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New education law should improve services for children 0-5 years
One of the perceived failings of the No Child Left Behind Act was that it attempted to address disparities by increasing standardized testing throughout the K-12 period. Ironically, it left children under 5 years … well, behind. To more effectively prevent problems and reduce disparities, our nation should improve its early detection and intervention system.
This means increasing standardized screening for developmental-behavioral problems or at-risk conditions from 0 through 5 years – and then, swiftly connecting at-risk children/families to the most effective and appropriate community services. This strategy is analogous to quickly detecting and putting out small fires before they morph into raging forest fires.
On Dec. 10, The Every Child Achieves Act of 2015 was signed into law by President Obama with bipartisan support. One seemingly minor, but important new change is that federal funds can be allocated for states, school districts, and schools to improve early childhood learning services. However, the extent to which different states invest in early childhood programs remains to be seen.
A month earlier, a Pediatrics article entitled “Systemwide Solutions to Improve Early Intervention for Developmental-Behavioral Concerns” offered expert advice on how to frugally invest those dollars (Pediatrics 2015 Nov. doi: 10.1542/peds.2015-1723). For children aged 0- 5 years, my coauthors and I proposed that every state needs:
• Systemwide screening and care coordination.
• Comprehensive, equitable, and tiered assessments for at-risk or referred children.
• Universal access to high-quality early learning or preschool programs.
• Continuous accountability for the early detection and intervention process.
Systemwide screening
The American Academy of Pediatrics (AAP), along with a federal-level initiative, Birth to 5: Watch Me Thrive! recommends every infant, toddler, and preschooler be periodically screened for developmental-behavioral problems. The new mantra is, “Learn the Signs. Act Early.”
Parents should know that high-quality screening does not prematurely label children with a diagnosis. Instead, regular screenings help raise awareness of their child’s development, making it easier to expect and celebrate developmental milestones. Very importantly, screening has also been proven to substantially improve the percentage of children receiving early intervention (EI).
Connecting the dots, high-quality EI substantially lowers rates of academic remediation or failure, teenage pregnancy, antisocial or criminal behavior, substance abuse, suicidal ideation and attempts, unemployment, and welfare dependency. Just think how preventing all these problems relates to what has been in the news recently.
In reality, many health care clinics, day care centers, and preschools still don’t offer high-quality screening. Even pediatricians can struggle with implementing the AAP’s recommendations . In a busy office, proper implementation requires teamwork. At a statewide level, entire populations need to be accurately screened and tracked.
Systemwide care coordination
Unfortunately, only about 50% of referred children are promptly connected to EI services (Clin Pediatr [Phila]. 2011 Sep;50[9]:853-68). Many overwhelmed or anxious parents don’t follow up. This is problematic because these same “lost to follow-up” children typically perform well below average and have numerous, predictive academic and psychosocial risk factors. Meanwhile, health care providers struggle with tracking at-risk children. And sometimes, pediatric offices don’t share referral information (including screening results) with EI agencies. However, if the child lives in a community with systemwide care coordination, then more than 80% of referred children will be linked to the EI intervention agency or an alternative resource like Early Head Start, a parenting program, or a home visitation program. Connecticut has more than double the EI enrollment rate (3.8%) of Georgia (1.5%), even though they share the exact same eligibility definition. The difference is Connecticut’s Help Me Grow program. Nevertheless, most states lack systemwide care coordination.
Comprehensive, equitable, and tiered assessments
Nonsensically, there are 22 state-specific numerical definitions for EI eligibility, and the majority of states have inappropriately strict criteria (Pediatrics 2013 Jan:131[1]38-46). The proportion of children enrolled in EI ranges from a shameful 1.5% (Georgia) to a meager 7% (Massachusetts). On average, approximately 2.8% of children receive EI even though 25% of moderate- to high-income and 48% of low-income kindergarteners are “not ready to learn.”
Instead of a state-specific EI-eligible versus EI-ineligible process, comprehensive and equitable assessments should lead to a tiered spectrum of high-quality interventions for all at-risk children – most especially, disadvantaged children who are frequently missed. For example, the infant with a poor depressed mother is frequently deemed “ineligible,” but then is significantly behind by kindergarten age. To avoid squandering time-sensitive windows of opportunity, states need a national, research-driven definition of what constitutes a developmental–behavioral delay or at-risk condition. Families need EI or supports that are appropriately intensive, based on their continuum of need.
Universal access
Expanding early learning initiatives would yield benefits to society of roughly $8.60 for every $1 spent, about half of which comes from increased earnings for children when they grow up, according to a White House study by the President’s Council of Economic Advisers. Critics frequently ignore systematic reviews, which demonstrate beneficial outcomes for “high-quality” or “comprehensive” programs – and the younger the intervention, the better the outcomes.
Continuous accountability
This is needed to ensure children are being screened and swiftly linked to high-quality services. Accountability should include a low-cost metric of developmental-behavioral status at 5 years (that is, a school-based kindergarten-readiness intake assessment). If our ultimate goal is to improve outcomes and reduce disparities, then we need to make certain the system is working. That way, states can tweak their processes to optimize child outcomes over time.
Without a doubt, acting early builds better brains. The leadership question remains: Will politicians adequately invest in these systemwide solutions?
Dr. Marks is a general pediatrician at PeaceHealth Medical Group in Eugene, Ore. He disclosed he is a coauthor of “Developmental Screening in Your Community: An Integrated Approach for Connecting Children with Services,” but has no other relevant disclosures. Email him at [email protected].
One of the perceived failings of the No Child Left Behind Act was that it attempted to address disparities by increasing standardized testing throughout the K-12 period. Ironically, it left children under 5 years … well, behind. To more effectively prevent problems and reduce disparities, our nation should improve its early detection and intervention system.
This means increasing standardized screening for developmental-behavioral problems or at-risk conditions from 0 through 5 years – and then, swiftly connecting at-risk children/families to the most effective and appropriate community services. This strategy is analogous to quickly detecting and putting out small fires before they morph into raging forest fires.
On Dec. 10, The Every Child Achieves Act of 2015 was signed into law by President Obama with bipartisan support. One seemingly minor, but important new change is that federal funds can be allocated for states, school districts, and schools to improve early childhood learning services. However, the extent to which different states invest in early childhood programs remains to be seen.
A month earlier, a Pediatrics article entitled “Systemwide Solutions to Improve Early Intervention for Developmental-Behavioral Concerns” offered expert advice on how to frugally invest those dollars (Pediatrics 2015 Nov. doi: 10.1542/peds.2015-1723). For children aged 0- 5 years, my coauthors and I proposed that every state needs:
• Systemwide screening and care coordination.
• Comprehensive, equitable, and tiered assessments for at-risk or referred children.
• Universal access to high-quality early learning or preschool programs.
• Continuous accountability for the early detection and intervention process.
Systemwide screening
The American Academy of Pediatrics (AAP), along with a federal-level initiative, Birth to 5: Watch Me Thrive! recommends every infant, toddler, and preschooler be periodically screened for developmental-behavioral problems. The new mantra is, “Learn the Signs. Act Early.”
Parents should know that high-quality screening does not prematurely label children with a diagnosis. Instead, regular screenings help raise awareness of their child’s development, making it easier to expect and celebrate developmental milestones. Very importantly, screening has also been proven to substantially improve the percentage of children receiving early intervention (EI).
Connecting the dots, high-quality EI substantially lowers rates of academic remediation or failure, teenage pregnancy, antisocial or criminal behavior, substance abuse, suicidal ideation and attempts, unemployment, and welfare dependency. Just think how preventing all these problems relates to what has been in the news recently.
In reality, many health care clinics, day care centers, and preschools still don’t offer high-quality screening. Even pediatricians can struggle with implementing the AAP’s recommendations . In a busy office, proper implementation requires teamwork. At a statewide level, entire populations need to be accurately screened and tracked.
Systemwide care coordination
Unfortunately, only about 50% of referred children are promptly connected to EI services (Clin Pediatr [Phila]. 2011 Sep;50[9]:853-68). Many overwhelmed or anxious parents don’t follow up. This is problematic because these same “lost to follow-up” children typically perform well below average and have numerous, predictive academic and psychosocial risk factors. Meanwhile, health care providers struggle with tracking at-risk children. And sometimes, pediatric offices don’t share referral information (including screening results) with EI agencies. However, if the child lives in a community with systemwide care coordination, then more than 80% of referred children will be linked to the EI intervention agency or an alternative resource like Early Head Start, a parenting program, or a home visitation program. Connecticut has more than double the EI enrollment rate (3.8%) of Georgia (1.5%), even though they share the exact same eligibility definition. The difference is Connecticut’s Help Me Grow program. Nevertheless, most states lack systemwide care coordination.
Comprehensive, equitable, and tiered assessments
Nonsensically, there are 22 state-specific numerical definitions for EI eligibility, and the majority of states have inappropriately strict criteria (Pediatrics 2013 Jan:131[1]38-46). The proportion of children enrolled in EI ranges from a shameful 1.5% (Georgia) to a meager 7% (Massachusetts). On average, approximately 2.8% of children receive EI even though 25% of moderate- to high-income and 48% of low-income kindergarteners are “not ready to learn.”
Instead of a state-specific EI-eligible versus EI-ineligible process, comprehensive and equitable assessments should lead to a tiered spectrum of high-quality interventions for all at-risk children – most especially, disadvantaged children who are frequently missed. For example, the infant with a poor depressed mother is frequently deemed “ineligible,” but then is significantly behind by kindergarten age. To avoid squandering time-sensitive windows of opportunity, states need a national, research-driven definition of what constitutes a developmental–behavioral delay or at-risk condition. Families need EI or supports that are appropriately intensive, based on their continuum of need.
Universal access
Expanding early learning initiatives would yield benefits to society of roughly $8.60 for every $1 spent, about half of which comes from increased earnings for children when they grow up, according to a White House study by the President’s Council of Economic Advisers. Critics frequently ignore systematic reviews, which demonstrate beneficial outcomes for “high-quality” or “comprehensive” programs – and the younger the intervention, the better the outcomes.
Continuous accountability
This is needed to ensure children are being screened and swiftly linked to high-quality services. Accountability should include a low-cost metric of developmental-behavioral status at 5 years (that is, a school-based kindergarten-readiness intake assessment). If our ultimate goal is to improve outcomes and reduce disparities, then we need to make certain the system is working. That way, states can tweak their processes to optimize child outcomes over time.
Without a doubt, acting early builds better brains. The leadership question remains: Will politicians adequately invest in these systemwide solutions?
Dr. Marks is a general pediatrician at PeaceHealth Medical Group in Eugene, Ore. He disclosed he is a coauthor of “Developmental Screening in Your Community: An Integrated Approach for Connecting Children with Services,” but has no other relevant disclosures. Email him at [email protected].
One of the perceived failings of the No Child Left Behind Act was that it attempted to address disparities by increasing standardized testing throughout the K-12 period. Ironically, it left children under 5 years … well, behind. To more effectively prevent problems and reduce disparities, our nation should improve its early detection and intervention system.
This means increasing standardized screening for developmental-behavioral problems or at-risk conditions from 0 through 5 years – and then, swiftly connecting at-risk children/families to the most effective and appropriate community services. This strategy is analogous to quickly detecting and putting out small fires before they morph into raging forest fires.
On Dec. 10, The Every Child Achieves Act of 2015 was signed into law by President Obama with bipartisan support. One seemingly minor, but important new change is that federal funds can be allocated for states, school districts, and schools to improve early childhood learning services. However, the extent to which different states invest in early childhood programs remains to be seen.
A month earlier, a Pediatrics article entitled “Systemwide Solutions to Improve Early Intervention for Developmental-Behavioral Concerns” offered expert advice on how to frugally invest those dollars (Pediatrics 2015 Nov. doi: 10.1542/peds.2015-1723). For children aged 0- 5 years, my coauthors and I proposed that every state needs:
• Systemwide screening and care coordination.
• Comprehensive, equitable, and tiered assessments for at-risk or referred children.
• Universal access to high-quality early learning or preschool programs.
• Continuous accountability for the early detection and intervention process.
Systemwide screening
The American Academy of Pediatrics (AAP), along with a federal-level initiative, Birth to 5: Watch Me Thrive! recommends every infant, toddler, and preschooler be periodically screened for developmental-behavioral problems. The new mantra is, “Learn the Signs. Act Early.”
Parents should know that high-quality screening does not prematurely label children with a diagnosis. Instead, regular screenings help raise awareness of their child’s development, making it easier to expect and celebrate developmental milestones. Very importantly, screening has also been proven to substantially improve the percentage of children receiving early intervention (EI).
Connecting the dots, high-quality EI substantially lowers rates of academic remediation or failure, teenage pregnancy, antisocial or criminal behavior, substance abuse, suicidal ideation and attempts, unemployment, and welfare dependency. Just think how preventing all these problems relates to what has been in the news recently.
In reality, many health care clinics, day care centers, and preschools still don’t offer high-quality screening. Even pediatricians can struggle with implementing the AAP’s recommendations . In a busy office, proper implementation requires teamwork. At a statewide level, entire populations need to be accurately screened and tracked.
Systemwide care coordination
Unfortunately, only about 50% of referred children are promptly connected to EI services (Clin Pediatr [Phila]. 2011 Sep;50[9]:853-68). Many overwhelmed or anxious parents don’t follow up. This is problematic because these same “lost to follow-up” children typically perform well below average and have numerous, predictive academic and psychosocial risk factors. Meanwhile, health care providers struggle with tracking at-risk children. And sometimes, pediatric offices don’t share referral information (including screening results) with EI agencies. However, if the child lives in a community with systemwide care coordination, then more than 80% of referred children will be linked to the EI intervention agency or an alternative resource like Early Head Start, a parenting program, or a home visitation program. Connecticut has more than double the EI enrollment rate (3.8%) of Georgia (1.5%), even though they share the exact same eligibility definition. The difference is Connecticut’s Help Me Grow program. Nevertheless, most states lack systemwide care coordination.
Comprehensive, equitable, and tiered assessments
Nonsensically, there are 22 state-specific numerical definitions for EI eligibility, and the majority of states have inappropriately strict criteria (Pediatrics 2013 Jan:131[1]38-46). The proportion of children enrolled in EI ranges from a shameful 1.5% (Georgia) to a meager 7% (Massachusetts). On average, approximately 2.8% of children receive EI even though 25% of moderate- to high-income and 48% of low-income kindergarteners are “not ready to learn.”
Instead of a state-specific EI-eligible versus EI-ineligible process, comprehensive and equitable assessments should lead to a tiered spectrum of high-quality interventions for all at-risk children – most especially, disadvantaged children who are frequently missed. For example, the infant with a poor depressed mother is frequently deemed “ineligible,” but then is significantly behind by kindergarten age. To avoid squandering time-sensitive windows of opportunity, states need a national, research-driven definition of what constitutes a developmental–behavioral delay or at-risk condition. Families need EI or supports that are appropriately intensive, based on their continuum of need.
Universal access
Expanding early learning initiatives would yield benefits to society of roughly $8.60 for every $1 spent, about half of which comes from increased earnings for children when they grow up, according to a White House study by the President’s Council of Economic Advisers. Critics frequently ignore systematic reviews, which demonstrate beneficial outcomes for “high-quality” or “comprehensive” programs – and the younger the intervention, the better the outcomes.
Continuous accountability
This is needed to ensure children are being screened and swiftly linked to high-quality services. Accountability should include a low-cost metric of developmental-behavioral status at 5 years (that is, a school-based kindergarten-readiness intake assessment). If our ultimate goal is to improve outcomes and reduce disparities, then we need to make certain the system is working. That way, states can tweak their processes to optimize child outcomes over time.
Without a doubt, acting early builds better brains. The leadership question remains: Will politicians adequately invest in these systemwide solutions?
Dr. Marks is a general pediatrician at PeaceHealth Medical Group in Eugene, Ore. He disclosed he is a coauthor of “Developmental Screening in Your Community: An Integrated Approach for Connecting Children with Services,” but has no other relevant disclosures. Email him at [email protected].
The ‘easy’ but ‘not-so-easy’ brow lift
One of the most apparent and difficult-to-treat aspects of the aging eye is the descent of the eyebrow. The change in the orbital bone structure as well as fat loss and fat redistribution along the upper and lower eyelids and loss of skin elasticity contribute to the skeletonization of the periorbital area and a “drooping” of the eyebrow. Patients either have loss of volume across the entire brow, or primarily across the lateral and central brow creating what is known as an “a-frame” deformity.
Nonsurgical techniques that help lift the brow include a combination of relaxation of the orbicularis oculi muscle with neurotoxins, in addition to the injection of hyaluronic acid fillers along the brow margin and upper third of the face.
Small amounts of hyaluronic acid fillers injected with a 22- to 25-gauge cannula both above and below the eyebrow along the orbital rim provide an instantaneous lifting effect with long-lasting results. Hyaluronic acid and poly-L-lactic acid in dilute concentrations can also be injected with a cannula in the forehead, which creates a repletion of the volume in the upper face that is often lost with aging to create a lift of the eyebrows. Temple hollows can also be filled with calcium hydroxylapatite, poly-L-lactic acid and less often with hyaluronic acid to revolumize and create a lift of the lateral brow. Care should be taken as fillers used in these areas are off-label and need to be done by trained, expert injectors. The periorbital area is a danger zone with many vessels and nerves, and proper injection technique is crucial to avoid arterial blockage, nerve damage, and long-term complications.
Nonablative skin tightening with radiofrequency energy or ultrasound can be used for achieving a brow-lift. Although these techniques do provide collagen remodeling, multiple procedures are often necessary, and results are not always substantial. In a study of 36 patients undergoing ultrasound tightening of the face and neck, 86% showed a clinically significant brow-lift 90 days after treatment. The average brow elevation in this study was 1.7 mm.
In practice, however, patients are often more satisfied with the brow elevation they achieve with neurotoxins and fillers. Injectables provide a faster onset of results, fewer treatments, and minimal discomfort. Combination treatments provide the best overall results and although injectables in the periorbital area are technically difficult, patients are often very satisfied and return for repeat treatments.
References Aesthet Surg J. 2009;May-Jun;29(3):174-9.
J Am Acad Dermatol. 2010;Feb;62(2):262-9.
Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub.
One of the most apparent and difficult-to-treat aspects of the aging eye is the descent of the eyebrow. The change in the orbital bone structure as well as fat loss and fat redistribution along the upper and lower eyelids and loss of skin elasticity contribute to the skeletonization of the periorbital area and a “drooping” of the eyebrow. Patients either have loss of volume across the entire brow, or primarily across the lateral and central brow creating what is known as an “a-frame” deformity.
Nonsurgical techniques that help lift the brow include a combination of relaxation of the orbicularis oculi muscle with neurotoxins, in addition to the injection of hyaluronic acid fillers along the brow margin and upper third of the face.
Small amounts of hyaluronic acid fillers injected with a 22- to 25-gauge cannula both above and below the eyebrow along the orbital rim provide an instantaneous lifting effect with long-lasting results. Hyaluronic acid and poly-L-lactic acid in dilute concentrations can also be injected with a cannula in the forehead, which creates a repletion of the volume in the upper face that is often lost with aging to create a lift of the eyebrows. Temple hollows can also be filled with calcium hydroxylapatite, poly-L-lactic acid and less often with hyaluronic acid to revolumize and create a lift of the lateral brow. Care should be taken as fillers used in these areas are off-label and need to be done by trained, expert injectors. The periorbital area is a danger zone with many vessels and nerves, and proper injection technique is crucial to avoid arterial blockage, nerve damage, and long-term complications.
Nonablative skin tightening with radiofrequency energy or ultrasound can be used for achieving a brow-lift. Although these techniques do provide collagen remodeling, multiple procedures are often necessary, and results are not always substantial. In a study of 36 patients undergoing ultrasound tightening of the face and neck, 86% showed a clinically significant brow-lift 90 days after treatment. The average brow elevation in this study was 1.7 mm.
In practice, however, patients are often more satisfied with the brow elevation they achieve with neurotoxins and fillers. Injectables provide a faster onset of results, fewer treatments, and minimal discomfort. Combination treatments provide the best overall results and although injectables in the periorbital area are technically difficult, patients are often very satisfied and return for repeat treatments.
References Aesthet Surg J. 2009;May-Jun;29(3):174-9.
J Am Acad Dermatol. 2010;Feb;62(2):262-9.
Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub.
One of the most apparent and difficult-to-treat aspects of the aging eye is the descent of the eyebrow. The change in the orbital bone structure as well as fat loss and fat redistribution along the upper and lower eyelids and loss of skin elasticity contribute to the skeletonization of the periorbital area and a “drooping” of the eyebrow. Patients either have loss of volume across the entire brow, or primarily across the lateral and central brow creating what is known as an “a-frame” deformity.
Nonsurgical techniques that help lift the brow include a combination of relaxation of the orbicularis oculi muscle with neurotoxins, in addition to the injection of hyaluronic acid fillers along the brow margin and upper third of the face.
Small amounts of hyaluronic acid fillers injected with a 22- to 25-gauge cannula both above and below the eyebrow along the orbital rim provide an instantaneous lifting effect with long-lasting results. Hyaluronic acid and poly-L-lactic acid in dilute concentrations can also be injected with a cannula in the forehead, which creates a repletion of the volume in the upper face that is often lost with aging to create a lift of the eyebrows. Temple hollows can also be filled with calcium hydroxylapatite, poly-L-lactic acid and less often with hyaluronic acid to revolumize and create a lift of the lateral brow. Care should be taken as fillers used in these areas are off-label and need to be done by trained, expert injectors. The periorbital area is a danger zone with many vessels and nerves, and proper injection technique is crucial to avoid arterial blockage, nerve damage, and long-term complications.
Nonablative skin tightening with radiofrequency energy or ultrasound can be used for achieving a brow-lift. Although these techniques do provide collagen remodeling, multiple procedures are often necessary, and results are not always substantial. In a study of 36 patients undergoing ultrasound tightening of the face and neck, 86% showed a clinically significant brow-lift 90 days after treatment. The average brow elevation in this study was 1.7 mm.
In practice, however, patients are often more satisfied with the brow elevation they achieve with neurotoxins and fillers. Injectables provide a faster onset of results, fewer treatments, and minimal discomfort. Combination treatments provide the best overall results and although injectables in the periorbital area are technically difficult, patients are often very satisfied and return for repeat treatments.
References Aesthet Surg J. 2009;May-Jun;29(3):174-9.
J Am Acad Dermatol. 2010;Feb;62(2):262-9.
Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub.
BOOK REVIEW: Kennedy navigates substance use, stigma, recovery
“A Common Struggle” by former Rep. Patrick J. Kennedy (D-R.I.) and journalist and author Stephen Fried, describes the fascinating odyssey of a young man attempting to sail intact through the stormy seas of treatment for a mental health/substance use disorder while fighting desperately for parity in mental health and substance abuse treatment in our medical system.
Mr. Kennedy, youngest son of the late Sen. Edward M. Kennedy, inherits more than a legacy of public service. His mother has acknowledged having had a severe alcohol use disorder, and one can trace a significant number of substance use disorders across the extended Kennedy clan. These inheritances produce a remarkable story of struggle that has opened the United States to a potential revolution in the perception and care of mental illness and substance use disorders. The book (New York: Blue Rider Press, 2015) thankfully includes a happy ending for an individual who has now dedicated his life to the cause of treatment parity for mental health and substance use disorders. In a recent interview, the younger Kennedy said he had been sober for 5 years.
The authors develop three parallel themes: the political fight for parity for mental health and substance use disorder treatment, the fight for Mr. Kennedy’s own personal treatment of a serious mental health/substance use disorder, and the evolution of treatment for mental illness and substance use disorders in the United States. Mr. Kennedy struggles early on with mental health issues and substance use disorders, and looks back to his days in high school as being “ill.” Many of the symptoms identified then and later in Mr. Kennedy’s life fit the diagnostic criteria for bipolar disorder, and alcohol and substance use disorders. But it is in Providence, R.I., in college, where the third theme evolves, beginning with his work as a volunteer on a suicide hotline.
Mr. Kennedy then interned at the Rhode Island State House, was elected as a delegate to the 1988 Democratic convention, and ran for the Rhode Island state legislature at the age of 20, while still a college student. From there, he launched a campaign for the House of Representatives from the first congressional district of Rhode Island and served four terms in the U.S. Congress. His political career was marked by a long and successful struggle on the three fronts of parity, stigma, and personal recovery.
The book is a fascinating tour through these themes. We watch a young man grapple with issues confronting many Americans, a battle characterized by secrecy, fear of stigma, misdiagnoses, mind-boggling polypharmacy, and finally, a revolution in treatment. We learn that there are effective behavioral and medical treatments, but they need to be more widely implemented. And more research is needed in brain science to make treatments even better.
The three themes of the book are still in flux. Parity for mental health and substance use disorders remains to be implemented by the medical profession and insurance payers. Congressman Kennedy’s personal treatment will continue to evolve. And the movement from a pure psychoanalytic approach to brain-based treatments of mental health and substance use disorders is an exciting new domain.
This book is a must-read, not only for those suffering from mental health and substance use disorders, but also for the professionals who treat them and for those who pay for that treatment.
Dr. Koob is director of the U.S. National Institute on Alcohol Abuse and Alcoholism. He joined the National Institutes of Health from the Scripps Research Institute in La Jolla, Calif., in 2014. An authority on drug addiction and stress, Dr. Koob has contributed to our understanding of the neurocircuitry associated with the acute reinforcing effects of drugs of abuse, and the neuroadaptations of the reward and stress circuits associated with the transition to dependence. He has published more than 650 peer-reviewed papers and several books, including the “Neurobiology of Addiction” (Academic Press, 2005), a comprehensive treatise on emerging research in the field; and a textbook for upper division undergraduates and graduate students called “Drugs, Addiction and the Brain” (Academic Press, 2014).
“A Common Struggle” by former Rep. Patrick J. Kennedy (D-R.I.) and journalist and author Stephen Fried, describes the fascinating odyssey of a young man attempting to sail intact through the stormy seas of treatment for a mental health/substance use disorder while fighting desperately for parity in mental health and substance abuse treatment in our medical system.
Mr. Kennedy, youngest son of the late Sen. Edward M. Kennedy, inherits more than a legacy of public service. His mother has acknowledged having had a severe alcohol use disorder, and one can trace a significant number of substance use disorders across the extended Kennedy clan. These inheritances produce a remarkable story of struggle that has opened the United States to a potential revolution in the perception and care of mental illness and substance use disorders. The book (New York: Blue Rider Press, 2015) thankfully includes a happy ending for an individual who has now dedicated his life to the cause of treatment parity for mental health and substance use disorders. In a recent interview, the younger Kennedy said he had been sober for 5 years.
The authors develop three parallel themes: the political fight for parity for mental health and substance use disorder treatment, the fight for Mr. Kennedy’s own personal treatment of a serious mental health/substance use disorder, and the evolution of treatment for mental illness and substance use disorders in the United States. Mr. Kennedy struggles early on with mental health issues and substance use disorders, and looks back to his days in high school as being “ill.” Many of the symptoms identified then and later in Mr. Kennedy’s life fit the diagnostic criteria for bipolar disorder, and alcohol and substance use disorders. But it is in Providence, R.I., in college, where the third theme evolves, beginning with his work as a volunteer on a suicide hotline.
Mr. Kennedy then interned at the Rhode Island State House, was elected as a delegate to the 1988 Democratic convention, and ran for the Rhode Island state legislature at the age of 20, while still a college student. From there, he launched a campaign for the House of Representatives from the first congressional district of Rhode Island and served four terms in the U.S. Congress. His political career was marked by a long and successful struggle on the three fronts of parity, stigma, and personal recovery.
The book is a fascinating tour through these themes. We watch a young man grapple with issues confronting many Americans, a battle characterized by secrecy, fear of stigma, misdiagnoses, mind-boggling polypharmacy, and finally, a revolution in treatment. We learn that there are effective behavioral and medical treatments, but they need to be more widely implemented. And more research is needed in brain science to make treatments even better.
The three themes of the book are still in flux. Parity for mental health and substance use disorders remains to be implemented by the medical profession and insurance payers. Congressman Kennedy’s personal treatment will continue to evolve. And the movement from a pure psychoanalytic approach to brain-based treatments of mental health and substance use disorders is an exciting new domain.
This book is a must-read, not only for those suffering from mental health and substance use disorders, but also for the professionals who treat them and for those who pay for that treatment.
Dr. Koob is director of the U.S. National Institute on Alcohol Abuse and Alcoholism. He joined the National Institutes of Health from the Scripps Research Institute in La Jolla, Calif., in 2014. An authority on drug addiction and stress, Dr. Koob has contributed to our understanding of the neurocircuitry associated with the acute reinforcing effects of drugs of abuse, and the neuroadaptations of the reward and stress circuits associated with the transition to dependence. He has published more than 650 peer-reviewed papers and several books, including the “Neurobiology of Addiction” (Academic Press, 2005), a comprehensive treatise on emerging research in the field; and a textbook for upper division undergraduates and graduate students called “Drugs, Addiction and the Brain” (Academic Press, 2014).
“A Common Struggle” by former Rep. Patrick J. Kennedy (D-R.I.) and journalist and author Stephen Fried, describes the fascinating odyssey of a young man attempting to sail intact through the stormy seas of treatment for a mental health/substance use disorder while fighting desperately for parity in mental health and substance abuse treatment in our medical system.
Mr. Kennedy, youngest son of the late Sen. Edward M. Kennedy, inherits more than a legacy of public service. His mother has acknowledged having had a severe alcohol use disorder, and one can trace a significant number of substance use disorders across the extended Kennedy clan. These inheritances produce a remarkable story of struggle that has opened the United States to a potential revolution in the perception and care of mental illness and substance use disorders. The book (New York: Blue Rider Press, 2015) thankfully includes a happy ending for an individual who has now dedicated his life to the cause of treatment parity for mental health and substance use disorders. In a recent interview, the younger Kennedy said he had been sober for 5 years.
The authors develop three parallel themes: the political fight for parity for mental health and substance use disorder treatment, the fight for Mr. Kennedy’s own personal treatment of a serious mental health/substance use disorder, and the evolution of treatment for mental illness and substance use disorders in the United States. Mr. Kennedy struggles early on with mental health issues and substance use disorders, and looks back to his days in high school as being “ill.” Many of the symptoms identified then and later in Mr. Kennedy’s life fit the diagnostic criteria for bipolar disorder, and alcohol and substance use disorders. But it is in Providence, R.I., in college, where the third theme evolves, beginning with his work as a volunteer on a suicide hotline.
Mr. Kennedy then interned at the Rhode Island State House, was elected as a delegate to the 1988 Democratic convention, and ran for the Rhode Island state legislature at the age of 20, while still a college student. From there, he launched a campaign for the House of Representatives from the first congressional district of Rhode Island and served four terms in the U.S. Congress. His political career was marked by a long and successful struggle on the three fronts of parity, stigma, and personal recovery.
The book is a fascinating tour through these themes. We watch a young man grapple with issues confronting many Americans, a battle characterized by secrecy, fear of stigma, misdiagnoses, mind-boggling polypharmacy, and finally, a revolution in treatment. We learn that there are effective behavioral and medical treatments, but they need to be more widely implemented. And more research is needed in brain science to make treatments even better.
The three themes of the book are still in flux. Parity for mental health and substance use disorders remains to be implemented by the medical profession and insurance payers. Congressman Kennedy’s personal treatment will continue to evolve. And the movement from a pure psychoanalytic approach to brain-based treatments of mental health and substance use disorders is an exciting new domain.
This book is a must-read, not only for those suffering from mental health and substance use disorders, but also for the professionals who treat them and for those who pay for that treatment.
Dr. Koob is director of the U.S. National Institute on Alcohol Abuse and Alcoholism. He joined the National Institutes of Health from the Scripps Research Institute in La Jolla, Calif., in 2014. An authority on drug addiction and stress, Dr. Koob has contributed to our understanding of the neurocircuitry associated with the acute reinforcing effects of drugs of abuse, and the neuroadaptations of the reward and stress circuits associated with the transition to dependence. He has published more than 650 peer-reviewed papers and several books, including the “Neurobiology of Addiction” (Academic Press, 2005), a comprehensive treatise on emerging research in the field; and a textbook for upper division undergraduates and graduate students called “Drugs, Addiction and the Brain” (Academic Press, 2014).
‘It Gets Better’ still offering hope to LGBTQ youth
It Gets Better turned 5 years old in 2015. It’s an organization and a project that has connected with LGBTQ youth through the Internet in the form of videos recorded mostly by celebrities and politicians. The organization started by Dan Savage and Terry Miller went so far to have President Obama featured in a video back in 2010.
The videos are short messages aimed at reaching LGBTQ (lesbian/gay/bisexual/transgender/questioning) youth who would otherwise be isolated from elders and mentors. It allows a mature queer community to communicate to these youths in their rural towns and provide hope that life will improve over time. It’s somewhat disturbing to wonder why such a project is necessary, but a quick review of some of the facts will underscore why messages like these are essential.
As stated by the Centers for Disease Control and Prevention, suicide is the second-leading cause of death of youths aged 10-24 years. As prevalent as that is, an LGB youth is four times as likely to attempt suicide. Being an LGB youth of color further increases that risk, and among those who identify as transgender, as many as 25% report having made a suicide attempt. These mental health disparities are not a result of an endemic characteristic of an LGBTQ youth but rather are tied to society’s lack of understanding and support of them.
A project like It Gets Better goes a long way in repairing society’s failure to provide basic support to a community that is impoverished when it comes to receiving empathy. Most of the country lacks mental health treatment that is knowledgeable about the LGBTQ community. The majority of the country also lacks access to a queer community, specifically in that there are no LGBT centers or organizations to provide a safe space to these youths to ask questions, learn, bond with each other, and grow into adults with strong self-esteem.
The population of the United States is just over 300 million, and about 5% of those people identify as LGBTQ in some form. That’s 9 million people who are or grew up as LGBTQ youths ... who were likely isolated, confused, and shamed for who they are. For one of these youths to watch a video – either with the U.S. president or another famous figure they look up to – speak to them, it can potentially provide them that small amount of hope that would be needed to see them through whatever challenges that might be before them.
Anyone can help a cause like this. If you are a mental health provider, educate yourself with the facts of the LGBTQ community and learn how to provide affirming therapy to a range of sexual orientations and gender identities. Organizations such as AGLP: The Association of LGBTQ Psychiatrists provide educational materials and give presentations to train clinicians on basic LGBTQ needs.
If you aren’t a mental health care provider, simply providing a caring ear and unconditional acceptance to a young person goes a long way. An adolescent in the straight community already has enough trouble with puberty, emotions, and feeling left out. An LGBTQ youth has these feelings amplified. We should all do our duty to let them know they belong to something larger than themselves and that we are happy to have them around.
Dr. Yarbrough is president of the AGLP: The Association of LGBTQ Psychiatrists. He works as director of psychiatry at Callen-Lorde Community Health Center, New York.
It Gets Better turned 5 years old in 2015. It’s an organization and a project that has connected with LGBTQ youth through the Internet in the form of videos recorded mostly by celebrities and politicians. The organization started by Dan Savage and Terry Miller went so far to have President Obama featured in a video back in 2010.
The videos are short messages aimed at reaching LGBTQ (lesbian/gay/bisexual/transgender/questioning) youth who would otherwise be isolated from elders and mentors. It allows a mature queer community to communicate to these youths in their rural towns and provide hope that life will improve over time. It’s somewhat disturbing to wonder why such a project is necessary, but a quick review of some of the facts will underscore why messages like these are essential.
As stated by the Centers for Disease Control and Prevention, suicide is the second-leading cause of death of youths aged 10-24 years. As prevalent as that is, an LGB youth is four times as likely to attempt suicide. Being an LGB youth of color further increases that risk, and among those who identify as transgender, as many as 25% report having made a suicide attempt. These mental health disparities are not a result of an endemic characteristic of an LGBTQ youth but rather are tied to society’s lack of understanding and support of them.
A project like It Gets Better goes a long way in repairing society’s failure to provide basic support to a community that is impoverished when it comes to receiving empathy. Most of the country lacks mental health treatment that is knowledgeable about the LGBTQ community. The majority of the country also lacks access to a queer community, specifically in that there are no LGBT centers or organizations to provide a safe space to these youths to ask questions, learn, bond with each other, and grow into adults with strong self-esteem.
The population of the United States is just over 300 million, and about 5% of those people identify as LGBTQ in some form. That’s 9 million people who are or grew up as LGBTQ youths ... who were likely isolated, confused, and shamed for who they are. For one of these youths to watch a video – either with the U.S. president or another famous figure they look up to – speak to them, it can potentially provide them that small amount of hope that would be needed to see them through whatever challenges that might be before them.
Anyone can help a cause like this. If you are a mental health provider, educate yourself with the facts of the LGBTQ community and learn how to provide affirming therapy to a range of sexual orientations and gender identities. Organizations such as AGLP: The Association of LGBTQ Psychiatrists provide educational materials and give presentations to train clinicians on basic LGBTQ needs.
If you aren’t a mental health care provider, simply providing a caring ear and unconditional acceptance to a young person goes a long way. An adolescent in the straight community already has enough trouble with puberty, emotions, and feeling left out. An LGBTQ youth has these feelings amplified. We should all do our duty to let them know they belong to something larger than themselves and that we are happy to have them around.
Dr. Yarbrough is president of the AGLP: The Association of LGBTQ Psychiatrists. He works as director of psychiatry at Callen-Lorde Community Health Center, New York.
It Gets Better turned 5 years old in 2015. It’s an organization and a project that has connected with LGBTQ youth through the Internet in the form of videos recorded mostly by celebrities and politicians. The organization started by Dan Savage and Terry Miller went so far to have President Obama featured in a video back in 2010.
The videos are short messages aimed at reaching LGBTQ (lesbian/gay/bisexual/transgender/questioning) youth who would otherwise be isolated from elders and mentors. It allows a mature queer community to communicate to these youths in their rural towns and provide hope that life will improve over time. It’s somewhat disturbing to wonder why such a project is necessary, but a quick review of some of the facts will underscore why messages like these are essential.
As stated by the Centers for Disease Control and Prevention, suicide is the second-leading cause of death of youths aged 10-24 years. As prevalent as that is, an LGB youth is four times as likely to attempt suicide. Being an LGB youth of color further increases that risk, and among those who identify as transgender, as many as 25% report having made a suicide attempt. These mental health disparities are not a result of an endemic characteristic of an LGBTQ youth but rather are tied to society’s lack of understanding and support of them.
A project like It Gets Better goes a long way in repairing society’s failure to provide basic support to a community that is impoverished when it comes to receiving empathy. Most of the country lacks mental health treatment that is knowledgeable about the LGBTQ community. The majority of the country also lacks access to a queer community, specifically in that there are no LGBT centers or organizations to provide a safe space to these youths to ask questions, learn, bond with each other, and grow into adults with strong self-esteem.
The population of the United States is just over 300 million, and about 5% of those people identify as LGBTQ in some form. That’s 9 million people who are or grew up as LGBTQ youths ... who were likely isolated, confused, and shamed for who they are. For one of these youths to watch a video – either with the U.S. president or another famous figure they look up to – speak to them, it can potentially provide them that small amount of hope that would be needed to see them through whatever challenges that might be before them.
Anyone can help a cause like this. If you are a mental health provider, educate yourself with the facts of the LGBTQ community and learn how to provide affirming therapy to a range of sexual orientations and gender identities. Organizations such as AGLP: The Association of LGBTQ Psychiatrists provide educational materials and give presentations to train clinicians on basic LGBTQ needs.
If you aren’t a mental health care provider, simply providing a caring ear and unconditional acceptance to a young person goes a long way. An adolescent in the straight community already has enough trouble with puberty, emotions, and feeling left out. An LGBTQ youth has these feelings amplified. We should all do our duty to let them know they belong to something larger than themselves and that we are happy to have them around.
Dr. Yarbrough is president of the AGLP: The Association of LGBTQ Psychiatrists. He works as director of psychiatry at Callen-Lorde Community Health Center, New York.
Benchmarks are coming
We have actively avoided benchmarks in medicine since time immemorial. There is a strong argument that rote, one-size-fits-all parameters for care medicine are bad for our patients, and obviously they interfere with our flexibility in dealing with complex obscure diseases. This flexibility is critical in dermatology, where we deal with over 3,000 diseases, and there truly is more art than science involved in treating some of them.
Nonetheless, here come the benchmarks. Since we have not provided them, they have been provided for us. Look no further than United Health Care’s Optum program, or Cigna’s star ratings, both of which rank on average costs, without regard to subspecialty or intensity of disease.
Benchmarks have proven useful in industry and have improved quality there. I expect they will be most annoying to practicing physicians. There are also great variations in practice patterns we must make sure are accounted for. A pediatric dermatologist, for example, does radically fewer skin biopsies than a Mohs surgeon, and diagnoses many fewer malignancies. However, some things are inexplicable, even after opening two standard deviations, and you need to be aware they may be coming.
The Medicare data release was an eye opener for many. This information is readily available on multiple web sites in numeric and graphic display. You should look yourself and your “peers” up on the Wall Street Journal or ProPublicaweb sites. For example, it is hard to fathom how every closure can be a flap, or how every Mohs case is four stages. Or even more bizarre, how you can do Mohs and never have a second stage. It is hard to understand how most dermatologists have a certain number of skin biopsies or shave excisions per patient encounter and others ten times as many. With this in mind, I encourage all of you to look at your own ratios of procedures compared to your peers. Recall that Medicare data lag two years before publication. Areas that could be under scrutiny include:
• Number of skin biopsies per encounter.
• Number of repeat patient encounters per year.
• Number of lesion destructions per patient.
• Ratio of first to additional layers of Mohs.
• Number of Mohs procedures on trunk and extremities, compared with head and neck.
• Percentage of closures done with adjacent tissue transfers.
• Number of shave excisions per patient.
• Number of complex closures, compared with layered closures, particularly on the trunk and extremities.
• Number of diagnostic frozen sections.
• Frequency of use of special stains on pathology specimens.
We need to be actively involved in the development of these so that we are not forced into a one size fits all mold. I expect this will start with the private insurers, including Medicare advantage plans, since they have real time data analysis, and a keen desire to save money. These “benchmarks” will be a work in progress and will infuriate some of you. They are, however, more credible, and better, than the current state of affairs, where insurance companies rank you by simply averaging your costs under your tax identification number.
So heads up, benchmarks are coming your way. Review your own public data, compared with your peers and see if you are an outlier, and if so, ponder the reason why. It is not too late to take corrective action.
Dr. Coldiron is a past president of the American Academy of Dermatology. He is currently in private practice, but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. Reach him at [email protected].
We have actively avoided benchmarks in medicine since time immemorial. There is a strong argument that rote, one-size-fits-all parameters for care medicine are bad for our patients, and obviously they interfere with our flexibility in dealing with complex obscure diseases. This flexibility is critical in dermatology, where we deal with over 3,000 diseases, and there truly is more art than science involved in treating some of them.
Nonetheless, here come the benchmarks. Since we have not provided them, they have been provided for us. Look no further than United Health Care’s Optum program, or Cigna’s star ratings, both of which rank on average costs, without regard to subspecialty or intensity of disease.
Benchmarks have proven useful in industry and have improved quality there. I expect they will be most annoying to practicing physicians. There are also great variations in practice patterns we must make sure are accounted for. A pediatric dermatologist, for example, does radically fewer skin biopsies than a Mohs surgeon, and diagnoses many fewer malignancies. However, some things are inexplicable, even after opening two standard deviations, and you need to be aware they may be coming.
The Medicare data release was an eye opener for many. This information is readily available on multiple web sites in numeric and graphic display. You should look yourself and your “peers” up on the Wall Street Journal or ProPublicaweb sites. For example, it is hard to fathom how every closure can be a flap, or how every Mohs case is four stages. Or even more bizarre, how you can do Mohs and never have a second stage. It is hard to understand how most dermatologists have a certain number of skin biopsies or shave excisions per patient encounter and others ten times as many. With this in mind, I encourage all of you to look at your own ratios of procedures compared to your peers. Recall that Medicare data lag two years before publication. Areas that could be under scrutiny include:
• Number of skin biopsies per encounter.
• Number of repeat patient encounters per year.
• Number of lesion destructions per patient.
• Ratio of first to additional layers of Mohs.
• Number of Mohs procedures on trunk and extremities, compared with head and neck.
• Percentage of closures done with adjacent tissue transfers.
• Number of shave excisions per patient.
• Number of complex closures, compared with layered closures, particularly on the trunk and extremities.
• Number of diagnostic frozen sections.
• Frequency of use of special stains on pathology specimens.
We need to be actively involved in the development of these so that we are not forced into a one size fits all mold. I expect this will start with the private insurers, including Medicare advantage plans, since they have real time data analysis, and a keen desire to save money. These “benchmarks” will be a work in progress and will infuriate some of you. They are, however, more credible, and better, than the current state of affairs, where insurance companies rank you by simply averaging your costs under your tax identification number.
So heads up, benchmarks are coming your way. Review your own public data, compared with your peers and see if you are an outlier, and if so, ponder the reason why. It is not too late to take corrective action.
Dr. Coldiron is a past president of the American Academy of Dermatology. He is currently in private practice, but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. Reach him at [email protected].
We have actively avoided benchmarks in medicine since time immemorial. There is a strong argument that rote, one-size-fits-all parameters for care medicine are bad for our patients, and obviously they interfere with our flexibility in dealing with complex obscure diseases. This flexibility is critical in dermatology, where we deal with over 3,000 diseases, and there truly is more art than science involved in treating some of them.
Nonetheless, here come the benchmarks. Since we have not provided them, they have been provided for us. Look no further than United Health Care’s Optum program, or Cigna’s star ratings, both of which rank on average costs, without regard to subspecialty or intensity of disease.
Benchmarks have proven useful in industry and have improved quality there. I expect they will be most annoying to practicing physicians. There are also great variations in practice patterns we must make sure are accounted for. A pediatric dermatologist, for example, does radically fewer skin biopsies than a Mohs surgeon, and diagnoses many fewer malignancies. However, some things are inexplicable, even after opening two standard deviations, and you need to be aware they may be coming.
The Medicare data release was an eye opener for many. This information is readily available on multiple web sites in numeric and graphic display. You should look yourself and your “peers” up on the Wall Street Journal or ProPublicaweb sites. For example, it is hard to fathom how every closure can be a flap, or how every Mohs case is four stages. Or even more bizarre, how you can do Mohs and never have a second stage. It is hard to understand how most dermatologists have a certain number of skin biopsies or shave excisions per patient encounter and others ten times as many. With this in mind, I encourage all of you to look at your own ratios of procedures compared to your peers. Recall that Medicare data lag two years before publication. Areas that could be under scrutiny include:
• Number of skin biopsies per encounter.
• Number of repeat patient encounters per year.
• Number of lesion destructions per patient.
• Ratio of first to additional layers of Mohs.
• Number of Mohs procedures on trunk and extremities, compared with head and neck.
• Percentage of closures done with adjacent tissue transfers.
• Number of shave excisions per patient.
• Number of complex closures, compared with layered closures, particularly on the trunk and extremities.
• Number of diagnostic frozen sections.
• Frequency of use of special stains on pathology specimens.
We need to be actively involved in the development of these so that we are not forced into a one size fits all mold. I expect this will start with the private insurers, including Medicare advantage plans, since they have real time data analysis, and a keen desire to save money. These “benchmarks” will be a work in progress and will infuriate some of you. They are, however, more credible, and better, than the current state of affairs, where insurance companies rank you by simply averaging your costs under your tax identification number.
So heads up, benchmarks are coming your way. Review your own public data, compared with your peers and see if you are an outlier, and if so, ponder the reason why. It is not too late to take corrective action.
Dr. Coldiron is a past president of the American Academy of Dermatology. He is currently in private practice, but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. Reach him at [email protected].
The “Impossible” Diagnosis
I was taught—and still believe—that obtaining a thorough history can direct you to a good working diagnosis. About 20 years ago, while in the Navy, I had a patient who showed me that I should not be fooled by a history that does not fit the current presentation.
The patient was a 34-year-old sailor with right-side knee pain, occurring intermittently for a long time but worsening in recent months. The pain did not prevent him from running, performing in the Navy’s semi-annual fitness test, or participating in departmental physical fitness activities.
However, his pain worsened after he was assigned to a ship, which required him to ascend and descend the steep shipboard stairs or ladders. He also complained of some intermittent buckling or “giving out.” But he was quite clear when he stated that he had sustained no recent injury to explain his condition.
His history was notable for an injury he sustained six years earlier, while running. Although he could not remember the exact mechanism of injury, he recalled that his knee hurt and was swollen the next day. He was seen in medical, where he was given crutches, modified duty, and ibuprofen for a few days. After a relatively short time, his activity returned to normal.
I had seen a lot of knee pain on board ship, mostly of the patellar tendonitis or patellofemoral syndrome types, that could often be treated conservatively with temporary duty modification to avoid aggravating activity. More serious injuries—such as meniscal, collateral, or cruciate ligament tears—were associated with recent or acute injuries and a history including a suspicious mechanism of injury.
This patient’s complete knee exam was largely unremarkable, except his anterior drawer test seemed to have no distinct endpoint. When I compared the results with his asymptomatic left knee, I could not appreciate any difference.
So I relayed to him my thought process: If he had done something serious to his knee six years ago, it probably would have manifested sooner. As other clinicians did previously, I treated him conservatively with duty limitations and advised him that if he failed to improve soon, I would refer him to an orthopedist for a second opinion.
Well, he did not improve soon. Since he was still concerned, I provided the referral, without obtaining an MRI.
To perhaps everyone’s surprise—but most definitely mine—the patient was diagnosed with a complete ACL tear by the orthopedist (again, without MRI). He was scheduled for surgery at a later date.
What surprised me most was that someone could perform the way he was required to perform in the Navy for six years with a torn ACL. As a result of this case, I have not let a remote history of injury cloud my judgment since!
I was taught—and still believe—that obtaining a thorough history can direct you to a good working diagnosis. About 20 years ago, while in the Navy, I had a patient who showed me that I should not be fooled by a history that does not fit the current presentation.
The patient was a 34-year-old sailor with right-side knee pain, occurring intermittently for a long time but worsening in recent months. The pain did not prevent him from running, performing in the Navy’s semi-annual fitness test, or participating in departmental physical fitness activities.
However, his pain worsened after he was assigned to a ship, which required him to ascend and descend the steep shipboard stairs or ladders. He also complained of some intermittent buckling or “giving out.” But he was quite clear when he stated that he had sustained no recent injury to explain his condition.
His history was notable for an injury he sustained six years earlier, while running. Although he could not remember the exact mechanism of injury, he recalled that his knee hurt and was swollen the next day. He was seen in medical, where he was given crutches, modified duty, and ibuprofen for a few days. After a relatively short time, his activity returned to normal.
I had seen a lot of knee pain on board ship, mostly of the patellar tendonitis or patellofemoral syndrome types, that could often be treated conservatively with temporary duty modification to avoid aggravating activity. More serious injuries—such as meniscal, collateral, or cruciate ligament tears—were associated with recent or acute injuries and a history including a suspicious mechanism of injury.
This patient’s complete knee exam was largely unremarkable, except his anterior drawer test seemed to have no distinct endpoint. When I compared the results with his asymptomatic left knee, I could not appreciate any difference.
So I relayed to him my thought process: If he had done something serious to his knee six years ago, it probably would have manifested sooner. As other clinicians did previously, I treated him conservatively with duty limitations and advised him that if he failed to improve soon, I would refer him to an orthopedist for a second opinion.
Well, he did not improve soon. Since he was still concerned, I provided the referral, without obtaining an MRI.
To perhaps everyone’s surprise—but most definitely mine—the patient was diagnosed with a complete ACL tear by the orthopedist (again, without MRI). He was scheduled for surgery at a later date.
What surprised me most was that someone could perform the way he was required to perform in the Navy for six years with a torn ACL. As a result of this case, I have not let a remote history of injury cloud my judgment since!
I was taught—and still believe—that obtaining a thorough history can direct you to a good working diagnosis. About 20 years ago, while in the Navy, I had a patient who showed me that I should not be fooled by a history that does not fit the current presentation.
The patient was a 34-year-old sailor with right-side knee pain, occurring intermittently for a long time but worsening in recent months. The pain did not prevent him from running, performing in the Navy’s semi-annual fitness test, or participating in departmental physical fitness activities.
However, his pain worsened after he was assigned to a ship, which required him to ascend and descend the steep shipboard stairs or ladders. He also complained of some intermittent buckling or “giving out.” But he was quite clear when he stated that he had sustained no recent injury to explain his condition.
His history was notable for an injury he sustained six years earlier, while running. Although he could not remember the exact mechanism of injury, he recalled that his knee hurt and was swollen the next day. He was seen in medical, where he was given crutches, modified duty, and ibuprofen for a few days. After a relatively short time, his activity returned to normal.
I had seen a lot of knee pain on board ship, mostly of the patellar tendonitis or patellofemoral syndrome types, that could often be treated conservatively with temporary duty modification to avoid aggravating activity. More serious injuries—such as meniscal, collateral, or cruciate ligament tears—were associated with recent or acute injuries and a history including a suspicious mechanism of injury.
This patient’s complete knee exam was largely unremarkable, except his anterior drawer test seemed to have no distinct endpoint. When I compared the results with his asymptomatic left knee, I could not appreciate any difference.
So I relayed to him my thought process: If he had done something serious to his knee six years ago, it probably would have manifested sooner. As other clinicians did previously, I treated him conservatively with duty limitations and advised him that if he failed to improve soon, I would refer him to an orthopedist for a second opinion.
Well, he did not improve soon. Since he was still concerned, I provided the referral, without obtaining an MRI.
To perhaps everyone’s surprise—but most definitely mine—the patient was diagnosed with a complete ACL tear by the orthopedist (again, without MRI). He was scheduled for surgery at a later date.
What surprised me most was that someone could perform the way he was required to perform in the Navy for six years with a torn ACL. As a result of this case, I have not let a remote history of injury cloud my judgment since!
Oral contraception and medical liability
Question: Oral contraceptives are prescription drugs sold with highly specific manufacturer instructions on how and when to take them, because the sequence of pill ingestion is critical to their anovulatory efficacy.
Suppose a manufacturing mishap resulted in improper labeling and sequencing of the pills, and some women, relying on the product, became pregnant. In a lawsuit against the manufacturer, which of the following choices is best?
A. This is a case of product liability.
B. Affected plaintiffs should consider filing a class-action lawsuit.
C. Mothers can sue for wrongful pregnancy.
D. Children can sue for wrongful life.
E. All are possible legal causes of action.
Answer: E. This hypothetical is adapted from a recent report that the use of mispackaged oral contraceptives had resulted in more than 100 women becoming pregnant. The prescription drugs, available in blister packs, were erroneously sequenced such that the daily use of active or inactive drug was asynchronous with the woman’s ovulatory cycle, thus foiling the drug’s pregnancy prevention efficacy.
Typically, each packet of oral contraceptives comes with 28 days’ worth of color-coded pills, with the first 21 containing the active principle to inhibit ovulation, followed by 7 inert pills. Each monthly pack begins with the same strict pill sequence.
In 2011, the manufacturer of several brands of oral contraceptives recalled half a million such packs when it was discovered that some of them had the pill sequence reversed. Foreseeably, this debacle resulted in a number of unplanned pregnancies – and live births. Legal action soon followed.
▶ Product liability: A simple negligence lawsuit would typically cover a situation in which a wrongdoer has breached the requisite standard of care, as appears to be the case here. However, when a product such as a prescription drug leads to “harm,” an injured party, using the law of product liability, can sue the manufacturer that had placed it into the stream of commerce. This allows the plaintiff to rely on legal theories other than negligence, including breach of warranty and strict liability.
Under the latter legal theory, there is no need to prove fault or contractual breach, and the significant part of the complaint is whether the product is both defective and unreasonably dangerous. “Defective” is usually defined as product quality that is less than what a reasonable consumer expects, and “unreasonably dangerous” is a conclusion that the risks that result from its condition outweigh the product’s advantages.
Although the medication itself in this case is not defective or unreasonably dangerous, the assembly and labeling fiasco would suffice to keep the lawsuit within the product liability category. According to Section 102(2) of the Uniform Product Liability Act, product liability includes “all claims or action brought for personal injury, death, or property damage caused by the manufacture, design, formula, preparation, assembly, installation, testing, warnings, instructions, marketing, packaging, or labeling of any product.”
▶ Class action: A class action lawsuit, governed by Rule 23 of the Federal Rules of Civil Procedure, describes a legal cause of action where a representative plaintiff asserts claims on behalf of a large class of similarly injured members, who then give up their rights to pursue an individual lawsuit. It confers several advantages upon the plaintiffs, including the potential of higher damages.
However, four prerequisites must be present before a lawsuit can be certified a class action: numerosity, commonality, typicality, and adequacy.
Although there is the possibility of going forward with a class action suit, a federal judge in Georgia refused to certify class action status in the 2011 recall case. The judge stated that only 53 of the half-million recalled blister packs had the pills arranged in reverse order, and each woman’s case should be individually adjudicated given the controlling laws in her state, the need to prove use of the product, and whether she became pregnant and carried the pregnancy to term.
▶ Wrongful life: Strictly speaking, tort issues in this case can be divided into two categories: wrongful pregnancy (sometimes confusingly referred to as wrongful birth) alleged by the mother, and wrongful life by the child. Unfortunately, these claims are frequently lumped together under the rubric of wrongful life.
The women affected by this mix-up are reportedly seeking damages for lost income, medical costs, and, in some cases, the cost of raising their children, including the cost of college. However, the common law has traditionally barred a wrongful life action, although state laws have evolved over the years. So, court decisions and statutes in each state should be carefully consulted for any individual case.
The prime reason for disallowing a wrongful life action is that life, even if imperfect, is always preferable to non-life. Besides, it will be impossible to assess the quantum of damages, because this necessarily requires placing a monetary worth on human existence.
The seminal case is the 1967 New Jersey decision of Gleitman v. Cosgrove (227 A.2d 689 [N.J. 1967]), but the state’s position has since changed. In Berman v. Allan (404 A.2d 8 [N.J. 1979]), the court allowed damages for maternal emotional distress, though not for medical and other expenses of raising the child.
Overall, the law of wrongful life appears to be increasingly willing to award damages to the mother for the physical, emotional, and financial costs of pregnancy and delivery, but not the cost associated with the normal rearing of a healthy child.
The legal situation is quite different for a lawsuit filed by the child, who in essence is arguing that he/she should not have been born at all. Courts continue to refuse a claim brought by a healthy infant for wrongful life, adopting the reasoning in Berman that the infant has not suffered any damage cognizable at law by being brought into existence. Even an infant with birth disabilities will not prevail in the majority of jurisdictions, with California being a notable exception.
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected].
Question: Oral contraceptives are prescription drugs sold with highly specific manufacturer instructions on how and when to take them, because the sequence of pill ingestion is critical to their anovulatory efficacy.
Suppose a manufacturing mishap resulted in improper labeling and sequencing of the pills, and some women, relying on the product, became pregnant. In a lawsuit against the manufacturer, which of the following choices is best?
A. This is a case of product liability.
B. Affected plaintiffs should consider filing a class-action lawsuit.
C. Mothers can sue for wrongful pregnancy.
D. Children can sue for wrongful life.
E. All are possible legal causes of action.
Answer: E. This hypothetical is adapted from a recent report that the use of mispackaged oral contraceptives had resulted in more than 100 women becoming pregnant. The prescription drugs, available in blister packs, were erroneously sequenced such that the daily use of active or inactive drug was asynchronous with the woman’s ovulatory cycle, thus foiling the drug’s pregnancy prevention efficacy.
Typically, each packet of oral contraceptives comes with 28 days’ worth of color-coded pills, with the first 21 containing the active principle to inhibit ovulation, followed by 7 inert pills. Each monthly pack begins with the same strict pill sequence.
In 2011, the manufacturer of several brands of oral contraceptives recalled half a million such packs when it was discovered that some of them had the pill sequence reversed. Foreseeably, this debacle resulted in a number of unplanned pregnancies – and live births. Legal action soon followed.
▶ Product liability: A simple negligence lawsuit would typically cover a situation in which a wrongdoer has breached the requisite standard of care, as appears to be the case here. However, when a product such as a prescription drug leads to “harm,” an injured party, using the law of product liability, can sue the manufacturer that had placed it into the stream of commerce. This allows the plaintiff to rely on legal theories other than negligence, including breach of warranty and strict liability.
Under the latter legal theory, there is no need to prove fault or contractual breach, and the significant part of the complaint is whether the product is both defective and unreasonably dangerous. “Defective” is usually defined as product quality that is less than what a reasonable consumer expects, and “unreasonably dangerous” is a conclusion that the risks that result from its condition outweigh the product’s advantages.
Although the medication itself in this case is not defective or unreasonably dangerous, the assembly and labeling fiasco would suffice to keep the lawsuit within the product liability category. According to Section 102(2) of the Uniform Product Liability Act, product liability includes “all claims or action brought for personal injury, death, or property damage caused by the manufacture, design, formula, preparation, assembly, installation, testing, warnings, instructions, marketing, packaging, or labeling of any product.”
▶ Class action: A class action lawsuit, governed by Rule 23 of the Federal Rules of Civil Procedure, describes a legal cause of action where a representative plaintiff asserts claims on behalf of a large class of similarly injured members, who then give up their rights to pursue an individual lawsuit. It confers several advantages upon the plaintiffs, including the potential of higher damages.
However, four prerequisites must be present before a lawsuit can be certified a class action: numerosity, commonality, typicality, and adequacy.
Although there is the possibility of going forward with a class action suit, a federal judge in Georgia refused to certify class action status in the 2011 recall case. The judge stated that only 53 of the half-million recalled blister packs had the pills arranged in reverse order, and each woman’s case should be individually adjudicated given the controlling laws in her state, the need to prove use of the product, and whether she became pregnant and carried the pregnancy to term.
▶ Wrongful life: Strictly speaking, tort issues in this case can be divided into two categories: wrongful pregnancy (sometimes confusingly referred to as wrongful birth) alleged by the mother, and wrongful life by the child. Unfortunately, these claims are frequently lumped together under the rubric of wrongful life.
The women affected by this mix-up are reportedly seeking damages for lost income, medical costs, and, in some cases, the cost of raising their children, including the cost of college. However, the common law has traditionally barred a wrongful life action, although state laws have evolved over the years. So, court decisions and statutes in each state should be carefully consulted for any individual case.
The prime reason for disallowing a wrongful life action is that life, even if imperfect, is always preferable to non-life. Besides, it will be impossible to assess the quantum of damages, because this necessarily requires placing a monetary worth on human existence.
The seminal case is the 1967 New Jersey decision of Gleitman v. Cosgrove (227 A.2d 689 [N.J. 1967]), but the state’s position has since changed. In Berman v. Allan (404 A.2d 8 [N.J. 1979]), the court allowed damages for maternal emotional distress, though not for medical and other expenses of raising the child.
Overall, the law of wrongful life appears to be increasingly willing to award damages to the mother for the physical, emotional, and financial costs of pregnancy and delivery, but not the cost associated with the normal rearing of a healthy child.
The legal situation is quite different for a lawsuit filed by the child, who in essence is arguing that he/she should not have been born at all. Courts continue to refuse a claim brought by a healthy infant for wrongful life, adopting the reasoning in Berman that the infant has not suffered any damage cognizable at law by being brought into existence. Even an infant with birth disabilities will not prevail in the majority of jurisdictions, with California being a notable exception.
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected].
Question: Oral contraceptives are prescription drugs sold with highly specific manufacturer instructions on how and when to take them, because the sequence of pill ingestion is critical to their anovulatory efficacy.
Suppose a manufacturing mishap resulted in improper labeling and sequencing of the pills, and some women, relying on the product, became pregnant. In a lawsuit against the manufacturer, which of the following choices is best?
A. This is a case of product liability.
B. Affected plaintiffs should consider filing a class-action lawsuit.
C. Mothers can sue for wrongful pregnancy.
D. Children can sue for wrongful life.
E. All are possible legal causes of action.
Answer: E. This hypothetical is adapted from a recent report that the use of mispackaged oral contraceptives had resulted in more than 100 women becoming pregnant. The prescription drugs, available in blister packs, were erroneously sequenced such that the daily use of active or inactive drug was asynchronous with the woman’s ovulatory cycle, thus foiling the drug’s pregnancy prevention efficacy.
Typically, each packet of oral contraceptives comes with 28 days’ worth of color-coded pills, with the first 21 containing the active principle to inhibit ovulation, followed by 7 inert pills. Each monthly pack begins with the same strict pill sequence.
In 2011, the manufacturer of several brands of oral contraceptives recalled half a million such packs when it was discovered that some of them had the pill sequence reversed. Foreseeably, this debacle resulted in a number of unplanned pregnancies – and live births. Legal action soon followed.
▶ Product liability: A simple negligence lawsuit would typically cover a situation in which a wrongdoer has breached the requisite standard of care, as appears to be the case here. However, when a product such as a prescription drug leads to “harm,” an injured party, using the law of product liability, can sue the manufacturer that had placed it into the stream of commerce. This allows the plaintiff to rely on legal theories other than negligence, including breach of warranty and strict liability.
Under the latter legal theory, there is no need to prove fault or contractual breach, and the significant part of the complaint is whether the product is both defective and unreasonably dangerous. “Defective” is usually defined as product quality that is less than what a reasonable consumer expects, and “unreasonably dangerous” is a conclusion that the risks that result from its condition outweigh the product’s advantages.
Although the medication itself in this case is not defective or unreasonably dangerous, the assembly and labeling fiasco would suffice to keep the lawsuit within the product liability category. According to Section 102(2) of the Uniform Product Liability Act, product liability includes “all claims or action brought for personal injury, death, or property damage caused by the manufacture, design, formula, preparation, assembly, installation, testing, warnings, instructions, marketing, packaging, or labeling of any product.”
▶ Class action: A class action lawsuit, governed by Rule 23 of the Federal Rules of Civil Procedure, describes a legal cause of action where a representative plaintiff asserts claims on behalf of a large class of similarly injured members, who then give up their rights to pursue an individual lawsuit. It confers several advantages upon the plaintiffs, including the potential of higher damages.
However, four prerequisites must be present before a lawsuit can be certified a class action: numerosity, commonality, typicality, and adequacy.
Although there is the possibility of going forward with a class action suit, a federal judge in Georgia refused to certify class action status in the 2011 recall case. The judge stated that only 53 of the half-million recalled blister packs had the pills arranged in reverse order, and each woman’s case should be individually adjudicated given the controlling laws in her state, the need to prove use of the product, and whether she became pregnant and carried the pregnancy to term.
▶ Wrongful life: Strictly speaking, tort issues in this case can be divided into two categories: wrongful pregnancy (sometimes confusingly referred to as wrongful birth) alleged by the mother, and wrongful life by the child. Unfortunately, these claims are frequently lumped together under the rubric of wrongful life.
The women affected by this mix-up are reportedly seeking damages for lost income, medical costs, and, in some cases, the cost of raising their children, including the cost of college. However, the common law has traditionally barred a wrongful life action, although state laws have evolved over the years. So, court decisions and statutes in each state should be carefully consulted for any individual case.
The prime reason for disallowing a wrongful life action is that life, even if imperfect, is always preferable to non-life. Besides, it will be impossible to assess the quantum of damages, because this necessarily requires placing a monetary worth on human existence.
The seminal case is the 1967 New Jersey decision of Gleitman v. Cosgrove (227 A.2d 689 [N.J. 1967]), but the state’s position has since changed. In Berman v. Allan (404 A.2d 8 [N.J. 1979]), the court allowed damages for maternal emotional distress, though not for medical and other expenses of raising the child.
Overall, the law of wrongful life appears to be increasingly willing to award damages to the mother for the physical, emotional, and financial costs of pregnancy and delivery, but not the cost associated with the normal rearing of a healthy child.
The legal situation is quite different for a lawsuit filed by the child, who in essence is arguing that he/she should not have been born at all. Courts continue to refuse a claim brought by a healthy infant for wrongful life, adopting the reasoning in Berman that the infant has not suffered any damage cognizable at law by being brought into existence. Even an infant with birth disabilities will not prevail in the majority of jurisdictions, with California being a notable exception.
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected].
Ophthalmic drugs in pregnancy and lactation
A number of drugs are available for ophthalmic use. This review focuses on single drug products and, although combination drug products are not discussed, these formulations typically include the drugs reviewed here.
Since it appears that ophthalmic medications are commonly used for a wide range of conditions and ages, one would expect to see numerous reports of their use in the eyes of pregnant or breastfeeding patients. Unfortunately, the opposite is true. The majority of the drugs have no human pregnancy or lactation data. When there are human data, it invariably involves the systemic use of the drug for other indications, rather than its ophthalmic use. Moreover, the animal reproduction data are usually not relevant because they involve systemic drugs (e.g., IV or oral). Consequently, determining the level of risk an ophthalmic drug presents to an embryo and/or fetus is primarily based on time and dose, the two cardinal principles of teratology.
Avoiding exposure during organogenesis – the period when a drug can cause developmental toxicity (altered growth, structural anomalies, functional and/or behavioral deficits, or death) – is usually best, but may not be possible in some cases, including glaucoma, eye infections, and eye surgery. Fortunately, the systemic concentrations of drugs applied topically to the eye are typically thought to be low, even though the levels of most drugs have not been studied. Thus, the risk to the embryo and/or fetus in most cases can be considered low and the drug classified as compatible in pregnancy and breastfeeding.
If a topical eye drug must be used during pregnancy or lactation, teach the patient how to decrease the amount of drug reaching the systemic circulation. This involves placing pressure over the tear duct in the corner of the eye for 1 minute or more, then removing any excess solution with absorbent tissue.
In the sections below, drugs are shown by indication or by pharmacologic class. The term “human eye data” refers to the use of the drug in pregnancy and/or lactation.
Glaucoma
If you are caring for a pregnant patient who is being treated for glaucoma, two recent reviews may be helpful: Surv Ophthalmol. 2011 Jul-Aug;56(4):324-35 and Curr Opin Ophthalmol. 2014 Mar;25(2):93-7.
Sympathomimetics (alpha-adrenergic agonists) include apraclonidine (Iopidine), which has no human eye data, and brimonidine (Alphagan P), which has one case report in pregnancy and breastfeeding showing no fetal or nursing infant harm.
Four of the five beta-adrenergic blockers have no human eye data: betaxolol (Betoptic), carteolol (Ocupress), levobunolol (Betagan), and metipranolol, but there are two case reports for timolol (Betimol, Istalol, Timoptic, Timoptic-XE) showing no fetal harm in one newborn and growth restriction in the other.
Among the miotics, there are limited human eye data for pilocarpine (Isopto Carpine) and no fetal harm was observed. For echothiophate iodide (Phospholine Iodide), there is one case report of a normal full-term infant whose mother was treated with the agent up to 32 weeks’ gestation and then with pilocarpine for 8 weeks (Arch Ophthalmol. 1968 Mar;79[3]:283-5).
Carbonic anhydrase inhibitors include brinzolamide (Azopt), which has no human eye data, and dorzolamide (Trusopt), which has growth restriction in one case treated with fixed combination of dorzolamide and timolol. There are no human eye data for unoprostone isopropyl (Rescula), a synthetic docosanoid.
Of the four prostaglandin analogs, three have no human eye data, bimatoprost (Lumigan), tafluprost (Zioptan), and travoprost (Travatan Z). There were 11 pregnancies exposed to latanoprost (Xalatan). The outcomes of these cases were one lost to follow-up, one miscarriage, and nine infants without congenital anomalies (Am J Ophthalmol. 2004 Aug;138[2]:305-6).
Mitomycin (Mitosol) is an antimetabolite that is given topically to the surgical site of glaucoma filtration surgery. No reports of its use in pregnant humans have been located. According to the manufacturer, clinically significant systemic concentrations are not expected.
Antiseptics
Povidone-iodine (Betadine) is indicated for prepping of the periocular region. There does not appear to be any risk to the embryo-fetus or nursing infant from this indication.
Antihistamines
The four ophthalmic agents in this class are alcaftadine (Lastacaft), azelastine (Optivar), emedastine (Emadine), and epinastine (Elestat). There are no human eye data for these agents but, like antihistamines given systemically, they are probably compatible in pregnancy and lactation.
Antihistamine-mast cell stabilizers
There are no human eye data for bepotastine (Bepreve), ketotifen (Alaway), and olopatadine (Pataday, Patanol). Peak plasma concentrations of bepotastine were 5.1-7.3 ng/mL for 1-2 hours after instillation and were less than 2 ng/mL at 24 hours. It appears that these drugs can also be classified as compatible in pregnancy and lactation.
Anti-infectives
Ten anti-infectives are available for topical treatment of eye infections (systemic concentrations if known): besifloxacin (Besivance) (0.43 ng/mL), ciprofloxacin (less than 2.5 ng/mL), gentamicin, gatifloxacin (Zymaxid) (less than 5 ng/mL), levofloxacin (Iquix) (10.9 ng/mL), moxifloxacin (Vigamox) (2.7 ng/mL), ofloxacin (1.9 ng/mL), sulfacetamide (Isopto Cetamide), and tobramycin. The tenth agent, natamycin (Natacyn), is an antifungal. According to the manufacturer, systemic absorption is not expected.
None of these agents have human eye data, but they are usually considered compatible in pregnancy and breastfeeding when systemic formulations are used, so they should be compatible when used in the eye.
Antivirals
Ganciclovir (Zirgan) has no human eye data but, according to the manufacturer, the daily ophthalmic dose is about 0.04% and 0.1% of the oral and IV doses, respectively. Thus, minimal systemic exposure is expected. Trifluridine (Viroptic) also has no eye human data. As reported in the product information, detectable blood concentrations of the drug were not found in healthy normal subjects indicating that systemic absorption was negligible.
Corticosteroids
Among the nine corticosteroid products, six are suspensions or ointments, one is an injection, and two are implants. In most nonpregnant patients receiving the dexamethasone (Ozurdex) intravitreal implant, plasma dexamethasone concentrations were undetectable (less than 50 pg/mL) but, in some, ranged from 52 pg/mL to 102 pg/mL. There is only one case report describing the use of topical dexamethasone suspension (Maxidex) in pregnancy. In that case, dexamethasone and clindamycin were given in the first and second trimesters and the woman eventually gave birth to a normal full term infant (Int Ophthalmol. 1998-1999;22[2]:85-8).
For the fluocinolone (Retisert) ocular implant, systemic absorption of detectable amounts of the drug have not been observed. In a second report, a patient who had type 1 diabetes and was 6 months pregnant received a 2-mg intravitreal injection of triamcinolone (Triesence) in both eyes. No adverse effects in the mother or fetus were noted (Clin Ophthalmol. 2011;5:439-41).
There are no human eye data for five topical corticosteroids: difluprednate (Durezol), fluorometholone (Flarex, Fluor-OP, FML), loteprednol (Alrex, Lotemax), prednisolone (Econopred), and rimexolone (Vexol). Only two of the five drugs had information about systemic absorption. For difluprednate, blood levels were below the quantification limit (50 ng/mL). Extremely low levels were detected after the use of rimexolone with a mean serum concentration of 130 pg/mL (range less than 80-470 pg/mL).
Cycloplegics-mydriatics
This class includes four anticholinergic agents: atropine, cyclopentolate (Cyclogyl), homatropine, and tropicamide (Mydriacyl). Systemic absorption has not been studied for these drugs and there are no reports of their use in pregnancy or lactation.
Cystine-depleting agents
There are no reports describing the use of cysteamine (Cystaran) in human pregnancy or lactation. Since the drug is given as one drop in each eye every waking hour, transfer to the systemic circulation should be expected, but the amount, if it occurs, has not been reported.
Immunologics
There are no reports on the use of cyclosporine (Restasis) eye drops in human pregnancy or during breastfeeding. However, data for the systemic use of the drug during these conditions has shown it to be low risk. After long term ophthalmic use, blood concentrations of the drug were below the quantitation limit of 0.1 ng/mL.
Local anesthetics
The three drugs in this class are lidocaine, proparacaine (Alcaine), and tetracaine (Altacaine, Tetravisc). There is no information regarding the use of these agents in pregnancy or lactation. Since they are used for brief periods, the risk to an embryo or nursing infant appears to be nil.
Mast cell stabilizers
There are three drugs in this class that can be used topically in the eye: cromolyn, lodoxamide (Alomide), and nedocromil (Alocril). There are no human eye data for these agents. Systemic concentrations of lodoxamide were below the detection limit of 2.5 ng/mL.
Miotics
The two miotics are acetylcholine (Miochol E) and carbachol (Carbastat, Miostat). Both are used immediately before eye surgery. The amount, if any, in the systemic circulation is unknown. No reports of human eye use in pregnancy or lactation have been found.
NSAIDs
The five drugs in this class are bromfenac (Xibrom), diclofenac (Voltaren), flurbiprofen (Ocufen), ketorolac, and nepafenac (Nevanac). Although it has not been studied, the estimated plasma level for bromfenac is less than 50 ng/mL. For diclofenac, the plasma concentration was below the limit of quantification (10 ng/mL). In a study conducted with ketorolac, only 5 of 26 subjects had detectable plasma concentrations (10.7 to 22.5 ng/mL). These levels were about 2% of the peak plasma levels after oral dosing. For nepafenac, the peak plasma concentrations of the parent drug and active metabolite were 0.3 and 0.4 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant are nil.
Photodynamic therapy
Verteporfin (Visudyne) is given intravenously. Three reports have described its use in three pregnancies. In all cases, the infants were healthy at birth and had normal growth (Acta Ophthalmol Scand. 2004 Oct;82[5]:623-4, Eye [Lond]. 2009 Jun;23[6]:1479, and Aust N Z J Obstet Gynaecol. 2009 Apr;49[2]:236-7).
Proteolytic enzymes
No human eye data were found for ocriplasmin (Jetrea), an agent given as an intravitreal injection. Although it was not studied, detectable levels of the drug in the systemic circulation are not expected, according to the manufacturer.
Selective vascular endothelial growth factor antagonists
There are three agents in this class: aflibercept (Eylea), pegaptanib (Macugen), and ranibizumab (Lucentis). There are no human eye data for these drugs. All are given as intravitreal injection. The systemic concentrations of the three drugs were a mean 0.02 mcg/mL; 80 ng/mL (after a dose of 10 times the recommended dose); and an estimated minimum 0.22 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant is nil.
Sympathomimetics (decongestants)
There are four ophthalmic agents in this class and none have human eye data. Naphazoline (Naphcon, Vasocon) is the only one of the four that requires a prescription. No reports describing the systemic absorption, if any, have been found. The other three agents are available over the counter. They are oxymetazoline (Visine L.R.), phenylephrine, and tetrahydrozoline (Opti-Clear). Although the amount reaching the systemic circulation was not provided by the manufacturers for these three agents, a caution was placed on phenylephrine stating that systemic absorption, although rare, might cause alpha-adrenergic effects, such as a rise in blood pressure and reflex atropine-sensitive bradycardia.
The risk to the embryo-fetus or nursing infant from ophthalmic drugs appears to be low, with the possible exception of phenylephrine. Nevertheless, if any of these agents are used in pregnancy or during breastfeeding, careful assessment of the embryo-fetus and nursing infant should be conducted. Moreover, research on the potential effects of ophthalmic drugs on the embryo-fetus and nursing infant are desperately needed.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.
A number of drugs are available for ophthalmic use. This review focuses on single drug products and, although combination drug products are not discussed, these formulations typically include the drugs reviewed here.
Since it appears that ophthalmic medications are commonly used for a wide range of conditions and ages, one would expect to see numerous reports of their use in the eyes of pregnant or breastfeeding patients. Unfortunately, the opposite is true. The majority of the drugs have no human pregnancy or lactation data. When there are human data, it invariably involves the systemic use of the drug for other indications, rather than its ophthalmic use. Moreover, the animal reproduction data are usually not relevant because they involve systemic drugs (e.g., IV or oral). Consequently, determining the level of risk an ophthalmic drug presents to an embryo and/or fetus is primarily based on time and dose, the two cardinal principles of teratology.
Avoiding exposure during organogenesis – the period when a drug can cause developmental toxicity (altered growth, structural anomalies, functional and/or behavioral deficits, or death) – is usually best, but may not be possible in some cases, including glaucoma, eye infections, and eye surgery. Fortunately, the systemic concentrations of drugs applied topically to the eye are typically thought to be low, even though the levels of most drugs have not been studied. Thus, the risk to the embryo and/or fetus in most cases can be considered low and the drug classified as compatible in pregnancy and breastfeeding.
If a topical eye drug must be used during pregnancy or lactation, teach the patient how to decrease the amount of drug reaching the systemic circulation. This involves placing pressure over the tear duct in the corner of the eye for 1 minute or more, then removing any excess solution with absorbent tissue.
In the sections below, drugs are shown by indication or by pharmacologic class. The term “human eye data” refers to the use of the drug in pregnancy and/or lactation.
Glaucoma
If you are caring for a pregnant patient who is being treated for glaucoma, two recent reviews may be helpful: Surv Ophthalmol. 2011 Jul-Aug;56(4):324-35 and Curr Opin Ophthalmol. 2014 Mar;25(2):93-7.
Sympathomimetics (alpha-adrenergic agonists) include apraclonidine (Iopidine), which has no human eye data, and brimonidine (Alphagan P), which has one case report in pregnancy and breastfeeding showing no fetal or nursing infant harm.
Four of the five beta-adrenergic blockers have no human eye data: betaxolol (Betoptic), carteolol (Ocupress), levobunolol (Betagan), and metipranolol, but there are two case reports for timolol (Betimol, Istalol, Timoptic, Timoptic-XE) showing no fetal harm in one newborn and growth restriction in the other.
Among the miotics, there are limited human eye data for pilocarpine (Isopto Carpine) and no fetal harm was observed. For echothiophate iodide (Phospholine Iodide), there is one case report of a normal full-term infant whose mother was treated with the agent up to 32 weeks’ gestation and then with pilocarpine for 8 weeks (Arch Ophthalmol. 1968 Mar;79[3]:283-5).
Carbonic anhydrase inhibitors include brinzolamide (Azopt), which has no human eye data, and dorzolamide (Trusopt), which has growth restriction in one case treated with fixed combination of dorzolamide and timolol. There are no human eye data for unoprostone isopropyl (Rescula), a synthetic docosanoid.
Of the four prostaglandin analogs, three have no human eye data, bimatoprost (Lumigan), tafluprost (Zioptan), and travoprost (Travatan Z). There were 11 pregnancies exposed to latanoprost (Xalatan). The outcomes of these cases were one lost to follow-up, one miscarriage, and nine infants without congenital anomalies (Am J Ophthalmol. 2004 Aug;138[2]:305-6).
Mitomycin (Mitosol) is an antimetabolite that is given topically to the surgical site of glaucoma filtration surgery. No reports of its use in pregnant humans have been located. According to the manufacturer, clinically significant systemic concentrations are not expected.
Antiseptics
Povidone-iodine (Betadine) is indicated for prepping of the periocular region. There does not appear to be any risk to the embryo-fetus or nursing infant from this indication.
Antihistamines
The four ophthalmic agents in this class are alcaftadine (Lastacaft), azelastine (Optivar), emedastine (Emadine), and epinastine (Elestat). There are no human eye data for these agents but, like antihistamines given systemically, they are probably compatible in pregnancy and lactation.
Antihistamine-mast cell stabilizers
There are no human eye data for bepotastine (Bepreve), ketotifen (Alaway), and olopatadine (Pataday, Patanol). Peak plasma concentrations of bepotastine were 5.1-7.3 ng/mL for 1-2 hours after instillation and were less than 2 ng/mL at 24 hours. It appears that these drugs can also be classified as compatible in pregnancy and lactation.
Anti-infectives
Ten anti-infectives are available for topical treatment of eye infections (systemic concentrations if known): besifloxacin (Besivance) (0.43 ng/mL), ciprofloxacin (less than 2.5 ng/mL), gentamicin, gatifloxacin (Zymaxid) (less than 5 ng/mL), levofloxacin (Iquix) (10.9 ng/mL), moxifloxacin (Vigamox) (2.7 ng/mL), ofloxacin (1.9 ng/mL), sulfacetamide (Isopto Cetamide), and tobramycin. The tenth agent, natamycin (Natacyn), is an antifungal. According to the manufacturer, systemic absorption is not expected.
None of these agents have human eye data, but they are usually considered compatible in pregnancy and breastfeeding when systemic formulations are used, so they should be compatible when used in the eye.
Antivirals
Ganciclovir (Zirgan) has no human eye data but, according to the manufacturer, the daily ophthalmic dose is about 0.04% and 0.1% of the oral and IV doses, respectively. Thus, minimal systemic exposure is expected. Trifluridine (Viroptic) also has no eye human data. As reported in the product information, detectable blood concentrations of the drug were not found in healthy normal subjects indicating that systemic absorption was negligible.
Corticosteroids
Among the nine corticosteroid products, six are suspensions or ointments, one is an injection, and two are implants. In most nonpregnant patients receiving the dexamethasone (Ozurdex) intravitreal implant, plasma dexamethasone concentrations were undetectable (less than 50 pg/mL) but, in some, ranged from 52 pg/mL to 102 pg/mL. There is only one case report describing the use of topical dexamethasone suspension (Maxidex) in pregnancy. In that case, dexamethasone and clindamycin were given in the first and second trimesters and the woman eventually gave birth to a normal full term infant (Int Ophthalmol. 1998-1999;22[2]:85-8).
For the fluocinolone (Retisert) ocular implant, systemic absorption of detectable amounts of the drug have not been observed. In a second report, a patient who had type 1 diabetes and was 6 months pregnant received a 2-mg intravitreal injection of triamcinolone (Triesence) in both eyes. No adverse effects in the mother or fetus were noted (Clin Ophthalmol. 2011;5:439-41).
There are no human eye data for five topical corticosteroids: difluprednate (Durezol), fluorometholone (Flarex, Fluor-OP, FML), loteprednol (Alrex, Lotemax), prednisolone (Econopred), and rimexolone (Vexol). Only two of the five drugs had information about systemic absorption. For difluprednate, blood levels were below the quantification limit (50 ng/mL). Extremely low levels were detected after the use of rimexolone with a mean serum concentration of 130 pg/mL (range less than 80-470 pg/mL).
Cycloplegics-mydriatics
This class includes four anticholinergic agents: atropine, cyclopentolate (Cyclogyl), homatropine, and tropicamide (Mydriacyl). Systemic absorption has not been studied for these drugs and there are no reports of their use in pregnancy or lactation.
Cystine-depleting agents
There are no reports describing the use of cysteamine (Cystaran) in human pregnancy or lactation. Since the drug is given as one drop in each eye every waking hour, transfer to the systemic circulation should be expected, but the amount, if it occurs, has not been reported.
Immunologics
There are no reports on the use of cyclosporine (Restasis) eye drops in human pregnancy or during breastfeeding. However, data for the systemic use of the drug during these conditions has shown it to be low risk. After long term ophthalmic use, blood concentrations of the drug were below the quantitation limit of 0.1 ng/mL.
Local anesthetics
The three drugs in this class are lidocaine, proparacaine (Alcaine), and tetracaine (Altacaine, Tetravisc). There is no information regarding the use of these agents in pregnancy or lactation. Since they are used for brief periods, the risk to an embryo or nursing infant appears to be nil.
Mast cell stabilizers
There are three drugs in this class that can be used topically in the eye: cromolyn, lodoxamide (Alomide), and nedocromil (Alocril). There are no human eye data for these agents. Systemic concentrations of lodoxamide were below the detection limit of 2.5 ng/mL.
Miotics
The two miotics are acetylcholine (Miochol E) and carbachol (Carbastat, Miostat). Both are used immediately before eye surgery. The amount, if any, in the systemic circulation is unknown. No reports of human eye use in pregnancy or lactation have been found.
NSAIDs
The five drugs in this class are bromfenac (Xibrom), diclofenac (Voltaren), flurbiprofen (Ocufen), ketorolac, and nepafenac (Nevanac). Although it has not been studied, the estimated plasma level for bromfenac is less than 50 ng/mL. For diclofenac, the plasma concentration was below the limit of quantification (10 ng/mL). In a study conducted with ketorolac, only 5 of 26 subjects had detectable plasma concentrations (10.7 to 22.5 ng/mL). These levels were about 2% of the peak plasma levels after oral dosing. For nepafenac, the peak plasma concentrations of the parent drug and active metabolite were 0.3 and 0.4 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant are nil.
Photodynamic therapy
Verteporfin (Visudyne) is given intravenously. Three reports have described its use in three pregnancies. In all cases, the infants were healthy at birth and had normal growth (Acta Ophthalmol Scand. 2004 Oct;82[5]:623-4, Eye [Lond]. 2009 Jun;23[6]:1479, and Aust N Z J Obstet Gynaecol. 2009 Apr;49[2]:236-7).
Proteolytic enzymes
No human eye data were found for ocriplasmin (Jetrea), an agent given as an intravitreal injection. Although it was not studied, detectable levels of the drug in the systemic circulation are not expected, according to the manufacturer.
Selective vascular endothelial growth factor antagonists
There are three agents in this class: aflibercept (Eylea), pegaptanib (Macugen), and ranibizumab (Lucentis). There are no human eye data for these drugs. All are given as intravitreal injection. The systemic concentrations of the three drugs were a mean 0.02 mcg/mL; 80 ng/mL (after a dose of 10 times the recommended dose); and an estimated minimum 0.22 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant is nil.
Sympathomimetics (decongestants)
There are four ophthalmic agents in this class and none have human eye data. Naphazoline (Naphcon, Vasocon) is the only one of the four that requires a prescription. No reports describing the systemic absorption, if any, have been found. The other three agents are available over the counter. They are oxymetazoline (Visine L.R.), phenylephrine, and tetrahydrozoline (Opti-Clear). Although the amount reaching the systemic circulation was not provided by the manufacturers for these three agents, a caution was placed on phenylephrine stating that systemic absorption, although rare, might cause alpha-adrenergic effects, such as a rise in blood pressure and reflex atropine-sensitive bradycardia.
The risk to the embryo-fetus or nursing infant from ophthalmic drugs appears to be low, with the possible exception of phenylephrine. Nevertheless, if any of these agents are used in pregnancy or during breastfeeding, careful assessment of the embryo-fetus and nursing infant should be conducted. Moreover, research on the potential effects of ophthalmic drugs on the embryo-fetus and nursing infant are desperately needed.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.
A number of drugs are available for ophthalmic use. This review focuses on single drug products and, although combination drug products are not discussed, these formulations typically include the drugs reviewed here.
Since it appears that ophthalmic medications are commonly used for a wide range of conditions and ages, one would expect to see numerous reports of their use in the eyes of pregnant or breastfeeding patients. Unfortunately, the opposite is true. The majority of the drugs have no human pregnancy or lactation data. When there are human data, it invariably involves the systemic use of the drug for other indications, rather than its ophthalmic use. Moreover, the animal reproduction data are usually not relevant because they involve systemic drugs (e.g., IV or oral). Consequently, determining the level of risk an ophthalmic drug presents to an embryo and/or fetus is primarily based on time and dose, the two cardinal principles of teratology.
Avoiding exposure during organogenesis – the period when a drug can cause developmental toxicity (altered growth, structural anomalies, functional and/or behavioral deficits, or death) – is usually best, but may not be possible in some cases, including glaucoma, eye infections, and eye surgery. Fortunately, the systemic concentrations of drugs applied topically to the eye are typically thought to be low, even though the levels of most drugs have not been studied. Thus, the risk to the embryo and/or fetus in most cases can be considered low and the drug classified as compatible in pregnancy and breastfeeding.
If a topical eye drug must be used during pregnancy or lactation, teach the patient how to decrease the amount of drug reaching the systemic circulation. This involves placing pressure over the tear duct in the corner of the eye for 1 minute or more, then removing any excess solution with absorbent tissue.
In the sections below, drugs are shown by indication or by pharmacologic class. The term “human eye data” refers to the use of the drug in pregnancy and/or lactation.
Glaucoma
If you are caring for a pregnant patient who is being treated for glaucoma, two recent reviews may be helpful: Surv Ophthalmol. 2011 Jul-Aug;56(4):324-35 and Curr Opin Ophthalmol. 2014 Mar;25(2):93-7.
Sympathomimetics (alpha-adrenergic agonists) include apraclonidine (Iopidine), which has no human eye data, and brimonidine (Alphagan P), which has one case report in pregnancy and breastfeeding showing no fetal or nursing infant harm.
Four of the five beta-adrenergic blockers have no human eye data: betaxolol (Betoptic), carteolol (Ocupress), levobunolol (Betagan), and metipranolol, but there are two case reports for timolol (Betimol, Istalol, Timoptic, Timoptic-XE) showing no fetal harm in one newborn and growth restriction in the other.
Among the miotics, there are limited human eye data for pilocarpine (Isopto Carpine) and no fetal harm was observed. For echothiophate iodide (Phospholine Iodide), there is one case report of a normal full-term infant whose mother was treated with the agent up to 32 weeks’ gestation and then with pilocarpine for 8 weeks (Arch Ophthalmol. 1968 Mar;79[3]:283-5).
Carbonic anhydrase inhibitors include brinzolamide (Azopt), which has no human eye data, and dorzolamide (Trusopt), which has growth restriction in one case treated with fixed combination of dorzolamide and timolol. There are no human eye data for unoprostone isopropyl (Rescula), a synthetic docosanoid.
Of the four prostaglandin analogs, three have no human eye data, bimatoprost (Lumigan), tafluprost (Zioptan), and travoprost (Travatan Z). There were 11 pregnancies exposed to latanoprost (Xalatan). The outcomes of these cases were one lost to follow-up, one miscarriage, and nine infants without congenital anomalies (Am J Ophthalmol. 2004 Aug;138[2]:305-6).
Mitomycin (Mitosol) is an antimetabolite that is given topically to the surgical site of glaucoma filtration surgery. No reports of its use in pregnant humans have been located. According to the manufacturer, clinically significant systemic concentrations are not expected.
Antiseptics
Povidone-iodine (Betadine) is indicated for prepping of the periocular region. There does not appear to be any risk to the embryo-fetus or nursing infant from this indication.
Antihistamines
The four ophthalmic agents in this class are alcaftadine (Lastacaft), azelastine (Optivar), emedastine (Emadine), and epinastine (Elestat). There are no human eye data for these agents but, like antihistamines given systemically, they are probably compatible in pregnancy and lactation.
Antihistamine-mast cell stabilizers
There are no human eye data for bepotastine (Bepreve), ketotifen (Alaway), and olopatadine (Pataday, Patanol). Peak plasma concentrations of bepotastine were 5.1-7.3 ng/mL for 1-2 hours after instillation and were less than 2 ng/mL at 24 hours. It appears that these drugs can also be classified as compatible in pregnancy and lactation.
Anti-infectives
Ten anti-infectives are available for topical treatment of eye infections (systemic concentrations if known): besifloxacin (Besivance) (0.43 ng/mL), ciprofloxacin (less than 2.5 ng/mL), gentamicin, gatifloxacin (Zymaxid) (less than 5 ng/mL), levofloxacin (Iquix) (10.9 ng/mL), moxifloxacin (Vigamox) (2.7 ng/mL), ofloxacin (1.9 ng/mL), sulfacetamide (Isopto Cetamide), and tobramycin. The tenth agent, natamycin (Natacyn), is an antifungal. According to the manufacturer, systemic absorption is not expected.
None of these agents have human eye data, but they are usually considered compatible in pregnancy and breastfeeding when systemic formulations are used, so they should be compatible when used in the eye.
Antivirals
Ganciclovir (Zirgan) has no human eye data but, according to the manufacturer, the daily ophthalmic dose is about 0.04% and 0.1% of the oral and IV doses, respectively. Thus, minimal systemic exposure is expected. Trifluridine (Viroptic) also has no eye human data. As reported in the product information, detectable blood concentrations of the drug were not found in healthy normal subjects indicating that systemic absorption was negligible.
Corticosteroids
Among the nine corticosteroid products, six are suspensions or ointments, one is an injection, and two are implants. In most nonpregnant patients receiving the dexamethasone (Ozurdex) intravitreal implant, plasma dexamethasone concentrations were undetectable (less than 50 pg/mL) but, in some, ranged from 52 pg/mL to 102 pg/mL. There is only one case report describing the use of topical dexamethasone suspension (Maxidex) in pregnancy. In that case, dexamethasone and clindamycin were given in the first and second trimesters and the woman eventually gave birth to a normal full term infant (Int Ophthalmol. 1998-1999;22[2]:85-8).
For the fluocinolone (Retisert) ocular implant, systemic absorption of detectable amounts of the drug have not been observed. In a second report, a patient who had type 1 diabetes and was 6 months pregnant received a 2-mg intravitreal injection of triamcinolone (Triesence) in both eyes. No adverse effects in the mother or fetus were noted (Clin Ophthalmol. 2011;5:439-41).
There are no human eye data for five topical corticosteroids: difluprednate (Durezol), fluorometholone (Flarex, Fluor-OP, FML), loteprednol (Alrex, Lotemax), prednisolone (Econopred), and rimexolone (Vexol). Only two of the five drugs had information about systemic absorption. For difluprednate, blood levels were below the quantification limit (50 ng/mL). Extremely low levels were detected after the use of rimexolone with a mean serum concentration of 130 pg/mL (range less than 80-470 pg/mL).
Cycloplegics-mydriatics
This class includes four anticholinergic agents: atropine, cyclopentolate (Cyclogyl), homatropine, and tropicamide (Mydriacyl). Systemic absorption has not been studied for these drugs and there are no reports of their use in pregnancy or lactation.
Cystine-depleting agents
There are no reports describing the use of cysteamine (Cystaran) in human pregnancy or lactation. Since the drug is given as one drop in each eye every waking hour, transfer to the systemic circulation should be expected, but the amount, if it occurs, has not been reported.
Immunologics
There are no reports on the use of cyclosporine (Restasis) eye drops in human pregnancy or during breastfeeding. However, data for the systemic use of the drug during these conditions has shown it to be low risk. After long term ophthalmic use, blood concentrations of the drug were below the quantitation limit of 0.1 ng/mL.
Local anesthetics
The three drugs in this class are lidocaine, proparacaine (Alcaine), and tetracaine (Altacaine, Tetravisc). There is no information regarding the use of these agents in pregnancy or lactation. Since they are used for brief periods, the risk to an embryo or nursing infant appears to be nil.
Mast cell stabilizers
There are three drugs in this class that can be used topically in the eye: cromolyn, lodoxamide (Alomide), and nedocromil (Alocril). There are no human eye data for these agents. Systemic concentrations of lodoxamide were below the detection limit of 2.5 ng/mL.
Miotics
The two miotics are acetylcholine (Miochol E) and carbachol (Carbastat, Miostat). Both are used immediately before eye surgery. The amount, if any, in the systemic circulation is unknown. No reports of human eye use in pregnancy or lactation have been found.
NSAIDs
The five drugs in this class are bromfenac (Xibrom), diclofenac (Voltaren), flurbiprofen (Ocufen), ketorolac, and nepafenac (Nevanac). Although it has not been studied, the estimated plasma level for bromfenac is less than 50 ng/mL. For diclofenac, the plasma concentration was below the limit of quantification (10 ng/mL). In a study conducted with ketorolac, only 5 of 26 subjects had detectable plasma concentrations (10.7 to 22.5 ng/mL). These levels were about 2% of the peak plasma levels after oral dosing. For nepafenac, the peak plasma concentrations of the parent drug and active metabolite were 0.3 and 0.4 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant are nil.
Photodynamic therapy
Verteporfin (Visudyne) is given intravenously. Three reports have described its use in three pregnancies. In all cases, the infants were healthy at birth and had normal growth (Acta Ophthalmol Scand. 2004 Oct;82[5]:623-4, Eye [Lond]. 2009 Jun;23[6]:1479, and Aust N Z J Obstet Gynaecol. 2009 Apr;49[2]:236-7).
Proteolytic enzymes
No human eye data were found for ocriplasmin (Jetrea), an agent given as an intravitreal injection. Although it was not studied, detectable levels of the drug in the systemic circulation are not expected, according to the manufacturer.
Selective vascular endothelial growth factor antagonists
There are three agents in this class: aflibercept (Eylea), pegaptanib (Macugen), and ranibizumab (Lucentis). There are no human eye data for these drugs. All are given as intravitreal injection. The systemic concentrations of the three drugs were a mean 0.02 mcg/mL; 80 ng/mL (after a dose of 10 times the recommended dose); and an estimated minimum 0.22 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant is nil.
Sympathomimetics (decongestants)
There are four ophthalmic agents in this class and none have human eye data. Naphazoline (Naphcon, Vasocon) is the only one of the four that requires a prescription. No reports describing the systemic absorption, if any, have been found. The other three agents are available over the counter. They are oxymetazoline (Visine L.R.), phenylephrine, and tetrahydrozoline (Opti-Clear). Although the amount reaching the systemic circulation was not provided by the manufacturers for these three agents, a caution was placed on phenylephrine stating that systemic absorption, although rare, might cause alpha-adrenergic effects, such as a rise in blood pressure and reflex atropine-sensitive bradycardia.
The risk to the embryo-fetus or nursing infant from ophthalmic drugs appears to be low, with the possible exception of phenylephrine. Nevertheless, if any of these agents are used in pregnancy or during breastfeeding, careful assessment of the embryo-fetus and nursing infant should be conducted. Moreover, research on the potential effects of ophthalmic drugs on the embryo-fetus and nursing infant are desperately needed.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.
Inside Out or Outside In: Does Atopic Dermatitis Disrupt Barrier Function or Does Disruption of Barrier Function Trigger Atopic Dermatitis?
Atopic dermatitis (AD) is a multifactorial inflammatory disorder with an estimated prevalence of 279,889,120 cases worldwide.1 Most cases of AD begin in early childhood (with almost 85% developing by 5 years of age),2 but recent studies have found that 40% to over 80% of cases persist into adulthood.1,3,4 Although a previous study focused largely on T helper type 1/T helper type 2 (Th2) immune dysregulation as the pathogenesis of the disease,5 disruption of the skin barrier and systemic inflammation are at the center of current AD research. In AD, breakdown of the skin barrier results in increased transepidermal water loss, reduced skin hydration, and increased antigen presentation by Langerhans cells initiating inflammation.6-8 The cascade largely activated is the Th2 and T helper type 22 cascade with resultant cytokine release (ie, IL-4, IL-13, IL-2, IL-8, IL-10, IL-17, IL-22, tumor necrosis factor α, interferon γ).9,10 In active AD, Th2 inflammation and barrier breakdown result in reduced filaggrin and claudin 1 expression, resulting in further exacerbation of the barrier defect and enhancing the risk of development of asthma and hay fever as well as transcutaneous sensitization to a variety of food allergens (eg, peanuts).9,11,12 Although all of these immunologic features are well established in AD, controversy remains as to whether AD is caused by systemic inflammation triggering barrier dysfunction (the “inside-out” hypothesis) or from the epidermal skin barrier disruption triggering immunologic imbalance (the “outside-in” hypothesis).
Inside-Out Hypothesis
While barrier impairment appears to occur in all patients with AD, it still is unclear how AD begins. The inside-out hypothesis suggests that cutaneous inflammation precedes barrier impairment and in fact may result in an impaired skin barrier. It has previously been reported that inflammatory states weaken the barrier by downregulating filaggrin production in the skin.13 Barrier disruption may be accompanied by transcutaneous penetration of allergens and increased Staphylococcus aureus counts. Recently, mutations and polymorphisms of inflammatory genes have been linked to AD (eg, single nucleotide polymorphisms of the IL4RA [interleukin 4 receptor, alpha] and CD14 [cluster of differentiation 14] genes, the serine protease inhibitor SPINK5 [serine peptidase inhibitor, Kazal type 5], RANTES [chemokine (C-C motif) ligand 5], IL-4, IL-13).14 These alterations highlight the role of systemic inflammation in triggering AD.
Outside-In Hypothesis
The outside-in hypothesis suggests that the impaired skin barrier precedes AD and is required for immune dysregulation to occur. This hypothesis was largely advanced by a study demonstrating that deactivating mutations of the filaggrin gene were linked to nearly 20% of AD cases in Northern European populations.15 Filaggrin (chromosome 1q21.3) performs an essential function in the skin barrier through its differential cleavage and the breakdown and release of natural moisturizing factor.16 Filaggrin gene mutations are associated with persistent AD, and it has been posited that environmental factors such as temperature and humidity also can affect filaggrin production as it relates to barrier function.17-19 Skin barrier disruption results in increased cutaneous and systemic Th2 responses (ie, IL-4/13), with thymic stromal lymphopoietin as the potential mechanism of Th2 cell recruitment.10,20 Inflammatory Th2 cells triggered by an impaired skin barrier also may predispose patients to the development of allergic diseases such as asthma, in line with Atopic March, or the progression of AD to other forms of atopy (eg, food allergy, asthma).5,7,21-23
The outside-in hypothesis may only explain the root pathogenesis of AD in a subset of patients, however, as only 1 in 5 cases of AD in Northern European and Asian populations are associated with underlying filaggrin mutations (which are only present in about 10% of those who are unaffected by AD).15 Filaggrin does not appear to account for the basis of AD in all cases. In a study of 762 newborns in Cincinnati, Ohio, 39% of children with at least one parent with atopy developed AD by 3 years of age, about quadruple of what would be projected based on filaggrin defects in general population studies, which are noted in only about 10% of white individuals.24 Furthermore, less than 5% of patients of African descent have mutations of the filaggrin 1 gene.25
Implications for the Prevention and Treatment of Atopic Dermatitis
Preventative strategies for AD currently are in development. Atopic dermatitis may be unpreventable because the in utero environment triggers some of the barrier alterations, which can be noted as early as 2 days following birth and will predict early-onset AD. The putative mechanism is via Th2 cytokines (IL-4, IL-13).26
Certainly, application of over-the-counter and prescription emollients are mainstays of treatment for AD and may suffice as monotherapy in cases of mild disease. In a recent randomized trial in the United States and the United Kingdom, emollients were used in newborns considered at high risk for AD (family history of atopy) until 6 months of age.27 The risk of AD development was reduced by half, irrespective of the emollient used. Unfortunately, 21.8% of children without a family history of atopy will develop AD; therefore, not all cases can be prevented if use of emollients is limited to newborns with a family history of atopy.28 Long-term follow-up is needed to track whether emollient use in newborns will prevent AD indefinitely.
Prevention of AD onset using systemic interventions has also been investigated. Probiotics have been suggested as a means to modify the gut microbiota and reduce systemic and mucosal inflammation. Lactobacillus reuteri taken prenatally by pregnant women and by newborns has shown mild benefit in preventing some forms of AD.29 Although they are not approved by the US Food and Drug Administration for this indication, systemic interventions for moderate-to-severe AD such as methotrexate and cyclosporine certainly have shown benefit in managing ongoing illness and breaking the cycle of disease.30 The efficacy of these agents points to the role of systemic inflammation in ongoing AD activity. Moreover, the inside-out hypothesis recently has led to the proliferation of promising new therapeutic agents in the pipeline to treat the systemic Th2 inflammation that occurs in severe AD (eg, anti–IL-4/13 receptor antibody, anti–IL-13 antibodies, and biologics targeting IL-12/23, IL-22, and IL-31 receptors).31
Final Thoughts
Atopic dermatitis is a multifactorial disease associated with barrier disruption and intense systemic inflammation. It is likely that both the inside-out and outside-in hypotheses hold true in different subsets of AD patients. It is clear that some individuals are born with filaggrin defects that sufficiently trigger systemic inflammation, resulting in AD. On the other hand, there are clearly some individuals with inflammatory dysregulation that results in systemic inflammation and secondary barrier disruption. Until we can determine the genomic triggering or promoting event in each individual patient, large-scale introduction of active prevention and severity reduction strategies may not be realistic. In the meantime, we can approach AD in childhood from the inside out, through appropriate treatment of systemic inflammation of AD, and from the outside in, with treatment and prevention via emollient use in newborns.
- Hay RJ, Johns NE, Williams HC, et al. The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions. J Invest Dermatol. 2014;134:1527-1534.
- Kay J, Gawkrodger DJ, Mortimer MJ, et al. The prevalence of childhood atopic eczema in a general population. J Am Acad Dermatol. 1994;30:35-39.
- Margolis JS, Abuabara K, Bilker W, et al. Persistence of mild to moderate atopic dermatitis. JAMA Dermatol. 2014;150:593-600.
- Shaw TE, Currie GP, Koudelka CW, et al. Eczema prevalence in the United States: data from the 2003 National Survey of Children’s Health. J Invest Dermatol. 2011;131:67-73.
- Zheng T, Jinho Y, Oh MH, et al. The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. Allergy Asthma Immunol Res. 2011;3:67-73.
- De Benedetto A, Kubo A, Beck LA. Skin barrier disruption: a requirement for allergen sensitization? J Invest Dermatol. 2012;132:949-963.
- Visscher MO, Adam R, Brink S, et al. Newborn infant skin: physiology, development, and care. Clin Dermatol. 2015;33:271-280.
- Hanifin JM. Evolving concepts of pathogenesis in atopic dermatitis and other eczemas. J Invest Dermatol. 2009;129:320-322.
- Kondo H, Ichikawa Y, Imokawa G. Percutaneous sensitization with allergens through barrier-disrupted skin elicits a Th2-dominant cytokine response. Eur J Immunol. 1998;28:769-779.
- Correa da Rosa J, Malajian D, Shemer A, et al. Patients with atopic dermatitis have attenuated and distinct contact hypersensitivity responses to common allergens in skin. J Allergy Clin Immunol. 2015;135:712-720.
- Paller AS. Latest approaches to treating atopic dermatitis. Chem Immunol Allergy. 2012;96:132-140.
- Batista DI, Perez L, Orfali RL, et al. Profile of skin barrier proteins (filaggrin, claudins 1 and 4) and Th1/Th2/Th17 cytokines in adults with atopic dermatitis. J Eur Acad Dermatol Venereol. 2015;29:1091-1095.
- Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Opin Allergy Clin Immunol. 2009;9:437-446.
- Hanifin JM. Evolving concepts of pathogenesis in atopic dermatitis and other eczemas. J Invest Dermatol. 2009;129:320-322.
- Brown SJ, Irvine AD. Atopic eczema and the filaggrin story. Semin Cutan Med Surg. 2008;27:128-137.
- Harding CR, Aho S, Bosko CA. Filaggrin—revisited. Int J Cosmet Sci. 2013;35:412-423.
- Carson CG, Rasmussen MA, Thyssen JP, et al. Clinical presentation of atopic dermatitis by filaggrin gene mutation status during the first 7 years of life in a prospective cohort study. PLoS One. 2012;7:e48678.
- Silverberg JI, Hanifin J, Simpson EL. Climatic factors are associated with childhood eczema prevalence in the United States. J Invest Dermatol. 2013;133:1752-1759.
- Sargen MR, Hoffstad O, Margolis DJ. Warm, humid, and high sun exposure climates are associated with poorly controlled eczema: PEER (Pediatric Eczema Elective Registry) cohort, 2004-2012. J Invest Dermatol. 2014;134:51-57.
- Hammad H, Lambrecht BN. Barrier epithelial cells and the control of type 2 immunity. Immunity. 2015;43:29-40.
- Silverberg JI. Association between adult atopic dermatitis, cardiovascular disease and increased heart attacks in 3 population-based studies [published online ahead of print July 4, 2015]. Allergy. doi:10.1111/all.12685.
- Amat F, Saint-Pierre P, Bourrat E, et al. Early-onset atopic dermatitis in children: which are the phenotypes at risk of asthma? results from the ORCA cohort. PLoS One. 2015;10:e0131369.
- Demehri S, Morimoto M, Holtzman MJ, et al. Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma. PLoS Biol. 2009;7:e1000067.
- Biagini Myers JM, Wang N, LeMasters GK, et al. Genetic and environmental risk factors for childhood eczema development and allergic sensitization in the CCAAPS cohort. J Invest Dermatol. 2010;130:430-437.
- Margolis DJ, Apter AJ, Gupta J, et al. The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort. J Allergy Clin Immunol. 2012;130:912-917.
- Kelleher M, Dunn-Galvin A, Hourihane JO, et al. Skin barrier dysfunction measured by transepidermal water loss at 2 days and 2 months predates and predicts atopic dermatitis at 1 year. J Allergy Clin Immunol. 2015;135:930-935.
- Simpson EL, Chalmers JR, Hanifin JM, et al. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J Allergy Clin Immunol. 2014;134:818-823.
- Parazzini F, Cipriani S, Zinetti C, et al. Perinatal factors and the risk of atopic dermatitis: a cohort study. Pediatr Allergy Immunol. 2014;25:43-50.
- Abrahamsson TR, Jakobsson T, Böttcher MF, et al. Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2007;119:1174-1180.
- Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71:327-349.
- Eczema drugs in development. National Eczema Association Web site. https://nationaleczema.org/research/phases-drug-development/. Accessed August 18, 2015.
Atopic dermatitis (AD) is a multifactorial inflammatory disorder with an estimated prevalence of 279,889,120 cases worldwide.1 Most cases of AD begin in early childhood (with almost 85% developing by 5 years of age),2 but recent studies have found that 40% to over 80% of cases persist into adulthood.1,3,4 Although a previous study focused largely on T helper type 1/T helper type 2 (Th2) immune dysregulation as the pathogenesis of the disease,5 disruption of the skin barrier and systemic inflammation are at the center of current AD research. In AD, breakdown of the skin barrier results in increased transepidermal water loss, reduced skin hydration, and increased antigen presentation by Langerhans cells initiating inflammation.6-8 The cascade largely activated is the Th2 and T helper type 22 cascade with resultant cytokine release (ie, IL-4, IL-13, IL-2, IL-8, IL-10, IL-17, IL-22, tumor necrosis factor α, interferon γ).9,10 In active AD, Th2 inflammation and barrier breakdown result in reduced filaggrin and claudin 1 expression, resulting in further exacerbation of the barrier defect and enhancing the risk of development of asthma and hay fever as well as transcutaneous sensitization to a variety of food allergens (eg, peanuts).9,11,12 Although all of these immunologic features are well established in AD, controversy remains as to whether AD is caused by systemic inflammation triggering barrier dysfunction (the “inside-out” hypothesis) or from the epidermal skin barrier disruption triggering immunologic imbalance (the “outside-in” hypothesis).
Inside-Out Hypothesis
While barrier impairment appears to occur in all patients with AD, it still is unclear how AD begins. The inside-out hypothesis suggests that cutaneous inflammation precedes barrier impairment and in fact may result in an impaired skin barrier. It has previously been reported that inflammatory states weaken the barrier by downregulating filaggrin production in the skin.13 Barrier disruption may be accompanied by transcutaneous penetration of allergens and increased Staphylococcus aureus counts. Recently, mutations and polymorphisms of inflammatory genes have been linked to AD (eg, single nucleotide polymorphisms of the IL4RA [interleukin 4 receptor, alpha] and CD14 [cluster of differentiation 14] genes, the serine protease inhibitor SPINK5 [serine peptidase inhibitor, Kazal type 5], RANTES [chemokine (C-C motif) ligand 5], IL-4, IL-13).14 These alterations highlight the role of systemic inflammation in triggering AD.
Outside-In Hypothesis
The outside-in hypothesis suggests that the impaired skin barrier precedes AD and is required for immune dysregulation to occur. This hypothesis was largely advanced by a study demonstrating that deactivating mutations of the filaggrin gene were linked to nearly 20% of AD cases in Northern European populations.15 Filaggrin (chromosome 1q21.3) performs an essential function in the skin barrier through its differential cleavage and the breakdown and release of natural moisturizing factor.16 Filaggrin gene mutations are associated with persistent AD, and it has been posited that environmental factors such as temperature and humidity also can affect filaggrin production as it relates to barrier function.17-19 Skin barrier disruption results in increased cutaneous and systemic Th2 responses (ie, IL-4/13), with thymic stromal lymphopoietin as the potential mechanism of Th2 cell recruitment.10,20 Inflammatory Th2 cells triggered by an impaired skin barrier also may predispose patients to the development of allergic diseases such as asthma, in line with Atopic March, or the progression of AD to other forms of atopy (eg, food allergy, asthma).5,7,21-23
The outside-in hypothesis may only explain the root pathogenesis of AD in a subset of patients, however, as only 1 in 5 cases of AD in Northern European and Asian populations are associated with underlying filaggrin mutations (which are only present in about 10% of those who are unaffected by AD).15 Filaggrin does not appear to account for the basis of AD in all cases. In a study of 762 newborns in Cincinnati, Ohio, 39% of children with at least one parent with atopy developed AD by 3 years of age, about quadruple of what would be projected based on filaggrin defects in general population studies, which are noted in only about 10% of white individuals.24 Furthermore, less than 5% of patients of African descent have mutations of the filaggrin 1 gene.25
Implications for the Prevention and Treatment of Atopic Dermatitis
Preventative strategies for AD currently are in development. Atopic dermatitis may be unpreventable because the in utero environment triggers some of the barrier alterations, which can be noted as early as 2 days following birth and will predict early-onset AD. The putative mechanism is via Th2 cytokines (IL-4, IL-13).26
Certainly, application of over-the-counter and prescription emollients are mainstays of treatment for AD and may suffice as monotherapy in cases of mild disease. In a recent randomized trial in the United States and the United Kingdom, emollients were used in newborns considered at high risk for AD (family history of atopy) until 6 months of age.27 The risk of AD development was reduced by half, irrespective of the emollient used. Unfortunately, 21.8% of children without a family history of atopy will develop AD; therefore, not all cases can be prevented if use of emollients is limited to newborns with a family history of atopy.28 Long-term follow-up is needed to track whether emollient use in newborns will prevent AD indefinitely.
Prevention of AD onset using systemic interventions has also been investigated. Probiotics have been suggested as a means to modify the gut microbiota and reduce systemic and mucosal inflammation. Lactobacillus reuteri taken prenatally by pregnant women and by newborns has shown mild benefit in preventing some forms of AD.29 Although they are not approved by the US Food and Drug Administration for this indication, systemic interventions for moderate-to-severe AD such as methotrexate and cyclosporine certainly have shown benefit in managing ongoing illness and breaking the cycle of disease.30 The efficacy of these agents points to the role of systemic inflammation in ongoing AD activity. Moreover, the inside-out hypothesis recently has led to the proliferation of promising new therapeutic agents in the pipeline to treat the systemic Th2 inflammation that occurs in severe AD (eg, anti–IL-4/13 receptor antibody, anti–IL-13 antibodies, and biologics targeting IL-12/23, IL-22, and IL-31 receptors).31
Final Thoughts
Atopic dermatitis is a multifactorial disease associated with barrier disruption and intense systemic inflammation. It is likely that both the inside-out and outside-in hypotheses hold true in different subsets of AD patients. It is clear that some individuals are born with filaggrin defects that sufficiently trigger systemic inflammation, resulting in AD. On the other hand, there are clearly some individuals with inflammatory dysregulation that results in systemic inflammation and secondary barrier disruption. Until we can determine the genomic triggering or promoting event in each individual patient, large-scale introduction of active prevention and severity reduction strategies may not be realistic. In the meantime, we can approach AD in childhood from the inside out, through appropriate treatment of systemic inflammation of AD, and from the outside in, with treatment and prevention via emollient use in newborns.
Atopic dermatitis (AD) is a multifactorial inflammatory disorder with an estimated prevalence of 279,889,120 cases worldwide.1 Most cases of AD begin in early childhood (with almost 85% developing by 5 years of age),2 but recent studies have found that 40% to over 80% of cases persist into adulthood.1,3,4 Although a previous study focused largely on T helper type 1/T helper type 2 (Th2) immune dysregulation as the pathogenesis of the disease,5 disruption of the skin barrier and systemic inflammation are at the center of current AD research. In AD, breakdown of the skin barrier results in increased transepidermal water loss, reduced skin hydration, and increased antigen presentation by Langerhans cells initiating inflammation.6-8 The cascade largely activated is the Th2 and T helper type 22 cascade with resultant cytokine release (ie, IL-4, IL-13, IL-2, IL-8, IL-10, IL-17, IL-22, tumor necrosis factor α, interferon γ).9,10 In active AD, Th2 inflammation and barrier breakdown result in reduced filaggrin and claudin 1 expression, resulting in further exacerbation of the barrier defect and enhancing the risk of development of asthma and hay fever as well as transcutaneous sensitization to a variety of food allergens (eg, peanuts).9,11,12 Although all of these immunologic features are well established in AD, controversy remains as to whether AD is caused by systemic inflammation triggering barrier dysfunction (the “inside-out” hypothesis) or from the epidermal skin barrier disruption triggering immunologic imbalance (the “outside-in” hypothesis).
Inside-Out Hypothesis
While barrier impairment appears to occur in all patients with AD, it still is unclear how AD begins. The inside-out hypothesis suggests that cutaneous inflammation precedes barrier impairment and in fact may result in an impaired skin barrier. It has previously been reported that inflammatory states weaken the barrier by downregulating filaggrin production in the skin.13 Barrier disruption may be accompanied by transcutaneous penetration of allergens and increased Staphylococcus aureus counts. Recently, mutations and polymorphisms of inflammatory genes have been linked to AD (eg, single nucleotide polymorphisms of the IL4RA [interleukin 4 receptor, alpha] and CD14 [cluster of differentiation 14] genes, the serine protease inhibitor SPINK5 [serine peptidase inhibitor, Kazal type 5], RANTES [chemokine (C-C motif) ligand 5], IL-4, IL-13).14 These alterations highlight the role of systemic inflammation in triggering AD.
Outside-In Hypothesis
The outside-in hypothesis suggests that the impaired skin barrier precedes AD and is required for immune dysregulation to occur. This hypothesis was largely advanced by a study demonstrating that deactivating mutations of the filaggrin gene were linked to nearly 20% of AD cases in Northern European populations.15 Filaggrin (chromosome 1q21.3) performs an essential function in the skin barrier through its differential cleavage and the breakdown and release of natural moisturizing factor.16 Filaggrin gene mutations are associated with persistent AD, and it has been posited that environmental factors such as temperature and humidity also can affect filaggrin production as it relates to barrier function.17-19 Skin barrier disruption results in increased cutaneous and systemic Th2 responses (ie, IL-4/13), with thymic stromal lymphopoietin as the potential mechanism of Th2 cell recruitment.10,20 Inflammatory Th2 cells triggered by an impaired skin barrier also may predispose patients to the development of allergic diseases such as asthma, in line with Atopic March, or the progression of AD to other forms of atopy (eg, food allergy, asthma).5,7,21-23
The outside-in hypothesis may only explain the root pathogenesis of AD in a subset of patients, however, as only 1 in 5 cases of AD in Northern European and Asian populations are associated with underlying filaggrin mutations (which are only present in about 10% of those who are unaffected by AD).15 Filaggrin does not appear to account for the basis of AD in all cases. In a study of 762 newborns in Cincinnati, Ohio, 39% of children with at least one parent with atopy developed AD by 3 years of age, about quadruple of what would be projected based on filaggrin defects in general population studies, which are noted in only about 10% of white individuals.24 Furthermore, less than 5% of patients of African descent have mutations of the filaggrin 1 gene.25
Implications for the Prevention and Treatment of Atopic Dermatitis
Preventative strategies for AD currently are in development. Atopic dermatitis may be unpreventable because the in utero environment triggers some of the barrier alterations, which can be noted as early as 2 days following birth and will predict early-onset AD. The putative mechanism is via Th2 cytokines (IL-4, IL-13).26
Certainly, application of over-the-counter and prescription emollients are mainstays of treatment for AD and may suffice as monotherapy in cases of mild disease. In a recent randomized trial in the United States and the United Kingdom, emollients were used in newborns considered at high risk for AD (family history of atopy) until 6 months of age.27 The risk of AD development was reduced by half, irrespective of the emollient used. Unfortunately, 21.8% of children without a family history of atopy will develop AD; therefore, not all cases can be prevented if use of emollients is limited to newborns with a family history of atopy.28 Long-term follow-up is needed to track whether emollient use in newborns will prevent AD indefinitely.
Prevention of AD onset using systemic interventions has also been investigated. Probiotics have been suggested as a means to modify the gut microbiota and reduce systemic and mucosal inflammation. Lactobacillus reuteri taken prenatally by pregnant women and by newborns has shown mild benefit in preventing some forms of AD.29 Although they are not approved by the US Food and Drug Administration for this indication, systemic interventions for moderate-to-severe AD such as methotrexate and cyclosporine certainly have shown benefit in managing ongoing illness and breaking the cycle of disease.30 The efficacy of these agents points to the role of systemic inflammation in ongoing AD activity. Moreover, the inside-out hypothesis recently has led to the proliferation of promising new therapeutic agents in the pipeline to treat the systemic Th2 inflammation that occurs in severe AD (eg, anti–IL-4/13 receptor antibody, anti–IL-13 antibodies, and biologics targeting IL-12/23, IL-22, and IL-31 receptors).31
Final Thoughts
Atopic dermatitis is a multifactorial disease associated with barrier disruption and intense systemic inflammation. It is likely that both the inside-out and outside-in hypotheses hold true in different subsets of AD patients. It is clear that some individuals are born with filaggrin defects that sufficiently trigger systemic inflammation, resulting in AD. On the other hand, there are clearly some individuals with inflammatory dysregulation that results in systemic inflammation and secondary barrier disruption. Until we can determine the genomic triggering or promoting event in each individual patient, large-scale introduction of active prevention and severity reduction strategies may not be realistic. In the meantime, we can approach AD in childhood from the inside out, through appropriate treatment of systemic inflammation of AD, and from the outside in, with treatment and prevention via emollient use in newborns.
- Hay RJ, Johns NE, Williams HC, et al. The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions. J Invest Dermatol. 2014;134:1527-1534.
- Kay J, Gawkrodger DJ, Mortimer MJ, et al. The prevalence of childhood atopic eczema in a general population. J Am Acad Dermatol. 1994;30:35-39.
- Margolis JS, Abuabara K, Bilker W, et al. Persistence of mild to moderate atopic dermatitis. JAMA Dermatol. 2014;150:593-600.
- Shaw TE, Currie GP, Koudelka CW, et al. Eczema prevalence in the United States: data from the 2003 National Survey of Children’s Health. J Invest Dermatol. 2011;131:67-73.
- Zheng T, Jinho Y, Oh MH, et al. The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. Allergy Asthma Immunol Res. 2011;3:67-73.
- De Benedetto A, Kubo A, Beck LA. Skin barrier disruption: a requirement for allergen sensitization? J Invest Dermatol. 2012;132:949-963.
- Visscher MO, Adam R, Brink S, et al. Newborn infant skin: physiology, development, and care. Clin Dermatol. 2015;33:271-280.
- Hanifin JM. Evolving concepts of pathogenesis in atopic dermatitis and other eczemas. J Invest Dermatol. 2009;129:320-322.
- Kondo H, Ichikawa Y, Imokawa G. Percutaneous sensitization with allergens through barrier-disrupted skin elicits a Th2-dominant cytokine response. Eur J Immunol. 1998;28:769-779.
- Correa da Rosa J, Malajian D, Shemer A, et al. Patients with atopic dermatitis have attenuated and distinct contact hypersensitivity responses to common allergens in skin. J Allergy Clin Immunol. 2015;135:712-720.
- Paller AS. Latest approaches to treating atopic dermatitis. Chem Immunol Allergy. 2012;96:132-140.
- Batista DI, Perez L, Orfali RL, et al. Profile of skin barrier proteins (filaggrin, claudins 1 and 4) and Th1/Th2/Th17 cytokines in adults with atopic dermatitis. J Eur Acad Dermatol Venereol. 2015;29:1091-1095.
- Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Opin Allergy Clin Immunol. 2009;9:437-446.
- Hanifin JM. Evolving concepts of pathogenesis in atopic dermatitis and other eczemas. J Invest Dermatol. 2009;129:320-322.
- Brown SJ, Irvine AD. Atopic eczema and the filaggrin story. Semin Cutan Med Surg. 2008;27:128-137.
- Harding CR, Aho S, Bosko CA. Filaggrin—revisited. Int J Cosmet Sci. 2013;35:412-423.
- Carson CG, Rasmussen MA, Thyssen JP, et al. Clinical presentation of atopic dermatitis by filaggrin gene mutation status during the first 7 years of life in a prospective cohort study. PLoS One. 2012;7:e48678.
- Silverberg JI, Hanifin J, Simpson EL. Climatic factors are associated with childhood eczema prevalence in the United States. J Invest Dermatol. 2013;133:1752-1759.
- Sargen MR, Hoffstad O, Margolis DJ. Warm, humid, and high sun exposure climates are associated with poorly controlled eczema: PEER (Pediatric Eczema Elective Registry) cohort, 2004-2012. J Invest Dermatol. 2014;134:51-57.
- Hammad H, Lambrecht BN. Barrier epithelial cells and the control of type 2 immunity. Immunity. 2015;43:29-40.
- Silverberg JI. Association between adult atopic dermatitis, cardiovascular disease and increased heart attacks in 3 population-based studies [published online ahead of print July 4, 2015]. Allergy. doi:10.1111/all.12685.
- Amat F, Saint-Pierre P, Bourrat E, et al. Early-onset atopic dermatitis in children: which are the phenotypes at risk of asthma? results from the ORCA cohort. PLoS One. 2015;10:e0131369.
- Demehri S, Morimoto M, Holtzman MJ, et al. Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma. PLoS Biol. 2009;7:e1000067.
- Biagini Myers JM, Wang N, LeMasters GK, et al. Genetic and environmental risk factors for childhood eczema development and allergic sensitization in the CCAAPS cohort. J Invest Dermatol. 2010;130:430-437.
- Margolis DJ, Apter AJ, Gupta J, et al. The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort. J Allergy Clin Immunol. 2012;130:912-917.
- Kelleher M, Dunn-Galvin A, Hourihane JO, et al. Skin barrier dysfunction measured by transepidermal water loss at 2 days and 2 months predates and predicts atopic dermatitis at 1 year. J Allergy Clin Immunol. 2015;135:930-935.
- Simpson EL, Chalmers JR, Hanifin JM, et al. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J Allergy Clin Immunol. 2014;134:818-823.
- Parazzini F, Cipriani S, Zinetti C, et al. Perinatal factors and the risk of atopic dermatitis: a cohort study. Pediatr Allergy Immunol. 2014;25:43-50.
- Abrahamsson TR, Jakobsson T, Böttcher MF, et al. Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2007;119:1174-1180.
- Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71:327-349.
- Eczema drugs in development. National Eczema Association Web site. https://nationaleczema.org/research/phases-drug-development/. Accessed August 18, 2015.
- Hay RJ, Johns NE, Williams HC, et al. The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions. J Invest Dermatol. 2014;134:1527-1534.
- Kay J, Gawkrodger DJ, Mortimer MJ, et al. The prevalence of childhood atopic eczema in a general population. J Am Acad Dermatol. 1994;30:35-39.
- Margolis JS, Abuabara K, Bilker W, et al. Persistence of mild to moderate atopic dermatitis. JAMA Dermatol. 2014;150:593-600.
- Shaw TE, Currie GP, Koudelka CW, et al. Eczema prevalence in the United States: data from the 2003 National Survey of Children’s Health. J Invest Dermatol. 2011;131:67-73.
- Zheng T, Jinho Y, Oh MH, et al. The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. Allergy Asthma Immunol Res. 2011;3:67-73.
- De Benedetto A, Kubo A, Beck LA. Skin barrier disruption: a requirement for allergen sensitization? J Invest Dermatol. 2012;132:949-963.
- Visscher MO, Adam R, Brink S, et al. Newborn infant skin: physiology, development, and care. Clin Dermatol. 2015;33:271-280.
- Hanifin JM. Evolving concepts of pathogenesis in atopic dermatitis and other eczemas. J Invest Dermatol. 2009;129:320-322.
- Kondo H, Ichikawa Y, Imokawa G. Percutaneous sensitization with allergens through barrier-disrupted skin elicits a Th2-dominant cytokine response. Eur J Immunol. 1998;28:769-779.
- Correa da Rosa J, Malajian D, Shemer A, et al. Patients with atopic dermatitis have attenuated and distinct contact hypersensitivity responses to common allergens in skin. J Allergy Clin Immunol. 2015;135:712-720.
- Paller AS. Latest approaches to treating atopic dermatitis. Chem Immunol Allergy. 2012;96:132-140.
- Batista DI, Perez L, Orfali RL, et al. Profile of skin barrier proteins (filaggrin, claudins 1 and 4) and Th1/Th2/Th17 cytokines in adults with atopic dermatitis. J Eur Acad Dermatol Venereol. 2015;29:1091-1095.
- Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Opin Allergy Clin Immunol. 2009;9:437-446.
- Hanifin JM. Evolving concepts of pathogenesis in atopic dermatitis and other eczemas. J Invest Dermatol. 2009;129:320-322.
- Brown SJ, Irvine AD. Atopic eczema and the filaggrin story. Semin Cutan Med Surg. 2008;27:128-137.
- Harding CR, Aho S, Bosko CA. Filaggrin—revisited. Int J Cosmet Sci. 2013;35:412-423.
- Carson CG, Rasmussen MA, Thyssen JP, et al. Clinical presentation of atopic dermatitis by filaggrin gene mutation status during the first 7 years of life in a prospective cohort study. PLoS One. 2012;7:e48678.
- Silverberg JI, Hanifin J, Simpson EL. Climatic factors are associated with childhood eczema prevalence in the United States. J Invest Dermatol. 2013;133:1752-1759.
- Sargen MR, Hoffstad O, Margolis DJ. Warm, humid, and high sun exposure climates are associated with poorly controlled eczema: PEER (Pediatric Eczema Elective Registry) cohort, 2004-2012. J Invest Dermatol. 2014;134:51-57.
- Hammad H, Lambrecht BN. Barrier epithelial cells and the control of type 2 immunity. Immunity. 2015;43:29-40.
- Silverberg JI. Association between adult atopic dermatitis, cardiovascular disease and increased heart attacks in 3 population-based studies [published online ahead of print July 4, 2015]. Allergy. doi:10.1111/all.12685.
- Amat F, Saint-Pierre P, Bourrat E, et al. Early-onset atopic dermatitis in children: which are the phenotypes at risk of asthma? results from the ORCA cohort. PLoS One. 2015;10:e0131369.
- Demehri S, Morimoto M, Holtzman MJ, et al. Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma. PLoS Biol. 2009;7:e1000067.
- Biagini Myers JM, Wang N, LeMasters GK, et al. Genetic and environmental risk factors for childhood eczema development and allergic sensitization in the CCAAPS cohort. J Invest Dermatol. 2010;130:430-437.
- Margolis DJ, Apter AJ, Gupta J, et al. The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort. J Allergy Clin Immunol. 2012;130:912-917.
- Kelleher M, Dunn-Galvin A, Hourihane JO, et al. Skin barrier dysfunction measured by transepidermal water loss at 2 days and 2 months predates and predicts atopic dermatitis at 1 year. J Allergy Clin Immunol. 2015;135:930-935.
- Simpson EL, Chalmers JR, Hanifin JM, et al. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J Allergy Clin Immunol. 2014;134:818-823.
- Parazzini F, Cipriani S, Zinetti C, et al. Perinatal factors and the risk of atopic dermatitis: a cohort study. Pediatr Allergy Immunol. 2014;25:43-50.
- Abrahamsson TR, Jakobsson T, Böttcher MF, et al. Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2007;119:1174-1180.
- Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71:327-349.
- Eczema drugs in development. National Eczema Association Web site. https://nationaleczema.org/research/phases-drug-development/. Accessed August 18, 2015.
Why 10 days of antibiotics for infections is not magic
In the United States, we treat almost all infections for 10 days. Why? In France, most infections are treated for 8 days. In the U.K., most infections are treated for 5 days. In many other countries, infections are treated until symptomatic improvement occurs. Can everyone outside the United States be wrong? What is the evidence base for the various recommended durations? Moreover, what is the harm in treating for longer than necessary?
The U.S. tradition of 10 days’ treatment for infections arose from the 1940 trials of injectable penicillin for prevention of acute rheumatic fever in military recruits who had group A streptococcal pharyngitis. Injections of penicillin G mixed in peanut oil produced therapeutic levels of penicillin for about 3 days. Soldiers who received three sequential injections had the lowest occurrence of rheumatic fever; two injections were not as good and four injections did not add to the prevention rate. So three injections meant 9 days’ treatment; 9 days was rounded up to 10 days, and there you have it.
We have come a long way since the 1940s. For strep throat, we now have three approved antibiotics for 5 days’ treatment: cefdinir, cefpodoxime proxetil, and azithromycin, all evidence based and U.S. Food and Drug Administration approved. One large study was done in the 1980s with cefadroxil for 5 days, and that duration was as effective in strep eradication as was 10 days, but the company never pursued the 5-day indication.
The optimal duration of antibiotic treatment is generally considered to be 10 days in the United States, however, there is scant evidence base for that recommendation. The recent American Academy of Pediatrics/American Academy of Family Physicians guidelines endorse 10 days of treatment duration as the standard for most acute otitis media (AOM) (Pediatrics 2013;131[3]:e964-99), but acknowledge that shorter treatment regimens may be as effective. Specifically, the guideline states: “A 7-day course of oral antibiotic appears to be equally effective in children 2- to 5 years of age with mild to moderate AOM. For children 6 years and older with mild to moderate AOM symptoms, a 5- to 7-day course is adequate treatment.” A systematic analysis and a meta-analysis have concluded that 5 days’ duration of antibiotics is as effective as 10 days’ treatment for all children over age 2 years and only marginally inferior to 10 days for children under the age of 2 years old (Cochrane Database Syst Rev. 2010;[9]:CD001095).
Thirty years ago, our group and others began to do studies involving “double tympanocentesis,” where an ear tap was done at time of diagnosis and again 3-5 days later to prove bacterial cure for various antibiotics that were in trials. We learned that if the organism was sensitive to the antibiotic chosen, then it was dead by days 3-5. Most of the failures were due to resistant bacteria. So treating longer was not going to help. It was time to change the antibiotic if clinical improvement had not occurred. Our group published a study 15 years ago of 2,172 children comparing 5-, 7-, and 10-days’ treatment of AOM, and concluded that 5 days’ treatment was equivalent to 7- and 10-days of treatment for all ages unless the child had a perforated tympanic membrane or the child had been treated for AOM within the preceding month since recently treated AOM was associated with more frequent causation of AOM by resistant bacteria and with a continued inflamed middle ear mucosa (Otolaryngol Head Neck Surg. 2001 Apr;124[4]:381-7). Since then we have treated all children with ear infections for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins unless the eardrum had perforated or the child had a recurrent AOM within the prior 30 days. That is a lot of patients in 15 years, and the results have been just as good as when we used 10 days as standard.
Acute sinusitis is another interesting story. The AAP guideline states: “The optimal duration of antimicrobial therapy for patients with acute bacterial sinusitis has not received systematic study. Recommendations based on clinical observation varied widely, from 1- to 28 days (Pediatrics. 2013 Jul;132[1]:e262-80). The prior AAP guideline endorsed “antibiotic therapy be continued for 7 days after the patient becomes free of symptoms and signs (Pediatrics. 2001 Sep;108[3]:798-808). Our group reasoned that the etiology and pathogenesis of sinusitis and AOM are identical, involving ascension of a bacterial inoculum from the nasopharynx via the osteomeatal complex to the sinuses just like ascension of infection via the eustachian tube to the middle ear. Therefore, beginning 25 years ago, we began to treat all children with sinus infections for 5 days, including amoxicillin and amoxicillin/clavulanate, as well as various cephalosporins. Again, that is a lot of patients, and the results have been just as good as when we used 10 days as standard.
What about community-acquired pneumonia? The Infectious Disease Society of America (IDSA) guideline states: “Treatment courses of 10 days [of antibiotics] have been best studied, although shorter courses may be just as effective, particularly for mild disease managed on an outpatient basis” (Clin Infect Dis. 2011 Oct;53[7]:617-30). Our group reasoned that antibiotics reach higher levels in the lungs than they do in the closed space of the middle ear or sinuses. Therefore, beginning 25 years ago, we began to treat all children with bronchopneumonia and lobar pneumonia for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins and azithromycin. That is a lot of patients, and the results have been just as good as when we used 10 days as standard.
What about skin and soft tissue infections? The IDSA guideline states that the duration of treatment for impetigo is 7 days, for cellulitis is 5 days, and for furuncles and carbuncles no duration is stated, but they allow no antibiotics be used at all if the patient is not febrile and white blood cell count is not elevated after incision and drainage (Clin Infect Dis. 2014 Jul 15;59[2]:e10-52).
So what is the harm to longer courses of antibiotics? As I have written in this column recently, we have learned a lot about the importance of our gut microbiome. The resident flora of our gut modulates our immune system favorably. Disturbing our gut flora with antibiotics is potentially harmful because the antibiotics often kill many species of healthy gut flora and cause disequilibrium of the flora, resulting in diminished innate immunity responses. Shorter treatment courses with antibiotics cause less disturbance of the healthy gut flora.
The rest of the world cannot all be wrong and the United States all right regarding the duration of antibiotic treatment for common infections. Moreover, in an era of evidence-based medicine, it is necessary to make changes from tradition. The evidence is there to recommend that 5 days’ treatment become the standard for treatment with selected cephalosporins as approved by the FDA – for AOM, for sinusitis, for community-acquired pneumonia, and for skin and soft tissue infections.
Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Research Institute, Rochester (N.Y.) General Hospital. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero said that he had no relevant financial disclosures. Email him at [email protected].
In the United States, we treat almost all infections for 10 days. Why? In France, most infections are treated for 8 days. In the U.K., most infections are treated for 5 days. In many other countries, infections are treated until symptomatic improvement occurs. Can everyone outside the United States be wrong? What is the evidence base for the various recommended durations? Moreover, what is the harm in treating for longer than necessary?
The U.S. tradition of 10 days’ treatment for infections arose from the 1940 trials of injectable penicillin for prevention of acute rheumatic fever in military recruits who had group A streptococcal pharyngitis. Injections of penicillin G mixed in peanut oil produced therapeutic levels of penicillin for about 3 days. Soldiers who received three sequential injections had the lowest occurrence of rheumatic fever; two injections were not as good and four injections did not add to the prevention rate. So three injections meant 9 days’ treatment; 9 days was rounded up to 10 days, and there you have it.
We have come a long way since the 1940s. For strep throat, we now have three approved antibiotics for 5 days’ treatment: cefdinir, cefpodoxime proxetil, and azithromycin, all evidence based and U.S. Food and Drug Administration approved. One large study was done in the 1980s with cefadroxil for 5 days, and that duration was as effective in strep eradication as was 10 days, but the company never pursued the 5-day indication.
The optimal duration of antibiotic treatment is generally considered to be 10 days in the United States, however, there is scant evidence base for that recommendation. The recent American Academy of Pediatrics/American Academy of Family Physicians guidelines endorse 10 days of treatment duration as the standard for most acute otitis media (AOM) (Pediatrics 2013;131[3]:e964-99), but acknowledge that shorter treatment regimens may be as effective. Specifically, the guideline states: “A 7-day course of oral antibiotic appears to be equally effective in children 2- to 5 years of age with mild to moderate AOM. For children 6 years and older with mild to moderate AOM symptoms, a 5- to 7-day course is adequate treatment.” A systematic analysis and a meta-analysis have concluded that 5 days’ duration of antibiotics is as effective as 10 days’ treatment for all children over age 2 years and only marginally inferior to 10 days for children under the age of 2 years old (Cochrane Database Syst Rev. 2010;[9]:CD001095).
Thirty years ago, our group and others began to do studies involving “double tympanocentesis,” where an ear tap was done at time of diagnosis and again 3-5 days later to prove bacterial cure for various antibiotics that were in trials. We learned that if the organism was sensitive to the antibiotic chosen, then it was dead by days 3-5. Most of the failures were due to resistant bacteria. So treating longer was not going to help. It was time to change the antibiotic if clinical improvement had not occurred. Our group published a study 15 years ago of 2,172 children comparing 5-, 7-, and 10-days’ treatment of AOM, and concluded that 5 days’ treatment was equivalent to 7- and 10-days of treatment for all ages unless the child had a perforated tympanic membrane or the child had been treated for AOM within the preceding month since recently treated AOM was associated with more frequent causation of AOM by resistant bacteria and with a continued inflamed middle ear mucosa (Otolaryngol Head Neck Surg. 2001 Apr;124[4]:381-7). Since then we have treated all children with ear infections for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins unless the eardrum had perforated or the child had a recurrent AOM within the prior 30 days. That is a lot of patients in 15 years, and the results have been just as good as when we used 10 days as standard.
Acute sinusitis is another interesting story. The AAP guideline states: “The optimal duration of antimicrobial therapy for patients with acute bacterial sinusitis has not received systematic study. Recommendations based on clinical observation varied widely, from 1- to 28 days (Pediatrics. 2013 Jul;132[1]:e262-80). The prior AAP guideline endorsed “antibiotic therapy be continued for 7 days after the patient becomes free of symptoms and signs (Pediatrics. 2001 Sep;108[3]:798-808). Our group reasoned that the etiology and pathogenesis of sinusitis and AOM are identical, involving ascension of a bacterial inoculum from the nasopharynx via the osteomeatal complex to the sinuses just like ascension of infection via the eustachian tube to the middle ear. Therefore, beginning 25 years ago, we began to treat all children with sinus infections for 5 days, including amoxicillin and amoxicillin/clavulanate, as well as various cephalosporins. Again, that is a lot of patients, and the results have been just as good as when we used 10 days as standard.
What about community-acquired pneumonia? The Infectious Disease Society of America (IDSA) guideline states: “Treatment courses of 10 days [of antibiotics] have been best studied, although shorter courses may be just as effective, particularly for mild disease managed on an outpatient basis” (Clin Infect Dis. 2011 Oct;53[7]:617-30). Our group reasoned that antibiotics reach higher levels in the lungs than they do in the closed space of the middle ear or sinuses. Therefore, beginning 25 years ago, we began to treat all children with bronchopneumonia and lobar pneumonia for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins and azithromycin. That is a lot of patients, and the results have been just as good as when we used 10 days as standard.
What about skin and soft tissue infections? The IDSA guideline states that the duration of treatment for impetigo is 7 days, for cellulitis is 5 days, and for furuncles and carbuncles no duration is stated, but they allow no antibiotics be used at all if the patient is not febrile and white blood cell count is not elevated after incision and drainage (Clin Infect Dis. 2014 Jul 15;59[2]:e10-52).
So what is the harm to longer courses of antibiotics? As I have written in this column recently, we have learned a lot about the importance of our gut microbiome. The resident flora of our gut modulates our immune system favorably. Disturbing our gut flora with antibiotics is potentially harmful because the antibiotics often kill many species of healthy gut flora and cause disequilibrium of the flora, resulting in diminished innate immunity responses. Shorter treatment courses with antibiotics cause less disturbance of the healthy gut flora.
The rest of the world cannot all be wrong and the United States all right regarding the duration of antibiotic treatment for common infections. Moreover, in an era of evidence-based medicine, it is necessary to make changes from tradition. The evidence is there to recommend that 5 days’ treatment become the standard for treatment with selected cephalosporins as approved by the FDA – for AOM, for sinusitis, for community-acquired pneumonia, and for skin and soft tissue infections.
Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Research Institute, Rochester (N.Y.) General Hospital. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero said that he had no relevant financial disclosures. Email him at [email protected].
In the United States, we treat almost all infections for 10 days. Why? In France, most infections are treated for 8 days. In the U.K., most infections are treated for 5 days. In many other countries, infections are treated until symptomatic improvement occurs. Can everyone outside the United States be wrong? What is the evidence base for the various recommended durations? Moreover, what is the harm in treating for longer than necessary?
The U.S. tradition of 10 days’ treatment for infections arose from the 1940 trials of injectable penicillin for prevention of acute rheumatic fever in military recruits who had group A streptococcal pharyngitis. Injections of penicillin G mixed in peanut oil produced therapeutic levels of penicillin for about 3 days. Soldiers who received three sequential injections had the lowest occurrence of rheumatic fever; two injections were not as good and four injections did not add to the prevention rate. So three injections meant 9 days’ treatment; 9 days was rounded up to 10 days, and there you have it.
We have come a long way since the 1940s. For strep throat, we now have three approved antibiotics for 5 days’ treatment: cefdinir, cefpodoxime proxetil, and azithromycin, all evidence based and U.S. Food and Drug Administration approved. One large study was done in the 1980s with cefadroxil for 5 days, and that duration was as effective in strep eradication as was 10 days, but the company never pursued the 5-day indication.
The optimal duration of antibiotic treatment is generally considered to be 10 days in the United States, however, there is scant evidence base for that recommendation. The recent American Academy of Pediatrics/American Academy of Family Physicians guidelines endorse 10 days of treatment duration as the standard for most acute otitis media (AOM) (Pediatrics 2013;131[3]:e964-99), but acknowledge that shorter treatment regimens may be as effective. Specifically, the guideline states: “A 7-day course of oral antibiotic appears to be equally effective in children 2- to 5 years of age with mild to moderate AOM. For children 6 years and older with mild to moderate AOM symptoms, a 5- to 7-day course is adequate treatment.” A systematic analysis and a meta-analysis have concluded that 5 days’ duration of antibiotics is as effective as 10 days’ treatment for all children over age 2 years and only marginally inferior to 10 days for children under the age of 2 years old (Cochrane Database Syst Rev. 2010;[9]:CD001095).
Thirty years ago, our group and others began to do studies involving “double tympanocentesis,” where an ear tap was done at time of diagnosis and again 3-5 days later to prove bacterial cure for various antibiotics that were in trials. We learned that if the organism was sensitive to the antibiotic chosen, then it was dead by days 3-5. Most of the failures were due to resistant bacteria. So treating longer was not going to help. It was time to change the antibiotic if clinical improvement had not occurred. Our group published a study 15 years ago of 2,172 children comparing 5-, 7-, and 10-days’ treatment of AOM, and concluded that 5 days’ treatment was equivalent to 7- and 10-days of treatment for all ages unless the child had a perforated tympanic membrane or the child had been treated for AOM within the preceding month since recently treated AOM was associated with more frequent causation of AOM by resistant bacteria and with a continued inflamed middle ear mucosa (Otolaryngol Head Neck Surg. 2001 Apr;124[4]:381-7). Since then we have treated all children with ear infections for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins unless the eardrum had perforated or the child had a recurrent AOM within the prior 30 days. That is a lot of patients in 15 years, and the results have been just as good as when we used 10 days as standard.
Acute sinusitis is another interesting story. The AAP guideline states: “The optimal duration of antimicrobial therapy for patients with acute bacterial sinusitis has not received systematic study. Recommendations based on clinical observation varied widely, from 1- to 28 days (Pediatrics. 2013 Jul;132[1]:e262-80). The prior AAP guideline endorsed “antibiotic therapy be continued for 7 days after the patient becomes free of symptoms and signs (Pediatrics. 2001 Sep;108[3]:798-808). Our group reasoned that the etiology and pathogenesis of sinusitis and AOM are identical, involving ascension of a bacterial inoculum from the nasopharynx via the osteomeatal complex to the sinuses just like ascension of infection via the eustachian tube to the middle ear. Therefore, beginning 25 years ago, we began to treat all children with sinus infections for 5 days, including amoxicillin and amoxicillin/clavulanate, as well as various cephalosporins. Again, that is a lot of patients, and the results have been just as good as when we used 10 days as standard.
What about community-acquired pneumonia? The Infectious Disease Society of America (IDSA) guideline states: “Treatment courses of 10 days [of antibiotics] have been best studied, although shorter courses may be just as effective, particularly for mild disease managed on an outpatient basis” (Clin Infect Dis. 2011 Oct;53[7]:617-30). Our group reasoned that antibiotics reach higher levels in the lungs than they do in the closed space of the middle ear or sinuses. Therefore, beginning 25 years ago, we began to treat all children with bronchopneumonia and lobar pneumonia for 5 days, including amoxicillin and amoxicillin/clavulanate as well as various cephalosporins and azithromycin. That is a lot of patients, and the results have been just as good as when we used 10 days as standard.
What about skin and soft tissue infections? The IDSA guideline states that the duration of treatment for impetigo is 7 days, for cellulitis is 5 days, and for furuncles and carbuncles no duration is stated, but they allow no antibiotics be used at all if the patient is not febrile and white blood cell count is not elevated after incision and drainage (Clin Infect Dis. 2014 Jul 15;59[2]:e10-52).
So what is the harm to longer courses of antibiotics? As I have written in this column recently, we have learned a lot about the importance of our gut microbiome. The resident flora of our gut modulates our immune system favorably. Disturbing our gut flora with antibiotics is potentially harmful because the antibiotics often kill many species of healthy gut flora and cause disequilibrium of the flora, resulting in diminished innate immunity responses. Shorter treatment courses with antibiotics cause less disturbance of the healthy gut flora.
The rest of the world cannot all be wrong and the United States all right regarding the duration of antibiotic treatment for common infections. Moreover, in an era of evidence-based medicine, it is necessary to make changes from tradition. The evidence is there to recommend that 5 days’ treatment become the standard for treatment with selected cephalosporins as approved by the FDA – for AOM, for sinusitis, for community-acquired pneumonia, and for skin and soft tissue infections.
Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Research Institute, Rochester (N.Y.) General Hospital. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero said that he had no relevant financial disclosures. Email him at [email protected].
