal C, Baune B, Mion M, et al. Bacteriuria in a geriatric hospital: impact of an antibiotic improvement program. J Am Med Dir Assoc. 2008;9:605-609.
13. Linares LA, Thornton DJ, Strymish J, et al. Electronic memorandum decreases unnecessary antimicrobial use for asymptomatic bacteriuria and culture-negative pyuria. Infect Control Hosp Epidemiol. 2011;32:644-648.
14. Daniel M, Keller S, Mozafarihashjin M, et al. An implementation guide to reducing overtreatment of asymptomatic bacteriuria. JAMA Intern Med. 2018;178:271-276.
15. Redwood R, Knobloch MJ, Pellegrini DC, et al. Reducing unnecessary culturing: a systems approach to evaluating urine culture ordering and collection practices among nurses in two acute care settings. Antimicrob Resist Infect Control. 2018;7:4.
16. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62:e51–e7.
17. Flokas ME, Andreatos N, Alevizakos M, et al. Inappropriate management of asymptomatic patients with positive urine cultures: a systematic review and meta-analysis. Open Forum Infect Dis. 2017;4:1-10.
1. Nicolle LE, Gupta K, Bradley SF, et al. Clinical practice guideline for the management of asymptomatic bacteriuria: 2019 update by the Infectious Diseases Society of America. Clin Infect Dis. 2019;68:e83–75.
2. Trautner BW, Grigoryan L, Petersen NJ, et al. Effectiveness of an antimicrobial stewardship approach for urinary catheter-associated asymptomatic bacteriuria. JAMA Intern Med. 2015;175:1120-1127.
3. Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control. 2008;36:309-332.
4. Trautner BW. Asymptomatic bacteriuria: when the treatment is worse than the disease. Nat Rev Urol. 2011;9:85-93.
5. Costelloe C, Metcalfe C, Lovering A, et al. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. BMJ. 2010;340:c2096.
6. The Joint Commission. Prepublication Requirements: New antimicrobial stewardship standard. Jun 22, 2016. www.jointcommission.org/assets/1/6/HAP-CAH_Antimicrobial_Prepub.pdf. Accessed January 24, 2019.
7. Federal Register. Medicare and Medicaid Programs; Hospital and Critical Access Hospital (CAH) Changes to Promote Innovation, Flexibility, and Improvement in Patient Care.Centers for Medicare & Medicaid Services. June 16, 2016. CMS-3295-P
8. Hartley SE, Kuhn L, Valley S, et al. Evaluating a hospitalist-based intervention to decrease unnecessary antimicrobial use in patients with asymptomatic bacteriuria. Infect Control Hosp Epidemiol. 2016;37:1044-1051.
9. Pavese P, Saurel N, Labarere J, et al. Does an educational session with an infectious diseases physician reduce the use of inappropriate antibiotic therapy for inpatients with positive urine culture results? A controlled before-and-after study. Infect Control Hosp Epidemiol. 2009;30:596-599.
10. Kelley D, Aaronson P, Poon E, et al. Evaluation of an antimicrobial stewardship approach to minimize overuse of antibiotics in patients with asymptomatic bacteriuria. Infect Control Hosp Epidemiol. 2014;35:193-195.
11. Chowdhury F, Sarkar K, Branche A, et al. Preventing the inappropriate treatment of asymptomatic bacteriuria at a community teaching hospital. J Community Hosp Intern Med Perspect. 2012;2.
12. Bonnal C, Baune B, Mion M, et al. Bacteriuria in a geriatric hospital: impact of an antibiotic improvement program. J Am Med Dir Assoc. 2008;9:605-609.
13. Linares LA, Thornton DJ, Strymish J, et al. Electronic memorandum decreases unnecessary antimicrobial use for asymptomatic bacteriuria and culture-negative pyuria. Infect Control Hosp Epidemiol. 2011;32:644-648.
14. Daniel M, Keller S, Mozafarihashjin M, et al. An implementation guide to reducing overtreatment of asymptomatic bacteriuria. JAMA Intern Med. 2018;178:271-276.
15. Redwood R, Knobloch MJ, Pellegrini DC, et al. Reducing unnecessary culturing: a systems approach to evaluating urine culture ordering and collection practices among nurses in two acute care settings. Antimicrob Resist Infect Control. 2018;7:4.
16. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62:e51–e7.
17. Flokas ME, Andreatos N, Alevizakos M, et al. Inappropriate management of asymptomatic patients with positive urine cultures: a systematic review and meta-analysis. Open Forum Infect Dis. 2017;4:1-10.
Sinusitis treatment depends on classification, duration of symptoms
ORLANDO – according to a speaker at the Cardiovascular & Respiratory Summit by Global Academy for Medical Education.
The major signs and symptoms of sinusitis are pressure and pain on the anterior side of the face or in a localized headache, nasal obstruction, and pus observed at exam that is clouded or colored. Patients may also present with a feeling of facial congestion or fullness, nasal discharge, and fever, noted Brian Bizik, MS, PA-C, from Asthma & Allergy of Idaho and Nevada. The condition can present as acute (up to 4 weeks), subacute (4-12 weeks, with resolution of symptoms), chronic (12 weeks or more), and recurrent acute chronic sinusitis. Most cases of sinusitis are accompanied with contiguous nasal mucosa inflammation, and therefore the term rhinosinusitis is preferred.
To diagnose sinusitis, “you want patients to tell you where they’re hurting, and where their pressure is,” Mr. Bizik said, noting that he instructs patients to “point with one finger and tell me how you feel without using the word ‘sinus.’ ” Clinicians should ask whether a patient’s pain is continuous or cyclic, if they have bad breath even after brushing their teeth, if they have a chronic cough as opposed to postnasal drip, whether they have pain when they chew or walk, and if they feel like they are always tired.
According to guidelines from the Infectious Diseases Society of America, if symptoms last longer than 10 days and patients have a fever above 39° C (102.2° F), it is more likely bacterial rather than viral. Another sign of bacterial infection is when patients get better after a few days before worsening again later, said Mr. Bizik. In patients where clinicians suspect bacterial infection, the IDSA recommends amoxicillin/clavulanate over amoxicillin alone because some acute bacterial rhinosinusitis could be Haemophilus influenzae, and up to 30% of these infections can produce beta-lactamase. Patients with an amoxicillin allergy should take doxycycline, which is the only currently recommended antibiotic for patients with acute bacterial rhinosinusitis.
In general, clinicians should treat acute bacterial rhinosinusitis based on whether the patient has the most severe disease, said Mr. Bizik. “Use those three criteria: fever, symptoms longer than 10 days, purulence, and feeling lousy. If you find these people are in the high-risk group, [the guidelines] recommend antibiotic treatment.”
In addition to antibiotics, patients can likely benefit from use of topical corticosteroids such as mometasone, fluticasone, flunisolide, and beclomethasone. “It comes down to simply what you like and what works well for you,” he said. With regard to oral steroids, patients with severe pain can benefit from medication like prednisone. Finally, decongestants and relief with sinus irrigation treatments like Neti pots can help relieve symptoms and promote healthy mucosal function.
On the other hand, sinusitis with a viral origin tends to have “light” flu symptoms that do not worsen over time and almost always resolve within 10 days. “If they fit the viral mold, we’re going to do everything the same [as bacterial sinusitis]; just skip the antibiotics,” he said.
In patients with chronic rhinosinusitis (CRS), the symptoms persist over a longer period of time. CRS has a large number of associated conditions, such as allergic rhinitis and gastroesophageal reflux, as well as environmental factors like cigarette smoke, viral illness, and rebound rhinitis. If a patient’s CRS is caused by allergies, treating the allergies aggressively will improve CRS symptoms. “If they have an allergic component, you really have to have a reason not to put them on montelukast. I would encourage you to do that,” said Mr. Bizik. “Cetirizine and montelukast at bedtime works very well. They’re cheap, effective, generic, and nonsteroidal.”
Other methods for treating symptoms of CRS include saline irrigation to increase mucociliary flow rates, high doses of mucolytics, and first- and second-generation antihistamines, which can take up to 10 days to see the full effect. “I have a 10-day reminder, and I call them on day 11,” said Mr. Bizik. “If they stick with it, they say it really did help. It’s a great way to avoid antibiotics.”
Intranasal corticosteroids are also effective first-line therapies for CRS. However, technique is important when using these medications. In his presentation, Mr. Bizik described the “opposite-hand” technique he teaches to patients to reduce some of the side effects patients experience when using intranasal corticosteroids, including nosebleeds.
“You insert it in the nose, you go in all the way until you just feel your fingers touching your nose, and you point it towards the earlobe so the left nostril goes to the left earlobe [and vice versa], and you just spray,” once or twice a day depending on indication, he said. “Using those consistently, when you do this, the flower smell is less, it doesn’t bother you, less goes down your throat, and it’s very effective.”
Dr. Bizik reports being a speaking and consultant for Grifols, Boehringer Ingelheim, Meda Pharmaceuticals, and an advisory board member for Circassia Pharmaceuticals.
Global Academy for Medical Education and this news organization are owned by the same parent company.
ORLANDO – according to a speaker at the Cardiovascular & Respiratory Summit by Global Academy for Medical Education.
The major signs and symptoms of sinusitis are pressure and pain on the anterior side of the face or in a localized headache, nasal obstruction, and pus observed at exam that is clouded or colored. Patients may also present with a feeling of facial congestion or fullness, nasal discharge, and fever, noted Brian Bizik, MS, PA-C, from Asthma & Allergy of Idaho and Nevada. The condition can present as acute (up to 4 weeks), subacute (4-12 weeks, with resolution of symptoms), chronic (12 weeks or more), and recurrent acute chronic sinusitis. Most cases of sinusitis are accompanied with contiguous nasal mucosa inflammation, and therefore the term rhinosinusitis is preferred.
To diagnose sinusitis, “you want patients to tell you where they’re hurting, and where their pressure is,” Mr. Bizik said, noting that he instructs patients to “point with one finger and tell me how you feel without using the word ‘sinus.’ ” Clinicians should ask whether a patient’s pain is continuous or cyclic, if they have bad breath even after brushing their teeth, if they have a chronic cough as opposed to postnasal drip, whether they have pain when they chew or walk, and if they feel like they are always tired.
According to guidelines from the Infectious Diseases Society of America, if symptoms last longer than 10 days and patients have a fever above 39° C (102.2° F), it is more likely bacterial rather than viral. Another sign of bacterial infection is when patients get better after a few days before worsening again later, said Mr. Bizik. In patients where clinicians suspect bacterial infection, the IDSA recommends amoxicillin/clavulanate over amoxicillin alone because some acute bacterial rhinosinusitis could be Haemophilus influenzae, and up to 30% of these infections can produce beta-lactamase. Patients with an amoxicillin allergy should take doxycycline, which is the only currently recommended antibiotic for patients with acute bacterial rhinosinusitis.
In general, clinicians should treat acute bacterial rhinosinusitis based on whether the patient has the most severe disease, said Mr. Bizik. “Use those three criteria: fever, symptoms longer than 10 days, purulence, and feeling lousy. If you find these people are in the high-risk group, [the guidelines] recommend antibiotic treatment.”
In addition to antibiotics, patients can likely benefit from use of topical corticosteroids such as mometasone, fluticasone, flunisolide, and beclomethasone. “It comes down to simply what you like and what works well for you,” he said. With regard to oral steroids, patients with severe pain can benefit from medication like prednisone. Finally, decongestants and relief with sinus irrigation treatments like Neti pots can help relieve symptoms and promote healthy mucosal function.
On the other hand, sinusitis with a viral origin tends to have “light” flu symptoms that do not worsen over time and almost always resolve within 10 days. “If they fit the viral mold, we’re going to do everything the same [as bacterial sinusitis]; just skip the antibiotics,” he said.
In patients with chronic rhinosinusitis (CRS), the symptoms persist over a longer period of time. CRS has a large number of associated conditions, such as allergic rhinitis and gastroesophageal reflux, as well as environmental factors like cigarette smoke, viral illness, and rebound rhinitis. If a patient’s CRS is caused by allergies, treating the allergies aggressively will improve CRS symptoms. “If they have an allergic component, you really have to have a reason not to put them on montelukast. I would encourage you to do that,” said Mr. Bizik. “Cetirizine and montelukast at bedtime works very well. They’re cheap, effective, generic, and nonsteroidal.”
Other methods for treating symptoms of CRS include saline irrigation to increase mucociliary flow rates, high doses of mucolytics, and first- and second-generation antihistamines, which can take up to 10 days to see the full effect. “I have a 10-day reminder, and I call them on day 11,” said Mr. Bizik. “If they stick with it, they say it really did help. It’s a great way to avoid antibiotics.”
Intranasal corticosteroids are also effective first-line therapies for CRS. However, technique is important when using these medications. In his presentation, Mr. Bizik described the “opposite-hand” technique he teaches to patients to reduce some of the side effects patients experience when using intranasal corticosteroids, including nosebleeds.
“You insert it in the nose, you go in all the way until you just feel your fingers touching your nose, and you point it towards the earlobe so the left nostril goes to the left earlobe [and vice versa], and you just spray,” once or twice a day depending on indication, he said. “Using those consistently, when you do this, the flower smell is less, it doesn’t bother you, less goes down your throat, and it’s very effective.”
Dr. Bizik reports being a speaking and consultant for Grifols, Boehringer Ingelheim, Meda Pharmaceuticals, and an advisory board member for Circassia Pharmaceuticals.
Global Academy for Medical Education and this news organization are owned by the same parent company.
ORLANDO – according to a speaker at the Cardiovascular & Respiratory Summit by Global Academy for Medical Education.
The major signs and symptoms of sinusitis are pressure and pain on the anterior side of the face or in a localized headache, nasal obstruction, and pus observed at exam that is clouded or colored. Patients may also present with a feeling of facial congestion or fullness, nasal discharge, and fever, noted Brian Bizik, MS, PA-C, from Asthma & Allergy of Idaho and Nevada. The condition can present as acute (up to 4 weeks), subacute (4-12 weeks, with resolution of symptoms), chronic (12 weeks or more), and recurrent acute chronic sinusitis. Most cases of sinusitis are accompanied with contiguous nasal mucosa inflammation, and therefore the term rhinosinusitis is preferred.
To diagnose sinusitis, “you want patients to tell you where they’re hurting, and where their pressure is,” Mr. Bizik said, noting that he instructs patients to “point with one finger and tell me how you feel without using the word ‘sinus.’ ” Clinicians should ask whether a patient’s pain is continuous or cyclic, if they have bad breath even after brushing their teeth, if they have a chronic cough as opposed to postnasal drip, whether they have pain when they chew or walk, and if they feel like they are always tired.
According to guidelines from the Infectious Diseases Society of America, if symptoms last longer than 10 days and patients have a fever above 39° C (102.2° F), it is more likely bacterial rather than viral. Another sign of bacterial infection is when patients get better after a few days before worsening again later, said Mr. Bizik. In patients where clinicians suspect bacterial infection, the IDSA recommends amoxicillin/clavulanate over amoxicillin alone because some acute bacterial rhinosinusitis could be Haemophilus influenzae, and up to 30% of these infections can produce beta-lactamase. Patients with an amoxicillin allergy should take doxycycline, which is the only currently recommended antibiotic for patients with acute bacterial rhinosinusitis.
In general, clinicians should treat acute bacterial rhinosinusitis based on whether the patient has the most severe disease, said Mr. Bizik. “Use those three criteria: fever, symptoms longer than 10 days, purulence, and feeling lousy. If you find these people are in the high-risk group, [the guidelines] recommend antibiotic treatment.”
In addition to antibiotics, patients can likely benefit from use of topical corticosteroids such as mometasone, fluticasone, flunisolide, and beclomethasone. “It comes down to simply what you like and what works well for you,” he said. With regard to oral steroids, patients with severe pain can benefit from medication like prednisone. Finally, decongestants and relief with sinus irrigation treatments like Neti pots can help relieve symptoms and promote healthy mucosal function.
On the other hand, sinusitis with a viral origin tends to have “light” flu symptoms that do not worsen over time and almost always resolve within 10 days. “If they fit the viral mold, we’re going to do everything the same [as bacterial sinusitis]; just skip the antibiotics,” he said.
In patients with chronic rhinosinusitis (CRS), the symptoms persist over a longer period of time. CRS has a large number of associated conditions, such as allergic rhinitis and gastroesophageal reflux, as well as environmental factors like cigarette smoke, viral illness, and rebound rhinitis. If a patient’s CRS is caused by allergies, treating the allergies aggressively will improve CRS symptoms. “If they have an allergic component, you really have to have a reason not to put them on montelukast. I would encourage you to do that,” said Mr. Bizik. “Cetirizine and montelukast at bedtime works very well. They’re cheap, effective, generic, and nonsteroidal.”
Other methods for treating symptoms of CRS include saline irrigation to increase mucociliary flow rates, high doses of mucolytics, and first- and second-generation antihistamines, which can take up to 10 days to see the full effect. “I have a 10-day reminder, and I call them on day 11,” said Mr. Bizik. “If they stick with it, they say it really did help. It’s a great way to avoid antibiotics.”
Intranasal corticosteroids are also effective first-line therapies for CRS. However, technique is important when using these medications. In his presentation, Mr. Bizik described the “opposite-hand” technique he teaches to patients to reduce some of the side effects patients experience when using intranasal corticosteroids, including nosebleeds.
“You insert it in the nose, you go in all the way until you just feel your fingers touching your nose, and you point it towards the earlobe so the left nostril goes to the left earlobe [and vice versa], and you just spray,” once or twice a day depending on indication, he said. “Using those consistently, when you do this, the flower smell is less, it doesn’t bother you, less goes down your throat, and it’s very effective.”
Dr. Bizik reports being a speaking and consultant for Grifols, Boehringer Ingelheim, Meda Pharmaceuticals, and an advisory board member for Circassia Pharmaceuticals.
Global Academy for Medical Education and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM CARPS 2019