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Teams find new way to kill malaria parasite
red blood cell; Credit: St Jude
Children’s Research Hospital
Two groups of researchers have found they can kill the malaria parasite by targeting a protein complex.
The research showed that a protein complex known as the Plasmodium translocon of exported proteins (PTEX) is needed for the export of malaria-parasite proteins into the cytoplasm of infected red blood cells, and such export is essential for parasite survival.
When the researchers disrupted passage of the proteins in cell cultures, malaria parasites stopped growing and died.
“The malaria parasite secretes hundreds of diverse proteins to seize control of red blood cells,” said Josh R. Beck, PhD, of the Washington University School of Medicine in St Louis.
“We’ve been searching for a single step that all those various proteins have to take to be secreted, and this looks like just such a bottleneck.”
He and his colleagues detailed their findings in a letter to Nature.
The researchers focused on heat shock protein 101 (HSP101), a component of PTEX. Previous studies had suggested that HSP101 might be involved in protein secretion.
So Dr Beck and his colleagues disabled HSP101 in cell cultures, expecting to block the discharge of some malarial proteins. To their surprise, they stopped all of them.
“We think this is a very promising target for drug development,” said study author Daniel Goldberg, MD, PhD, also of Washington University.
“We’re a long way from getting a new drug, but, in the short term, we may look at screening a variety of compounds to see if they have the potential to block HSP101.”
The researchers think HSP101 may ready malarial proteins for secretion through a pore that opens into the red blood cell. Part of this preparation may involve unfolding the proteins into a linear form that allows them to more easily pass through the pore. HSP101 may also give the proteins a biochemical kick that pushes them through the pore.
A separate study published in the same issue of Nature also highlights the importance of PTEX to the malaria parasite’s survival.
Brendan Elsworth, of the Macfarlane Burnet Institute for Medical Research and Public Health in Melbourne, Australia, and his colleagues neutralized the malaria parasite by disabling either HSP101 or PTEX150, another component of PTEX.
“That suggests there are multiple components of the process that we may be able to target with drugs,” Dr Beck said. “In addition, many of the proteins involved in secretion are unlike any human proteins, which means we may be able to disable them without adversely affecting important human proteins.” 
red blood cell; Credit: St Jude
Children’s Research Hospital
Two groups of researchers have found they can kill the malaria parasite by targeting a protein complex.
The research showed that a protein complex known as the Plasmodium translocon of exported proteins (PTEX) is needed for the export of malaria-parasite proteins into the cytoplasm of infected red blood cells, and such export is essential for parasite survival.
When the researchers disrupted passage of the proteins in cell cultures, malaria parasites stopped growing and died.
“The malaria parasite secretes hundreds of diverse proteins to seize control of red blood cells,” said Josh R. Beck, PhD, of the Washington University School of Medicine in St Louis.
“We’ve been searching for a single step that all those various proteins have to take to be secreted, and this looks like just such a bottleneck.”
He and his colleagues detailed their findings in a letter to Nature.
The researchers focused on heat shock protein 101 (HSP101), a component of PTEX. Previous studies had suggested that HSP101 might be involved in protein secretion.
So Dr Beck and his colleagues disabled HSP101 in cell cultures, expecting to block the discharge of some malarial proteins. To their surprise, they stopped all of them.
“We think this is a very promising target for drug development,” said study author Daniel Goldberg, MD, PhD, also of Washington University.
“We’re a long way from getting a new drug, but, in the short term, we may look at screening a variety of compounds to see if they have the potential to block HSP101.”
The researchers think HSP101 may ready malarial proteins for secretion through a pore that opens into the red blood cell. Part of this preparation may involve unfolding the proteins into a linear form that allows them to more easily pass through the pore. HSP101 may also give the proteins a biochemical kick that pushes them through the pore.
A separate study published in the same issue of Nature also highlights the importance of PTEX to the malaria parasite’s survival.
Brendan Elsworth, of the Macfarlane Burnet Institute for Medical Research and Public Health in Melbourne, Australia, and his colleagues neutralized the malaria parasite by disabling either HSP101 or PTEX150, another component of PTEX.
“That suggests there are multiple components of the process that we may be able to target with drugs,” Dr Beck said. “In addition, many of the proteins involved in secretion are unlike any human proteins, which means we may be able to disable them without adversely affecting important human proteins.”
red blood cell; Credit: St Jude
Children’s Research Hospital
Two groups of researchers have found they can kill the malaria parasite by targeting a protein complex.
The research showed that a protein complex known as the Plasmodium translocon of exported proteins (PTEX) is needed for the export of malaria-parasite proteins into the cytoplasm of infected red blood cells, and such export is essential for parasite survival.
When the researchers disrupted passage of the proteins in cell cultures, malaria parasites stopped growing and died.
“The malaria parasite secretes hundreds of diverse proteins to seize control of red blood cells,” said Josh R. Beck, PhD, of the Washington University School of Medicine in St Louis.
“We’ve been searching for a single step that all those various proteins have to take to be secreted, and this looks like just such a bottleneck.”
He and his colleagues detailed their findings in a letter to Nature.
The researchers focused on heat shock protein 101 (HSP101), a component of PTEX. Previous studies had suggested that HSP101 might be involved in protein secretion.
So Dr Beck and his colleagues disabled HSP101 in cell cultures, expecting to block the discharge of some malarial proteins. To their surprise, they stopped all of them.
“We think this is a very promising target for drug development,” said study author Daniel Goldberg, MD, PhD, also of Washington University.
“We’re a long way from getting a new drug, but, in the short term, we may look at screening a variety of compounds to see if they have the potential to block HSP101.”
The researchers think HSP101 may ready malarial proteins for secretion through a pore that opens into the red blood cell. Part of this preparation may involve unfolding the proteins into a linear form that allows them to more easily pass through the pore. HSP101 may also give the proteins a biochemical kick that pushes them through the pore.
A separate study published in the same issue of Nature also highlights the importance of PTEX to the malaria parasite’s survival.
Brendan Elsworth, of the Macfarlane Burnet Institute for Medical Research and Public Health in Melbourne, Australia, and his colleagues neutralized the malaria parasite by disabling either HSP101 or PTEX150, another component of PTEX.
“That suggests there are multiple components of the process that we may be able to target with drugs,” Dr Beck said. “In addition, many of the proteins involved in secretion are unlike any human proteins, which means we may be able to disable them without adversely affecting important human proteins.”
Should you hire a social media consultant?
Over the last few years, I have spoken with hundreds of physicians who tell me that they want to be engaged on social media, but they just don’t have the time or resources. I understand. If this sounds like you, then it’s time to consider hiring a social media consultant.
Hiring the right social media consultant or agency for your medical practice can provide many benefits, including:
• Shaping and marketing your brand.
• Handling daily social media updates and tasks.
• Devising a strategic plan to engage with social media influencers in your specialty.
• Developing a strategic plan to engage with your desired audience. Do you want new patients? More traffic to your practice website?
• Directing you to the best social media platforms for your specific goals, such as Facebook, YouTube, or Pinterest.
• If applicable, developing a plan to promote and market your products and unique services.
• Coaching you and your staff to become better and more efficient at social media.
• Helping you navigate social media analytics.
• Taking the stress off doing it all yourself.
There is no foolproof formula for choosing the best social media consultant for your practice, but here are some key points to keep in mind when considering candidates:
• Do they have experience? How long have they been consulting? How many clients have they had? How many do they currently have? Have they been published online or in print magazines? Do they teach any courses, either online or in person? Do they have success stories they can share?
• Check out their website. It is modern? User friendly? Does it include bios of the employees and client testimonials?
• Check out their social media involvement. Are they actively engaged on social media sites that they suggest you use? Look at their Facebook, Twitter, LinkedIn, and Pinterest accounts, as well as any other sites they may use.
• Are they willing to create unique content for your practice? Some agencies create boilerplate content that they use on multiple client sites. You want to be certain that the content they create for your practice aligns with your marketing and branding goals.
• Do you like them? This is a critical question because social media is, by nature, social. Do the staff members of your potential agency have likable personalities? Are they good listeners? Do they respond promptly to e-mails and phone calls? Do they seem confident or perpetually stressed?
• Do they understand your business? If the firm you hire has only restaurants as clients, then you might be at a disadvantage. Make certain that whomever you hire understands your area of medicine and has a track record of success with medical practices.
• Do they have clearly defined costs? Many firms will offer pricing based on 1- to 3-month intervals. Will they be creating and posting new content daily, weekly, biweekly? Will they work weekends and off-hours? How frequently will they meet with you in person? All of these factors will affect price. Of course, the more hands-on your social media consultants are, the higher the price is likely to be.
Outsourcing your social media is a decision that you and staff must consider carefully. As with most important decisions, it’s advisable to interview several different firms before choosing one. As for price, it ranges dramatically. Some agencies might charge $300 a month, while others might charge $3,000. It’s up to you and your office staff to determine which agency is best suited for your practice’s budget, needs, and goals.
In my next column, I’ll address pitfalls to avoid when choosing a social media consultant or agency.
Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is on Twitter @Dermdoc.
Over the last few years, I have spoken with hundreds of physicians who tell me that they want to be engaged on social media, but they just don’t have the time or resources. I understand. If this sounds like you, then it’s time to consider hiring a social media consultant.
Hiring the right social media consultant or agency for your medical practice can provide many benefits, including:
• Shaping and marketing your brand.
• Handling daily social media updates and tasks.
• Devising a strategic plan to engage with social media influencers in your specialty.
• Developing a strategic plan to engage with your desired audience. Do you want new patients? More traffic to your practice website?
• Directing you to the best social media platforms for your specific goals, such as Facebook, YouTube, or Pinterest.
• If applicable, developing a plan to promote and market your products and unique services.
• Coaching you and your staff to become better and more efficient at social media.
• Helping you navigate social media analytics.
• Taking the stress off doing it all yourself.
There is no foolproof formula for choosing the best social media consultant for your practice, but here are some key points to keep in mind when considering candidates:
• Do they have experience? How long have they been consulting? How many clients have they had? How many do they currently have? Have they been published online or in print magazines? Do they teach any courses, either online or in person? Do they have success stories they can share?
• Check out their website. It is modern? User friendly? Does it include bios of the employees and client testimonials?
• Check out their social media involvement. Are they actively engaged on social media sites that they suggest you use? Look at their Facebook, Twitter, LinkedIn, and Pinterest accounts, as well as any other sites they may use.
• Are they willing to create unique content for your practice? Some agencies create boilerplate content that they use on multiple client sites. You want to be certain that the content they create for your practice aligns with your marketing and branding goals.
• Do you like them? This is a critical question because social media is, by nature, social. Do the staff members of your potential agency have likable personalities? Are they good listeners? Do they respond promptly to e-mails and phone calls? Do they seem confident or perpetually stressed?
• Do they understand your business? If the firm you hire has only restaurants as clients, then you might be at a disadvantage. Make certain that whomever you hire understands your area of medicine and has a track record of success with medical practices.
• Do they have clearly defined costs? Many firms will offer pricing based on 1- to 3-month intervals. Will they be creating and posting new content daily, weekly, biweekly? Will they work weekends and off-hours? How frequently will they meet with you in person? All of these factors will affect price. Of course, the more hands-on your social media consultants are, the higher the price is likely to be.
Outsourcing your social media is a decision that you and staff must consider carefully. As with most important decisions, it’s advisable to interview several different firms before choosing one. As for price, it ranges dramatically. Some agencies might charge $300 a month, while others might charge $3,000. It’s up to you and your office staff to determine which agency is best suited for your practice’s budget, needs, and goals.
In my next column, I’ll address pitfalls to avoid when choosing a social media consultant or agency.
Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is on Twitter @Dermdoc.
Over the last few years, I have spoken with hundreds of physicians who tell me that they want to be engaged on social media, but they just don’t have the time or resources. I understand. If this sounds like you, then it’s time to consider hiring a social media consultant.
Hiring the right social media consultant or agency for your medical practice can provide many benefits, including:
• Shaping and marketing your brand.
• Handling daily social media updates and tasks.
• Devising a strategic plan to engage with social media influencers in your specialty.
• Developing a strategic plan to engage with your desired audience. Do you want new patients? More traffic to your practice website?
• Directing you to the best social media platforms for your specific goals, such as Facebook, YouTube, or Pinterest.
• If applicable, developing a plan to promote and market your products and unique services.
• Coaching you and your staff to become better and more efficient at social media.
• Helping you navigate social media analytics.
• Taking the stress off doing it all yourself.
There is no foolproof formula for choosing the best social media consultant for your practice, but here are some key points to keep in mind when considering candidates:
• Do they have experience? How long have they been consulting? How many clients have they had? How many do they currently have? Have they been published online or in print magazines? Do they teach any courses, either online or in person? Do they have success stories they can share?
• Check out their website. It is modern? User friendly? Does it include bios of the employees and client testimonials?
• Check out their social media involvement. Are they actively engaged on social media sites that they suggest you use? Look at their Facebook, Twitter, LinkedIn, and Pinterest accounts, as well as any other sites they may use.
• Are they willing to create unique content for your practice? Some agencies create boilerplate content that they use on multiple client sites. You want to be certain that the content they create for your practice aligns with your marketing and branding goals.
• Do you like them? This is a critical question because social media is, by nature, social. Do the staff members of your potential agency have likable personalities? Are they good listeners? Do they respond promptly to e-mails and phone calls? Do they seem confident or perpetually stressed?
• Do they understand your business? If the firm you hire has only restaurants as clients, then you might be at a disadvantage. Make certain that whomever you hire understands your area of medicine and has a track record of success with medical practices.
• Do they have clearly defined costs? Many firms will offer pricing based on 1- to 3-month intervals. Will they be creating and posting new content daily, weekly, biweekly? Will they work weekends and off-hours? How frequently will they meet with you in person? All of these factors will affect price. Of course, the more hands-on your social media consultants are, the higher the price is likely to be.
Outsourcing your social media is a decision that you and staff must consider carefully. As with most important decisions, it’s advisable to interview several different firms before choosing one. As for price, it ranges dramatically. Some agencies might charge $300 a month, while others might charge $3,000. It’s up to you and your office staff to determine which agency is best suited for your practice’s budget, needs, and goals.
In my next column, I’ll address pitfalls to avoid when choosing a social media consultant or agency.
Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is on Twitter @Dermdoc.
Group takes first step toward treating rare pediatric disease
Credit: Petr Kratochvil
Investigators say they’ve discovered the genetic defect that underlies STING-associated vasculopathy with onset in infancy (SAVI), which has led to a potential treatment for this rare condition.
The team found that SAVI patients have a mutation in a gene that encodes the protein STING, a signaling molecule whose activation leads to interferon production.
So it followed that JAK inhibitors, which block the interferon pathway, showed activity in samples from SAVI patients.
And based on these results, the investigators are enrolling SAVI patients on a compassionate use protocol for the JAK1/2 inhibitor baricitinib.
Raphaela Goldbach-Mansky, MD, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Maryland, and her colleagues described the results in NEJM.
The research began in 2004, when Dr Goldbach-Mansky was called upon to advise on a patient with a baffling problem. The 10-year-old girl had signs of systemic inflammation, especially in the blood vessels, and she had not responded to any treatments.
She had blistering rashes on her fingers, toes, ears, nose, and cheeks, and she had lost parts of her fingers to the disease. The child also had severe scarring in her lungs and was having trouble breathing. She had shown signs of the disease as an infant and had progressively worsened. She died a few years later.
By 2010, Dr Goldbach-Mansky had seen 2 other patients with the same symptoms. She suspected that all 3 had the same disease, and it was caused by a genetic defect that arose in the children, as their parents were not affected.
Her hunch suggested a strategy for identifying the genetic defect. By comparing the DNA of an affected child with the DNA of the child’s parents, scientists would be able to spot the differences and possibly identify the disease-causing mutation.
The DNA comparison revealed a novel mutation in TMEM173, the gene encoding STING, a protein whose activation leads to the production of interferon. When overproduced, interferon can trigger inflammation.
“Blood tests on the affected children had shown high levels of interferon-induced proteins, so we were not surprised when the mutated gene turned out to be related to interferon signaling,” Dr Goldbach-Mansky said.
When they tested the DNA of 5 other patients with similar symptoms, the investigators found mutations in the same gene, confirming STING’s role in the disease. The excessive inflammation observed in the patients, along with other evidence of interferon pathway activation, indicated that mutations in STING boosted the protein’s activity.
The investigators found that STING was present in high levels in the cells lining the blood vessels and the lungs, which would likely explain why these tissues are predominantly affected by SAVI.
Dr Goldbach-Mansky’s team next looked for ways to dampen the inflammatory response in patients with SAVI.
“When mutations that cause autoinflammatory conditions hit an important pathway, the outcome for patients can be dismal,” Dr Goldbach-Mansky said. “But because SAVI is caused by a single gene defect and interferon has such a strong role, I’m optimistic that we’ll be able to target the pathway and potentially make a huge difference in the lives of these children.”
The JAK inhibitors tofacitinib, ruxolitinib, and baricitinib are known to work by blocking the interferon pathway, so the investigators reasoned the drugs might be effective in patients with SAVI as well.
When they tested the effect of the drugs on SAVI patients’ blood cells in the lab, the team saw a marked reduction in interferon-pathway activation.
The investigators are now enrolling SAVI patients in a compassionate use protocol for baricitinib.
Dr Goldbach-Mansky’s team is also planning to investigate STING’s exact role in the interferon pathway and examine how the mutations that cause SAVI lead to interferon overproduction.
Credit: Petr Kratochvil
Investigators say they’ve discovered the genetic defect that underlies STING-associated vasculopathy with onset in infancy (SAVI), which has led to a potential treatment for this rare condition.
The team found that SAVI patients have a mutation in a gene that encodes the protein STING, a signaling molecule whose activation leads to interferon production.
So it followed that JAK inhibitors, which block the interferon pathway, showed activity in samples from SAVI patients.
And based on these results, the investigators are enrolling SAVI patients on a compassionate use protocol for the JAK1/2 inhibitor baricitinib.
Raphaela Goldbach-Mansky, MD, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Maryland, and her colleagues described the results in NEJM.
The research began in 2004, when Dr Goldbach-Mansky was called upon to advise on a patient with a baffling problem. The 10-year-old girl had signs of systemic inflammation, especially in the blood vessels, and she had not responded to any treatments.
She had blistering rashes on her fingers, toes, ears, nose, and cheeks, and she had lost parts of her fingers to the disease. The child also had severe scarring in her lungs and was having trouble breathing. She had shown signs of the disease as an infant and had progressively worsened. She died a few years later.
By 2010, Dr Goldbach-Mansky had seen 2 other patients with the same symptoms. She suspected that all 3 had the same disease, and it was caused by a genetic defect that arose in the children, as their parents were not affected.
Her hunch suggested a strategy for identifying the genetic defect. By comparing the DNA of an affected child with the DNA of the child’s parents, scientists would be able to spot the differences and possibly identify the disease-causing mutation.
The DNA comparison revealed a novel mutation in TMEM173, the gene encoding STING, a protein whose activation leads to the production of interferon. When overproduced, interferon can trigger inflammation.
“Blood tests on the affected children had shown high levels of interferon-induced proteins, so we were not surprised when the mutated gene turned out to be related to interferon signaling,” Dr Goldbach-Mansky said.
When they tested the DNA of 5 other patients with similar symptoms, the investigators found mutations in the same gene, confirming STING’s role in the disease. The excessive inflammation observed in the patients, along with other evidence of interferon pathway activation, indicated that mutations in STING boosted the protein’s activity.
The investigators found that STING was present in high levels in the cells lining the blood vessels and the lungs, which would likely explain why these tissues are predominantly affected by SAVI.
Dr Goldbach-Mansky’s team next looked for ways to dampen the inflammatory response in patients with SAVI.
“When mutations that cause autoinflammatory conditions hit an important pathway, the outcome for patients can be dismal,” Dr Goldbach-Mansky said. “But because SAVI is caused by a single gene defect and interferon has such a strong role, I’m optimistic that we’ll be able to target the pathway and potentially make a huge difference in the lives of these children.”
The JAK inhibitors tofacitinib, ruxolitinib, and baricitinib are known to work by blocking the interferon pathway, so the investigators reasoned the drugs might be effective in patients with SAVI as well.
When they tested the effect of the drugs on SAVI patients’ blood cells in the lab, the team saw a marked reduction in interferon-pathway activation.
The investigators are now enrolling SAVI patients in a compassionate use protocol for baricitinib.
Dr Goldbach-Mansky’s team is also planning to investigate STING’s exact role in the interferon pathway and examine how the mutations that cause SAVI lead to interferon overproduction.
Credit: Petr Kratochvil
Investigators say they’ve discovered the genetic defect that underlies STING-associated vasculopathy with onset in infancy (SAVI), which has led to a potential treatment for this rare condition.
The team found that SAVI patients have a mutation in a gene that encodes the protein STING, a signaling molecule whose activation leads to interferon production.
So it followed that JAK inhibitors, which block the interferon pathway, showed activity in samples from SAVI patients.
And based on these results, the investigators are enrolling SAVI patients on a compassionate use protocol for the JAK1/2 inhibitor baricitinib.
Raphaela Goldbach-Mansky, MD, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Maryland, and her colleagues described the results in NEJM.
The research began in 2004, when Dr Goldbach-Mansky was called upon to advise on a patient with a baffling problem. The 10-year-old girl had signs of systemic inflammation, especially in the blood vessels, and she had not responded to any treatments.
She had blistering rashes on her fingers, toes, ears, nose, and cheeks, and she had lost parts of her fingers to the disease. The child also had severe scarring in her lungs and was having trouble breathing. She had shown signs of the disease as an infant and had progressively worsened. She died a few years later.
By 2010, Dr Goldbach-Mansky had seen 2 other patients with the same symptoms. She suspected that all 3 had the same disease, and it was caused by a genetic defect that arose in the children, as their parents were not affected.
Her hunch suggested a strategy for identifying the genetic defect. By comparing the DNA of an affected child with the DNA of the child’s parents, scientists would be able to spot the differences and possibly identify the disease-causing mutation.
The DNA comparison revealed a novel mutation in TMEM173, the gene encoding STING, a protein whose activation leads to the production of interferon. When overproduced, interferon can trigger inflammation.
“Blood tests on the affected children had shown high levels of interferon-induced proteins, so we were not surprised when the mutated gene turned out to be related to interferon signaling,” Dr Goldbach-Mansky said.
When they tested the DNA of 5 other patients with similar symptoms, the investigators found mutations in the same gene, confirming STING’s role in the disease. The excessive inflammation observed in the patients, along with other evidence of interferon pathway activation, indicated that mutations in STING boosted the protein’s activity.
The investigators found that STING was present in high levels in the cells lining the blood vessels and the lungs, which would likely explain why these tissues are predominantly affected by SAVI.
Dr Goldbach-Mansky’s team next looked for ways to dampen the inflammatory response in patients with SAVI.
“When mutations that cause autoinflammatory conditions hit an important pathway, the outcome for patients can be dismal,” Dr Goldbach-Mansky said. “But because SAVI is caused by a single gene defect and interferon has such a strong role, I’m optimistic that we’ll be able to target the pathway and potentially make a huge difference in the lives of these children.”
The JAK inhibitors tofacitinib, ruxolitinib, and baricitinib are known to work by blocking the interferon pathway, so the investigators reasoned the drugs might be effective in patients with SAVI as well.
When they tested the effect of the drugs on SAVI patients’ blood cells in the lab, the team saw a marked reduction in interferon-pathway activation.
The investigators are now enrolling SAVI patients in a compassionate use protocol for baricitinib.
Dr Goldbach-Mansky’s team is also planning to investigate STING’s exact role in the interferon pathway and examine how the mutations that cause SAVI lead to interferon overproduction.
FDA approves new product for chronic ITP
Credit: Octapharma USA
The US Food and Drug Administration (FDA) has approved an intravenous immunoglobulin product (octagam 10%) for the treatment of chronic immune thrombocytopenia (ITP).
The product is a solvent/detergent-treated, sterile preparation of highly purified immunoglobulin G derived from large pools of human plasma.
It is intended to raise platelet counts to control or prevent bleeding.
The approval of octagam 10% is based on results of a phase 3 trial (Robak et al, Hematology, Oct. 2010). The trial included 66 patients with chronic ITP and 49 with newly diagnosed ITP.
Among the chronic ITP patients, 81.8% attained the primary efficacy endpoint of clinical response—a platelet count of at least 50×109/L within 7 days of dosing.
Among chronic ITP patients with bleeding at baseline (n=45), 77.7% reported no bleeding at day 7 after treatment.
There were no unexpected tolerability issues, even at the maximum infusion rate of 0.12 mL/kg/minute (720 mg/kg/hour).
The most common treatment-related adverse events in the entire patient cohort were headache (25%), fever (15%), and increased heart rate (11%). The most serious adverse event was headache.
octagam 10% has a black box warning detailing the risk of thrombosis, renal dysfunction, and acute renal failure associated with use of the product. For patients at risk of thrombosis, renal dysfunction, or renal failure, octagam 10% should be given at the minimum infusion rate practicable.
Healthcare providers should ensure adequate hydration in these patients before administering octagam 10%. Providers should also monitor patients for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.
octagam 10% is contraindicated in patients who have a history of severe systemic hypersensitivity reactions, such as anaphylaxis, to human immunoglobulin. The product contains trace amounts of IgA (average 106 µg/mL in a 10% solution). It is contraindicated in IgA-deficient patients with antibodies against IgA and a history of hypersensitivity.
For more details, see the full prescribing information.
The makers of octagam 10%, Octapharma USA, said the product should be available in the US in September.
Credit: Octapharma USA
The US Food and Drug Administration (FDA) has approved an intravenous immunoglobulin product (octagam 10%) for the treatment of chronic immune thrombocytopenia (ITP).
The product is a solvent/detergent-treated, sterile preparation of highly purified immunoglobulin G derived from large pools of human plasma.
It is intended to raise platelet counts to control or prevent bleeding.
The approval of octagam 10% is based on results of a phase 3 trial (Robak et al, Hematology, Oct. 2010). The trial included 66 patients with chronic ITP and 49 with newly diagnosed ITP.
Among the chronic ITP patients, 81.8% attained the primary efficacy endpoint of clinical response—a platelet count of at least 50×109/L within 7 days of dosing.
Among chronic ITP patients with bleeding at baseline (n=45), 77.7% reported no bleeding at day 7 after treatment.
There were no unexpected tolerability issues, even at the maximum infusion rate of 0.12 mL/kg/minute (720 mg/kg/hour).
The most common treatment-related adverse events in the entire patient cohort were headache (25%), fever (15%), and increased heart rate (11%). The most serious adverse event was headache.
octagam 10% has a black box warning detailing the risk of thrombosis, renal dysfunction, and acute renal failure associated with use of the product. For patients at risk of thrombosis, renal dysfunction, or renal failure, octagam 10% should be given at the minimum infusion rate practicable.
Healthcare providers should ensure adequate hydration in these patients before administering octagam 10%. Providers should also monitor patients for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.
octagam 10% is contraindicated in patients who have a history of severe systemic hypersensitivity reactions, such as anaphylaxis, to human immunoglobulin. The product contains trace amounts of IgA (average 106 µg/mL in a 10% solution). It is contraindicated in IgA-deficient patients with antibodies against IgA and a history of hypersensitivity.
For more details, see the full prescribing information.
The makers of octagam 10%, Octapharma USA, said the product should be available in the US in September.
Credit: Octapharma USA
The US Food and Drug Administration (FDA) has approved an intravenous immunoglobulin product (octagam 10%) for the treatment of chronic immune thrombocytopenia (ITP).
The product is a solvent/detergent-treated, sterile preparation of highly purified immunoglobulin G derived from large pools of human plasma.
It is intended to raise platelet counts to control or prevent bleeding.
The approval of octagam 10% is based on results of a phase 3 trial (Robak et al, Hematology, Oct. 2010). The trial included 66 patients with chronic ITP and 49 with newly diagnosed ITP.
Among the chronic ITP patients, 81.8% attained the primary efficacy endpoint of clinical response—a platelet count of at least 50×109/L within 7 days of dosing.
Among chronic ITP patients with bleeding at baseline (n=45), 77.7% reported no bleeding at day 7 after treatment.
There were no unexpected tolerability issues, even at the maximum infusion rate of 0.12 mL/kg/minute (720 mg/kg/hour).
The most common treatment-related adverse events in the entire patient cohort were headache (25%), fever (15%), and increased heart rate (11%). The most serious adverse event was headache.
octagam 10% has a black box warning detailing the risk of thrombosis, renal dysfunction, and acute renal failure associated with use of the product. For patients at risk of thrombosis, renal dysfunction, or renal failure, octagam 10% should be given at the minimum infusion rate practicable.
Healthcare providers should ensure adequate hydration in these patients before administering octagam 10%. Providers should also monitor patients for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.
octagam 10% is contraindicated in patients who have a history of severe systemic hypersensitivity reactions, such as anaphylaxis, to human immunoglobulin. The product contains trace amounts of IgA (average 106 µg/mL in a 10% solution). It is contraindicated in IgA-deficient patients with antibodies against IgA and a history of hypersensitivity.
For more details, see the full prescribing information.
The makers of octagam 10%, Octapharma USA, said the product should be available in the US in September.
Nanoparticles could improve cancer diagnosis
Self-assembling nanoparticles may help physicians diagnose cancers earlier, according to a study published in Angewandte Chemie.
The nanoparticles boost the effectiveness of magnetic resonance imaging (MRI) by specifically seeking out CXCR4 receptors, which are found in cancerous cells.
The iron oxide nanoparticles are coated with peptide ligands that target tumor sites. When the particles find a tumor, they begin to interact with the cancerous cells.
Cancer-specific matrix metalloproteinase biomarkers prompt the nanoparticles to self-assemble into larger particles. And these larger particles are more visible on an MRI scan.
Researchers used cancer cells and mouse models to compare the effects of the self-assembling nanoparticles in MRI scanning against commonly used imaging agents. The nanoparticles produced a more powerful signal and created a clearer image of the tumor.
The team said the nanoparticles increase the sensitivity of MRI scans and could ultimately improve physicians’ ability to detect cancerous cells at much earlier stages of development.
“By improving the sensitivity of an MRI examination, our aim is to help doctors spot something that might be cancerous much more quickly,” said study author Nicholas Long, PhD, of Imperial College London in the UK. “This would enable patients to receive effective treatment sooner, which would hopefully improve survival rates from cancer.”
In addition to improving the sensitivity of MRI scans, the nanoparticles also appear to be safe. Before testing and injecting the particles into mice, the researchers had to ensure the particles would not become so big as to cause damage.
The team injected the particles into a saline solution inside a petri dish and monitored their growth over a 4-hour period. The nanoparticles grew from 100 nm to 800 nm, which was still small enough not to cause any harm.
Now, the researchers are working to enhance the effectiveness of the nanoparticles. And they hope to test their design in a human trial within the next 3 to 5 years.
“We would like to improve the design to make it even easier for doctors to spot a tumor and for surgeons to then operate on it,” Dr Long said. “We’re now trying to add an extra optical signal so that the nanoparticle would light up with a luminescent probe once it had found its target. So, combined with the better MRI signal, it will make it even easier to identify tumors.”
Self-assembling nanoparticles may help physicians diagnose cancers earlier, according to a study published in Angewandte Chemie.
The nanoparticles boost the effectiveness of magnetic resonance imaging (MRI) by specifically seeking out CXCR4 receptors, which are found in cancerous cells.
The iron oxide nanoparticles are coated with peptide ligands that target tumor sites. When the particles find a tumor, they begin to interact with the cancerous cells.
Cancer-specific matrix metalloproteinase biomarkers prompt the nanoparticles to self-assemble into larger particles. And these larger particles are more visible on an MRI scan.
Researchers used cancer cells and mouse models to compare the effects of the self-assembling nanoparticles in MRI scanning against commonly used imaging agents. The nanoparticles produced a more powerful signal and created a clearer image of the tumor.
The team said the nanoparticles increase the sensitivity of MRI scans and could ultimately improve physicians’ ability to detect cancerous cells at much earlier stages of development.
“By improving the sensitivity of an MRI examination, our aim is to help doctors spot something that might be cancerous much more quickly,” said study author Nicholas Long, PhD, of Imperial College London in the UK. “This would enable patients to receive effective treatment sooner, which would hopefully improve survival rates from cancer.”
In addition to improving the sensitivity of MRI scans, the nanoparticles also appear to be safe. Before testing and injecting the particles into mice, the researchers had to ensure the particles would not become so big as to cause damage.
The team injected the particles into a saline solution inside a petri dish and monitored their growth over a 4-hour period. The nanoparticles grew from 100 nm to 800 nm, which was still small enough not to cause any harm.
Now, the researchers are working to enhance the effectiveness of the nanoparticles. And they hope to test their design in a human trial within the next 3 to 5 years.
“We would like to improve the design to make it even easier for doctors to spot a tumor and for surgeons to then operate on it,” Dr Long said. “We’re now trying to add an extra optical signal so that the nanoparticle would light up with a luminescent probe once it had found its target. So, combined with the better MRI signal, it will make it even easier to identify tumors.”
Self-assembling nanoparticles may help physicians diagnose cancers earlier, according to a study published in Angewandte Chemie.
The nanoparticles boost the effectiveness of magnetic resonance imaging (MRI) by specifically seeking out CXCR4 receptors, which are found in cancerous cells.
The iron oxide nanoparticles are coated with peptide ligands that target tumor sites. When the particles find a tumor, they begin to interact with the cancerous cells.
Cancer-specific matrix metalloproteinase biomarkers prompt the nanoparticles to self-assemble into larger particles. And these larger particles are more visible on an MRI scan.
Researchers used cancer cells and mouse models to compare the effects of the self-assembling nanoparticles in MRI scanning against commonly used imaging agents. The nanoparticles produced a more powerful signal and created a clearer image of the tumor.
The team said the nanoparticles increase the sensitivity of MRI scans and could ultimately improve physicians’ ability to detect cancerous cells at much earlier stages of development.
“By improving the sensitivity of an MRI examination, our aim is to help doctors spot something that might be cancerous much more quickly,” said study author Nicholas Long, PhD, of Imperial College London in the UK. “This would enable patients to receive effective treatment sooner, which would hopefully improve survival rates from cancer.”
In addition to improving the sensitivity of MRI scans, the nanoparticles also appear to be safe. Before testing and injecting the particles into mice, the researchers had to ensure the particles would not become so big as to cause damage.
The team injected the particles into a saline solution inside a petri dish and monitored their growth over a 4-hour period. The nanoparticles grew from 100 nm to 800 nm, which was still small enough not to cause any harm.
Now, the researchers are working to enhance the effectiveness of the nanoparticles. And they hope to test their design in a human trial within the next 3 to 5 years.
“We would like to improve the design to make it even easier for doctors to spot a tumor and for surgeons to then operate on it,” Dr Long said. “We’re now trying to add an extra optical signal so that the nanoparticle would light up with a luminescent probe once it had found its target. So, combined with the better MRI signal, it will make it even easier to identify tumors.”
FDA approves product to treat attacks in HAE
The US Food and Drug Administration (FDA) has approved the first recombinant C1-esterase inhibitor product (Ruconest) for the treatment of acute attacks in adults and adolescents with hereditary angioedema (HAE).
HAE, which is caused by insufficient amounts of a plasma protein called C1-esterase inhibitor, affects approximately 6000 to 10,000 people in the US.
People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract, or airway. These acute attacks can occur spontaneously or may be triggered by stress, surgery, or infection.
“Hereditary angioedema is a rare and potentially life-threatening disease,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research. “[The approval of Ruconest] provides an important treatment option for these patients.”
Ruconest is a human recombinant C1-esterase inhibitor purified from the milk of genetically modified rabbits. The product is intended to restore the level of functional C1-esterase inhibitor in a patient’s plasma, thereby treating the acute attack of swelling.
Trial results have suggested Ruconest is superior to placebo in treating most HAE attacks. However, due to the limited number of patients with laryngeal attacks, Ruconest has not been established as an effective treatment for these attacks.
The FDA approval of Ruconest to treat HAE is based on results of a phase 3, randomized, controlled trial (RCT), which included an open-label extension (OLE) phase, and is supported by the results of 2 additional RCTs and 2 additional OLE studies.
The pivotal RCT and OLE studies included 44 subjects who experienced 170 HAE attacks. The primary efficacy endpoint was the time to the beginning of symptom relief, assessed using patient-reported responses to 2 questions about the change in overall severity of their HAE attack symptoms after the start of treatment.
The researchers assessed these responses at regular time points for each of the affected anatomical locations for up to 24 hours. To achieve the primary endpoint, a patient had to have a positive response to both questions, along with persistence of improvement at the next assessment time (ie, the same or a better response).
There was a statistically significant difference in the time to the beginning of symptom relief in the intent-to-treat population (n=75) between the Ruconest and placebo arms (P=0.031).
The median time to the beginning of symptom relief was 90 minutes for Ruconest-treated patients (n=44) and 152 minutes for placebo-treated patients (n=31).
The most common adverse events, reported in at least 2% of patients receiving Ruconest, were headache, nausea, and diarrhea.
Serious adverse events associated with the treatment include anaphylaxis and arterial and venous thromboembolic events in patients with risk factors, such as an indwelling venous catheter/access device, a prior history of thrombosis, underlying atherosclerosis, the use of oral contraceptives or certain androgens, morbid obesity, and immobility.
Ruconest is manufactured by Pharming Group NV, located in Leiden, the Netherlands, and will be distributed in the US by Santarus Inc., a wholly owned subsidiary of Salix Pharmaceuticals Inc., which is located in Raleigh, North Carolina.
Salix is planning to make Ruconest available to patients later this year.
The US Food and Drug Administration (FDA) has approved the first recombinant C1-esterase inhibitor product (Ruconest) for the treatment of acute attacks in adults and adolescents with hereditary angioedema (HAE).
HAE, which is caused by insufficient amounts of a plasma protein called C1-esterase inhibitor, affects approximately 6000 to 10,000 people in the US.
People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract, or airway. These acute attacks can occur spontaneously or may be triggered by stress, surgery, or infection.
“Hereditary angioedema is a rare and potentially life-threatening disease,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research. “[The approval of Ruconest] provides an important treatment option for these patients.”
Ruconest is a human recombinant C1-esterase inhibitor purified from the milk of genetically modified rabbits. The product is intended to restore the level of functional C1-esterase inhibitor in a patient’s plasma, thereby treating the acute attack of swelling.
Trial results have suggested Ruconest is superior to placebo in treating most HAE attacks. However, due to the limited number of patients with laryngeal attacks, Ruconest has not been established as an effective treatment for these attacks.
The FDA approval of Ruconest to treat HAE is based on results of a phase 3, randomized, controlled trial (RCT), which included an open-label extension (OLE) phase, and is supported by the results of 2 additional RCTs and 2 additional OLE studies.
The pivotal RCT and OLE studies included 44 subjects who experienced 170 HAE attacks. The primary efficacy endpoint was the time to the beginning of symptom relief, assessed using patient-reported responses to 2 questions about the change in overall severity of their HAE attack symptoms after the start of treatment.
The researchers assessed these responses at regular time points for each of the affected anatomical locations for up to 24 hours. To achieve the primary endpoint, a patient had to have a positive response to both questions, along with persistence of improvement at the next assessment time (ie, the same or a better response).
There was a statistically significant difference in the time to the beginning of symptom relief in the intent-to-treat population (n=75) between the Ruconest and placebo arms (P=0.031).
The median time to the beginning of symptom relief was 90 minutes for Ruconest-treated patients (n=44) and 152 minutes for placebo-treated patients (n=31).
The most common adverse events, reported in at least 2% of patients receiving Ruconest, were headache, nausea, and diarrhea.
Serious adverse events associated with the treatment include anaphylaxis and arterial and venous thromboembolic events in patients with risk factors, such as an indwelling venous catheter/access device, a prior history of thrombosis, underlying atherosclerosis, the use of oral contraceptives or certain androgens, morbid obesity, and immobility.
Ruconest is manufactured by Pharming Group NV, located in Leiden, the Netherlands, and will be distributed in the US by Santarus Inc., a wholly owned subsidiary of Salix Pharmaceuticals Inc., which is located in Raleigh, North Carolina.
Salix is planning to make Ruconest available to patients later this year.
The US Food and Drug Administration (FDA) has approved the first recombinant C1-esterase inhibitor product (Ruconest) for the treatment of acute attacks in adults and adolescents with hereditary angioedema (HAE).
HAE, which is caused by insufficient amounts of a plasma protein called C1-esterase inhibitor, affects approximately 6000 to 10,000 people in the US.
People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract, or airway. These acute attacks can occur spontaneously or may be triggered by stress, surgery, or infection.
“Hereditary angioedema is a rare and potentially life-threatening disease,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research. “[The approval of Ruconest] provides an important treatment option for these patients.”
Ruconest is a human recombinant C1-esterase inhibitor purified from the milk of genetically modified rabbits. The product is intended to restore the level of functional C1-esterase inhibitor in a patient’s plasma, thereby treating the acute attack of swelling.
Trial results have suggested Ruconest is superior to placebo in treating most HAE attacks. However, due to the limited number of patients with laryngeal attacks, Ruconest has not been established as an effective treatment for these attacks.
The FDA approval of Ruconest to treat HAE is based on results of a phase 3, randomized, controlled trial (RCT), which included an open-label extension (OLE) phase, and is supported by the results of 2 additional RCTs and 2 additional OLE studies.
The pivotal RCT and OLE studies included 44 subjects who experienced 170 HAE attacks. The primary efficacy endpoint was the time to the beginning of symptom relief, assessed using patient-reported responses to 2 questions about the change in overall severity of their HAE attack symptoms after the start of treatment.
The researchers assessed these responses at regular time points for each of the affected anatomical locations for up to 24 hours. To achieve the primary endpoint, a patient had to have a positive response to both questions, along with persistence of improvement at the next assessment time (ie, the same or a better response).
There was a statistically significant difference in the time to the beginning of symptom relief in the intent-to-treat population (n=75) between the Ruconest and placebo arms (P=0.031).
The median time to the beginning of symptom relief was 90 minutes for Ruconest-treated patients (n=44) and 152 minutes for placebo-treated patients (n=31).
The most common adverse events, reported in at least 2% of patients receiving Ruconest, were headache, nausea, and diarrhea.
Serious adverse events associated with the treatment include anaphylaxis and arterial and venous thromboembolic events in patients with risk factors, such as an indwelling venous catheter/access device, a prior history of thrombosis, underlying atherosclerosis, the use of oral contraceptives or certain androgens, morbid obesity, and immobility.
Ruconest is manufactured by Pharming Group NV, located in Leiden, the Netherlands, and will be distributed in the US by Santarus Inc., a wholly owned subsidiary of Salix Pharmaceuticals Inc., which is located in Raleigh, North Carolina.
Salix is planning to make Ruconest available to patients later this year.
IV Antibiotic Duration in Children
Rationally defining the appropriate duration of intravenous (IV) antibiotics for children with bacterial infections is challenging. For example, how long should a 2‐week‐old infant with a urinary tract infection (UTI) caused by Escherichia coli (E coli) be treated intravenously if the infant has responded to treatment and is back to baseline within 1 to 2 days? What if the blood culture was also positive for E coli? What are the risks and benefits of continuing IV antibiotics?
Such questions are common for pediatric hospitalists. Bacterial infections remain a relatively frequent cause of pediatric hospitalization, especially in neonates where 5 of the top 10 causes of hospitalizations are related to bacterial infections.[1] For some conditions, children remain hospitalized after clinical improvement simply for ongoing provision of IV antibiotics. Alternatively, some children are discharged home with a peripherally inserted central catheter (PICC) to complete an IV course.
The decision regarding the duration of IV antibiotics varies according to the condition for which the antibiotic is prescribed and often by practitioner or hospital. Many recommendations are numerically based (eg, 10 days for group B Streptococcus [GBS] bacteremia, 21 days for E coli meningitis), without taking into account patient‐level factors such as initial severity or response to therapy. These concrete recommendations may in fact be preferred by some practitioners, as suggested by a former chairman of the Committee on Infectious Disease for the American Academy of Pediatrics (AAP): The Red Book is designed for people who make decisions. It cannot waffle on an issue. It has to make a positive recommendation even if the data are incomplete.[2] A potential downside of this mentality, however, is that some practitioners may then feel obligated to follow these recommendations despite the lack of supportive evidence.
EXTENDING IV ANTIBIOTICS BEYOND CLINICAL RECOVERY
What is the rationale for continuing IV antibiotics in infants whose symptoms have completely resolved? Several factors likely drive these decisions: prevention of recurrences, concerns about bioavailability of enteral antibiotics and patient compliance, adherence to expert recommendations/guidelines, and perhaps a general sense that more is betterthat serious infections and/or their sequelae require more aggressive treatments.
Recurrence of a potentially life‐threatening infection is an understandable concern. Even when symptoms have resolved and there is documented clearance of the infection, such clearance does not necessarily signify that the body has rid itself of the pathogen completely. Some infections are deep seated and may warrant continuing treatment despite apparent recovery. To some, the risks of prolonging IV therapy may seem inconsequential when juxtaposed to a potentially devastating recurrence. However, in many conditions, recurrences may be related to host issues or ongoing exposures rather than inadequate treatment of the original infection. Recurrent UTIs, for example, are more likely in infants with urologic abnormalities,[3] and recurrent GBS bacteremia has been associated with GBS colonization of maternal breast milk and/or maternal mastitis.[4, 5, 6, 7] Although it is tempting to extend IV courses to prevent recurrences, it is not clear that the benefits of such an approach outweigh the risks.
Concerns over enteral absorption and bioavailability are also understandable, especially in young infants. The superior efficacy of IV over oral antibiotics in general is well accepted for many pediatric conditions, and in some cases (eg, septic shock) it would be unethical to perform a head‐to‐head trial. However, the lack of any published trials (to our knowledge) in pediatrics confirming the superiority of IV antibiotics suggests that oral antibiotic absorption is sufficient for many infections. Even in neonates, several studies have demonstrated that therapeutic serum levels are easily reached with oral dosing of amoxicillin in term and preterm neonates.[8, 9]
For the remainder of this review, the published recommendations and available evidence behind the duration of IV therapy are summarized for 4 bacterial infections in children in which IV antibiotic therapy often continues after clinical recovery: meningitis, bacteremia, UTI, and acute osteomyelitis. We conclude by proposing additional considerations for IV antibiotic durations, especially in situations where guidelines and/or evidence are either nonexistent, dated, conflicting, or contrary to evidence from published studies.
BACTERIAL MENINGITIS
The Infectious Disease Society of America and the British National Institute for Clinical Evidence have both published guidelines with pediatric recommendations for duration of therapy in bacterial meningitis,[10, 11] though the recommendations differ somewhat for 3 of the 4 most common pathogens, and are not always concordant with evidence from randomized controlled trials (Table 1).[12, 13, 14]
| Pathogen | IDSA | NICE | Minimum Range Achieving Equivalent Outcomes in Recent Randomized Trials |
|---|---|---|---|
| |||
| Group B Streptococcus | 1421 days | 14 days | None available |
| Neisseria meningititis | 7 days | 7 days | 15 days[12, 13, 14] |
| Haemophilus influenzae type b | 7 days | 10 days | 45 days[12, 13] |
| Streptococcus pneumoniae | 1014 days | 14 days | 45 days[12, 13] |
A recent meta‐analysis on duration of therapy in meningitis included 5 open‐label trials of ceftriaxone for bacterial meningitis in children.[12] These trials included the 3 most common pathogens and were categorized as short‐course (47 days, n=196 patients) and long‐course (714 days, n=187 patients) therapy. There was no significant difference in clinical success or long‐term neurological complications between groups. Subsequently, a multicountry trial enrolled over 1000 children 2 months to 12 years of age with meningitis caused by Haemophilus influenzae type b, Streptococcus pneumonia, or Neisseria meningititis who were stable after 5 days of IV ceftriaxone therapy and randomized them to receive placebo or an additional 5 days of ceftriaxone.[13] Patients with persistence of seizures, bacteremia, abscess or distant infections, or who were judged to be deteriorating or still severely ill at the 5‐day point were excluded (4.7% of the children who were recruited on day 0). There were no significant differences in bacteriologic failures, clinical failures, or clinical sequelae in survivors. The authors concluded that ceftriaxone can be discontinued in children with bacterial meningitis who are clinically stable after 5 days of IV therapy. Further trials in developed countries are needed.
BACTEREMIA
Because of routine vaccination against H influenzae type b and S pneumoniae, bacteremia beyond the first few months of life in otherwise healthy children is now rare.[15] Even in infants too young to benefit directly from vaccination, the epidemiology of bacteremia has changed considerably over the last few decades, with E coli and GBS constituting the majority (65%77%) of cases.[16, 17] We will limit this review on bacteremia to these 2 organisms in young infants.
Most cases of E coli bacteremia are associated with UTI (91%98%),[16, 17] and most bacteremic UTIs (88%92%) are caused by E coli.[18, 19, 20, 21] There are no official recommendations for the duration of treatment of bacteremic UTI, and only a limited amount of evidence can be gleaned from existing studies. In a trial of oral cefixime for infants aged 1 to 24 months with UTI, all 13 infants with bacteremia fared well whether they received oral cefixime only or IV cefotaxime for 3 days followed by oral cefixime.[18] In a study on length of IV antibiotic therapy in over 12,000 infants <6 months old with UTI, the presence of bacteremia predicted longer IV treatment length (bacteremia was present in 0.5% of the short IV group vs 0.8% of the long IV group, P=0.02) but did not predict treatment failure, defined as readmission within 30 days.[3] In a multicenter investigation of 229 infants <3 months old with bacteremic UTI, the duration of parenteral antibiotics was extremely variable (range, 117 days) and was not associated with treatment failure, defined as recurrent UTI caused by the same organism within 30 days (mean duration 7.8 days in the treatment‐failure group vs 7.7 days in the no‐failure group, P=0.99).[21] In summary, there is no evidence to support a prolonged course (ie, >35 days) of IV antibiotics for bacteremic UTI.
For bacteremia caused by GBS, although the Red Book Committee on Infectious Disease recommends 10 days of IV antibiotics,[22] to our knowledge there are no experimental or observational investigations to support this recommendation. Although available studies suggest that IV courses of at least 10 days are generally provided,[7, 23] no studies have compared outcomes of infants treated with short versus long courses. However, in a study that included 29 full‐term neonates with GBS bacteremia, all 29 had responded initially to 48 hours of intravenous antibiotics (defined as being asymptomatic and fed enterally), and were then treated successfully with high‐dose oral amoxicillin for the remainder of the course, with no recurrences.[8] Although recurrences are estimated to occur in 0.5% to 3% of babies treated for GBS infections, many recurrences are associated with exposure factors such as GBS colonization of the breast milk.[4, 5, 6, 7] In summary, although 10 or more days of IV antibiotic therapy remains a common published recommendation, there is no supportive evidence. More research is needed to assess whether shorter IV courses are safe.
UTI
Most UTIs can be treated with oral antibiotics.[24] In its practice parameter on febrile UTIs in infants 2 months to 2 years of age, the AAP recommends oral antibiotics for well‐appearing children.[25] This recommendation is supported by a recent Cochrane review on the topic,[26] and at least 3 additional trials that have demonstrated that long IV courses do not yield better outcomes than shorter IV courses or oral only courses.[27, 28, 29]
However, all of these trials exclude infants <1 month old, and there are no published recommendations for the <2‐month‐old age group. The study by Brady et al. on >12,000 infants <6 months old with UTI demonstrated no significant differences in UTI readmission rates between infants who were given 4 days of IV antibiotics versus those who were given <4 days.[3] There were 3,383 infants <30 days old in this study, and about one‐third of these babies received a short IV course. Failure rates were nearly identical in each group (2.3% in short course vs 2.4% in long course) even after risk adjustment (personal communication with Patrick Brady, MD, on February 7, 2014). Magin et al. describe 172 neonates (median age 19 days) with UTI who were treated intravenously for a median duration of 4 days (interquartile range, 36 days) and did not experience treatment failures or relapses.[30]
In summary, most cases of UTI can be managed with oral antibiotics. Uncertainty remains over the optimal approach for infants <1 to 2 months old, an age range not considered in current published guidelines. Current evidence suggests that IV treatment for 3 to 4 days followed by oral therapy may be sufficient treatment in this age group.
ACUTE OSTEOMYELITIS
Given the excellent blood supply to rapidly growing tissues in children, shorter durations of IV therapy have been studied with increasing frequency. A 2002 systematic review included 12 prospective cohort studies with at least 6 months of follow‐up.[31] Studies were stratified into 7 days or >7 days IV therapy, and there were no differences in cure rates. Subsequently, a large Finnish trial reported on 131 children who received an initial short IV course (24 days) followed by 20 versus 30 total days of therapy with very low treatment failure rates.[32]
The largest study from the United States to date analyzed nearly 2000 cases of osteomyelitis from 29 hospitals.[33] This study defined a prolonged IV course by placement of a central venous catheter. The rates of prolonged IV therapy varied significantly across hospitals, ranging from 10% to 95% of patients, without detectable differences in outcomes. Furthermore, the readmission rate for catheter related complications (3%) was nearly as high as the overall treatment failure rate (4%5%). Recently, Arnold et al. reported 8 years' experience with a management algorithm to guide the transition to oral antibiotics in pediatric osteoarticular infections in a patient specific manner.[34] This study included 194 patients (154 uncomplicated and 40 complicated cases), all with culture‐proven disease. Transition to oral antibiotics occurred based on resolution of fever and pain, improved function of the affected region, and a C‐reactive protein level of <3 mg/dL, and occurred at an average of 10 days into the treatment course. These authors also provided extensive information about complications to demonstrate that the proposed strategy can be used with a wide range of patients and pathogens. There was a single microbiologic treatment failure after oral step‐down therapy in a complicated osteoarticular infection, with a retained bony fragment. This study represents a successful example of a patient‐centered approach to IV antibiotic duration.
A PATIENT‐CENTERED APPROACH
Returning to the example above of the 2‐week‐old with UTI (with or without bacteremia), there are no published guidelines and only limited available evidence to help guide the duration of IV antibiotics in this case. When standards of care (eg, from published guidelines, review articles, textbooks, or local expert guidance) are nonexistent, conflicting, dated, or contrary to existing evidence, patient‐level factors can be incorporated into the decision‐making process (Table 2). In these cases, tailoring the IV antibiotic course to the individual's response (referred to in 1 review as the ultimate bioassay of the therapy[2]), while also weighing risks and benefits of ongoing therapy, is a logical approach.
| Consideration | Description |
|---|---|
| |
| Severity of initial infection | If concern of recurrence is the justification for a longer IV course, then a more prolonged course might be considered for a more severe initial presentation (eg, septic shock, multisystem organ failure, intensive care unit admission). |
| Response to therapy | Continued IV antibiotics might be warranted in patients who are still symptomatic (eg, fever, vomiting). Inflammatory markers have been used to guide therapy in osteomyelitis.[34] |
| Patient compliance | If a child does not tolerate oral antibiotics or there are concerns about family adherence, a longer IV course may be considered. |
| Family preferences | Shared decision making can be employed, especially when there is no clear evidence supporting a specific duration. |
| Assessment of harms of ongoing hospitalization and/or prolonged IV therapy | See Table 3 |
SEVERITY OF INITIAL INFECTION AND RESPONSE TO THERAPY
The severity of the initial infection, whether in terms of presentation or clinical recovery, can factor into the duration of therapy. Provision of a longer IV course to prevent (albeit theoretically) a recurrence makes more logical sense in an infant with GBS bacteremia who was ill enough to warrant intensive care unit admission than in an infant whose only symptom was a fever. Similarly, most practitioners would be reluctant to stop IV antibiotics and discharge a patient with a bacterial infection who is persistently febrile or vomiting. Although the use of inflammatory markers and other clinical symptoms to guide therapy has been limited to osteomyelitis, this approach might be useful and should be studied in other conditions.
SHARED DECISION MAKING
Shared decision making can also be employed. Parents of sick, hospitalized children generally prefer to be involved in the decision‐making process.[35] For a parent who has concerns about their child's well‐being in the hospital, or has multiple other children at home, competing career obligations, and/or limited family support, the burden of ongoing hospitalization can be significant, and should be factored into decision making. Involving parents in medical decisions may lead to a reduction in utilization for some conditions.[36]
ASSESSMENT OF RISKS/COSTS
The risks and costs of pediatric hospitalization and prolonged IV antibiotics are well described in the literature and are summarized in Table 3. Although the benefits of prolonging IV antibiotics in a child who has recovered from an acute bacterial infection are largely theoretical, many of the risks are concrete and quantifiable. For example, a young infant being treated for a bacteremic UTI may run out of potential IV sites and need a PICC line to continue IV therapy, which according to a recent review of 2574 PICC lines has a 21% complication rate. This rate is even higher in children for whom the PICC line indication was provision of antibiotics (27%) and for infants <1 year of age (44%).[37] Moreover, this procedure often requires sedation or anesthesia for placement, which has both known and unknown risks, including concerns about subsequent adverse effects on development in young children.[38] Nosocomial exposure to seasonal viruses poses an additional risk to hospitalized children.[39]
| Harm of Intravenous Antibiotic Therapy | Description or Example |
|---|---|
| |
| Complications from peripheral IV catheter | Leading source of pain and distress for hospitalized children.[44] |
| Serious complications can occur following IV infiltrates.[45] | |
| Complications from PICC line | Approximately 20% overall complication rate (44% in infants <1 year old).[37] |
| Complications led to rehospitalization of 3% of children being treated with prolonged antibiotics for osteomyelitis.[33] | |
| When thrombosis occurs (up to 9% risk in neonates[46]), 3 months of anticoagulation is recommended.[47] | |
| Complications may arise from sedation/anesthesia necessary to place catheter. Anesthesia has been associated with adverse behavioral or developmental outcomes in children <4 years of age.[38] | |
| Risk of nosocomial infection while hospitalized | An estimated 6% of hospital RSV infections are nosocomial, which are associated with a more prolonged LOS than hospitalizations for community‐acquired RSV.[39] |
| Medication error | In 1 investigation, serious medication errors occurred in 22 per 1,000 patient‐days in a large children's hospital.[48] |
| Emotional and financial burdens | Hospitalization can pose a significant strain on the child, parents, and siblings. |
| Financial costs to healthcare system | In 2003, infection‐related hospitalizations in infants had an average cost of $4,000 (average LOS 3.5 days).[1] |
| Harms associated with prolonged courses of antibiotics in general (IV or PO) | Antibiotic resistance, diarrhea (including Clostridium difficile), allergic reactions, increased costs.[49] |
These additional considerations for the duration of IV antibiotics are not evidence based and should not be used to justify an IV duration that differs dramatically from an accepted standard of care. These are merely considerations that incorporate clinical judgment and a comprehensive analysis of risks and benefits in situations where the available evidence is suboptimal. This approach can be adopted both as a framework for future research and directly in clinical practice.
CONCLUSION
In an era of increasing focus on overtreatment/waste,[40] patient safety,[41] and patient‐centered care,[42] the duration of IV antibiotics for common bacterial infections is a prime target for improving pediatric healthcare value. As emphasized by Michael Porter recently in The New England Journal of Medicine, value should always be defined around the customer.[43] A high‐value approach to IV antibiotic duration incorporates a rigorous assessment of risks and benefits that focuses on best evidence and patient‐level factors.
In discussing published guidelines in a review on bacterial meningitis therapy, Michael Radetsky noted that [R]ecommended criteria, even if provisional, may inadvertently become invested with an independent power to force submission and prohibit deviation. The danger is that sensitivity to individual responsiveness and variability will be lost.[2] Guidelines are useful tools in pediatrics and should continue to be used to direct IV antibiotic durations for bacterial infections in children. However, the emphasis on fixed durations of IV antibiotics might not always serve the best interest of the patient. When guidelines are lacking or contradictory, patient factors should also be considered.
Acknowledgements
The authors thank Ellen R. Wald, MD, and Kenneth B. Roberts, MD, for their thoughtful and valuable additions to this review.
Disclosure: Nothing to report.
- , , , , . Infectious disease hospitalizations among infants in the United States. Pediatrics. 2008;121(2):244–252.
- . Duration of treatment in bacterial meningitis: a historical inquiry. Pediatr Infect Dis J. 1990;9(1):2–9.
- , , . Length of intravenous antibiotic therapy and treatment failure in infants with urinary tract infections. Pediatrics. 2010;126(2):196–203.
- , , , et al. Group B streptococci in milk and late neonatal infections: an analysis of cases in the literature. Arch Dis Child Fetal Neonatal Ed. 2014;99(1):F41–F47.
- , , . Recurrent late‐onset group B Streptococcus sepsis in a preterm infant acquired by expressed breastmilk transmission: a case report. Breastfeed Med. 2013;8(1):134–136.
- , , , , , . Late‐onset and recurrent neonatal Group B streptococcal disease associated with breast‐milk transmission. Pediatr Dev Pathol. 2003;6(3):251–256.
- , , , , . A 5‐year review of recurrent group B streptococcal disease: lessons from twin infants. Clin Infect Dis. 2000;30(2):282–287.
- , , , et al. Therapeutic amoxicillin levels achieved with oral administration in term neonates. Eur J Clin Pharmacol. 2007;63(7):657–662.
- , , , , , . Population pharmacokinetics and dosing of amoxicillin in (pre)term neonates. Ther Drug Monit. 2006;28(2):226–231.
- , , , et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267–1284.
- , , , , , . Management of bacterial meningitis and meningococcal septicaemia in children and young people: summary of NICE guidance. BMJ. 2010;340:c3209.
- , , , , . Short versus long duration of antibiotic therapy for bacterial meningitis: a meta‐analysis of randomised controlled trials in children. Arch Dis Child. 2009;94(8):607–614.
- , , , et al. 5 versus 10 days of treatment with ceftriaxone for bacterial meningitis in children: a double‐blind randomised equivalence study. Lancet. 2011;377(9780):1837–1845.
- , , , et al. Ceftriaxone as effective as long‐acting chloramphenicol in short‐course treatment of meningococcal meningitis during epidemics: a randomised non‐inferiority study. Lancet. 2005;366(9482):308–313.
- , , , et al. Changing epidemiology of outpatient bacteremia in 3‐ to 36‐month‐old children after the introduction of the heptavalent‐conjugated pneumococcal vaccine. Pediatr Infect Dis J. 2006;25(4):293–300.
- , , , et al. Epidemiology of bacteremia in febrile infants in the United States. Pediatrics. 2013;132(6):990–996.
- , , . Changing epidemiology of bacteremia in infants aged 1 week to 3 months. Pediatrics. 2012;129(3):e590–e596.
- , , , et al. Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Pediatrics. 1999;104(1 pt 1):79–86.
- , , , , . Bacteremic urinary tract infection in children. Pediatr Infect Dis J. 2000;19(7):630–634.
- , , , , , . Urine testing and urinary tract infections in febrile infants seen in office settings: the Pediatric Research in Office Settings' Febrile Infant Study. Arch Pediatr Adolesc Med. 2002;156(1):44–54.
- , , , , , . Management of bacteremic urinary tract infections in infants less than 3 months of age. Abstract presented at: Pediatric Academic Societies Annual Meeting; May 5, 2014; Vancouver BC, Canada.
- , , , . Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012.
- , . Recurrent group B streptococcal bacteremia. Clin Pediatr (Phila). 2012;51(9):884–887.
- , , , . Antibiotics for treating lower urinary tract infection in children. Cochrane Database Syst Rev. 2012;8:CD006857.
- . Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics. 2011;128(3):595–610.
- , , . Antibiotics for acute pyelonephritis in children. Cochrane Database Syst Rev. 2007(4):CD003772.
- , , , et al. Randomized trial of oral versus sequential IV/oral antibiotic for acute pyelonephritis in children. Pediatrics. 2012;129(2):e269–e275.
- , , , et al. Prospective, randomized trial comparing short and long intravenous antibiotic treatment of acute pyelonephritis in children: dimercaptosuccinic acid scintigraphic evaluation at 9 months. Pediatrics. 2008;121(3):e553–e560.
- , , , et al. Randomised trial of oral versus sequential intravenous/oral cephalosporins in children with pyelonephritis. Eur J Pediatr. 2008;167(9):1037–1047.
- , , , , . Efficacy of short‐term intravenous antibiotic in neonates with urinary tract infection. Pediatr Emerg Care. 2007;23(2):83–86.
- , , , , , . Shorter courses of parenteral antibiotic therapy do not appear to influence response rates for children with acute hematogenous osteomyelitis: a systematic review. BMC Infect Dis. 2002;2:16.
- , , , . Short‐ versus long‐term antimicrobial treatment for acute hematogenous osteomyelitis of childhood: prospective, randomized trial on 131 culture‐positive cases. Pediatr Infect Dis J. 2010;29(12):1123–1128.
- , , , , , . Prolonged intravenous therapy versus early transition to oral antimicrobial therapy for acute osteomyelitis in children. Pediatrics. 2009;123(2):636–642.
- , , , et al. Acute bacterial osteoarticular infections: eight‐year analysis of C‐reactive protein for oral step‐down therapy. Pediatrics. 2012;130(4):e821–e828.
- , , , , , . Parental decision‐making preferences in the pediatric intensive care unit. Crit Care Med. 2012;40(10):2876–2882.
- , , , , . An assessment of the shared‐decision model in parents of children with acute otitis media. Pediatrics. 2005;116(6):1267–1275.
- , , , , . Risk factors for peripherally inserted central venous catheter complications in children. JAMA Pediatr. 2013;167(5):429–435.
- , , . Current clinical evidence on the effect of general anesthesia on neurodevelopment in children: an updated systematic review with meta‐regression. PLoS One. 2014;9(1):e85760.
- , , , et al. Nosocomial respiratory syncytial virus infection in Canadian pediatric hospitals: a Pediatric Investigators Collaborative Network on Infections in Canada Study. Pediatrics. 1997;100(6):943–946.
- , . Eliminating waste in US health care. JAMA. 2012;307(14):1513–1516.
- , , . Safely doing less: a missing component of the patient safety dialogue. Pediatrics. 2011;128(6):e1596–e1597.
- Committee On Hospital Care and Institute For Patient‐ and Family‐Centered Care. Patient‐ and family‐centered care and the pediatrician's role. Pediatrics. 2012;129(2):394–404.
- . What is value in health care? N Engl J Med. 2010;363(26):2477–2481.
- , , , , . Prevalence and source of pain in pediatric inpatients. Pain. 1996;68(1):25–31.
- , , , . Acute compartment syndrome of the upper extremity in children: diagnosis, management, and outcomes. J Child Orthop. 2013;7(3):225–233.
- , , , , . Neonatal central venous catheter thrombosis: diagnosis, management and outcome. Blood Coagul Fibrinolysis. 2014;25(2):97–106.
- , , , et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American C ollege of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e737S–801S.
- , , , et al. Effect of computer order entry on prevention of serious medication errors in hospitalized children. Pediatrics. 2008;121(3):e421–e427.
- Duration and cessation of antimicrobial treatment. J Hosp Med. 2012;7(suppl 1):S22–S33.
Rationally defining the appropriate duration of intravenous (IV) antibiotics for children with bacterial infections is challenging. For example, how long should a 2‐week‐old infant with a urinary tract infection (UTI) caused by Escherichia coli (E coli) be treated intravenously if the infant has responded to treatment and is back to baseline within 1 to 2 days? What if the blood culture was also positive for E coli? What are the risks and benefits of continuing IV antibiotics?
Such questions are common for pediatric hospitalists. Bacterial infections remain a relatively frequent cause of pediatric hospitalization, especially in neonates where 5 of the top 10 causes of hospitalizations are related to bacterial infections.[1] For some conditions, children remain hospitalized after clinical improvement simply for ongoing provision of IV antibiotics. Alternatively, some children are discharged home with a peripherally inserted central catheter (PICC) to complete an IV course.
The decision regarding the duration of IV antibiotics varies according to the condition for which the antibiotic is prescribed and often by practitioner or hospital. Many recommendations are numerically based (eg, 10 days for group B Streptococcus [GBS] bacteremia, 21 days for E coli meningitis), without taking into account patient‐level factors such as initial severity or response to therapy. These concrete recommendations may in fact be preferred by some practitioners, as suggested by a former chairman of the Committee on Infectious Disease for the American Academy of Pediatrics (AAP): The Red Book is designed for people who make decisions. It cannot waffle on an issue. It has to make a positive recommendation even if the data are incomplete.[2] A potential downside of this mentality, however, is that some practitioners may then feel obligated to follow these recommendations despite the lack of supportive evidence.
EXTENDING IV ANTIBIOTICS BEYOND CLINICAL RECOVERY
What is the rationale for continuing IV antibiotics in infants whose symptoms have completely resolved? Several factors likely drive these decisions: prevention of recurrences, concerns about bioavailability of enteral antibiotics and patient compliance, adherence to expert recommendations/guidelines, and perhaps a general sense that more is betterthat serious infections and/or their sequelae require more aggressive treatments.
Recurrence of a potentially life‐threatening infection is an understandable concern. Even when symptoms have resolved and there is documented clearance of the infection, such clearance does not necessarily signify that the body has rid itself of the pathogen completely. Some infections are deep seated and may warrant continuing treatment despite apparent recovery. To some, the risks of prolonging IV therapy may seem inconsequential when juxtaposed to a potentially devastating recurrence. However, in many conditions, recurrences may be related to host issues or ongoing exposures rather than inadequate treatment of the original infection. Recurrent UTIs, for example, are more likely in infants with urologic abnormalities,[3] and recurrent GBS bacteremia has been associated with GBS colonization of maternal breast milk and/or maternal mastitis.[4, 5, 6, 7] Although it is tempting to extend IV courses to prevent recurrences, it is not clear that the benefits of such an approach outweigh the risks.
Concerns over enteral absorption and bioavailability are also understandable, especially in young infants. The superior efficacy of IV over oral antibiotics in general is well accepted for many pediatric conditions, and in some cases (eg, septic shock) it would be unethical to perform a head‐to‐head trial. However, the lack of any published trials (to our knowledge) in pediatrics confirming the superiority of IV antibiotics suggests that oral antibiotic absorption is sufficient for many infections. Even in neonates, several studies have demonstrated that therapeutic serum levels are easily reached with oral dosing of amoxicillin in term and preterm neonates.[8, 9]
For the remainder of this review, the published recommendations and available evidence behind the duration of IV therapy are summarized for 4 bacterial infections in children in which IV antibiotic therapy often continues after clinical recovery: meningitis, bacteremia, UTI, and acute osteomyelitis. We conclude by proposing additional considerations for IV antibiotic durations, especially in situations where guidelines and/or evidence are either nonexistent, dated, conflicting, or contrary to evidence from published studies.
BACTERIAL MENINGITIS
The Infectious Disease Society of America and the British National Institute for Clinical Evidence have both published guidelines with pediatric recommendations for duration of therapy in bacterial meningitis,[10, 11] though the recommendations differ somewhat for 3 of the 4 most common pathogens, and are not always concordant with evidence from randomized controlled trials (Table 1).[12, 13, 14]
| Pathogen | IDSA | NICE | Minimum Range Achieving Equivalent Outcomes in Recent Randomized Trials |
|---|---|---|---|
| |||
| Group B Streptococcus | 1421 days | 14 days | None available |
| Neisseria meningititis | 7 days | 7 days | 15 days[12, 13, 14] |
| Haemophilus influenzae type b | 7 days | 10 days | 45 days[12, 13] |
| Streptococcus pneumoniae | 1014 days | 14 days | 45 days[12, 13] |
A recent meta‐analysis on duration of therapy in meningitis included 5 open‐label trials of ceftriaxone for bacterial meningitis in children.[12] These trials included the 3 most common pathogens and were categorized as short‐course (47 days, n=196 patients) and long‐course (714 days, n=187 patients) therapy. There was no significant difference in clinical success or long‐term neurological complications between groups. Subsequently, a multicountry trial enrolled over 1000 children 2 months to 12 years of age with meningitis caused by Haemophilus influenzae type b, Streptococcus pneumonia, or Neisseria meningititis who were stable after 5 days of IV ceftriaxone therapy and randomized them to receive placebo or an additional 5 days of ceftriaxone.[13] Patients with persistence of seizures, bacteremia, abscess or distant infections, or who were judged to be deteriorating or still severely ill at the 5‐day point were excluded (4.7% of the children who were recruited on day 0). There were no significant differences in bacteriologic failures, clinical failures, or clinical sequelae in survivors. The authors concluded that ceftriaxone can be discontinued in children with bacterial meningitis who are clinically stable after 5 days of IV therapy. Further trials in developed countries are needed.
BACTEREMIA
Because of routine vaccination against H influenzae type b and S pneumoniae, bacteremia beyond the first few months of life in otherwise healthy children is now rare.[15] Even in infants too young to benefit directly from vaccination, the epidemiology of bacteremia has changed considerably over the last few decades, with E coli and GBS constituting the majority (65%77%) of cases.[16, 17] We will limit this review on bacteremia to these 2 organisms in young infants.
Most cases of E coli bacteremia are associated with UTI (91%98%),[16, 17] and most bacteremic UTIs (88%92%) are caused by E coli.[18, 19, 20, 21] There are no official recommendations for the duration of treatment of bacteremic UTI, and only a limited amount of evidence can be gleaned from existing studies. In a trial of oral cefixime for infants aged 1 to 24 months with UTI, all 13 infants with bacteremia fared well whether they received oral cefixime only or IV cefotaxime for 3 days followed by oral cefixime.[18] In a study on length of IV antibiotic therapy in over 12,000 infants <6 months old with UTI, the presence of bacteremia predicted longer IV treatment length (bacteremia was present in 0.5% of the short IV group vs 0.8% of the long IV group, P=0.02) but did not predict treatment failure, defined as readmission within 30 days.[3] In a multicenter investigation of 229 infants <3 months old with bacteremic UTI, the duration of parenteral antibiotics was extremely variable (range, 117 days) and was not associated with treatment failure, defined as recurrent UTI caused by the same organism within 30 days (mean duration 7.8 days in the treatment‐failure group vs 7.7 days in the no‐failure group, P=0.99).[21] In summary, there is no evidence to support a prolonged course (ie, >35 days) of IV antibiotics for bacteremic UTI.
For bacteremia caused by GBS, although the Red Book Committee on Infectious Disease recommends 10 days of IV antibiotics,[22] to our knowledge there are no experimental or observational investigations to support this recommendation. Although available studies suggest that IV courses of at least 10 days are generally provided,[7, 23] no studies have compared outcomes of infants treated with short versus long courses. However, in a study that included 29 full‐term neonates with GBS bacteremia, all 29 had responded initially to 48 hours of intravenous antibiotics (defined as being asymptomatic and fed enterally), and were then treated successfully with high‐dose oral amoxicillin for the remainder of the course, with no recurrences.[8] Although recurrences are estimated to occur in 0.5% to 3% of babies treated for GBS infections, many recurrences are associated with exposure factors such as GBS colonization of the breast milk.[4, 5, 6, 7] In summary, although 10 or more days of IV antibiotic therapy remains a common published recommendation, there is no supportive evidence. More research is needed to assess whether shorter IV courses are safe.
UTI
Most UTIs can be treated with oral antibiotics.[24] In its practice parameter on febrile UTIs in infants 2 months to 2 years of age, the AAP recommends oral antibiotics for well‐appearing children.[25] This recommendation is supported by a recent Cochrane review on the topic,[26] and at least 3 additional trials that have demonstrated that long IV courses do not yield better outcomes than shorter IV courses or oral only courses.[27, 28, 29]
However, all of these trials exclude infants <1 month old, and there are no published recommendations for the <2‐month‐old age group. The study by Brady et al. on >12,000 infants <6 months old with UTI demonstrated no significant differences in UTI readmission rates between infants who were given 4 days of IV antibiotics versus those who were given <4 days.[3] There were 3,383 infants <30 days old in this study, and about one‐third of these babies received a short IV course. Failure rates were nearly identical in each group (2.3% in short course vs 2.4% in long course) even after risk adjustment (personal communication with Patrick Brady, MD, on February 7, 2014). Magin et al. describe 172 neonates (median age 19 days) with UTI who were treated intravenously for a median duration of 4 days (interquartile range, 36 days) and did not experience treatment failures or relapses.[30]
In summary, most cases of UTI can be managed with oral antibiotics. Uncertainty remains over the optimal approach for infants <1 to 2 months old, an age range not considered in current published guidelines. Current evidence suggests that IV treatment for 3 to 4 days followed by oral therapy may be sufficient treatment in this age group.
ACUTE OSTEOMYELITIS
Given the excellent blood supply to rapidly growing tissues in children, shorter durations of IV therapy have been studied with increasing frequency. A 2002 systematic review included 12 prospective cohort studies with at least 6 months of follow‐up.[31] Studies were stratified into 7 days or >7 days IV therapy, and there were no differences in cure rates. Subsequently, a large Finnish trial reported on 131 children who received an initial short IV course (24 days) followed by 20 versus 30 total days of therapy with very low treatment failure rates.[32]
The largest study from the United States to date analyzed nearly 2000 cases of osteomyelitis from 29 hospitals.[33] This study defined a prolonged IV course by placement of a central venous catheter. The rates of prolonged IV therapy varied significantly across hospitals, ranging from 10% to 95% of patients, without detectable differences in outcomes. Furthermore, the readmission rate for catheter related complications (3%) was nearly as high as the overall treatment failure rate (4%5%). Recently, Arnold et al. reported 8 years' experience with a management algorithm to guide the transition to oral antibiotics in pediatric osteoarticular infections in a patient specific manner.[34] This study included 194 patients (154 uncomplicated and 40 complicated cases), all with culture‐proven disease. Transition to oral antibiotics occurred based on resolution of fever and pain, improved function of the affected region, and a C‐reactive protein level of <3 mg/dL, and occurred at an average of 10 days into the treatment course. These authors also provided extensive information about complications to demonstrate that the proposed strategy can be used with a wide range of patients and pathogens. There was a single microbiologic treatment failure after oral step‐down therapy in a complicated osteoarticular infection, with a retained bony fragment. This study represents a successful example of a patient‐centered approach to IV antibiotic duration.
A PATIENT‐CENTERED APPROACH
Returning to the example above of the 2‐week‐old with UTI (with or without bacteremia), there are no published guidelines and only limited available evidence to help guide the duration of IV antibiotics in this case. When standards of care (eg, from published guidelines, review articles, textbooks, or local expert guidance) are nonexistent, conflicting, dated, or contrary to existing evidence, patient‐level factors can be incorporated into the decision‐making process (Table 2). In these cases, tailoring the IV antibiotic course to the individual's response (referred to in 1 review as the ultimate bioassay of the therapy[2]), while also weighing risks and benefits of ongoing therapy, is a logical approach.
| Consideration | Description |
|---|---|
| |
| Severity of initial infection | If concern of recurrence is the justification for a longer IV course, then a more prolonged course might be considered for a more severe initial presentation (eg, septic shock, multisystem organ failure, intensive care unit admission). |
| Response to therapy | Continued IV antibiotics might be warranted in patients who are still symptomatic (eg, fever, vomiting). Inflammatory markers have been used to guide therapy in osteomyelitis.[34] |
| Patient compliance | If a child does not tolerate oral antibiotics or there are concerns about family adherence, a longer IV course may be considered. |
| Family preferences | Shared decision making can be employed, especially when there is no clear evidence supporting a specific duration. |
| Assessment of harms of ongoing hospitalization and/or prolonged IV therapy | See Table 3 |
SEVERITY OF INITIAL INFECTION AND RESPONSE TO THERAPY
The severity of the initial infection, whether in terms of presentation or clinical recovery, can factor into the duration of therapy. Provision of a longer IV course to prevent (albeit theoretically) a recurrence makes more logical sense in an infant with GBS bacteremia who was ill enough to warrant intensive care unit admission than in an infant whose only symptom was a fever. Similarly, most practitioners would be reluctant to stop IV antibiotics and discharge a patient with a bacterial infection who is persistently febrile or vomiting. Although the use of inflammatory markers and other clinical symptoms to guide therapy has been limited to osteomyelitis, this approach might be useful and should be studied in other conditions.
SHARED DECISION MAKING
Shared decision making can also be employed. Parents of sick, hospitalized children generally prefer to be involved in the decision‐making process.[35] For a parent who has concerns about their child's well‐being in the hospital, or has multiple other children at home, competing career obligations, and/or limited family support, the burden of ongoing hospitalization can be significant, and should be factored into decision making. Involving parents in medical decisions may lead to a reduction in utilization for some conditions.[36]
ASSESSMENT OF RISKS/COSTS
The risks and costs of pediatric hospitalization and prolonged IV antibiotics are well described in the literature and are summarized in Table 3. Although the benefits of prolonging IV antibiotics in a child who has recovered from an acute bacterial infection are largely theoretical, many of the risks are concrete and quantifiable. For example, a young infant being treated for a bacteremic UTI may run out of potential IV sites and need a PICC line to continue IV therapy, which according to a recent review of 2574 PICC lines has a 21% complication rate. This rate is even higher in children for whom the PICC line indication was provision of antibiotics (27%) and for infants <1 year of age (44%).[37] Moreover, this procedure often requires sedation or anesthesia for placement, which has both known and unknown risks, including concerns about subsequent adverse effects on development in young children.[38] Nosocomial exposure to seasonal viruses poses an additional risk to hospitalized children.[39]
| Harm of Intravenous Antibiotic Therapy | Description or Example |
|---|---|
| |
| Complications from peripheral IV catheter | Leading source of pain and distress for hospitalized children.[44] |
| Serious complications can occur following IV infiltrates.[45] | |
| Complications from PICC line | Approximately 20% overall complication rate (44% in infants <1 year old).[37] |
| Complications led to rehospitalization of 3% of children being treated with prolonged antibiotics for osteomyelitis.[33] | |
| When thrombosis occurs (up to 9% risk in neonates[46]), 3 months of anticoagulation is recommended.[47] | |
| Complications may arise from sedation/anesthesia necessary to place catheter. Anesthesia has been associated with adverse behavioral or developmental outcomes in children <4 years of age.[38] | |
| Risk of nosocomial infection while hospitalized | An estimated 6% of hospital RSV infections are nosocomial, which are associated with a more prolonged LOS than hospitalizations for community‐acquired RSV.[39] |
| Medication error | In 1 investigation, serious medication errors occurred in 22 per 1,000 patient‐days in a large children's hospital.[48] |
| Emotional and financial burdens | Hospitalization can pose a significant strain on the child, parents, and siblings. |
| Financial costs to healthcare system | In 2003, infection‐related hospitalizations in infants had an average cost of $4,000 (average LOS 3.5 days).[1] |
| Harms associated with prolonged courses of antibiotics in general (IV or PO) | Antibiotic resistance, diarrhea (including Clostridium difficile), allergic reactions, increased costs.[49] |
These additional considerations for the duration of IV antibiotics are not evidence based and should not be used to justify an IV duration that differs dramatically from an accepted standard of care. These are merely considerations that incorporate clinical judgment and a comprehensive analysis of risks and benefits in situations where the available evidence is suboptimal. This approach can be adopted both as a framework for future research and directly in clinical practice.
CONCLUSION
In an era of increasing focus on overtreatment/waste,[40] patient safety,[41] and patient‐centered care,[42] the duration of IV antibiotics for common bacterial infections is a prime target for improving pediatric healthcare value. As emphasized by Michael Porter recently in The New England Journal of Medicine, value should always be defined around the customer.[43] A high‐value approach to IV antibiotic duration incorporates a rigorous assessment of risks and benefits that focuses on best evidence and patient‐level factors.
In discussing published guidelines in a review on bacterial meningitis therapy, Michael Radetsky noted that [R]ecommended criteria, even if provisional, may inadvertently become invested with an independent power to force submission and prohibit deviation. The danger is that sensitivity to individual responsiveness and variability will be lost.[2] Guidelines are useful tools in pediatrics and should continue to be used to direct IV antibiotic durations for bacterial infections in children. However, the emphasis on fixed durations of IV antibiotics might not always serve the best interest of the patient. When guidelines are lacking or contradictory, patient factors should also be considered.
Acknowledgements
The authors thank Ellen R. Wald, MD, and Kenneth B. Roberts, MD, for their thoughtful and valuable additions to this review.
Disclosure: Nothing to report.
Rationally defining the appropriate duration of intravenous (IV) antibiotics for children with bacterial infections is challenging. For example, how long should a 2‐week‐old infant with a urinary tract infection (UTI) caused by Escherichia coli (E coli) be treated intravenously if the infant has responded to treatment and is back to baseline within 1 to 2 days? What if the blood culture was also positive for E coli? What are the risks and benefits of continuing IV antibiotics?
Such questions are common for pediatric hospitalists. Bacterial infections remain a relatively frequent cause of pediatric hospitalization, especially in neonates where 5 of the top 10 causes of hospitalizations are related to bacterial infections.[1] For some conditions, children remain hospitalized after clinical improvement simply for ongoing provision of IV antibiotics. Alternatively, some children are discharged home with a peripherally inserted central catheter (PICC) to complete an IV course.
The decision regarding the duration of IV antibiotics varies according to the condition for which the antibiotic is prescribed and often by practitioner or hospital. Many recommendations are numerically based (eg, 10 days for group B Streptococcus [GBS] bacteremia, 21 days for E coli meningitis), without taking into account patient‐level factors such as initial severity or response to therapy. These concrete recommendations may in fact be preferred by some practitioners, as suggested by a former chairman of the Committee on Infectious Disease for the American Academy of Pediatrics (AAP): The Red Book is designed for people who make decisions. It cannot waffle on an issue. It has to make a positive recommendation even if the data are incomplete.[2] A potential downside of this mentality, however, is that some practitioners may then feel obligated to follow these recommendations despite the lack of supportive evidence.
EXTENDING IV ANTIBIOTICS BEYOND CLINICAL RECOVERY
What is the rationale for continuing IV antibiotics in infants whose symptoms have completely resolved? Several factors likely drive these decisions: prevention of recurrences, concerns about bioavailability of enteral antibiotics and patient compliance, adherence to expert recommendations/guidelines, and perhaps a general sense that more is betterthat serious infections and/or their sequelae require more aggressive treatments.
Recurrence of a potentially life‐threatening infection is an understandable concern. Even when symptoms have resolved and there is documented clearance of the infection, such clearance does not necessarily signify that the body has rid itself of the pathogen completely. Some infections are deep seated and may warrant continuing treatment despite apparent recovery. To some, the risks of prolonging IV therapy may seem inconsequential when juxtaposed to a potentially devastating recurrence. However, in many conditions, recurrences may be related to host issues or ongoing exposures rather than inadequate treatment of the original infection. Recurrent UTIs, for example, are more likely in infants with urologic abnormalities,[3] and recurrent GBS bacteremia has been associated with GBS colonization of maternal breast milk and/or maternal mastitis.[4, 5, 6, 7] Although it is tempting to extend IV courses to prevent recurrences, it is not clear that the benefits of such an approach outweigh the risks.
Concerns over enteral absorption and bioavailability are also understandable, especially in young infants. The superior efficacy of IV over oral antibiotics in general is well accepted for many pediatric conditions, and in some cases (eg, septic shock) it would be unethical to perform a head‐to‐head trial. However, the lack of any published trials (to our knowledge) in pediatrics confirming the superiority of IV antibiotics suggests that oral antibiotic absorption is sufficient for many infections. Even in neonates, several studies have demonstrated that therapeutic serum levels are easily reached with oral dosing of amoxicillin in term and preterm neonates.[8, 9]
For the remainder of this review, the published recommendations and available evidence behind the duration of IV therapy are summarized for 4 bacterial infections in children in which IV antibiotic therapy often continues after clinical recovery: meningitis, bacteremia, UTI, and acute osteomyelitis. We conclude by proposing additional considerations for IV antibiotic durations, especially in situations where guidelines and/or evidence are either nonexistent, dated, conflicting, or contrary to evidence from published studies.
BACTERIAL MENINGITIS
The Infectious Disease Society of America and the British National Institute for Clinical Evidence have both published guidelines with pediatric recommendations for duration of therapy in bacterial meningitis,[10, 11] though the recommendations differ somewhat for 3 of the 4 most common pathogens, and are not always concordant with evidence from randomized controlled trials (Table 1).[12, 13, 14]
| Pathogen | IDSA | NICE | Minimum Range Achieving Equivalent Outcomes in Recent Randomized Trials |
|---|---|---|---|
| |||
| Group B Streptococcus | 1421 days | 14 days | None available |
| Neisseria meningititis | 7 days | 7 days | 15 days[12, 13, 14] |
| Haemophilus influenzae type b | 7 days | 10 days | 45 days[12, 13] |
| Streptococcus pneumoniae | 1014 days | 14 days | 45 days[12, 13] |
A recent meta‐analysis on duration of therapy in meningitis included 5 open‐label trials of ceftriaxone for bacterial meningitis in children.[12] These trials included the 3 most common pathogens and were categorized as short‐course (47 days, n=196 patients) and long‐course (714 days, n=187 patients) therapy. There was no significant difference in clinical success or long‐term neurological complications between groups. Subsequently, a multicountry trial enrolled over 1000 children 2 months to 12 years of age with meningitis caused by Haemophilus influenzae type b, Streptococcus pneumonia, or Neisseria meningititis who were stable after 5 days of IV ceftriaxone therapy and randomized them to receive placebo or an additional 5 days of ceftriaxone.[13] Patients with persistence of seizures, bacteremia, abscess or distant infections, or who were judged to be deteriorating or still severely ill at the 5‐day point were excluded (4.7% of the children who were recruited on day 0). There were no significant differences in bacteriologic failures, clinical failures, or clinical sequelae in survivors. The authors concluded that ceftriaxone can be discontinued in children with bacterial meningitis who are clinically stable after 5 days of IV therapy. Further trials in developed countries are needed.
BACTEREMIA
Because of routine vaccination against H influenzae type b and S pneumoniae, bacteremia beyond the first few months of life in otherwise healthy children is now rare.[15] Even in infants too young to benefit directly from vaccination, the epidemiology of bacteremia has changed considerably over the last few decades, with E coli and GBS constituting the majority (65%77%) of cases.[16, 17] We will limit this review on bacteremia to these 2 organisms in young infants.
Most cases of E coli bacteremia are associated with UTI (91%98%),[16, 17] and most bacteremic UTIs (88%92%) are caused by E coli.[18, 19, 20, 21] There are no official recommendations for the duration of treatment of bacteremic UTI, and only a limited amount of evidence can be gleaned from existing studies. In a trial of oral cefixime for infants aged 1 to 24 months with UTI, all 13 infants with bacteremia fared well whether they received oral cefixime only or IV cefotaxime for 3 days followed by oral cefixime.[18] In a study on length of IV antibiotic therapy in over 12,000 infants <6 months old with UTI, the presence of bacteremia predicted longer IV treatment length (bacteremia was present in 0.5% of the short IV group vs 0.8% of the long IV group, P=0.02) but did not predict treatment failure, defined as readmission within 30 days.[3] In a multicenter investigation of 229 infants <3 months old with bacteremic UTI, the duration of parenteral antibiotics was extremely variable (range, 117 days) and was not associated with treatment failure, defined as recurrent UTI caused by the same organism within 30 days (mean duration 7.8 days in the treatment‐failure group vs 7.7 days in the no‐failure group, P=0.99).[21] In summary, there is no evidence to support a prolonged course (ie, >35 days) of IV antibiotics for bacteremic UTI.
For bacteremia caused by GBS, although the Red Book Committee on Infectious Disease recommends 10 days of IV antibiotics,[22] to our knowledge there are no experimental or observational investigations to support this recommendation. Although available studies suggest that IV courses of at least 10 days are generally provided,[7, 23] no studies have compared outcomes of infants treated with short versus long courses. However, in a study that included 29 full‐term neonates with GBS bacteremia, all 29 had responded initially to 48 hours of intravenous antibiotics (defined as being asymptomatic and fed enterally), and were then treated successfully with high‐dose oral amoxicillin for the remainder of the course, with no recurrences.[8] Although recurrences are estimated to occur in 0.5% to 3% of babies treated for GBS infections, many recurrences are associated with exposure factors such as GBS colonization of the breast milk.[4, 5, 6, 7] In summary, although 10 or more days of IV antibiotic therapy remains a common published recommendation, there is no supportive evidence. More research is needed to assess whether shorter IV courses are safe.
UTI
Most UTIs can be treated with oral antibiotics.[24] In its practice parameter on febrile UTIs in infants 2 months to 2 years of age, the AAP recommends oral antibiotics for well‐appearing children.[25] This recommendation is supported by a recent Cochrane review on the topic,[26] and at least 3 additional trials that have demonstrated that long IV courses do not yield better outcomes than shorter IV courses or oral only courses.[27, 28, 29]
However, all of these trials exclude infants <1 month old, and there are no published recommendations for the <2‐month‐old age group. The study by Brady et al. on >12,000 infants <6 months old with UTI demonstrated no significant differences in UTI readmission rates between infants who were given 4 days of IV antibiotics versus those who were given <4 days.[3] There were 3,383 infants <30 days old in this study, and about one‐third of these babies received a short IV course. Failure rates were nearly identical in each group (2.3% in short course vs 2.4% in long course) even after risk adjustment (personal communication with Patrick Brady, MD, on February 7, 2014). Magin et al. describe 172 neonates (median age 19 days) with UTI who were treated intravenously for a median duration of 4 days (interquartile range, 36 days) and did not experience treatment failures or relapses.[30]
In summary, most cases of UTI can be managed with oral antibiotics. Uncertainty remains over the optimal approach for infants <1 to 2 months old, an age range not considered in current published guidelines. Current evidence suggests that IV treatment for 3 to 4 days followed by oral therapy may be sufficient treatment in this age group.
ACUTE OSTEOMYELITIS
Given the excellent blood supply to rapidly growing tissues in children, shorter durations of IV therapy have been studied with increasing frequency. A 2002 systematic review included 12 prospective cohort studies with at least 6 months of follow‐up.[31] Studies were stratified into 7 days or >7 days IV therapy, and there were no differences in cure rates. Subsequently, a large Finnish trial reported on 131 children who received an initial short IV course (24 days) followed by 20 versus 30 total days of therapy with very low treatment failure rates.[32]
The largest study from the United States to date analyzed nearly 2000 cases of osteomyelitis from 29 hospitals.[33] This study defined a prolonged IV course by placement of a central venous catheter. The rates of prolonged IV therapy varied significantly across hospitals, ranging from 10% to 95% of patients, without detectable differences in outcomes. Furthermore, the readmission rate for catheter related complications (3%) was nearly as high as the overall treatment failure rate (4%5%). Recently, Arnold et al. reported 8 years' experience with a management algorithm to guide the transition to oral antibiotics in pediatric osteoarticular infections in a patient specific manner.[34] This study included 194 patients (154 uncomplicated and 40 complicated cases), all with culture‐proven disease. Transition to oral antibiotics occurred based on resolution of fever and pain, improved function of the affected region, and a C‐reactive protein level of <3 mg/dL, and occurred at an average of 10 days into the treatment course. These authors also provided extensive information about complications to demonstrate that the proposed strategy can be used with a wide range of patients and pathogens. There was a single microbiologic treatment failure after oral step‐down therapy in a complicated osteoarticular infection, with a retained bony fragment. This study represents a successful example of a patient‐centered approach to IV antibiotic duration.
A PATIENT‐CENTERED APPROACH
Returning to the example above of the 2‐week‐old with UTI (with or without bacteremia), there are no published guidelines and only limited available evidence to help guide the duration of IV antibiotics in this case. When standards of care (eg, from published guidelines, review articles, textbooks, or local expert guidance) are nonexistent, conflicting, dated, or contrary to existing evidence, patient‐level factors can be incorporated into the decision‐making process (Table 2). In these cases, tailoring the IV antibiotic course to the individual's response (referred to in 1 review as the ultimate bioassay of the therapy[2]), while also weighing risks and benefits of ongoing therapy, is a logical approach.
| Consideration | Description |
|---|---|
| |
| Severity of initial infection | If concern of recurrence is the justification for a longer IV course, then a more prolonged course might be considered for a more severe initial presentation (eg, septic shock, multisystem organ failure, intensive care unit admission). |
| Response to therapy | Continued IV antibiotics might be warranted in patients who are still symptomatic (eg, fever, vomiting). Inflammatory markers have been used to guide therapy in osteomyelitis.[34] |
| Patient compliance | If a child does not tolerate oral antibiotics or there are concerns about family adherence, a longer IV course may be considered. |
| Family preferences | Shared decision making can be employed, especially when there is no clear evidence supporting a specific duration. |
| Assessment of harms of ongoing hospitalization and/or prolonged IV therapy | See Table 3 |
SEVERITY OF INITIAL INFECTION AND RESPONSE TO THERAPY
The severity of the initial infection, whether in terms of presentation or clinical recovery, can factor into the duration of therapy. Provision of a longer IV course to prevent (albeit theoretically) a recurrence makes more logical sense in an infant with GBS bacteremia who was ill enough to warrant intensive care unit admission than in an infant whose only symptom was a fever. Similarly, most practitioners would be reluctant to stop IV antibiotics and discharge a patient with a bacterial infection who is persistently febrile or vomiting. Although the use of inflammatory markers and other clinical symptoms to guide therapy has been limited to osteomyelitis, this approach might be useful and should be studied in other conditions.
SHARED DECISION MAKING
Shared decision making can also be employed. Parents of sick, hospitalized children generally prefer to be involved in the decision‐making process.[35] For a parent who has concerns about their child's well‐being in the hospital, or has multiple other children at home, competing career obligations, and/or limited family support, the burden of ongoing hospitalization can be significant, and should be factored into decision making. Involving parents in medical decisions may lead to a reduction in utilization for some conditions.[36]
ASSESSMENT OF RISKS/COSTS
The risks and costs of pediatric hospitalization and prolonged IV antibiotics are well described in the literature and are summarized in Table 3. Although the benefits of prolonging IV antibiotics in a child who has recovered from an acute bacterial infection are largely theoretical, many of the risks are concrete and quantifiable. For example, a young infant being treated for a bacteremic UTI may run out of potential IV sites and need a PICC line to continue IV therapy, which according to a recent review of 2574 PICC lines has a 21% complication rate. This rate is even higher in children for whom the PICC line indication was provision of antibiotics (27%) and for infants <1 year of age (44%).[37] Moreover, this procedure often requires sedation or anesthesia for placement, which has both known and unknown risks, including concerns about subsequent adverse effects on development in young children.[38] Nosocomial exposure to seasonal viruses poses an additional risk to hospitalized children.[39]
| Harm of Intravenous Antibiotic Therapy | Description or Example |
|---|---|
| |
| Complications from peripheral IV catheter | Leading source of pain and distress for hospitalized children.[44] |
| Serious complications can occur following IV infiltrates.[45] | |
| Complications from PICC line | Approximately 20% overall complication rate (44% in infants <1 year old).[37] |
| Complications led to rehospitalization of 3% of children being treated with prolonged antibiotics for osteomyelitis.[33] | |
| When thrombosis occurs (up to 9% risk in neonates[46]), 3 months of anticoagulation is recommended.[47] | |
| Complications may arise from sedation/anesthesia necessary to place catheter. Anesthesia has been associated with adverse behavioral or developmental outcomes in children <4 years of age.[38] | |
| Risk of nosocomial infection while hospitalized | An estimated 6% of hospital RSV infections are nosocomial, which are associated with a more prolonged LOS than hospitalizations for community‐acquired RSV.[39] |
| Medication error | In 1 investigation, serious medication errors occurred in 22 per 1,000 patient‐days in a large children's hospital.[48] |
| Emotional and financial burdens | Hospitalization can pose a significant strain on the child, parents, and siblings. |
| Financial costs to healthcare system | In 2003, infection‐related hospitalizations in infants had an average cost of $4,000 (average LOS 3.5 days).[1] |
| Harms associated with prolonged courses of antibiotics in general (IV or PO) | Antibiotic resistance, diarrhea (including Clostridium difficile), allergic reactions, increased costs.[49] |
These additional considerations for the duration of IV antibiotics are not evidence based and should not be used to justify an IV duration that differs dramatically from an accepted standard of care. These are merely considerations that incorporate clinical judgment and a comprehensive analysis of risks and benefits in situations where the available evidence is suboptimal. This approach can be adopted both as a framework for future research and directly in clinical practice.
CONCLUSION
In an era of increasing focus on overtreatment/waste,[40] patient safety,[41] and patient‐centered care,[42] the duration of IV antibiotics for common bacterial infections is a prime target for improving pediatric healthcare value. As emphasized by Michael Porter recently in The New England Journal of Medicine, value should always be defined around the customer.[43] A high‐value approach to IV antibiotic duration incorporates a rigorous assessment of risks and benefits that focuses on best evidence and patient‐level factors.
In discussing published guidelines in a review on bacterial meningitis therapy, Michael Radetsky noted that [R]ecommended criteria, even if provisional, may inadvertently become invested with an independent power to force submission and prohibit deviation. The danger is that sensitivity to individual responsiveness and variability will be lost.[2] Guidelines are useful tools in pediatrics and should continue to be used to direct IV antibiotic durations for bacterial infections in children. However, the emphasis on fixed durations of IV antibiotics might not always serve the best interest of the patient. When guidelines are lacking or contradictory, patient factors should also be considered.
Acknowledgements
The authors thank Ellen R. Wald, MD, and Kenneth B. Roberts, MD, for their thoughtful and valuable additions to this review.
Disclosure: Nothing to report.
- , , , , . Infectious disease hospitalizations among infants in the United States. Pediatrics. 2008;121(2):244–252.
- . Duration of treatment in bacterial meningitis: a historical inquiry. Pediatr Infect Dis J. 1990;9(1):2–9.
- , , . Length of intravenous antibiotic therapy and treatment failure in infants with urinary tract infections. Pediatrics. 2010;126(2):196–203.
- , , , et al. Group B streptococci in milk and late neonatal infections: an analysis of cases in the literature. Arch Dis Child Fetal Neonatal Ed. 2014;99(1):F41–F47.
- , , . Recurrent late‐onset group B Streptococcus sepsis in a preterm infant acquired by expressed breastmilk transmission: a case report. Breastfeed Med. 2013;8(1):134–136.
- , , , , , . Late‐onset and recurrent neonatal Group B streptococcal disease associated with breast‐milk transmission. Pediatr Dev Pathol. 2003;6(3):251–256.
- , , , , . A 5‐year review of recurrent group B streptococcal disease: lessons from twin infants. Clin Infect Dis. 2000;30(2):282–287.
- , , , et al. Therapeutic amoxicillin levels achieved with oral administration in term neonates. Eur J Clin Pharmacol. 2007;63(7):657–662.
- , , , , , . Population pharmacokinetics and dosing of amoxicillin in (pre)term neonates. Ther Drug Monit. 2006;28(2):226–231.
- , , , et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267–1284.
- , , , , , . Management of bacterial meningitis and meningococcal septicaemia in children and young people: summary of NICE guidance. BMJ. 2010;340:c3209.
- , , , , . Short versus long duration of antibiotic therapy for bacterial meningitis: a meta‐analysis of randomised controlled trials in children. Arch Dis Child. 2009;94(8):607–614.
- , , , et al. 5 versus 10 days of treatment with ceftriaxone for bacterial meningitis in children: a double‐blind randomised equivalence study. Lancet. 2011;377(9780):1837–1845.
- , , , et al. Ceftriaxone as effective as long‐acting chloramphenicol in short‐course treatment of meningococcal meningitis during epidemics: a randomised non‐inferiority study. Lancet. 2005;366(9482):308–313.
- , , , et al. Changing epidemiology of outpatient bacteremia in 3‐ to 36‐month‐old children after the introduction of the heptavalent‐conjugated pneumococcal vaccine. Pediatr Infect Dis J. 2006;25(4):293–300.
- , , , et al. Epidemiology of bacteremia in febrile infants in the United States. Pediatrics. 2013;132(6):990–996.
- , , . Changing epidemiology of bacteremia in infants aged 1 week to 3 months. Pediatrics. 2012;129(3):e590–e596.
- , , , et al. Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Pediatrics. 1999;104(1 pt 1):79–86.
- , , , , . Bacteremic urinary tract infection in children. Pediatr Infect Dis J. 2000;19(7):630–634.
- , , , , , . Urine testing and urinary tract infections in febrile infants seen in office settings: the Pediatric Research in Office Settings' Febrile Infant Study. Arch Pediatr Adolesc Med. 2002;156(1):44–54.
- , , , , , . Management of bacteremic urinary tract infections in infants less than 3 months of age. Abstract presented at: Pediatric Academic Societies Annual Meeting; May 5, 2014; Vancouver BC, Canada.
- , , , . Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012.
- , . Recurrent group B streptococcal bacteremia. Clin Pediatr (Phila). 2012;51(9):884–887.
- , , , . Antibiotics for treating lower urinary tract infection in children. Cochrane Database Syst Rev. 2012;8:CD006857.
- . Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics. 2011;128(3):595–610.
- , , . Antibiotics for acute pyelonephritis in children. Cochrane Database Syst Rev. 2007(4):CD003772.
- , , , et al. Randomized trial of oral versus sequential IV/oral antibiotic for acute pyelonephritis in children. Pediatrics. 2012;129(2):e269–e275.
- , , , et al. Prospective, randomized trial comparing short and long intravenous antibiotic treatment of acute pyelonephritis in children: dimercaptosuccinic acid scintigraphic evaluation at 9 months. Pediatrics. 2008;121(3):e553–e560.
- , , , et al. Randomised trial of oral versus sequential intravenous/oral cephalosporins in children with pyelonephritis. Eur J Pediatr. 2008;167(9):1037–1047.
- , , , , . Efficacy of short‐term intravenous antibiotic in neonates with urinary tract infection. Pediatr Emerg Care. 2007;23(2):83–86.
- , , , , , . Shorter courses of parenteral antibiotic therapy do not appear to influence response rates for children with acute hematogenous osteomyelitis: a systematic review. BMC Infect Dis. 2002;2:16.
- , , , . Short‐ versus long‐term antimicrobial treatment for acute hematogenous osteomyelitis of childhood: prospective, randomized trial on 131 culture‐positive cases. Pediatr Infect Dis J. 2010;29(12):1123–1128.
- , , , , , . Prolonged intravenous therapy versus early transition to oral antimicrobial therapy for acute osteomyelitis in children. Pediatrics. 2009;123(2):636–642.
- , , , et al. Acute bacterial osteoarticular infections: eight‐year analysis of C‐reactive protein for oral step‐down therapy. Pediatrics. 2012;130(4):e821–e828.
- , , , , , . Parental decision‐making preferences in the pediatric intensive care unit. Crit Care Med. 2012;40(10):2876–2882.
- , , , , . An assessment of the shared‐decision model in parents of children with acute otitis media. Pediatrics. 2005;116(6):1267–1275.
- , , , , . Risk factors for peripherally inserted central venous catheter complications in children. JAMA Pediatr. 2013;167(5):429–435.
- , , . Current clinical evidence on the effect of general anesthesia on neurodevelopment in children: an updated systematic review with meta‐regression. PLoS One. 2014;9(1):e85760.
- , , , et al. Nosocomial respiratory syncytial virus infection in Canadian pediatric hospitals: a Pediatric Investigators Collaborative Network on Infections in Canada Study. Pediatrics. 1997;100(6):943–946.
- , . Eliminating waste in US health care. JAMA. 2012;307(14):1513–1516.
- , , . Safely doing less: a missing component of the patient safety dialogue. Pediatrics. 2011;128(6):e1596–e1597.
- Committee On Hospital Care and Institute For Patient‐ and Family‐Centered Care. Patient‐ and family‐centered care and the pediatrician's role. Pediatrics. 2012;129(2):394–404.
- . What is value in health care? N Engl J Med. 2010;363(26):2477–2481.
- , , , , . Prevalence and source of pain in pediatric inpatients. Pain. 1996;68(1):25–31.
- , , , . Acute compartment syndrome of the upper extremity in children: diagnosis, management, and outcomes. J Child Orthop. 2013;7(3):225–233.
- , , , , . Neonatal central venous catheter thrombosis: diagnosis, management and outcome. Blood Coagul Fibrinolysis. 2014;25(2):97–106.
- , , , et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American C ollege of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e737S–801S.
- , , , et al. Effect of computer order entry on prevention of serious medication errors in hospitalized children. Pediatrics. 2008;121(3):e421–e427.
- Duration and cessation of antimicrobial treatment. J Hosp Med. 2012;7(suppl 1):S22–S33.
- , , , , . Infectious disease hospitalizations among infants in the United States. Pediatrics. 2008;121(2):244–252.
- . Duration of treatment in bacterial meningitis: a historical inquiry. Pediatr Infect Dis J. 1990;9(1):2–9.
- , , . Length of intravenous antibiotic therapy and treatment failure in infants with urinary tract infections. Pediatrics. 2010;126(2):196–203.
- , , , et al. Group B streptococci in milk and late neonatal infections: an analysis of cases in the literature. Arch Dis Child Fetal Neonatal Ed. 2014;99(1):F41–F47.
- , , . Recurrent late‐onset group B Streptococcus sepsis in a preterm infant acquired by expressed breastmilk transmission: a case report. Breastfeed Med. 2013;8(1):134–136.
- , , , , , . Late‐onset and recurrent neonatal Group B streptococcal disease associated with breast‐milk transmission. Pediatr Dev Pathol. 2003;6(3):251–256.
- , , , , . A 5‐year review of recurrent group B streptococcal disease: lessons from twin infants. Clin Infect Dis. 2000;30(2):282–287.
- , , , et al. Therapeutic amoxicillin levels achieved with oral administration in term neonates. Eur J Clin Pharmacol. 2007;63(7):657–662.
- , , , , , . Population pharmacokinetics and dosing of amoxicillin in (pre)term neonates. Ther Drug Monit. 2006;28(2):226–231.
- , , , et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267–1284.
- , , , , , . Management of bacterial meningitis and meningococcal septicaemia in children and young people: summary of NICE guidance. BMJ. 2010;340:c3209.
- , , , , . Short versus long duration of antibiotic therapy for bacterial meningitis: a meta‐analysis of randomised controlled trials in children. Arch Dis Child. 2009;94(8):607–614.
- , , , et al. 5 versus 10 days of treatment with ceftriaxone for bacterial meningitis in children: a double‐blind randomised equivalence study. Lancet. 2011;377(9780):1837–1845.
- , , , et al. Ceftriaxone as effective as long‐acting chloramphenicol in short‐course treatment of meningococcal meningitis during epidemics: a randomised non‐inferiority study. Lancet. 2005;366(9482):308–313.
- , , , et al. Changing epidemiology of outpatient bacteremia in 3‐ to 36‐month‐old children after the introduction of the heptavalent‐conjugated pneumococcal vaccine. Pediatr Infect Dis J. 2006;25(4):293–300.
- , , , et al. Epidemiology of bacteremia in febrile infants in the United States. Pediatrics. 2013;132(6):990–996.
- , , . Changing epidemiology of bacteremia in infants aged 1 week to 3 months. Pediatrics. 2012;129(3):e590–e596.
- , , , et al. Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Pediatrics. 1999;104(1 pt 1):79–86.
- , , , , . Bacteremic urinary tract infection in children. Pediatr Infect Dis J. 2000;19(7):630–634.
- , , , , , . Urine testing and urinary tract infections in febrile infants seen in office settings: the Pediatric Research in Office Settings' Febrile Infant Study. Arch Pediatr Adolesc Med. 2002;156(1):44–54.
- , , , , , . Management of bacteremic urinary tract infections in infants less than 3 months of age. Abstract presented at: Pediatric Academic Societies Annual Meeting; May 5, 2014; Vancouver BC, Canada.
- , , , . Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012.
- , . Recurrent group B streptococcal bacteremia. Clin Pediatr (Phila). 2012;51(9):884–887.
- , , , . Antibiotics for treating lower urinary tract infection in children. Cochrane Database Syst Rev. 2012;8:CD006857.
- . Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics. 2011;128(3):595–610.
- , , . Antibiotics for acute pyelonephritis in children. Cochrane Database Syst Rev. 2007(4):CD003772.
- , , , et al. Randomized trial of oral versus sequential IV/oral antibiotic for acute pyelonephritis in children. Pediatrics. 2012;129(2):e269–e275.
- , , , et al. Prospective, randomized trial comparing short and long intravenous antibiotic treatment of acute pyelonephritis in children: dimercaptosuccinic acid scintigraphic evaluation at 9 months. Pediatrics. 2008;121(3):e553–e560.
- , , , et al. Randomised trial of oral versus sequential intravenous/oral cephalosporins in children with pyelonephritis. Eur J Pediatr. 2008;167(9):1037–1047.
- , , , , . Efficacy of short‐term intravenous antibiotic in neonates with urinary tract infection. Pediatr Emerg Care. 2007;23(2):83–86.
- , , , , , . Shorter courses of parenteral antibiotic therapy do not appear to influence response rates for children with acute hematogenous osteomyelitis: a systematic review. BMC Infect Dis. 2002;2:16.
- , , , . Short‐ versus long‐term antimicrobial treatment for acute hematogenous osteomyelitis of childhood: prospective, randomized trial on 131 culture‐positive cases. Pediatr Infect Dis J. 2010;29(12):1123–1128.
- , , , , , . Prolonged intravenous therapy versus early transition to oral antimicrobial therapy for acute osteomyelitis in children. Pediatrics. 2009;123(2):636–642.
- , , , et al. Acute bacterial osteoarticular infections: eight‐year analysis of C‐reactive protein for oral step‐down therapy. Pediatrics. 2012;130(4):e821–e828.
- , , , , , . Parental decision‐making preferences in the pediatric intensive care unit. Crit Care Med. 2012;40(10):2876–2882.
- , , , , . An assessment of the shared‐decision model in parents of children with acute otitis media. Pediatrics. 2005;116(6):1267–1275.
- , , , , . Risk factors for peripherally inserted central venous catheter complications in children. JAMA Pediatr. 2013;167(5):429–435.
- , , . Current clinical evidence on the effect of general anesthesia on neurodevelopment in children: an updated systematic review with meta‐regression. PLoS One. 2014;9(1):e85760.
- , , , et al. Nosocomial respiratory syncytial virus infection in Canadian pediatric hospitals: a Pediatric Investigators Collaborative Network on Infections in Canada Study. Pediatrics. 1997;100(6):943–946.
- , . Eliminating waste in US health care. JAMA. 2012;307(14):1513–1516.
- , , . Safely doing less: a missing component of the patient safety dialogue. Pediatrics. 2011;128(6):e1596–e1597.
- Committee On Hospital Care and Institute For Patient‐ and Family‐Centered Care. Patient‐ and family‐centered care and the pediatrician's role. Pediatrics. 2012;129(2):394–404.
- . What is value in health care? N Engl J Med. 2010;363(26):2477–2481.
- , , , , . Prevalence and source of pain in pediatric inpatients. Pain. 1996;68(1):25–31.
- , , , . Acute compartment syndrome of the upper extremity in children: diagnosis, management, and outcomes. J Child Orthop. 2013;7(3):225–233.
- , , , , . Neonatal central venous catheter thrombosis: diagnosis, management and outcome. Blood Coagul Fibrinolysis. 2014;25(2):97–106.
- , , , et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American C ollege of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e737S–801S.
- , , , et al. Effect of computer order entry on prevention of serious medication errors in hospitalized children. Pediatrics. 2008;121(3):e421–e427.
- Duration and cessation of antimicrobial treatment. J Hosp Med. 2012;7(suppl 1):S22–S33.
VIDEO: Dementia risk spikes in older veterans with sleep disorders, PTSD
COPENHAGEN – Older veterans who had sleep disturbances were at a 30% greater risk of developing dementia, according to a retrospective analysis of 200,000 medical records presented at the Alzheimer’s Association International Conference 2014.
And having posttraumatic stress disorder (PTSD) in addition to sleep disturbances put veterans at an 80% greater risk.
"As veterans are turning 65 and older, it’s important for us to understand who in that population is at an increased risk of developing dementia, so when we have that therapy or lifestyle intervention, we can intervene at that point," said Heather M. Snyder, Ph.D., director of medical and scientific operations at the Alzheimer’s Association. Dr. Snyder was not involved in the study.
For the study, researchers studied the records of veterans 55 years and older for 8 years. They found that almost 11% of the veterans with sleep disturbance developed dementia, compared with 9% of those without sleep disturbance, almost a 30% risk increase. The results were similar for veterans who had sleep apnea and nonapnea insomnia.
Meanwhile, researchers found no significant interaction between sleep disturbance and traumatic brain injury or PTSD, with regard to increased risk of dementia. However, veterans who had both PTSD and sleep disturbance had an 80% increased risk of developing dementia.
In a video interview, Dr. Kristine Yaffe, professor of psychiatry and neurology at the University of California, San Francisco, explains the study’s findings, shares practice pearls, and discusses the implications for younger veterans.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @naseemmiller
COPENHAGEN – Older veterans who had sleep disturbances were at a 30% greater risk of developing dementia, according to a retrospective analysis of 200,000 medical records presented at the Alzheimer’s Association International Conference 2014.
And having posttraumatic stress disorder (PTSD) in addition to sleep disturbances put veterans at an 80% greater risk.
"As veterans are turning 65 and older, it’s important for us to understand who in that population is at an increased risk of developing dementia, so when we have that therapy or lifestyle intervention, we can intervene at that point," said Heather M. Snyder, Ph.D., director of medical and scientific operations at the Alzheimer’s Association. Dr. Snyder was not involved in the study.
For the study, researchers studied the records of veterans 55 years and older for 8 years. They found that almost 11% of the veterans with sleep disturbance developed dementia, compared with 9% of those without sleep disturbance, almost a 30% risk increase. The results were similar for veterans who had sleep apnea and nonapnea insomnia.
Meanwhile, researchers found no significant interaction between sleep disturbance and traumatic brain injury or PTSD, with regard to increased risk of dementia. However, veterans who had both PTSD and sleep disturbance had an 80% increased risk of developing dementia.
In a video interview, Dr. Kristine Yaffe, professor of psychiatry and neurology at the University of California, San Francisco, explains the study’s findings, shares practice pearls, and discusses the implications for younger veterans.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @naseemmiller
COPENHAGEN – Older veterans who had sleep disturbances were at a 30% greater risk of developing dementia, according to a retrospective analysis of 200,000 medical records presented at the Alzheimer’s Association International Conference 2014.
And having posttraumatic stress disorder (PTSD) in addition to sleep disturbances put veterans at an 80% greater risk.
"As veterans are turning 65 and older, it’s important for us to understand who in that population is at an increased risk of developing dementia, so when we have that therapy or lifestyle intervention, we can intervene at that point," said Heather M. Snyder, Ph.D., director of medical and scientific operations at the Alzheimer’s Association. Dr. Snyder was not involved in the study.
For the study, researchers studied the records of veterans 55 years and older for 8 years. They found that almost 11% of the veterans with sleep disturbance developed dementia, compared with 9% of those without sleep disturbance, almost a 30% risk increase. The results were similar for veterans who had sleep apnea and nonapnea insomnia.
Meanwhile, researchers found no significant interaction between sleep disturbance and traumatic brain injury or PTSD, with regard to increased risk of dementia. However, veterans who had both PTSD and sleep disturbance had an 80% increased risk of developing dementia.
In a video interview, Dr. Kristine Yaffe, professor of psychiatry and neurology at the University of California, San Francisco, explains the study’s findings, shares practice pearls, and discusses the implications for younger veterans.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @naseemmiller
AT AAIC 2014
Team uncovers secrets of prothrombin structure, function
Credit: Darren Baker
In recreating the structure of prothrombin, researchers have improved their understanding of how the clotting factor functions.
By deleting a disordered linker region, they were able to visualize the complete structure of prothrombin.
This deleted version was activated to thrombin much faster than the intact version of prothrombin.
And results suggested that cofactor Va enhances the activation of prothrombin by altering the architecture of the linker.
Enrico Di Cera, MD, of Saint Louis University in Missouri, and his colleagues reported these findings in PNAS.
Last year, Dr Di Cera’s team published the first structure of prothrombin. This structure lacked a domain responsible for interaction with membranes, and certain other sections were not detected by X-ray analysis.
Though the researchers were able to crystallize the protein, there were disordered regions in the structure they could not see.
Within prothrombin, there are 2 kringle domains connected by a linker region that intrigued the researchers because of its intrinsic disorder.
“We deleted this linker, and crystals grew in a few days instead of months, revealing, for the first time, the full architecture of prothrombin,” Dr Di Cera said.
The crystal structure revealed a contorted conformation where the domains are not vertically stacked, kringle-1 comes close to the protease domain, and the Gla-domain contacts kringle-2.
The researchers also found the deleted version of prothrombin is activated to thrombin much faster than intact prothrombin.
Specifically, deletion of the linker reduced the enhancement of thrombin generation by cofactor Va from the more than 3000-fold observed with wild-type prothrombin to 60-fold. So it appears that deletion of the linker mimics the effect of cofactor Va on prothrombin activation.
“It took us almost 2 years to discover that the disordered linker was the key,” Dr Di Cera said. “Finally, prothrombin revealed its secrets, and, with that, the molecular mechanism of a key reaction of blood clotting finally becomes amenable to rational drug design for therapeutic intervention.”
Credit: Darren Baker
In recreating the structure of prothrombin, researchers have improved their understanding of how the clotting factor functions.
By deleting a disordered linker region, they were able to visualize the complete structure of prothrombin.
This deleted version was activated to thrombin much faster than the intact version of prothrombin.
And results suggested that cofactor Va enhances the activation of prothrombin by altering the architecture of the linker.
Enrico Di Cera, MD, of Saint Louis University in Missouri, and his colleagues reported these findings in PNAS.
Last year, Dr Di Cera’s team published the first structure of prothrombin. This structure lacked a domain responsible for interaction with membranes, and certain other sections were not detected by X-ray analysis.
Though the researchers were able to crystallize the protein, there were disordered regions in the structure they could not see.
Within prothrombin, there are 2 kringle domains connected by a linker region that intrigued the researchers because of its intrinsic disorder.
“We deleted this linker, and crystals grew in a few days instead of months, revealing, for the first time, the full architecture of prothrombin,” Dr Di Cera said.
The crystal structure revealed a contorted conformation where the domains are not vertically stacked, kringle-1 comes close to the protease domain, and the Gla-domain contacts kringle-2.
The researchers also found the deleted version of prothrombin is activated to thrombin much faster than intact prothrombin.
Specifically, deletion of the linker reduced the enhancement of thrombin generation by cofactor Va from the more than 3000-fold observed with wild-type prothrombin to 60-fold. So it appears that deletion of the linker mimics the effect of cofactor Va on prothrombin activation.
“It took us almost 2 years to discover that the disordered linker was the key,” Dr Di Cera said. “Finally, prothrombin revealed its secrets, and, with that, the molecular mechanism of a key reaction of blood clotting finally becomes amenable to rational drug design for therapeutic intervention.”
Credit: Darren Baker
In recreating the structure of prothrombin, researchers have improved their understanding of how the clotting factor functions.
By deleting a disordered linker region, they were able to visualize the complete structure of prothrombin.
This deleted version was activated to thrombin much faster than the intact version of prothrombin.
And results suggested that cofactor Va enhances the activation of prothrombin by altering the architecture of the linker.
Enrico Di Cera, MD, of Saint Louis University in Missouri, and his colleagues reported these findings in PNAS.
Last year, Dr Di Cera’s team published the first structure of prothrombin. This structure lacked a domain responsible for interaction with membranes, and certain other sections were not detected by X-ray analysis.
Though the researchers were able to crystallize the protein, there were disordered regions in the structure they could not see.
Within prothrombin, there are 2 kringle domains connected by a linker region that intrigued the researchers because of its intrinsic disorder.
“We deleted this linker, and crystals grew in a few days instead of months, revealing, for the first time, the full architecture of prothrombin,” Dr Di Cera said.
The crystal structure revealed a contorted conformation where the domains are not vertically stacked, kringle-1 comes close to the protease domain, and the Gla-domain contacts kringle-2.
The researchers also found the deleted version of prothrombin is activated to thrombin much faster than intact prothrombin.
Specifically, deletion of the linker reduced the enhancement of thrombin generation by cofactor Va from the more than 3000-fold observed with wild-type prothrombin to 60-fold. So it appears that deletion of the linker mimics the effect of cofactor Va on prothrombin activation.
“It took us almost 2 years to discover that the disordered linker was the key,” Dr Di Cera said. “Finally, prothrombin revealed its secrets, and, with that, the molecular mechanism of a key reaction of blood clotting finally becomes amenable to rational drug design for therapeutic intervention.”
Assay can detect counterfeit malaria drugs
Credit: CDC
A new assay can be used to determine if a product actually contains the antimalarial drug artesunate, according to a paper published in the journal Talanta.
The testing system looks about as simple, and is almost as cheap, as a sheet of paper.
But it’s actually a colorimetric assay consumers could use to tell whether or not they are getting the medication they paid for—artesunate.
The assay also verifies that an adequate level of the drug is present.
“There are laboratory methods to analyze medications such as this, but they often are not available or widely used in the developing world, where malaria kills thousands of people every year,” said study author Vincent Remcho, PhD, of Oregon State University in Corvallis.
“What we need are inexpensive, accurate assays that can detect adulterated pharmaceuticals in the field, simple enough that anyone can use them. Our technology should provide that.”
The technology is an application of microfluidics in which a film is impressed onto paper that can then detect the presence and level of artesunate in a product.
A single pill can be crushed and dissolved in water. When a drop of the solution is placed on the paper, it turns yellow if the drug is present. The intensity of the color indicates the level of the drug, which can be compared to a simple color chart.
The system can also include another step. The researchers created an iPhone app that could be used to measure the color and tell with an even higher degree of accuracy both the presence and level of artesunate.
“This is conceptually similar to what we do with integrated circuit chips in computers, but we’re pushing fluids around instead of electrons, to reveal chemical information that’s useful to us,” Dr Remcho said. “Chemical communication is how Mother Nature does it, and the long-term applications of this approach really are mind-blowing.”
Aside from ensuring patients receive the appropriate treatment, the assay could help government officials combat the larger problem of drug counterfeiting. Researchers have found that, in some places in the developing world, more than 80% of outlets are selling counterfeit pharmaceuticals.
Dr Remcho and his colleagues also believe their technique could be expanded for a wide range of other medical conditions, pharmaceutical and diagnostic tests, pathogen detection, environmental analysis, and other uses.
Credit: CDC
A new assay can be used to determine if a product actually contains the antimalarial drug artesunate, according to a paper published in the journal Talanta.
The testing system looks about as simple, and is almost as cheap, as a sheet of paper.
But it’s actually a colorimetric assay consumers could use to tell whether or not they are getting the medication they paid for—artesunate.
The assay also verifies that an adequate level of the drug is present.
“There are laboratory methods to analyze medications such as this, but they often are not available or widely used in the developing world, where malaria kills thousands of people every year,” said study author Vincent Remcho, PhD, of Oregon State University in Corvallis.
“What we need are inexpensive, accurate assays that can detect adulterated pharmaceuticals in the field, simple enough that anyone can use them. Our technology should provide that.”
The technology is an application of microfluidics in which a film is impressed onto paper that can then detect the presence and level of artesunate in a product.
A single pill can be crushed and dissolved in water. When a drop of the solution is placed on the paper, it turns yellow if the drug is present. The intensity of the color indicates the level of the drug, which can be compared to a simple color chart.
The system can also include another step. The researchers created an iPhone app that could be used to measure the color and tell with an even higher degree of accuracy both the presence and level of artesunate.
“This is conceptually similar to what we do with integrated circuit chips in computers, but we’re pushing fluids around instead of electrons, to reveal chemical information that’s useful to us,” Dr Remcho said. “Chemical communication is how Mother Nature does it, and the long-term applications of this approach really are mind-blowing.”
Aside from ensuring patients receive the appropriate treatment, the assay could help government officials combat the larger problem of drug counterfeiting. Researchers have found that, in some places in the developing world, more than 80% of outlets are selling counterfeit pharmaceuticals.
Dr Remcho and his colleagues also believe their technique could be expanded for a wide range of other medical conditions, pharmaceutical and diagnostic tests, pathogen detection, environmental analysis, and other uses.
Credit: CDC
A new assay can be used to determine if a product actually contains the antimalarial drug artesunate, according to a paper published in the journal Talanta.
The testing system looks about as simple, and is almost as cheap, as a sheet of paper.
But it’s actually a colorimetric assay consumers could use to tell whether or not they are getting the medication they paid for—artesunate.
The assay also verifies that an adequate level of the drug is present.
“There are laboratory methods to analyze medications such as this, but they often are not available or widely used in the developing world, where malaria kills thousands of people every year,” said study author Vincent Remcho, PhD, of Oregon State University in Corvallis.
“What we need are inexpensive, accurate assays that can detect adulterated pharmaceuticals in the field, simple enough that anyone can use them. Our technology should provide that.”
The technology is an application of microfluidics in which a film is impressed onto paper that can then detect the presence and level of artesunate in a product.
A single pill can be crushed and dissolved in water. When a drop of the solution is placed on the paper, it turns yellow if the drug is present. The intensity of the color indicates the level of the drug, which can be compared to a simple color chart.
The system can also include another step. The researchers created an iPhone app that could be used to measure the color and tell with an even higher degree of accuracy both the presence and level of artesunate.
“This is conceptually similar to what we do with integrated circuit chips in computers, but we’re pushing fluids around instead of electrons, to reveal chemical information that’s useful to us,” Dr Remcho said. “Chemical communication is how Mother Nature does it, and the long-term applications of this approach really are mind-blowing.”
Aside from ensuring patients receive the appropriate treatment, the assay could help government officials combat the larger problem of drug counterfeiting. Researchers have found that, in some places in the developing world, more than 80% of outlets are selling counterfeit pharmaceuticals.
Dr Remcho and his colleagues also believe their technique could be expanded for a wide range of other medical conditions, pharmaceutical and diagnostic tests, pathogen detection, environmental analysis, and other uses.