Michael E. Pichichero

As physicians who care for children, it's easy for us to become so focused on vaccinating the children in our practices that we neglect our own immunizations. But it's critically important to get vaccinated, not only for our own sakes but for the sake of our patients.

There have been several additions to the adult immunization schedule in the last few years, so I thought it would be useful to review the ones that pediatricians should consider for themselves, and also consider offering to the parents and other caregivers of our pediatric patients:

▸ Tetanus-diphtheria-acellular pertussis. Most physicians are aware that we're now seeing a resurgence of pertussis around the country. The focus has been on California, but there are other pockets as well that have not received as much attention, including recent outbreaks in Ohio and Michigan. But pertussis is also endemic in the United States, so that although we tend to see peaks every 3 years or so, there is no year when it isn't circulating. Most pediatricians also are aware of and endorse the concept of “cocooning” newborns younger than 6 months of age who have not yet received all three doses of DTaP by vaccinating all the people around the infant, including parents, siblings, grandparents, babysitters, child care providers, and yes, physicians who care for children.

The Tdap vaccine is the adolescent-adult formulation containing the same amount of tetanus and diphtheria as the Td vaccine but with lower amounts of pertussis antigen than the pediatric DTaP. The Centers for Disease Control and Prevention recommends Tdap for adults of any age who have not previously received it (including those aged 65 and older) who are in contact with infants younger than age 12 months, and for health care personnel of all ages, including doctors. Last fall, the CDC removed the 2-year interval requirement, so that now Tdap can be given regardless of the interval since the previous Td. After an adult receives one dose of Tdap, a booster of Td should be given every 10 years thereafter.

I recently asked 10 pediatricians if they had received the Tdap, and 8 said no. They ranged in age from those just out of residency to 68 years. Reasons included simply not getting around to it, thinking they didn't need it, or believing that they were already protected from the DTaP they received in childhood. In fact, immunity against pertussis wanes, and DTwP (whole-cell pertussis) and DTaP vaccines don't last forever, which is part of the reason we're seeing these outbreaks.

▸ Influenza. I meet physicians all the time who tell me they haven't received a flu shot. Older physicians sometimes will cite the fear of Guillain-Barré syndrome that initially arose with the 1976 swine flu vaccine debacle. That fear never really went away, and was reignited with the 2009 vaccine that was rapidly manufactured against pandemic H1N1. Many people, including some physicians, fear that the vaccine was not tested sufficiently before it was brought to market during the pandemic. Of course, most of these same physicians do immunize their patients with the vaccine.

The other reason I hear from physicians for not getting the flu vaccine is the mistaken belief that their immune system is strong enough to resist influenza. Although it may be true that as a group, physicians who see sick people all day long are more resistant to viral infections than is the general population, some still may be susceptible. And those who do contract influenza will be contagious for a few days before symptoms appear, even with the use of antivirals.

▸ Pneumococcus. Currently, the only pneumococcal vaccine recommended for adults is the 23-valent polysaccharide vaccine (Pneumovax). It is recommended for everyone aged 65 and older, and for people younger than 65 years who have chronic illness or other risk factors, including chronic cardiac or pulmonary disease (including asthma), chronic liver disease, alcoholism, diabetes, cerebrospinal fluid leaks, and cigarette smoking, as well as candidates for or recipients of cochlear implants and people living in special environments or social settings (including American Indian/Alaska Natives aged 50–64 years if vaccination is recommended by local public health authorities). Certainly, physicians can fall into most of these groups (although we hope not the smoking category).

But stay tuned for the 13-valent conjugate pneumococcal vaccine to be licensed and recommended for adults aged 50 and older. In December 2010, Pfizer announced that it submitted supplemental applications to both the U.S. Food and Drug Administration and the European Medicines Agency (EMA) to expand the use of Prevnar 13 to adults aged 50 years and older for the prevention of pneumococcal disease caused by the 13 serotypes contained in the vaccine. The FDA is expected to respond in October 2011.

Routine use of the 7-valent pneumococcal conjugate vaccine in infants beginning 11 years ago prevented an estimated 211,000 serious pneumococcal infections and 13,000 deaths during 2000–2008, including those among both children and adults. The switch to PCV13 in 2010 is expected to further reduce disease by covering those extra six strains, particularly 19A. The vaccination of adults aged 50 and older will expand that protection. Once PCV13 is approved for adults aged 50 and older, physicians in that age range should get the vaccine.

▸ Human Papillomavirus. Recommended for all previously unvaccinated women through age 26 years, Gardasil or Cervarix should be considered by all young female physicians. Moreover, although not a strict recommendation, Gardasil (but not Cervarix) is also suggested for men through age 26 years in order to reduce the likelihood of acquiring genital warts. The risk is particularly increased among men who have sex with men. There are physicians who fall into the above categories.

▸ Zoster. The zoster vaccine (Zostavax) is recommended for the prevention of shingles in all adults aged 60 years and older, including physicians.

Physician, vaccinate thyself.

As physicians who care for children, it's easy for us to become so focused on vaccinating the children in our practices that we neglect our own immunizations. But it's critically important to get vaccinated, not only for our own sakes but for the sake of our patients.

There have been several additions to the adult immunization schedule in the last few years, so I thought it would be useful to review the ones that pediatricians should consider for themselves, and also consider offering to the parents and other caregivers of our pediatric patients:

▸ Tetanus-diphtheria-acellular pertussis. Most physicians are aware that we're now seeing a resurgence of pertussis around the country. The focus has been on California, but there are other pockets as well that have not received as much attention, including recent outbreaks in Ohio and Michigan. But pertussis is also endemic in the United States, so that although we tend to see peaks every 3 years or so, there is no year when it isn't circulating. Most pediatricians also are aware of and endorse the concept of “cocooning” newborns younger than 6 months of age who have not yet received all three doses of DTaP by vaccinating all the people around the infant, including parents, siblings, grandparents, babysitters, child care providers, and yes, physicians who care for children.

The Tdap vaccine is the adolescent-adult formulation containing the same amount of tetanus and diphtheria as the Td vaccine but with lower amounts of pertussis antigen than the pediatric DTaP. The Centers for Disease Control and Prevention recommends Tdap for adults of any age who have not previously received it (including those aged 65 and older) who are in contact with infants younger than age 12 months, and for health care personnel of all ages, including doctors. Last fall, the CDC removed the 2-year interval requirement, so that now Tdap can be given regardless of the interval since the previous Td. After an adult receives one dose of Tdap, a booster of Td should be given every 10 years thereafter.

I recently asked 10 pediatricians if they had received the Tdap, and 8 said no. They ranged in age from those just out of residency to 68 years. Reasons included simply not getting around to it, thinking they didn't need it, or believing that they were already protected from the DTaP they received in childhood. In fact, immunity against pertussis wanes, and DTwP (whole-cell pertussis) and DTaP vaccines don't last forever, which is part of the reason we're seeing these outbreaks.

▸ Influenza. I meet physicians all the time who tell me they haven't received a flu shot. Older physicians sometimes will cite the fear of Guillain-Barré syndrome that initially arose with the 1976 swine flu vaccine debacle. That fear never really went away, and was reignited with the 2009 vaccine that was rapidly manufactured against pandemic H1N1. Many people, including some physicians, fear that the vaccine was not tested sufficiently before it was brought to market during the pandemic. Of course, most of these same physicians do immunize their patients with the vaccine.

The other reason I hear from physicians for not getting the flu vaccine is the mistaken belief that their immune system is strong enough to resist influenza. Although it may be true that as a group, physicians who see sick people all day long are more resistant to viral infections than is the general population, some still may be susceptible. And those who do contract influenza will be contagious for a few days before symptoms appear, even with the use of antivirals.

▸ Pneumococcus. Currently, the only pneumococcal vaccine recommended for adults is the 23-valent polysaccharide vaccine (Pneumovax). It is recommended for everyone aged 65 and older, and for people younger than 65 years who have chronic illness or other risk factors, including chronic cardiac or pulmonary disease (including asthma), chronic liver disease, alcoholism, diabetes, cerebrospinal fluid leaks, and cigarette smoking, as well as candidates for or recipients of cochlear implants and people living in special environments or social settings (including American Indian/Alaska Natives aged 50–64 years if vaccination is recommended by local public health authorities). Certainly, physicians can fall into most of these groups (although we hope not the smoking category).

But stay tuned for the 13-valent conjugate pneumococcal vaccine to be licensed and recommended for adults aged 50 and older. In December 2010, Pfizer announced that it submitted supplemental applications to both the U.S. Food and Drug Administration and the European Medicines Agency (EMA) to expand the use of Prevnar 13 to adults aged 50 years and older for the prevention of pneumococcal disease caused by the 13 serotypes contained in the vaccine. The FDA is expected to respond in October 2011.

Routine use of the 7-valent pneumococcal conjugate vaccine in infants beginning 11 years ago prevented an estimated 211,000 serious pneumococcal infections and 13,000 deaths during 2000–2008, including those among both children and adults. The switch to PCV13 in 2010 is expected to further reduce disease by covering those extra six strains, particularly 19A. The vaccination of adults aged 50 and older will expand that protection. Once PCV13 is approved for adults aged 50 and older, physicians in that age range should get the vaccine.

▸ Human Papillomavirus. Recommended for all previously unvaccinated women through age 26 years, Gardasil or Cervarix should be considered by all young female physicians. Moreover, although not a strict recommendation, Gardasil (but not Cervarix) is also suggested for men through age 26 years in order to reduce the likelihood of acquiring genital warts. The risk is particularly increased among men who have sex with men. There are physicians who fall into the above categories.

▸ Zoster. The zoster vaccine (Zostavax) is recommended for the prevention of shingles in all adults aged 60 years and older, including physicians.

Physician, vaccinate thyself.

As physicians who care for children, it's easy for us to become so focused on vaccinating the children in our practices that we neglect our own immunizations. But it's critically important to get vaccinated, not only for our own sakes but for the sake of our patients.

There have been several additions to the adult immunization schedule in the last few years, so I thought it would be useful to review the ones that pediatricians should consider for themselves, and also consider offering to the parents and other caregivers of our pediatric patients:

▸ Tetanus-diphtheria-acellular pertussis. Most physicians are aware that we're now seeing a resurgence of pertussis around the country. The focus has been on California, but there are other pockets as well that have not received as much attention, including recent outbreaks in Ohio and Michigan. But pertussis is also endemic in the United States, so that although we tend to see peaks every 3 years or so, there is no year when it isn't circulating. Most pediatricians also are aware of and endorse the concept of “cocooning” newborns younger than 6 months of age who have not yet received all three doses of DTaP by vaccinating all the people around the infant, including parents, siblings, grandparents, babysitters, child care providers, and yes, physicians who care for children.

The Tdap vaccine is the adolescent-adult formulation containing the same amount of tetanus and diphtheria as the Td vaccine but with lower amounts of pertussis antigen than the pediatric DTaP. The Centers for Disease Control and Prevention recommends Tdap for adults of any age who have not previously received it (including those aged 65 and older) who are in contact with infants younger than age 12 months, and for health care personnel of all ages, including doctors. Last fall, the CDC removed the 2-year interval requirement, so that now Tdap can be given regardless of the interval since the previous Td. After an adult receives one dose of Tdap, a booster of Td should be given every 10 years thereafter.

I recently asked 10 pediatricians if they had received the Tdap, and 8 said no. They ranged in age from those just out of residency to 68 years. Reasons included simply not getting around to it, thinking they didn't need it, or believing that they were already protected from the DTaP they received in childhood. In fact, immunity against pertussis wanes, and DTwP (whole-cell pertussis) and DTaP vaccines don't last forever, which is part of the reason we're seeing these outbreaks.

▸ Influenza. I meet physicians all the time who tell me they haven't received a flu shot. Older physicians sometimes will cite the fear of Guillain-Barré syndrome that initially arose with the 1976 swine flu vaccine debacle. That fear never really went away, and was reignited with the 2009 vaccine that was rapidly manufactured against pandemic H1N1. Many people, including some physicians, fear that the vaccine was not tested sufficiently before it was brought to market during the pandemic. Of course, most of these same physicians do immunize their patients with the vaccine.

The other reason I hear from physicians for not getting the flu vaccine is the mistaken belief that their immune system is strong enough to resist influenza. Although it may be true that as a group, physicians who see sick people all day long are more resistant to viral infections than is the general population, some still may be susceptible. And those who do contract influenza will be contagious for a few days before symptoms appear, even with the use of antivirals.

▸ Pneumococcus. Currently, the only pneumococcal vaccine recommended for adults is the 23-valent polysaccharide vaccine (Pneumovax). It is recommended for everyone aged 65 and older, and for people younger than 65 years who have chronic illness or other risk factors, including chronic cardiac or pulmonary disease (including asthma), chronic liver disease, alcoholism, diabetes, cerebrospinal fluid leaks, and cigarette smoking, as well as candidates for or recipients of cochlear implants and people living in special environments or social settings (including American Indian/Alaska Natives aged 50–64 years if vaccination is recommended by local public health authorities). Certainly, physicians can fall into most of these groups (although we hope not the smoking category).

But stay tuned for the 13-valent conjugate pneumococcal vaccine to be licensed and recommended for adults aged 50 and older. In December 2010, Pfizer announced that it submitted supplemental applications to both the U.S. Food and Drug Administration and the European Medicines Agency (EMA) to expand the use of Prevnar 13 to adults aged 50 years and older for the prevention of pneumococcal disease caused by the 13 serotypes contained in the vaccine. The FDA is expected to respond in October 2011.

Routine use of the 7-valent pneumococcal conjugate vaccine in infants beginning 11 years ago prevented an estimated 211,000 serious pneumococcal infections and 13,000 deaths during 2000–2008, including those among both children and adults. The switch to PCV13 in 2010 is expected to further reduce disease by covering those extra six strains, particularly 19A. The vaccination of adults aged 50 and older will expand that protection. Once PCV13 is approved for adults aged 50 and older, physicians in that age range should get the vaccine.

▸ Human Papillomavirus. Recommended for all previously unvaccinated women through age 26 years, Gardasil or Cervarix should be considered by all young female physicians. Moreover, although not a strict recommendation, Gardasil (but not Cervarix) is also suggested for men through age 26 years in order to reduce the likelihood of acquiring genital warts. The risk is particularly increased among men who have sex with men. There are physicians who fall into the above categories.

▸ Zoster. The zoster vaccine (Zostavax) is recommended for the prevention of shingles in all adults aged 60 years and older, including physicians.

Physician, vaccinate thyself.

[email protected]

Two new, well-designed trials published in the New England Journal of Medicine have demonstrated that when acute otitis media is correctly diagnosed, treatment with effective antibiotics is of clear and substantial benefit. To me, this suggests that the confusion about whether antibiotics help children get better faster is about getting the diagnosis right, a challenging task for pediatricians and family physicians with squirming patients and ear canal wax occluding visualization of the eardrum.

All along, I have believed that the American Academy of Pediatrics' 2004 “watchful waiting” option for treating acute otitis media (AOM) was well intentioned but not based on good evidence. In an effort to address the growing problem of antimicrobial resistance, the AAP recommended the “observation option” for otherwise healthy children aged 6 months to 2 years with nonsevere illness and an uncertain diagnosis, and for all children above the age of 2 years who were not systemically ill (Pediatrics 2004;113:1451–65).

Problem is, the studies cited by the AAP as evidence for this recommendation were nearly all seriously flawed, because they excluded children with the very criteria that signal a true AOM diagnosis: a full or bulging eardrum … and in some studies, because it was determined that they were too “unwell” and/or they “needed an antibiotic”! And, many of these trials excluded children younger than 2 years old and included many children who likely did not have AOM at all or had otitis media with effusion.

Dr. Janet R. Casey and I reviewed 25 of the studies in a paper published 3 years ago (Pediatr. Infect. Dis. J. 2008;27:958–62).hWe found so many serious flaws in the inclusion and exclusion criteria, and diagnostic and outcome criteria, that we were obliged to conclude that no evidence-based conclusion could be drawn.

The flaws we found in individual AOM trials call into question the validity of the conclusions of two major meta-analyses cited by the AAP, one involving 5,400 children from 33 randomized trials (J. Pediatr. 1994;124:355–67), the other of 6 studies of children aged 7 months to 15 years (BMJ 1997;314:1526–9), both of which found only modest benefit for the use of antimicrobials.

Now in the New England Journal of Medicine papers, we have two well-designed studies clearly demonstrating that treatment should not be withheld in children with proven AOM.

One of the studies, from the University of Pittsburgh, randomized 291 children aged 6–23 months to receive amoxicillin-clavulanate or placebo for 10 days. To be eligible, patients had to have AOM that was diagnosed on the basis of three criteria:

▸ onset of symptoms within 48 hours that parents rated with a score of at least 3 on the Acute Otitis Media Severity of Symptoms scale,

▸ presence of middle-ear effusion, and

▸ moderate or marked bulging of the tympanic membrane or slight bulging accompanied by either otalgia or marked erythema of the membrane.

Patients also had to have received at least two doses of pneumococcal conjugate vaccine.

Among the children who received amoxicillin-clavulanate, 35% had initial resolution of symptoms by day 2, 61% by day 4, and 80% by day 7, compared with 28%, 54%, and 74% among those who received placebo, respectively. For sustained resolution of symptoms, the corresponding values were 20%, 41%, and 67% with amoxicillin-clavulanate, vs. 14%, 36%, and 53% with placebo (N. Engl. J. Med. 2011;364:105–15).

The other trial, from Finland, used equally strict criteria for 319 children aged 6–35 months who were randomized to receive amoxicillin-clavulanate or placebo for 7 days. Treatment failure occurred in 18.6% of the children who received amoxicillin-clavulanate, compared with 44.9% of the children who received placebo, a highly statistically significant difference that was already apparent at the first scheduled visit on day 3 (13.7% vs. 25.3%). Overall, amoxicillin-clavulanate reduced the progression to treatment failure by 62% (N. Engl. J. Med. 2011;364:116–26).

As I see it, the problem really lies in our inability to adequately diagnose AOM. For one thing, it's essential to clean the wax out of the child's ear in order to visualize the eardrum, given that two-thirds of children diagnosed with AOM have partially or fully occluded ear canals blocking visualization of the eardrum. Yet, physicians often don't do that because it takes time and it's difficult to get the child to hold still. It's far simpler to simply take a quick look and say that the diagnosis is “uncertain,” or to say that the eardrum is “red” in order to justify a diagnosis and antibiotic prescription.

Pediatricians and family physicians should all have a good, high-grade otoscope with a fresh battery and bulb, along with the training and ability to use the pneumatic attachment in order to distinguish between a bulging and retracted eardrum, which often look alike with just the otoscope.

Frankly, I find it embarrassing that with a condition as common as AOM, pediatricians and family physicians receive so little training in diagnosing it and, therefore, just don't do a good job. In otitis media workshops that include testing for competency in diagnosis (Outcomes Management Educational Workshops, West Palm Beach, Fla.), I found that physicians got the diagnosis of AOM wrong at least 50% of the time on video presentation testing. And that was without wax, under ideal classroom conditions.

Diagnosing otitis media needs to become a critical part of medical education, and physicians in practice should be retrained via CME courses. Pharmaceutical companies no longer sponsor those, so now the professional societies such as the American Academy of Pediatrics, the American Academy of Family Physicians, and the nursing organizations need to step up.

With the new evidence from the two well-controlled trials, I don't see how any clinician can withhold antibiotic treatment in good conscience. AOM is a painful condition that infants and toddlers are too young to explain to us. Can you imagine asking an adult to agree to withholding effective treatment when they are in pain and propose they take acetaminophen instead? Or can you imagine telling an adult who seeks care for an earache that the diagnosis is uncertain after examination, so the recommendation is to “observe”?

As advocates for our pediatric patients, how in the world can we allow a child to remain in severe pain for 24–48 hours longer than is necessary and keep parents up all night and away from work for 2–3 extra days?

Once everyone learns how to better diagnose AOM, we will stop overprescribing antibiotics for those children who don't have the condition. For the rest, I contend that treatment is a moral imperative.

[email protected]

Two new, well-designed trials published in the New England Journal of Medicine have demonstrated that when acute otitis media is correctly diagnosed, treatment with effective antibiotics is of clear and substantial benefit. To me, this suggests that the confusion about whether antibiotics help children get better faster is about getting the diagnosis right, a challenging task for pediatricians and family physicians with squirming patients and ear canal wax occluding visualization of the eardrum.

All along, I have believed that the American Academy of Pediatrics' 2004 “watchful waiting” option for treating acute otitis media (AOM) was well intentioned but not based on good evidence. In an effort to address the growing problem of antimicrobial resistance, the AAP recommended the “observation option” for otherwise healthy children aged 6 months to 2 years with nonsevere illness and an uncertain diagnosis, and for all children above the age of 2 years who were not systemically ill (Pediatrics 2004;113:1451–65).

Problem is, the studies cited by the AAP as evidence for this recommendation were nearly all seriously flawed, because they excluded children with the very criteria that signal a true AOM diagnosis: a full or bulging eardrum … and in some studies, because it was determined that they were too “unwell” and/or they “needed an antibiotic”! And, many of these trials excluded children younger than 2 years old and included many children who likely did not have AOM at all or had otitis media with effusion.

Dr. Janet R. Casey and I reviewed 25 of the studies in a paper published 3 years ago (Pediatr. Infect. Dis. J. 2008;27:958–62).hWe found so many serious flaws in the inclusion and exclusion criteria, and diagnostic and outcome criteria, that we were obliged to conclude that no evidence-based conclusion could be drawn.

The flaws we found in individual AOM trials call into question the validity of the conclusions of two major meta-analyses cited by the AAP, one involving 5,400 children from 33 randomized trials (J. Pediatr. 1994;124:355–67), the other of 6 studies of children aged 7 months to 15 years (BMJ 1997;314:1526–9), both of which found only modest benefit for the use of antimicrobials.

Now in the New England Journal of Medicine papers, we have two well-designed studies clearly demonstrating that treatment should not be withheld in children with proven AOM.

One of the studies, from the University of Pittsburgh, randomized 291 children aged 6–23 months to receive amoxicillin-clavulanate or placebo for 10 days. To be eligible, patients had to have AOM that was diagnosed on the basis of three criteria:

▸ onset of symptoms within 48 hours that parents rated with a score of at least 3 on the Acute Otitis Media Severity of Symptoms scale,

▸ presence of middle-ear effusion, and

▸ moderate or marked bulging of the tympanic membrane or slight bulging accompanied by either otalgia or marked erythema of the membrane.

Patients also had to have received at least two doses of pneumococcal conjugate vaccine.

Among the children who received amoxicillin-clavulanate, 35% had initial resolution of symptoms by day 2, 61% by day 4, and 80% by day 7, compared with 28%, 54%, and 74% among those who received placebo, respectively. For sustained resolution of symptoms, the corresponding values were 20%, 41%, and 67% with amoxicillin-clavulanate, vs. 14%, 36%, and 53% with placebo (N. Engl. J. Med. 2011;364:105–15).

The other trial, from Finland, used equally strict criteria for 319 children aged 6–35 months who were randomized to receive amoxicillin-clavulanate or placebo for 7 days. Treatment failure occurred in 18.6% of the children who received amoxicillin-clavulanate, compared with 44.9% of the children who received placebo, a highly statistically significant difference that was already apparent at the first scheduled visit on day 3 (13.7% vs. 25.3%). Overall, amoxicillin-clavulanate reduced the progression to treatment failure by 62% (N. Engl. J. Med. 2011;364:116–26).

As I see it, the problem really lies in our inability to adequately diagnose AOM. For one thing, it's essential to clean the wax out of the child's ear in order to visualize the eardrum, given that two-thirds of children diagnosed with AOM have partially or fully occluded ear canals blocking visualization of the eardrum. Yet, physicians often don't do that because it takes time and it's difficult to get the child to hold still. It's far simpler to simply take a quick look and say that the diagnosis is “uncertain,” or to say that the eardrum is “red” in order to justify a diagnosis and antibiotic prescription.

Pediatricians and family physicians should all have a good, high-grade otoscope with a fresh battery and bulb, along with the training and ability to use the pneumatic attachment in order to distinguish between a bulging and retracted eardrum, which often look alike with just the otoscope.

Frankly, I find it embarrassing that with a condition as common as AOM, pediatricians and family physicians receive so little training in diagnosing it and, therefore, just don't do a good job. In otitis media workshops that include testing for competency in diagnosis (Outcomes Management Educational Workshops, West Palm Beach, Fla.), I found that physicians got the diagnosis of AOM wrong at least 50% of the time on video presentation testing. And that was without wax, under ideal classroom conditions.

Diagnosing otitis media needs to become a critical part of medical education, and physicians in practice should be retrained via CME courses. Pharmaceutical companies no longer sponsor those, so now the professional societies such as the American Academy of Pediatrics, the American Academy of Family Physicians, and the nursing organizations need to step up.

With the new evidence from the two well-controlled trials, I don't see how any clinician can withhold antibiotic treatment in good conscience. AOM is a painful condition that infants and toddlers are too young to explain to us. Can you imagine asking an adult to agree to withholding effective treatment when they are in pain and propose they take acetaminophen instead? Or can you imagine telling an adult who seeks care for an earache that the diagnosis is uncertain after examination, so the recommendation is to “observe”?

As advocates for our pediatric patients, how in the world can we allow a child to remain in severe pain for 24–48 hours longer than is necessary and keep parents up all night and away from work for 2–3 extra days?

Once everyone learns how to better diagnose AOM, we will stop overprescribing antibiotics for those children who don't have the condition. For the rest, I contend that treatment is a moral imperative.

[email protected]

Two new, well-designed trials published in the New England Journal of Medicine have demonstrated that when acute otitis media is correctly diagnosed, treatment with effective antibiotics is of clear and substantial benefit. To me, this suggests that the confusion about whether antibiotics help children get better faster is about getting the diagnosis right, a challenging task for pediatricians and family physicians with squirming patients and ear canal wax occluding visualization of the eardrum.

All along, I have believed that the American Academy of Pediatrics' 2004 “watchful waiting” option for treating acute otitis media (AOM) was well intentioned but not based on good evidence. In an effort to address the growing problem of antimicrobial resistance, the AAP recommended the “observation option” for otherwise healthy children aged 6 months to 2 years with nonsevere illness and an uncertain diagnosis, and for all children above the age of 2 years who were not systemically ill (Pediatrics 2004;113:1451–65).

Problem is, the studies cited by the AAP as evidence for this recommendation were nearly all seriously flawed, because they excluded children with the very criteria that signal a true AOM diagnosis: a full or bulging eardrum … and in some studies, because it was determined that they were too “unwell” and/or they “needed an antibiotic”! And, many of these trials excluded children younger than 2 years old and included many children who likely did not have AOM at all or had otitis media with effusion.

Dr. Janet R. Casey and I reviewed 25 of the studies in a paper published 3 years ago (Pediatr. Infect. Dis. J. 2008;27:958–62).hWe found so many serious flaws in the inclusion and exclusion criteria, and diagnostic and outcome criteria, that we were obliged to conclude that no evidence-based conclusion could be drawn.

The flaws we found in individual AOM trials call into question the validity of the conclusions of two major meta-analyses cited by the AAP, one involving 5,400 children from 33 randomized trials (J. Pediatr. 1994;124:355–67), the other of 6 studies of children aged 7 months to 15 years (BMJ 1997;314:1526–9), both of which found only modest benefit for the use of antimicrobials.

Now in the New England Journal of Medicine papers, we have two well-designed studies clearly demonstrating that treatment should not be withheld in children with proven AOM.

One of the studies, from the University of Pittsburgh, randomized 291 children aged 6–23 months to receive amoxicillin-clavulanate or placebo for 10 days. To be eligible, patients had to have AOM that was diagnosed on the basis of three criteria:

▸ onset of symptoms within 48 hours that parents rated with a score of at least 3 on the Acute Otitis Media Severity of Symptoms scale,

▸ presence of middle-ear effusion, and

▸ moderate or marked bulging of the tympanic membrane or slight bulging accompanied by either otalgia or marked erythema of the membrane.

Patients also had to have received at least two doses of pneumococcal conjugate vaccine.

Among the children who received amoxicillin-clavulanate, 35% had initial resolution of symptoms by day 2, 61% by day 4, and 80% by day 7, compared with 28%, 54%, and 74% among those who received placebo, respectively. For sustained resolution of symptoms, the corresponding values were 20%, 41%, and 67% with amoxicillin-clavulanate, vs. 14%, 36%, and 53% with placebo (N. Engl. J. Med. 2011;364:105–15).

The other trial, from Finland, used equally strict criteria for 319 children aged 6–35 months who were randomized to receive amoxicillin-clavulanate or placebo for 7 days. Treatment failure occurred in 18.6% of the children who received amoxicillin-clavulanate, compared with 44.9% of the children who received placebo, a highly statistically significant difference that was already apparent at the first scheduled visit on day 3 (13.7% vs. 25.3%). Overall, amoxicillin-clavulanate reduced the progression to treatment failure by 62% (N. Engl. J. Med. 2011;364:116–26).

As I see it, the problem really lies in our inability to adequately diagnose AOM. For one thing, it's essential to clean the wax out of the child's ear in order to visualize the eardrum, given that two-thirds of children diagnosed with AOM have partially or fully occluded ear canals blocking visualization of the eardrum. Yet, physicians often don't do that because it takes time and it's difficult to get the child to hold still. It's far simpler to simply take a quick look and say that the diagnosis is “uncertain,” or to say that the eardrum is “red” in order to justify a diagnosis and antibiotic prescription.

Pediatricians and family physicians should all have a good, high-grade otoscope with a fresh battery and bulb, along with the training and ability to use the pneumatic attachment in order to distinguish between a bulging and retracted eardrum, which often look alike with just the otoscope.

Frankly, I find it embarrassing that with a condition as common as AOM, pediatricians and family physicians receive so little training in diagnosing it and, therefore, just don't do a good job. In otitis media workshops that include testing for competency in diagnosis (Outcomes Management Educational Workshops, West Palm Beach, Fla.), I found that physicians got the diagnosis of AOM wrong at least 50% of the time on video presentation testing. And that was without wax, under ideal classroom conditions.

Diagnosing otitis media needs to become a critical part of medical education, and physicians in practice should be retrained via CME courses. Pharmaceutical companies no longer sponsor those, so now the professional societies such as the American Academy of Pediatrics, the American Academy of Family Physicians, and the nursing organizations need to step up.

With the new evidence from the two well-controlled trials, I don't see how any clinician can withhold antibiotic treatment in good conscience. AOM is a painful condition that infants and toddlers are too young to explain to us. Can you imagine asking an adult to agree to withholding effective treatment when they are in pain and propose they take acetaminophen instead? Or can you imagine telling an adult who seeks care for an earache that the diagnosis is uncertain after examination, so the recommendation is to “observe”?

As advocates for our pediatric patients, how in the world can we allow a child to remain in severe pain for 24–48 hours longer than is necessary and keep parents up all night and away from work for 2–3 extra days?

Once everyone learns how to better diagnose AOM, we will stop overprescribing antibiotics for those children who don't have the condition. For the rest, I contend that treatment is a moral imperative.

[email protected]

The treatment of bacterial conjunctivitis has become more challenging in this era of increasing antimicrobial resistance.

Conjunctivitis in children is extremely common, accounting for an estimated 1%–4% of all pediatric office visits. Yet, with so much focus on otitis media, the impact of antimicrobial resistance on conjunctivitis treatment has been widely overlooked. This is despite that approximately one-third of children with bacterial conjunctivitis have concurrent otitis media, most commonly caused by Haemophilus influenzae. In fact, my interest in conjunctivitis stems from its connection with otitis media.

Many of the traditional topical ocular agents we've used in the past to treat bacterial conjunctivitis—including those of the aminoglycoside, polymixin B combination, and macrolide classes—are less effective than they once were, thanks to increasing resistance. At the same time, many of these agents have tolerability issues, which render them even less effective. After all, if a child won't allow the medicine to be placed in her eyes, it most certainly won't work.

Fluoroquinolones, while remaining highly effective with far less resistance, are about 10 times as expensive as older agents available generically. Is it worth the cost to speed up the cure and reduce the contagion of a self-limited disease by a day or two at the most? The answer to that depends on a variety of factors, including the degree of the child's discomfort, the potential burden to the parent of missing days from work, and whether the child attends day care. It's not a simple decision.

Of course, it's important to determine whether the conjunctivitis is bacterial. Acute bacterial conjunctivitis begins abruptly with early symptoms of irritation or foreign body sensation and tearing. Mucopurulent or purulent discharge, morning crusting, swelling, and comorbid otitis media are common indicators. In contrast, viral conjunctivitis is characterized by watery discharge and conjunctival injection, while allergic conjunctivitis is more likely to involve itching, stringy or ropy discharge, lid edema, red/hyperemic conjunctiva, and comorbid allergic rhinitis.

The age of the child is also predictive. Conjunctivitis in preschool children is most likely bacterial, usually either H. influenzae or Streptococcus pneumoniae. In a newborn, the cause is most likely chemical irritation (from silver nitrate), while in older children the conjunctivitis is usually viral or allergic.

Oral antibiotics are recommended for any child who has concurrent otitis media. But for uncomplicated bacterial conjunctivitis, topical ophthalmic agents are recommended over systemic agents because they achieve a greater concentration of antibiotic to the eye while avoiding systemic side effects. Most of the topicals discussed below are approved for children 1 year of age and older.

Aminoglycosides, including gentamicin, tobramycin, and neomycin, are most active against gram-negative bacteria such as Pseudomonas aeruginosa (except neomycin) and methicillin-sensitive Staphylococcus aureus (MSSA). However, they do not cover streptococci or methicillin-resistant Staph. aureus (MRSA), and studies have shown increasing resistance of Streptococcus pneumoniae to these agents, reaching 65% by 2006 in the Ocular TRUST (Tracking Resistance in U.S. Today) 1 survey (Am. J. Ophthalmol. 2008;145:951–8).

Polymixin B is active only against gram-negative bacteria and therefore is given in combination with other antibiotics, including trimethoprim, bacitracin, and neomycin/bacitracin, which broaden the coverage to include staphylococci, streptococci, and some gram-negative bacteria including H. influenzae. While most H. influenzae strains remain susceptible to polymixin B alone or in combination, there is high resistance among Strep. pneumoniae and MSSA isolates.

The macrolide erythromycin—used as a 0.5% ointment—is one of the oldest ocular antibiotics, but now is rarely effective in bacterial conjunctivitis because of the high resistance among Staphylococcus species and poor activity against H. influenzae. The newer topical macrolide azithromycin is also hampered by high levels of resistance. In the TRUST survey, resistance to azithromycin was 22% for Strep. pneumoniae isolates, 46% among MSSA bacteria, and 91% among MRSA isolates. Other studies have shown significant resistance among H. influenzae as well.

Fluoroquinolones offer broad-spectrum coverage against both gram-positive and gram-negative organisms. The older topical agents ofloxacin and ciprofloxacin have largely been replaced by the newer agents levofloxacin, moxifloxacin, gatifloxacin, and now besifloxacin, which was approved by the U.S. Food and Drug Administration in May 2009. Numerous randomized, double-masked, controlled clinical trials in children and adults with bacterial conjunctivitis have demonstrated clinical cure rates of approximately 66%–96% and microbial eradication rates ranging from 84% to 96% for the newer fluoroquinolones.

There has been almost no resistance to fluoroquinolones among Strep. pneumoniae or H. influenzae organisms, but there is some fluoroquinolone resistance among MSSA isolates and a high level for MRSA, reaching 85% in Ocular TRUST 1.

Although most topical ophthalmic antibiotics used for the treatment of bacterial conjunctivitis are generally safe and well tolerated, ocular adverse events can cause discomfort that leads to noncompliance. Topical aminoglycosides have been associated with corneal and conjunctival toxicity, especially when used frequently, as well as ocular allergic reactions. Bacitracin has been associated with cases of contact dermatitis in the conjunctival area, and the polymixin B combinations can also cause local irritation. Macrolides, too, can cause minor ocular irritation, redness, and hypersensitivity.

In contrast, the fluoroquinolones have been well tolerated and associated with less toxicity than the other ophthalmic antibacterial classes, although crystalline precipitates have been seen with ciprofloxacin when it is administered frequently.

The ideal treatment for acute bacterial conjunctivitis should be a well-tolerated, broad-spectrum, highly potent, and bactericidal agent with a high concentration on the ocular surface and a rapid kill time. Convenience in dosing is also an important consideration. The newer fluoroquinolones, with potent efficacy against H. influenzae and Strep. pneumoniae, may best fulfill those requirements. But of course, cost remains a problem for many.

[email protected]

The treatment of bacterial conjunctivitis has become more challenging in this era of increasing antimicrobial resistance.

Conjunctivitis in children is extremely common, accounting for an estimated 1%–4% of all pediatric office visits. Yet, with so much focus on otitis media, the impact of antimicrobial resistance on conjunctivitis treatment has been widely overlooked. This is despite that approximately one-third of children with bacterial conjunctivitis have concurrent otitis media, most commonly caused by Haemophilus influenzae. In fact, my interest in conjunctivitis stems from its connection with otitis media.

Many of the traditional topical ocular agents we've used in the past to treat bacterial conjunctivitis—including those of the aminoglycoside, polymixin B combination, and macrolide classes—are less effective than they once were, thanks to increasing resistance. At the same time, many of these agents have tolerability issues, which render them even less effective. After all, if a child won't allow the medicine to be placed in her eyes, it most certainly won't work.

Fluoroquinolones, while remaining highly effective with far less resistance, are about 10 times as expensive as older agents available generically. Is it worth the cost to speed up the cure and reduce the contagion of a self-limited disease by a day or two at the most? The answer to that depends on a variety of factors, including the degree of the child's discomfort, the potential burden to the parent of missing days from work, and whether the child attends day care. It's not a simple decision.

Of course, it's important to determine whether the conjunctivitis is bacterial. Acute bacterial conjunctivitis begins abruptly with early symptoms of irritation or foreign body sensation and tearing. Mucopurulent or purulent discharge, morning crusting, swelling, and comorbid otitis media are common indicators. In contrast, viral conjunctivitis is characterized by watery discharge and conjunctival injection, while allergic conjunctivitis is more likely to involve itching, stringy or ropy discharge, lid edema, red/hyperemic conjunctiva, and comorbid allergic rhinitis.

The age of the child is also predictive. Conjunctivitis in preschool children is most likely bacterial, usually either H. influenzae or Streptococcus pneumoniae. In a newborn, the cause is most likely chemical irritation (from silver nitrate), while in older children the conjunctivitis is usually viral or allergic.

Oral antibiotics are recommended for any child who has concurrent otitis media. But for uncomplicated bacterial conjunctivitis, topical ophthalmic agents are recommended over systemic agents because they achieve a greater concentration of antibiotic to the eye while avoiding systemic side effects. Most of the topicals discussed below are approved for children 1 year of age and older.

Aminoglycosides, including gentamicin, tobramycin, and neomycin, are most active against gram-negative bacteria such as Pseudomonas aeruginosa (except neomycin) and methicillin-sensitive Staphylococcus aureus (MSSA). However, they do not cover streptococci or methicillin-resistant Staph. aureus (MRSA), and studies have shown increasing resistance of Streptococcus pneumoniae to these agents, reaching 65% by 2006 in the Ocular TRUST (Tracking Resistance in U.S. Today) 1 survey (Am. J. Ophthalmol. 2008;145:951–8).

Polymixin B is active only against gram-negative bacteria and therefore is given in combination with other antibiotics, including trimethoprim, bacitracin, and neomycin/bacitracin, which broaden the coverage to include staphylococci, streptococci, and some gram-negative bacteria including H. influenzae. While most H. influenzae strains remain susceptible to polymixin B alone or in combination, there is high resistance among Strep. pneumoniae and MSSA isolates.

The macrolide erythromycin—used as a 0.5% ointment—is one of the oldest ocular antibiotics, but now is rarely effective in bacterial conjunctivitis because of the high resistance among Staphylococcus species and poor activity against H. influenzae. The newer topical macrolide azithromycin is also hampered by high levels of resistance. In the TRUST survey, resistance to azithromycin was 22% for Strep. pneumoniae isolates, 46% among MSSA bacteria, and 91% among MRSA isolates. Other studies have shown significant resistance among H. influenzae as well.

Fluoroquinolones offer broad-spectrum coverage against both gram-positive and gram-negative organisms. The older topical agents ofloxacin and ciprofloxacin have largely been replaced by the newer agents levofloxacin, moxifloxacin, gatifloxacin, and now besifloxacin, which was approved by the U.S. Food and Drug Administration in May 2009. Numerous randomized, double-masked, controlled clinical trials in children and adults with bacterial conjunctivitis have demonstrated clinical cure rates of approximately 66%–96% and microbial eradication rates ranging from 84% to 96% for the newer fluoroquinolones.

There has been almost no resistance to fluoroquinolones among Strep. pneumoniae or H. influenzae organisms, but there is some fluoroquinolone resistance among MSSA isolates and a high level for MRSA, reaching 85% in Ocular TRUST 1.

Although most topical ophthalmic antibiotics used for the treatment of bacterial conjunctivitis are generally safe and well tolerated, ocular adverse events can cause discomfort that leads to noncompliance. Topical aminoglycosides have been associated with corneal and conjunctival toxicity, especially when used frequently, as well as ocular allergic reactions. Bacitracin has been associated with cases of contact dermatitis in the conjunctival area, and the polymixin B combinations can also cause local irritation. Macrolides, too, can cause minor ocular irritation, redness, and hypersensitivity.

In contrast, the fluoroquinolones have been well tolerated and associated with less toxicity than the other ophthalmic antibacterial classes, although crystalline precipitates have been seen with ciprofloxacin when it is administered frequently.

The ideal treatment for acute bacterial conjunctivitis should be a well-tolerated, broad-spectrum, highly potent, and bactericidal agent with a high concentration on the ocular surface and a rapid kill time. Convenience in dosing is also an important consideration. The newer fluoroquinolones, with potent efficacy against H. influenzae and Strep. pneumoniae, may best fulfill those requirements. But of course, cost remains a problem for many.

[email protected]

The treatment of bacterial conjunctivitis has become more challenging in this era of increasing antimicrobial resistance.

Conjunctivitis in children is extremely common, accounting for an estimated 1%–4% of all pediatric office visits. Yet, with so much focus on otitis media, the impact of antimicrobial resistance on conjunctivitis treatment has been widely overlooked. This is despite that approximately one-third of children with bacterial conjunctivitis have concurrent otitis media, most commonly caused by Haemophilus influenzae. In fact, my interest in conjunctivitis stems from its connection with otitis media.

Many of the traditional topical ocular agents we've used in the past to treat bacterial conjunctivitis—including those of the aminoglycoside, polymixin B combination, and macrolide classes—are less effective than they once were, thanks to increasing resistance. At the same time, many of these agents have tolerability issues, which render them even less effective. After all, if a child won't allow the medicine to be placed in her eyes, it most certainly won't work.

Fluoroquinolones, while remaining highly effective with far less resistance, are about 10 times as expensive as older agents available generically. Is it worth the cost to speed up the cure and reduce the contagion of a self-limited disease by a day or two at the most? The answer to that depends on a variety of factors, including the degree of the child's discomfort, the potential burden to the parent of missing days from work, and whether the child attends day care. It's not a simple decision.

Of course, it's important to determine whether the conjunctivitis is bacterial. Acute bacterial conjunctivitis begins abruptly with early symptoms of irritation or foreign body sensation and tearing. Mucopurulent or purulent discharge, morning crusting, swelling, and comorbid otitis media are common indicators. In contrast, viral conjunctivitis is characterized by watery discharge and conjunctival injection, while allergic conjunctivitis is more likely to involve itching, stringy or ropy discharge, lid edema, red/hyperemic conjunctiva, and comorbid allergic rhinitis.

The age of the child is also predictive. Conjunctivitis in preschool children is most likely bacterial, usually either H. influenzae or Streptococcus pneumoniae. In a newborn, the cause is most likely chemical irritation (from silver nitrate), while in older children the conjunctivitis is usually viral or allergic.

Oral antibiotics are recommended for any child who has concurrent otitis media. But for uncomplicated bacterial conjunctivitis, topical ophthalmic agents are recommended over systemic agents because they achieve a greater concentration of antibiotic to the eye while avoiding systemic side effects. Most of the topicals discussed below are approved for children 1 year of age and older.

Aminoglycosides, including gentamicin, tobramycin, and neomycin, are most active against gram-negative bacteria such as Pseudomonas aeruginosa (except neomycin) and methicillin-sensitive Staphylococcus aureus (MSSA). However, they do not cover streptococci or methicillin-resistant Staph. aureus (MRSA), and studies have shown increasing resistance of Streptococcus pneumoniae to these agents, reaching 65% by 2006 in the Ocular TRUST (Tracking Resistance in U.S. Today) 1 survey (Am. J. Ophthalmol. 2008;145:951–8).

Polymixin B is active only against gram-negative bacteria and therefore is given in combination with other antibiotics, including trimethoprim, bacitracin, and neomycin/bacitracin, which broaden the coverage to include staphylococci, streptococci, and some gram-negative bacteria including H. influenzae. While most H. influenzae strains remain susceptible to polymixin B alone or in combination, there is high resistance among Strep. pneumoniae and MSSA isolates.

The macrolide erythromycin—used as a 0.5% ointment—is one of the oldest ocular antibiotics, but now is rarely effective in bacterial conjunctivitis because of the high resistance among Staphylococcus species and poor activity against H. influenzae. The newer topical macrolide azithromycin is also hampered by high levels of resistance. In the TRUST survey, resistance to azithromycin was 22% for Strep. pneumoniae isolates, 46% among MSSA bacteria, and 91% among MRSA isolates. Other studies have shown significant resistance among H. influenzae as well.

Fluoroquinolones offer broad-spectrum coverage against both gram-positive and gram-negative organisms. The older topical agents ofloxacin and ciprofloxacin have largely been replaced by the newer agents levofloxacin, moxifloxacin, gatifloxacin, and now besifloxacin, which was approved by the U.S. Food and Drug Administration in May 2009. Numerous randomized, double-masked, controlled clinical trials in children and adults with bacterial conjunctivitis have demonstrated clinical cure rates of approximately 66%–96% and microbial eradication rates ranging from 84% to 96% for the newer fluoroquinolones.

There has been almost no resistance to fluoroquinolones among Strep. pneumoniae or H. influenzae organisms, but there is some fluoroquinolone resistance among MSSA isolates and a high level for MRSA, reaching 85% in Ocular TRUST 1.

Although most topical ophthalmic antibiotics used for the treatment of bacterial conjunctivitis are generally safe and well tolerated, ocular adverse events can cause discomfort that leads to noncompliance. Topical aminoglycosides have been associated with corneal and conjunctival toxicity, especially when used frequently, as well as ocular allergic reactions. Bacitracin has been associated with cases of contact dermatitis in the conjunctival area, and the polymixin B combinations can also cause local irritation. Macrolides, too, can cause minor ocular irritation, redness, and hypersensitivity.

In contrast, the fluoroquinolones have been well tolerated and associated with less toxicity than the other ophthalmic antibacterial classes, although crystalline precipitates have been seen with ciprofloxacin when it is administered frequently.

The ideal treatment for acute bacterial conjunctivitis should be a well-tolerated, broad-spectrum, highly potent, and bactericidal agent with a high concentration on the ocular surface and a rapid kill time. Convenience in dosing is also an important consideration. The newer fluoroquinolones, with potent efficacy against H. influenzae and Strep. pneumoniae, may best fulfill those requirements. But of course, cost remains a problem for many.

With the licensure of GlaxoSmithKline's human papillomavirus vaccine Cervarix in October, we will soon have two vaccines that prevent cervical cancer in women. But they're not interchangeable, and this could lead to problems.

Cervarix is expected to join Merck's Gardasil on the U.S. market in February. For the first time ever in vaccine history, we will have a situation in which two competing vaccines have very different components and adjuvants that could complicate the decision for practicing physicians—as well as insurers and buying groups—regarding which one to use. I think we need to view human papillomavirus (HPV) vaccines as exceptions to the usual rules of “equivalent and interchangeable” and consider stocking both.

Patients should be informed of the features of each vaccine, and the decision to use one or the other should be made with informed consent.

Most clinicians know that both vaccines protect against HPV serotypes 16 and 18, the dominant causes of cervical cancer. But Gardasil also protects against HPV-6 and −11, primarily associated with genital warts, and has recently received approval for use in males, which Cervarix has not. But other differences between the two vaccines are less well recognized, and I believe will turn out to be important.

Although both vaccines are manufactured with similar technology using viruslike particles, Cervarix contains a novel adjuvant, ASO4, that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and −18, compared with Gardasil.

According to a head-to-head comparison conducted by GSK, geometric mean titers of serum neutralizing antibodies ranged from 2.3- to 4.8-fold higher for HPV-16 and 6.8- to 9.1-fold higher for HPV-18 after vaccination with Cervarix, compared with Gardasil, across all ages (Hum. Vaccin. 2009;5:705-19).

Although not proven, we might infer from those data that Cervarix might provide longer-lasting protection against HPV serotypes 16 and 18 and, therefore, a longer duration of time before a booster is needed.

Both companies are currently studying duration of protection with their respective vaccines, and a just-published study showed sustained efficacy and immunogenicity of Cervarix up to 6.4 years (Lancet 2009 Dec. 3 []). For both vaccines, we should have answers before current vaccinees begin to lose protection.

Both vaccines are indicated for the prevention of cervical cancer and cervical intraepithelial neoplasia (CIN) grades 1-3 due to HPV-16 and −18, and cervical adenocarcinoma in situ. However, Gardasil also has indications for the prevention of vulvar and vaginal intraepithelial neoplasias.

Although not specifically mentioned in Gardasil's label, there is evidence that HPV strains 6 and 11, while not associated with cervical cancer, are responsible for 8%–10% of cases of CIN 1 (mild atypia).

These lesions typically resolve, and guidelines from the American College of Obstetricians and Gynecologists do not recommend intervention beyond monitoring after CIN 1 is recognized, with the intent to intervene only if the lesion progresses to CIN 2. However, in practice women often request that the lesions be removed, and their physicians often do so, thereby incurring excess time, money, and some risk. Gardasil could potentially reduce a significant number of those procedures.

Meanwhile, data included in the label for Cervarix show that it provides cross-protection against the carcinogenic HPV strain 31, which is responsible for a small yet significant proportion of cervical cancer cases.

In one landmark study, serotype 31 accounted for 3.4% of squamous cell cancers in 1,739 patients (N. Engl. J. Med. 2003;348:518-27). Gardasil's label, in contrast, states that it has not demonstrated cross-protection against diseases caused by HPV strains not included in the vaccine.

These differences may seem slight, but consider a case in which a young woman who received Gardasil later develops a case of cervical cancer due to HPV-31. Might she be quite upset that she wasn't informed that there was another vaccine that could have prevented it? Conversely, a male or female patient given Cervarix later develops genital warts, or a female develops cervical atypia associated with HPV-6 or −11. Might these patients similarly feel that they were denied the chance to have prevented those outcomes?

Who decides which vaccine is used? In managed care settings, the decision is often made based on cost when vaccines are equivalent, but what about the HPV vaccines where the products are not equivalent? The same goes for the manufacturer-run vaccine buying groups that offer discounts to increasing numbers of participating physicians who sign contracts that impose strict limits on the amount of vaccine that can be purchased outside of the specified brands.

This has never happened before with vaccines: The two competing brands are not interchangeable. I believe that health plans and vaccine buying groups need to recognize these factors and grant an exception to HPV vaccines.

I think we all should stock both in our practices, and explain the differences to parents. I plan to distribute pamphlets to patients and families and let them choose, with signatures confirming informed consent.

I serve as a consultant to both GSK and Merck & Co. and have shared this information with both companies.

This is going to be complicated.

DR. PICHICHERO, a specialist in pediatric infectious diseases, is director of the Rochester (N.Y.) General Research Institute.doi:10.1016/S0140-6736(09)61567-1

With the licensure of GlaxoSmithKline's human papillomavirus vaccine Cervarix in October, we will soon have two vaccines that prevent cervical cancer in women. But they're not interchangeable, and this could lead to problems.

Cervarix is expected to join Merck's Gardasil on the U.S. market in February. For the first time ever in vaccine history, we will have a situation in which two competing vaccines have very different components and adjuvants that could complicate the decision for practicing physicians—as well as insurers and buying groups—regarding which one to use. I think we need to view human papillomavirus (HPV) vaccines as exceptions to the usual rules of “equivalent and interchangeable” and consider stocking both.

Patients should be informed of the features of each vaccine, and the decision to use one or the other should be made with informed consent.

Most clinicians know that both vaccines protect against HPV serotypes 16 and 18, the dominant causes of cervical cancer. But Gardasil also protects against HPV-6 and −11, primarily associated with genital warts, and has recently received approval for use in males, which Cervarix has not. But other differences between the two vaccines are less well recognized, and I believe will turn out to be important.

Although both vaccines are manufactured with similar technology using viruslike particles, Cervarix contains a novel adjuvant, ASO4, that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and −18, compared with Gardasil.

According to a head-to-head comparison conducted by GSK, geometric mean titers of serum neutralizing antibodies ranged from 2.3- to 4.8-fold higher for HPV-16 and 6.8- to 9.1-fold higher for HPV-18 after vaccination with Cervarix, compared with Gardasil, across all ages (Hum. Vaccin. 2009;5:705-19).

Although not proven, we might infer from those data that Cervarix might provide longer-lasting protection against HPV serotypes 16 and 18 and, therefore, a longer duration of time before a booster is needed.

Both companies are currently studying duration of protection with their respective vaccines, and a just-published study showed sustained efficacy and immunogenicity of Cervarix up to 6.4 years (Lancet 2009 Dec. 3 []). For both vaccines, we should have answers before current vaccinees begin to lose protection.

Both vaccines are indicated for the prevention of cervical cancer and cervical intraepithelial neoplasia (CIN) grades 1-3 due to HPV-16 and −18, and cervical adenocarcinoma in situ. However, Gardasil also has indications for the prevention of vulvar and vaginal intraepithelial neoplasias.

Although not specifically mentioned in Gardasil's label, there is evidence that HPV strains 6 and 11, while not associated with cervical cancer, are responsible for 8%–10% of cases of CIN 1 (mild atypia).

These lesions typically resolve, and guidelines from the American College of Obstetricians and Gynecologists do not recommend intervention beyond monitoring after CIN 1 is recognized, with the intent to intervene only if the lesion progresses to CIN 2. However, in practice women often request that the lesions be removed, and their physicians often do so, thereby incurring excess time, money, and some risk. Gardasil could potentially reduce a significant number of those procedures.

Meanwhile, data included in the label for Cervarix show that it provides cross-protection against the carcinogenic HPV strain 31, which is responsible for a small yet significant proportion of cervical cancer cases.

In one landmark study, serotype 31 accounted for 3.4% of squamous cell cancers in 1,739 patients (N. Engl. J. Med. 2003;348:518-27). Gardasil's label, in contrast, states that it has not demonstrated cross-protection against diseases caused by HPV strains not included in the vaccine.

These differences may seem slight, but consider a case in which a young woman who received Gardasil later develops a case of cervical cancer due to HPV-31. Might she be quite upset that she wasn't informed that there was another vaccine that could have prevented it? Conversely, a male or female patient given Cervarix later develops genital warts, or a female develops cervical atypia associated with HPV-6 or −11. Might these patients similarly feel that they were denied the chance to have prevented those outcomes?

Who decides which vaccine is used? In managed care settings, the decision is often made based on cost when vaccines are equivalent, but what about the HPV vaccines where the products are not equivalent? The same goes for the manufacturer-run vaccine buying groups that offer discounts to increasing numbers of participating physicians who sign contracts that impose strict limits on the amount of vaccine that can be purchased outside of the specified brands.

This has never happened before with vaccines: The two competing brands are not interchangeable. I believe that health plans and vaccine buying groups need to recognize these factors and grant an exception to HPV vaccines.

I think we all should stock both in our practices, and explain the differences to parents. I plan to distribute pamphlets to patients and families and let them choose, with signatures confirming informed consent.

I serve as a consultant to both GSK and Merck & Co. and have shared this information with both companies.

This is going to be complicated.

DR. PICHICHERO, a specialist in pediatric infectious diseases, is director of the Rochester (N.Y.) General Research Institute.doi:10.1016/S0140-6736(09)61567-1

With the licensure of GlaxoSmithKline's human papillomavirus vaccine Cervarix in October, we will soon have two vaccines that prevent cervical cancer in women. But they're not interchangeable, and this could lead to problems.

Cervarix is expected to join Merck's Gardasil on the U.S. market in February. For the first time ever in vaccine history, we will have a situation in which two competing vaccines have very different components and adjuvants that could complicate the decision for practicing physicians—as well as insurers and buying groups—regarding which one to use. I think we need to view human papillomavirus (HPV) vaccines as exceptions to the usual rules of “equivalent and interchangeable” and consider stocking both.

Patients should be informed of the features of each vaccine, and the decision to use one or the other should be made with informed consent.

Most clinicians know that both vaccines protect against HPV serotypes 16 and 18, the dominant causes of cervical cancer. But Gardasil also protects against HPV-6 and −11, primarily associated with genital warts, and has recently received approval for use in males, which Cervarix has not. But other differences between the two vaccines are less well recognized, and I believe will turn out to be important.

Although both vaccines are manufactured with similar technology using viruslike particles, Cervarix contains a novel adjuvant, ASO4, that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and −18, compared with Gardasil.

According to a head-to-head comparison conducted by GSK, geometric mean titers of serum neutralizing antibodies ranged from 2.3- to 4.8-fold higher for HPV-16 and 6.8- to 9.1-fold higher for HPV-18 after vaccination with Cervarix, compared with Gardasil, across all ages (Hum. Vaccin. 2009;5:705-19).

Although not proven, we might infer from those data that Cervarix might provide longer-lasting protection against HPV serotypes 16 and 18 and, therefore, a longer duration of time before a booster is needed.

Both companies are currently studying duration of protection with their respective vaccines, and a just-published study showed sustained efficacy and immunogenicity of Cervarix up to 6.4 years (Lancet 2009 Dec. 3 []). For both vaccines, we should have answers before current vaccinees begin to lose protection.

Both vaccines are indicated for the prevention of cervical cancer and cervical intraepithelial neoplasia (CIN) grades 1-3 due to HPV-16 and −18, and cervical adenocarcinoma in situ. However, Gardasil also has indications for the prevention of vulvar and vaginal intraepithelial neoplasias.

Although not specifically mentioned in Gardasil's label, there is evidence that HPV strains 6 and 11, while not associated with cervical cancer, are responsible for 8%–10% of cases of CIN 1 (mild atypia).

These lesions typically resolve, and guidelines from the American College of Obstetricians and Gynecologists do not recommend intervention beyond monitoring after CIN 1 is recognized, with the intent to intervene only if the lesion progresses to CIN 2. However, in practice women often request that the lesions be removed, and their physicians often do so, thereby incurring excess time, money, and some risk. Gardasil could potentially reduce a significant number of those procedures.

Meanwhile, data included in the label for Cervarix show that it provides cross-protection against the carcinogenic HPV strain 31, which is responsible for a small yet significant proportion of cervical cancer cases.

In one landmark study, serotype 31 accounted for 3.4% of squamous cell cancers in 1,739 patients (N. Engl. J. Med. 2003;348:518-27). Gardasil's label, in contrast, states that it has not demonstrated cross-protection against diseases caused by HPV strains not included in the vaccine.

These differences may seem slight, but consider a case in which a young woman who received Gardasil later develops a case of cervical cancer due to HPV-31. Might she be quite upset that she wasn't informed that there was another vaccine that could have prevented it? Conversely, a male or female patient given Cervarix later develops genital warts, or a female develops cervical atypia associated with HPV-6 or −11. Might these patients similarly feel that they were denied the chance to have prevented those outcomes?

Who decides which vaccine is used? In managed care settings, the decision is often made based on cost when vaccines are equivalent, but what about the HPV vaccines where the products are not equivalent? The same goes for the manufacturer-run vaccine buying groups that offer discounts to increasing numbers of participating physicians who sign contracts that impose strict limits on the amount of vaccine that can be purchased outside of the specified brands.

This has never happened before with vaccines: The two competing brands are not interchangeable. I believe that health plans and vaccine buying groups need to recognize these factors and grant an exception to HPV vaccines.

I think we all should stock both in our practices, and explain the differences to parents. I plan to distribute pamphlets to patients and families and let them choose, with signatures confirming informed consent.

I serve as a consultant to both GSK and Merck & Co. and have shared this information with both companies.

This is going to be complicated.

DR. PICHICHERO, a specialist in pediatric infectious diseases, is director of the Rochester (N.Y.) General Research Institute.doi:10.1016/S0140-6736(09)61567-1

[email protected]

With the licensure of GlaxoSmithKline's human papillomavirus vaccine Cervarix in October, we will soon have two vaccines that prevent cervical cancer in women. But they're not interchangeable, and this could lead to problems.

Cervarix is expected to join Merck's Gardasil on the U.S. market in February 2010. For the first time ever in vaccine history, we will have a situation in which two competing vaccines have very different components and adjuvants that could complicate the decision for practicing physicians—as well as insurers and buying groups—regarding which one to use. I think we need to view human papillomavirus (HPV) vaccines as exceptions to the usual rules of “equivalent and interchangeable” and consider stocking both. Parents should be informed of the features of each vaccine, and the decision to use one or the other should be made with informed consent.

Most clinicians know that both vaccines protect against HPV serotypes 16 and 18, the dominant causes of cervical cancer. But Gardasil also protects against HPV-6 and −11, primarily associated with genital warts, and has recently received approval for use in males, which Cervarix has not. But other differences between the two vaccines are less well recognized, and I believe will turn out to be important.

Although both vaccines are manufactured with similar technology using viruslike particles, Cervarix contains a novel adjuvant, ASO4, that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and −18, compared with Gardasil. According to a head-to-head comparison conducted by GSK, geometric mean titers of serum neutralizing antibodies ranged from 2.3- to 4.8-fold higher for HPV-16 and 6.8- to 9.1-fold higher for HPV-18 after vaccination with Cervarix, compared with Gardasil, across all ages (Hum. Vaccin. 2009;5:705-19).

Although not proven, we might infer from those data that Cervarix might provide longer-lasting protection against HPV serotypes 16 and 18 and, therefore, a longer duration of time before a booster is needed. Both companies are studying duration of protection with their respective vaccines, and a just-published study showed sustained efficacy and immunogenicity of Cervarix up to 6.4 years (Lancet 2009 Dec. 3 [doi:10.1016/S0140-6736(09)61567-1]). For both vaccines, we should have answers before current vaccinees begin to lose protection.

Both vaccines are indicated for the prevention of cervical cancer and cervical intraepithelial neoplasia (CIN) grades 1–3 due to HPV-16 and −18, and cervical adenocarcinoma in situ. However, Gardasil also has indications for the prevention of vulvar and vaginal intraepithelial neoplasias, which Cervarix does not.

Although not specifically mentioned in Gardasil's label (www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_pi.pdf

Meanwhile, data included in the label for Cervarix (http://us.gsk.com/products/assets/us_cervarix.pdf

These differences may seem slight, but consider a case in which a young woman who received Gardasil later develops a case of cervical cancer due to HPV-31. Might she be quite upset that she wasn't informed that there was another vaccine that could have prevented it? Conversely, a male or female patient given Cervarix later develops genital warts, or a female develops cervical atypia associated with HPV-6 or −11. Might these patients similarly feel that they were denied the chance to have prevented those outcomes?

Who decides which vaccine is used? In managed care settings, the decision is often made based on cost when vaccines are equivalent, but what about the HPV vaccines where the products are not equivalent?

The same goes for the manufacturer-run vaccine buying groups that offer discounts to increasing numbers of participating physicians who sign contracts that impose strict limits on the amount of vaccine that can be purchased outside of the specified brands.

This has not happened before with vaccines: The two competing brands are not interchangeable. I believe that health plans and vaccine buying groups need to recognize these factors and grant an exception to HPV vaccines.

I think we all should stock both vaccines in our practices, and explain the differences to parents. I plan to distribute pamphlets to patients and families and let them choose, with signatures confirming informed consent. I serve as a consultant to both GSK and Merck & Co. and have shared this information with both companies.

This is going to be complicated.

[email protected]

With the licensure of GlaxoSmithKline's human papillomavirus vaccine Cervarix in October, we will soon have two vaccines that prevent cervical cancer in women. But they're not interchangeable, and this could lead to problems.

Cervarix is expected to join Merck's Gardasil on the U.S. market in February 2010. For the first time ever in vaccine history, we will have a situation in which two competing vaccines have very different components and adjuvants that could complicate the decision for practicing physicians—as well as insurers and buying groups—regarding which one to use. I think we need to view human papillomavirus (HPV) vaccines as exceptions to the usual rules of “equivalent and interchangeable” and consider stocking both. Parents should be informed of the features of each vaccine, and the decision to use one or the other should be made with informed consent.

Most clinicians know that both vaccines protect against HPV serotypes 16 and 18, the dominant causes of cervical cancer. But Gardasil also protects against HPV-6 and −11, primarily associated with genital warts, and has recently received approval for use in males, which Cervarix has not. But other differences between the two vaccines are less well recognized, and I believe will turn out to be important.

Although both vaccines are manufactured with similar technology using viruslike particles, Cervarix contains a novel adjuvant, ASO4, that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and −18, compared with Gardasil. According to a head-to-head comparison conducted by GSK, geometric mean titers of serum neutralizing antibodies ranged from 2.3- to 4.8-fold higher for HPV-16 and 6.8- to 9.1-fold higher for HPV-18 after vaccination with Cervarix, compared with Gardasil, across all ages (Hum. Vaccin. 2009;5:705-19).

Although not proven, we might infer from those data that Cervarix might provide longer-lasting protection against HPV serotypes 16 and 18 and, therefore, a longer duration of time before a booster is needed. Both companies are studying duration of protection with their respective vaccines, and a just-published study showed sustained efficacy and immunogenicity of Cervarix up to 6.4 years (Lancet 2009 Dec. 3 [doi:10.1016/S0140-6736(09)61567-1]). For both vaccines, we should have answers before current vaccinees begin to lose protection.

Both vaccines are indicated for the prevention of cervical cancer and cervical intraepithelial neoplasia (CIN) grades 1–3 due to HPV-16 and −18, and cervical adenocarcinoma in situ. However, Gardasil also has indications for the prevention of vulvar and vaginal intraepithelial neoplasias, which Cervarix does not.

Although not specifically mentioned in Gardasil's label (www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_pi.pdf

Meanwhile, data included in the label for Cervarix (http://us.gsk.com/products/assets/us_cervarix.pdf

These differences may seem slight, but consider a case in which a young woman who received Gardasil later develops a case of cervical cancer due to HPV-31. Might she be quite upset that she wasn't informed that there was another vaccine that could have prevented it? Conversely, a male or female patient given Cervarix later develops genital warts, or a female develops cervical atypia associated with HPV-6 or −11. Might these patients similarly feel that they were denied the chance to have prevented those outcomes?

Who decides which vaccine is used? In managed care settings, the decision is often made based on cost when vaccines are equivalent, but what about the HPV vaccines where the products are not equivalent?

The same goes for the manufacturer-run vaccine buying groups that offer discounts to increasing numbers of participating physicians who sign contracts that impose strict limits on the amount of vaccine that can be purchased outside of the specified brands.

This has not happened before with vaccines: The two competing brands are not interchangeable. I believe that health plans and vaccine buying groups need to recognize these factors and grant an exception to HPV vaccines.

I think we all should stock both vaccines in our practices, and explain the differences to parents. I plan to distribute pamphlets to patients and families and let them choose, with signatures confirming informed consent. I serve as a consultant to both GSK and Merck & Co. and have shared this information with both companies.

This is going to be complicated.

[email protected]

With the licensure of GlaxoSmithKline's human papillomavirus vaccine Cervarix in October, we will soon have two vaccines that prevent cervical cancer in women. But they're not interchangeable, and this could lead to problems.

Cervarix is expected to join Merck's Gardasil on the U.S. market in February 2010. For the first time ever in vaccine history, we will have a situation in which two competing vaccines have very different components and adjuvants that could complicate the decision for practicing physicians—as well as insurers and buying groups—regarding which one to use. I think we need to view human papillomavirus (HPV) vaccines as exceptions to the usual rules of “equivalent and interchangeable” and consider stocking both. Parents should be informed of the features of each vaccine, and the decision to use one or the other should be made with informed consent.

Most clinicians know that both vaccines protect against HPV serotypes 16 and 18, the dominant causes of cervical cancer. But Gardasil also protects against HPV-6 and −11, primarily associated with genital warts, and has recently received approval for use in males, which Cervarix has not. But other differences between the two vaccines are less well recognized, and I believe will turn out to be important.

Although both vaccines are manufactured with similar technology using viruslike particles, Cervarix contains a novel adjuvant, ASO4, that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and −18, compared with Gardasil. According to a head-to-head comparison conducted by GSK, geometric mean titers of serum neutralizing antibodies ranged from 2.3- to 4.8-fold higher for HPV-16 and 6.8- to 9.1-fold higher for HPV-18 after vaccination with Cervarix, compared with Gardasil, across all ages (Hum. Vaccin. 2009;5:705-19).

Although not proven, we might infer from those data that Cervarix might provide longer-lasting protection against HPV serotypes 16 and 18 and, therefore, a longer duration of time before a booster is needed. Both companies are studying duration of protection with their respective vaccines, and a just-published study showed sustained efficacy and immunogenicity of Cervarix up to 6.4 years (Lancet 2009 Dec. 3 [doi:10.1016/S0140-6736(09)61567-1]). For both vaccines, we should have answers before current vaccinees begin to lose protection.

Both vaccines are indicated for the prevention of cervical cancer and cervical intraepithelial neoplasia (CIN) grades 1–3 due to HPV-16 and −18, and cervical adenocarcinoma in situ. However, Gardasil also has indications for the prevention of vulvar and vaginal intraepithelial neoplasias, which Cervarix does not.

Although not specifically mentioned in Gardasil's label (www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_pi.pdf

Meanwhile, data included in the label for Cervarix (http://us.gsk.com/products/assets/us_cervarix.pdf

These differences may seem slight, but consider a case in which a young woman who received Gardasil later develops a case of cervical cancer due to HPV-31. Might she be quite upset that she wasn't informed that there was another vaccine that could have prevented it? Conversely, a male or female patient given Cervarix later develops genital warts, or a female develops cervical atypia associated with HPV-6 or −11. Might these patients similarly feel that they were denied the chance to have prevented those outcomes?

Who decides which vaccine is used? In managed care settings, the decision is often made based on cost when vaccines are equivalent, but what about the HPV vaccines where the products are not equivalent?

The same goes for the manufacturer-run vaccine buying groups that offer discounts to increasing numbers of participating physicians who sign contracts that impose strict limits on the amount of vaccine that can be purchased outside of the specified brands.

This has not happened before with vaccines: The two competing brands are not interchangeable. I believe that health plans and vaccine buying groups need to recognize these factors and grant an exception to HPV vaccines.

I think we all should stock both vaccines in our practices, and explain the differences to parents. I plan to distribute pamphlets to patients and families and let them choose, with signatures confirming informed consent. I serve as a consultant to both GSK and Merck & Co. and have shared this information with both companies.

This is going to be complicated.

[email protected]

I believe the time has come to consider cost-effectiveness when deciding which vaccines the government—that's your tax dollars—will pay for.

At its October meeting, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention made a paradoxical decision: The committee gave a “permissive” recommendation for use of Merck's quadrivalent human papillomavirus (HPV) vaccine (Gardasil) in males aged 9–26 years, but then voted for coverage of the vaccine under the federal Vaccines for Children (VFC) program, which provides free vaccine to children up through 18 years of age who fall into certain need categories. The program covers approximately 48% of all U.S. children.

A permissive recommendation generally indicates that the vaccine is safe and effective but not cost effective. Permissive recommendations usually are not voted into the VFC program. Although the permissive recommendation still awaits approval by the CDC's director, ACIP's vote for VFC coverage is binding, so it is now official. We will have to wait and see what insurance companies do with the dichotomous signal.

A decade ago, ACIP rarely discussed cost when making its vaccine use recommendations. Now, cost-effectiveness analyses are routine. At the October ACIP meeting, Harrell Chesson, Ph.D., of the CDC, presented data from six studies—four published, two unpublished—demonstrating wide variation in cost per quality-adjusted life year (QALY) estimates for use of Gardasil in adolescent and young adult men, depending in large part on the vaccination status of the female population. In general, he showed that as coverage of Gardasil among females increases, the cost per QALY gained by male vaccination decreases.

Use of the vaccine in males is aimed primarily at preventing warts caused by HPV serotypes 6 and 11. The rates of penile and head/neck cancer caused by the cervical cancer HPV serotypes 16 and 18 are miniscule and do not even factor into the cost calculation. Prevention of transmission of HPV-16 and −18 to females through sexual contact is also a goal of the vaccine, but if it's already being routinely offered to females, the data suggest that there's very little additional gain costwise from giving it to males.

Indeed, Dr. Chesson concluded, “In most scenarios, adding male vaccination to female-only vaccination is not the most cost-effective use of public health resources. Improving vaccination coverage of females is likely to be a more effective—and cost-effective—strategy to reduce the overall burden of HPV-associated conditions.”

As readers who follow this column and my other writings know, I am a strong proponent of vaccines. In fact, I serve on the advisory boards for both Merck & Co. and GlaxoSmithKline, which manufactures the bivalent HPV vaccine Cervarix. But in an era where we're debating how to provide even basic health insurance for uninsured Americans, I am becoming concerned about whether our country can afford every vaccine for every person.

I'm looking ahead to other vaccines in the very near pipeline. In December we're likely to see approval of the 13-valent pneumococcal conjugate vaccine for the U.S. market. That vaccine is expected to cost more than the current PCV7 (Prevnar), thus raising the overall costs of routine immunization when the switch is made to the new vaccine. Beyond that we will need to provide catch-up vaccination as well for kids who already received PCV7 in order to provide protection against the newly emerging, virulent, and multidrug-resistant serotype 19A, which is included in PCV13 but not PCV7. This new “superbug” causes fatal sepsis, meningitis, and pneumonia. How can ACIP not vote that into VFC as well?

On the heels of PCV13, there are two new meningococcal conjugate vaccines awaiting licensure: GSK's Haemophilus influenzae type b (Hib)–Neisseria meningitidis serogroups C (MenC) and Y (MenY)–tetanus toxoid combination, and Novartis's MenACWY-CRM (Menveo). The Hib-MenCY-TT conjugate is likely to be licensed for infants at 2, 4, and 6 months of age, with a booster at 15–18 months. Menveo, which will compete with Menactra, is expected to first be licensed for use in adolescents, then toddlers, then infants. These vaccines also prevent a significant amount of serious and potentially fatal disease.

Although competition usually lowers cost in the marketplace, the same phenomenon generally isn't seen when new vaccine competitors enter the market. Rather, the major companies with competing vaccines make combination products with ingredients that differ from others so that staying within their family of products is more convenient than switching between companies.

Moreover, companies also provide price advantages to physicians through national buying groups that provide bigger discounts to those who purchase vaccines within their own family of products. This impacts any price reduction that might occur with brand competition.

So where should we draw the line? At one point or another, ACIP may have to say the government can't afford to pay for vaccines that do not have a strong cost-benefit argument behind them. Yes, the alternative is a two-tiered system where those who can afford the vaccine can get it, and those who can't, don't. ACIP has tried to avoid that scenario in the past, but I fear it won't be able to do so much longer.

[email protected]

I believe the time has come to consider cost-effectiveness when deciding which vaccines the government—that's your tax dollars—will pay for.

At its October meeting, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention made a paradoxical decision: The committee gave a “permissive” recommendation for use of Merck's quadrivalent human papillomavirus (HPV) vaccine (Gardasil) in males aged 9–26 years, but then voted for coverage of the vaccine under the federal Vaccines for Children (VFC) program, which provides free vaccine to children up through 18 years of age who fall into certain need categories. The program covers approximately 48% of all U.S. children.

A permissive recommendation generally indicates that the vaccine is safe and effective but not cost effective. Permissive recommendations usually are not voted into the VFC program. Although the permissive recommendation still awaits approval by the CDC's director, ACIP's vote for VFC coverage is binding, so it is now official. We will have to wait and see what insurance companies do with the dichotomous signal.

A decade ago, ACIP rarely discussed cost when making its vaccine use recommendations. Now, cost-effectiveness analyses are routine. At the October ACIP meeting, Harrell Chesson, Ph.D., of the CDC, presented data from six studies—four published, two unpublished—demonstrating wide variation in cost per quality-adjusted life year (QALY) estimates for use of Gardasil in adolescent and young adult men, depending in large part on the vaccination status of the female population. In general, he showed that as coverage of Gardasil among females increases, the cost per QALY gained by male vaccination decreases.

Use of the vaccine in males is aimed primarily at preventing warts caused by HPV serotypes 6 and 11. The rates of penile and head/neck cancer caused by the cervical cancer HPV serotypes 16 and 18 are miniscule and do not even factor into the cost calculation. Prevention of transmission of HPV-16 and −18 to females through sexual contact is also a goal of the vaccine, but if it's already being routinely offered to females, the data suggest that there's very little additional gain costwise from giving it to males.

Indeed, Dr. Chesson concluded, “In most scenarios, adding male vaccination to female-only vaccination is not the most cost-effective use of public health resources. Improving vaccination coverage of females is likely to be a more effective—and cost-effective—strategy to reduce the overall burden of HPV-associated conditions.”

As readers who follow this column and my other writings know, I am a strong proponent of vaccines. In fact, I serve on the advisory boards for both Merck & Co. and GlaxoSmithKline, which manufactures the bivalent HPV vaccine Cervarix. But in an era where we're debating how to provide even basic health insurance for uninsured Americans, I am becoming concerned about whether our country can afford every vaccine for every person.

I'm looking ahead to other vaccines in the very near pipeline. In December we're likely to see approval of the 13-valent pneumococcal conjugate vaccine for the U.S. market. That vaccine is expected to cost more than the current PCV7 (Prevnar), thus raising the overall costs of routine immunization when the switch is made to the new vaccine. Beyond that we will need to provide catch-up vaccination as well for kids who already received PCV7 in order to provide protection against the newly emerging, virulent, and multidrug-resistant serotype 19A, which is included in PCV13 but not PCV7. This new “superbug” causes fatal sepsis, meningitis, and pneumonia. How can ACIP not vote that into VFC as well?

On the heels of PCV13, there are two new meningococcal conjugate vaccines awaiting licensure: GSK's Haemophilus influenzae type b (Hib)–Neisseria meningitidis serogroups C (MenC) and Y (MenY)–tetanus toxoid combination, and Novartis's MenACWY-CRM (Menveo). The Hib-MenCY-TT conjugate is likely to be licensed for infants at 2, 4, and 6 months of age, with a booster at 15–18 months. Menveo, which will compete with Menactra, is expected to first be licensed for use in adolescents, then toddlers, then infants. These vaccines also prevent a significant amount of serious and potentially fatal disease.

Although competition usually lowers cost in the marketplace, the same phenomenon generally isn't seen when new vaccine competitors enter the market. Rather, the major companies with competing vaccines make combination products with ingredients that differ from others so that staying within their family of products is more convenient than switching between companies.

Moreover, companies also provide price advantages to physicians through national buying groups that provide bigger discounts to those who purchase vaccines within their own family of products. This impacts any price reduction that might occur with brand competition.

So where should we draw the line? At one point or another, ACIP may have to say the government can't afford to pay for vaccines that do not have a strong cost-benefit argument behind them. Yes, the alternative is a two-tiered system where those who can afford the vaccine can get it, and those who can't, don't. ACIP has tried to avoid that scenario in the past, but I fear it won't be able to do so much longer.

[email protected]

I believe the time has come to consider cost-effectiveness when deciding which vaccines the government—that's your tax dollars—will pay for.

At its October meeting, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention made a paradoxical decision: The committee gave a “permissive” recommendation for use of Merck's quadrivalent human papillomavirus (HPV) vaccine (Gardasil) in males aged 9–26 years, but then voted for coverage of the vaccine under the federal Vaccines for Children (VFC) program, which provides free vaccine to children up through 18 years of age who fall into certain need categories. The program covers approximately 48% of all U.S. children.

A permissive recommendation generally indicates that the vaccine is safe and effective but not cost effective. Permissive recommendations usually are not voted into the VFC program. Although the permissive recommendation still awaits approval by the CDC's director, ACIP's vote for VFC coverage is binding, so it is now official. We will have to wait and see what insurance companies do with the dichotomous signal.

A decade ago, ACIP rarely discussed cost when making its vaccine use recommendations. Now, cost-effectiveness analyses are routine. At the October ACIP meeting, Harrell Chesson, Ph.D., of the CDC, presented data from six studies—four published, two unpublished—demonstrating wide variation in cost per quality-adjusted life year (QALY) estimates for use of Gardasil in adolescent and young adult men, depending in large part on the vaccination status of the female population. In general, he showed that as coverage of Gardasil among females increases, the cost per QALY gained by male vaccination decreases.

Use of the vaccine in males is aimed primarily at preventing warts caused by HPV serotypes 6 and 11. The rates of penile and head/neck cancer caused by the cervical cancer HPV serotypes 16 and 18 are miniscule and do not even factor into the cost calculation. Prevention of transmission of HPV-16 and −18 to females through sexual contact is also a goal of the vaccine, but if it's already being routinely offered to females, the data suggest that there's very little additional gain costwise from giving it to males.

Indeed, Dr. Chesson concluded, “In most scenarios, adding male vaccination to female-only vaccination is not the most cost-effective use of public health resources. Improving vaccination coverage of females is likely to be a more effective—and cost-effective—strategy to reduce the overall burden of HPV-associated conditions.”

As readers who follow this column and my other writings know, I am a strong proponent of vaccines. In fact, I serve on the advisory boards for both Merck & Co. and GlaxoSmithKline, which manufactures the bivalent HPV vaccine Cervarix. But in an era where we're debating how to provide even basic health insurance for uninsured Americans, I am becoming concerned about whether our country can afford every vaccine for every person.

I'm looking ahead to other vaccines in the very near pipeline. In December we're likely to see approval of the 13-valent pneumococcal conjugate vaccine for the U.S. market. That vaccine is expected to cost more than the current PCV7 (Prevnar), thus raising the overall costs of routine immunization when the switch is made to the new vaccine. Beyond that we will need to provide catch-up vaccination as well for kids who already received PCV7 in order to provide protection against the newly emerging, virulent, and multidrug-resistant serotype 19A, which is included in PCV13 but not PCV7. This new “superbug” causes fatal sepsis, meningitis, and pneumonia. How can ACIP not vote that into VFC as well?

On the heels of PCV13, there are two new meningococcal conjugate vaccines awaiting licensure: GSK's Haemophilus influenzae type b (Hib)–Neisseria meningitidis serogroups C (MenC) and Y (MenY)–tetanus toxoid combination, and Novartis's MenACWY-CRM (Menveo). The Hib-MenCY-TT conjugate is likely to be licensed for infants at 2, 4, and 6 months of age, with a booster at 15–18 months. Menveo, which will compete with Menactra, is expected to first be licensed for use in adolescents, then toddlers, then infants. These vaccines also prevent a significant amount of serious and potentially fatal disease.

Although competition usually lowers cost in the marketplace, the same phenomenon generally isn't seen when new vaccine competitors enter the market. Rather, the major companies with competing vaccines make combination products with ingredients that differ from others so that staying within their family of products is more convenient than switching between companies.

Moreover, companies also provide price advantages to physicians through national buying groups that provide bigger discounts to those who purchase vaccines within their own family of products. This impacts any price reduction that might occur with brand competition.

So where should we draw the line? At one point or another, ACIP may have to say the government can't afford to pay for vaccines that do not have a strong cost-benefit argument behind them. Yes, the alternative is a two-tiered system where those who can afford the vaccine can get it, and those who can't, don't. ACIP has tried to avoid that scenario in the past, but I fear it won't be able to do so much longer.

[email protected]

We're seeing a lot of new viruses lately, but that's nothing new.

The novel pandemic H1N1 flu is just one of many emerging viruses that we're seeing clinically, although we may not always recognize them. Metapneumovirus, bocavirus, and norovirus are three others. But new viruses have been emerging since time began. One of my favorite books, Jared Diamond's “Guns, Germs, and Steel: The Fates of Human Societies” (New York: W.W. Norton & Co., 1997), describes how the Europeans who conquered the New World were aided in large part by the diseases they brought with them to a vulnerable population, a weapon at least as successful as those designed for warfare.

Diamond, a geography professor at the University of California, Los Angeles, who won a Pulitzer prize for his book, also points out that from the beginning of time, humans have acquired mutated germs from animals, resulting in disease of varying severity. The Europeans conquered by spreading new disease.

Of course, the current pandemic influenza A(H1N1) strain that we're dealing with now didn't come from human conquerors, but it did come from animals—more than one type, in fact. The virus was originally referred to as swine flu because laboratory testing showed that many of its genes were similar to those of influenza viruses that normally occur in pigs in North America.

However, now it is clear that this new virus is different from that which normally circulates in North American pigs, and actually includes genes from influenza viruses that normally circulate in pigs in Europe and Asia, along with avian genes and human genes, according to the Centers for Disease Control and Prevention.

Although this influenza strain surprised us in a couple of ways—it didn't come from birds and it isn't as virulent as we would have expected from a genetically “shifted” virus—the fact that a novel strain has arisen and is being transmitted from human to human is not a surprise.

Clinically, we are hoping that we have a safe and effective vaccine against the new H1N1 strain and that the supply will be sufficient to allow us to vaccinate all of our patients in a timely manner. In the meantime, the CDC's Advisory Committee on Immunization Practices has drafted new recommendations for the use of antivirals in the upcoming influenza season.

A second emerging virus, human metapneumovirus, was first isolated just 8 years ago, in previously virus-negative nasopharyngeal aspirates from children with respiratory tract infections. Since then, it has been seen worldwide, mainly circulating during the winter and spring. It is closely related to respiratory syncytial virus (RSV), and its clinical appearance resembles that of RSV in many ways, ranging from mild upper respiratory tract infections to wheezing to bronchiolitis, particularly in children less than 1 year of age. Metapneumovirus is generally milder than RSV, although the two infections often occur together.

The two infections are also essentially managed the same way—supportively, or with oxygen if the child becomes hypoxic. But this approach is far less likely with metapneumovirus than with RSV.

In a child with a clinical picture suggesting viral bronchiolitis in the hospital setting, a rapid test for RSV can help to determine whether the child can room with another child who also has RSV. If the test is negative, assume that you're dealing with metapneumovirus alone, and keep the child away from RSV-infected children. In the ambulatory setting, such testing is unlikely to be helpful.

Be aware that like RSV, metapneumovirus can also exacerbate asthma symptoms.

Bocavirus, another newly identified viral pathogen, is closely related to the parvovirus that pediatricians know as the cause of Fifth disease. Clinically, bocavirus is another RSV mimic. Children often present with wheezing in the context of an upper respiratory infection, which can easily be mistaken for asthma. In terms of severity, it probably ranks about the same as metapneumovirus.

Finally, norovirus is an emerging gastrointestinal virus that's been in the news a lot in recent years as the cause of gastritis on cruise ships. Symptoms include diarrhea, abdominal pain, and vomiting. In young children, it's fast surpassing rotavirus as the most common cause of this clinical picture, now that rotavirus vaccination is routine. Like rotavirus, norovirus is highly contagious. It may be transmitted through food, and is the likely culprit when more than one family member is affected. On the bright side, the course of illness for norovirus is shorter than that of rotavirus. Symptoms are usually gone after 1–2 days, as opposed to 5–7 days for rotavirus.

If you haven't had a chance, I highly recommend “Germs, Guns, and Steel.” It came out in 1997, but still resonates today. Diamond's 2005 book, “Collapse: How Societies Choose to Fail or Succeed” (New York: Penguin Group [USA] Inc.) is also worth reading. While the first book shows us how societies succeed, the 2005 book discusses how they can fail. We certainly see both sides in our battles with emerging and ongoing infections.

[email protected]

We're seeing a lot of new viruses lately, but that's nothing new.

The novel pandemic H1N1 flu is just one of many emerging viruses that we're seeing clinically, although we may not always recognize them. Metapneumovirus, bocavirus, and norovirus are three others. But new viruses have been emerging since time began. One of my favorite books, Jared Diamond's “Guns, Germs, and Steel: The Fates of Human Societies” (New York: W.W. Norton & Co., 1997), describes how the Europeans who conquered the New World were aided in large part by the diseases they brought with them to a vulnerable population, a weapon at least as successful as those designed for warfare.

Diamond, a geography professor at the University of California, Los Angeles, who won a Pulitzer prize for his book, also points out that from the beginning of time, humans have acquired mutated germs from animals, resulting in disease of varying severity. The Europeans conquered by spreading new disease.

Of course, the current pandemic influenza A(H1N1) strain that we're dealing with now didn't come from human conquerors, but it did come from animals—more than one type, in fact. The virus was originally referred to as swine flu because laboratory testing showed that many of its genes were similar to those of influenza viruses that normally occur in pigs in North America.

However, now it is clear that this new virus is different from that which normally circulates in North American pigs, and actually includes genes from influenza viruses that normally circulate in pigs in Europe and Asia, along with avian genes and human genes, according to the Centers for Disease Control and Prevention.

Although this influenza strain surprised us in a couple of ways—it didn't come from birds and it isn't as virulent as we would have expected from a genetically “shifted” virus—the fact that a novel strain has arisen and is being transmitted from human to human is not a surprise.

Clinically, we are hoping that we have a safe and effective vaccine against the new H1N1 strain and that the supply will be sufficient to allow us to vaccinate all of our patients in a timely manner. In the meantime, the CDC's Advisory Committee on Immunization Practices has drafted new recommendations for the use of antivirals in the upcoming influenza season.

A second emerging virus, human metapneumovirus, was first isolated just 8 years ago, in previously virus-negative nasopharyngeal aspirates from children with respiratory tract infections. Since then, it has been seen worldwide, mainly circulating during the winter and spring. It is closely related to respiratory syncytial virus (RSV), and its clinical appearance resembles that of RSV in many ways, ranging from mild upper respiratory tract infections to wheezing to bronchiolitis, particularly in children less than 1 year of age. Metapneumovirus is generally milder than RSV, although the two infections often occur together.

The two infections are also essentially managed the same way—supportively, or with oxygen if the child becomes hypoxic. But this approach is far less likely with metapneumovirus than with RSV.

In a child with a clinical picture suggesting viral bronchiolitis in the hospital setting, a rapid test for RSV can help to determine whether the child can room with another child who also has RSV. If the test is negative, assume that you're dealing with metapneumovirus alone, and keep the child away from RSV-infected children. In the ambulatory setting, such testing is unlikely to be helpful.

Be aware that like RSV, metapneumovirus can also exacerbate asthma symptoms.

Bocavirus, another newly identified viral pathogen, is closely related to the parvovirus that pediatricians know as the cause of Fifth disease. Clinically, bocavirus is another RSV mimic. Children often present with wheezing in the context of an upper respiratory infection, which can easily be mistaken for asthma. In terms of severity, it probably ranks about the same as metapneumovirus.

Finally, norovirus is an emerging gastrointestinal virus that's been in the news a lot in recent years as the cause of gastritis on cruise ships. Symptoms include diarrhea, abdominal pain, and vomiting. In young children, it's fast surpassing rotavirus as the most common cause of this clinical picture, now that rotavirus vaccination is routine. Like rotavirus, norovirus is highly contagious. It may be transmitted through food, and is the likely culprit when more than one family member is affected. On the bright side, the course of illness for norovirus is shorter than that of rotavirus. Symptoms are usually gone after 1–2 days, as opposed to 5–7 days for rotavirus.

If you haven't had a chance, I highly recommend “Germs, Guns, and Steel.” It came out in 1997, but still resonates today. Diamond's 2005 book, “Collapse: How Societies Choose to Fail or Succeed” (New York: Penguin Group [USA] Inc.) is also worth reading. While the first book shows us how societies succeed, the 2005 book discusses how they can fail. We certainly see both sides in our battles with emerging and ongoing infections.

[email protected]

We're seeing a lot of new viruses lately, but that's nothing new.

The novel pandemic H1N1 flu is just one of many emerging viruses that we're seeing clinically, although we may not always recognize them. Metapneumovirus, bocavirus, and norovirus are three others. But new viruses have been emerging since time began. One of my favorite books, Jared Diamond's “Guns, Germs, and Steel: The Fates of Human Societies” (New York: W.W. Norton & Co., 1997), describes how the Europeans who conquered the New World were aided in large part by the diseases they brought with them to a vulnerable population, a weapon at least as successful as those designed for warfare.

Diamond, a geography professor at the University of California, Los Angeles, who won a Pulitzer prize for his book, also points out that from the beginning of time, humans have acquired mutated germs from animals, resulting in disease of varying severity. The Europeans conquered by spreading new disease.

Of course, the current pandemic influenza A(H1N1) strain that we're dealing with now didn't come from human conquerors, but it did come from animals—more than one type, in fact. The virus was originally referred to as swine flu because laboratory testing showed that many of its genes were similar to those of influenza viruses that normally occur in pigs in North America.

However, now it is clear that this new virus is different from that which normally circulates in North American pigs, and actually includes genes from influenza viruses that normally circulate in pigs in Europe and Asia, along with avian genes and human genes, according to the Centers for Disease Control and Prevention.

Although this influenza strain surprised us in a couple of ways—it didn't come from birds and it isn't as virulent as we would have expected from a genetically “shifted” virus—the fact that a novel strain has arisen and is being transmitted from human to human is not a surprise.

Clinically, we are hoping that we have a safe and effective vaccine against the new H1N1 strain and that the supply will be sufficient to allow us to vaccinate all of our patients in a timely manner. In the meantime, the CDC's Advisory Committee on Immunization Practices has drafted new recommendations for the use of antivirals in the upcoming influenza season.

A second emerging virus, human metapneumovirus, was first isolated just 8 years ago, in previously virus-negative nasopharyngeal aspirates from children with respiratory tract infections. Since then, it has been seen worldwide, mainly circulating during the winter and spring. It is closely related to respiratory syncytial virus (RSV), and its clinical appearance resembles that of RSV in many ways, ranging from mild upper respiratory tract infections to wheezing to bronchiolitis, particularly in children less than 1 year of age. Metapneumovirus is generally milder than RSV, although the two infections often occur together.

The two infections are also essentially managed the same way—supportively, or with oxygen if the child becomes hypoxic. But this approach is far less likely with metapneumovirus than with RSV.

In a child with a clinical picture suggesting viral bronchiolitis in the hospital setting, a rapid test for RSV can help to determine whether the child can room with another child who also has RSV. If the test is negative, assume that you're dealing with metapneumovirus alone, and keep the child away from RSV-infected children. In the ambulatory setting, such testing is unlikely to be helpful.

Be aware that like RSV, metapneumovirus can also exacerbate asthma symptoms.

Bocavirus, another newly identified viral pathogen, is closely related to the parvovirus that pediatricians know as the cause of Fifth disease. Clinically, bocavirus is another RSV mimic. Children often present with wheezing in the context of an upper respiratory infection, which can easily be mistaken for asthma. In terms of severity, it probably ranks about the same as metapneumovirus.

Finally, norovirus is an emerging gastrointestinal virus that's been in the news a lot in recent years as the cause of gastritis on cruise ships. Symptoms include diarrhea, abdominal pain, and vomiting. In young children, it's fast surpassing rotavirus as the most common cause of this clinical picture, now that rotavirus vaccination is routine. Like rotavirus, norovirus is highly contagious. It may be transmitted through food, and is the likely culprit when more than one family member is affected. On the bright side, the course of illness for norovirus is shorter than that of rotavirus. Symptoms are usually gone after 1–2 days, as opposed to 5–7 days for rotavirus.

If you haven't had a chance, I highly recommend “Germs, Guns, and Steel.” It came out in 1997, but still resonates today. Diamond's 2005 book, “Collapse: How Societies Choose to Fail or Succeed” (New York: Penguin Group [USA] Inc.) is also worth reading. While the first book shows us how societies succeed, the 2005 book discusses how they can fail. We certainly see both sides in our battles with emerging and ongoing infections.

www.pediatricnews.com

I'd like to clear up some of the controversy regarding short-course antibiotic therapy for streptococcal tonsillopharyngitis versus longer-term therapy.

A meta-analysis published this summer from a group in Athens is the latest to call into question the wisdom of using antibiotics for less than 10 days in the treatment of group A β-hemolytic streptococcal (GABHS) tonsillopharyngitis. They examined 11 randomized controlled trials (including one of mine) comparing short-course (7 days or less) versus long-course (at least 2 days longer than short course) treatment.

The investigators concluded that short-course therapy produced inferior bacteriologic cure rates, even though the results were only statistically significant among the studies that compared short vs. long courses of penicillin (Mayo Clin. Proc. 2008;83:880–9).

In fact, in the study from my group that they included, 5 days of twice-daily treatment with cefpodoxime was as efficacious in bacteriologic eradication and clinical response (defined as cure plus improvement) as 10 days of cefpodoxime therapy, and both regimens produced superior bacteriologic efficacy, compared with a 10-day regimen of penicillin V three times daily in the treatment of GABHS tonsillopharyngitis in children (Arch. Pediatr. Adolesc. Med. 1994;148:1053–60).

Indeed, the Food and Drug Administration has approved three oral antibiotics for 5-day strep throat treatment in both children and adults: cefdinir (Omnicef), cefpodoxime (Vantin), and azithromycin (Zithromax). With the FDA approval, use of these three agents is considered a standard of care and therefore medicolegally safe. Nonetheless, the American Academy of Pediatrics continues to recommend 10 days of penicillin as the treatment of choice, and many practitioners are reluctant to embrace the short-course concept.

When I advocate in favor of short-course therapy, I'm speaking only of those that have the FDA labeling to back it up. I wouldn't use first-generation cephalosporins such as cephalexin (Keflex) or cefadroxil (Duricef) in short course, for example, even though those generics are nearly as cheap as penicillin and might be more effective than 10 days of penicillin or as effective as 5 days of one of the approved agents (although they probably aren't). Without the FDA indication for 5-day use, the medicolegal risk is too great.

But with cefdinir, cefpodoxime, and azithromycin, the literature clearly supports 5-day efficacy—defined by the FDA as 85% or better bacterial eradication at the end of treatment—in treating strep throat. Cefdinir and cefpodoxime have recently become available as generics and thus are less costly than they were before, although they are still more expensive than the first-generation cephalosporins.

In a meta-analysis Dr. Janet Casey and I conducted of 22 trials involving a total of 7,470 patients, short-course second- and third-generation cephalosporins produced a bacterial cure rate superior to 10 days of penicillin, with an odds ratio of 1.47 and cure rates of 90% vs. 70%. On the other hand, we found that 5 days of penicillin is inferior to 10 days of penicillin, just as the Mayo group did (Pediatr. Infect. Dis. J. 2005;24:909–17).

The Athens group lumped together studies using different types of comparisons in making their overall conclusion, which I don't think is a helpful way of reporting meta-analysis data. Moreover, as Dr. Casey and I pointed out in our article, in the real world few children complete 10 days of treatment anyway. When you factor that in, the 5-day option looks even better.

Another important issue affecting the results of these studies is whether strep carriers were excluded. Penicillin does not do a good job of eradicating carrier status, whereas cephalosporins do. In addition, a strep carrier who has symptoms caused by a virus would be mistakenly recorded as a clinical failure.

We separately analyzed the nine studies that excluded strep carriers in our 2005 meta-analysis, as well as in another meta-analysis that we published in 2004 in which we showed that the likelihood of bacteriologic and clinical failure of GABHS tonsillopharyngitis in children is significantly less with 10 days of treatment with an oral cephalosporin than with oral penicillin for 10 days (Pediatrics 2004;113:866–82). In both analyses, the cephalosporins still came out ahead.

Finally, cure rates for azithromycin should not be lumped into the same category as rates for the cephalosporins, because azithromycin has a half-life of about 96 hours, compared with 2–4 hours with the cephalosporins. Thus, when you give azithromycin for 5 days, it stays in the body as long as 10 days of another antibiotic.

The issue here is in the dosing, which often causes confusion among practitioners. For strep throat, the 5-day dose of azithromycin for children is a single 10- to 12-mg/kg per day dose for each of the 5 days. This is different from the dosage given for otitis media or sinusitis, which is 10–12 mg/kg per day for just the first day, followed by 5 mg/kg per day for the next 4 days. It's easy to forget that, because we write far more prescriptions for ear and sinus infections.

Dr. Casey and I have shown that the otitis media dose of azithromycin is inferior for the treatment of strep throat (Clin. Infect. Dis. 2005;40:1748–55). If you accidentally prescribe the lower dose for strep throat and the child develops rheumatic fever, you may have a lawsuit on your hands.

In adolescents and adults with strep throat, this means that you need two of the standard “Z-PAKs” in order to give a high enough dose for eradication. The Z-PAKs label doesn't say this because our data showing inferiority weren't published until after the product was approved for treating strep throat. Thus, in this case you won't get sued if you just prescribe one pack, … but there's a better chance the patient will be cured if you prescribe two.

I hope I've convinced you that 5-day treatment is a viable option for strep throat, because the guidelines from AAP and other organizations aren't likely to change any time soon. Guidelines should be based on data, but the current guideline writers prefer to harken back to penicillin studies done in the 1940s and 1950s, when rheumatic fever was still prevalent. However, a recommendation for 10 days of cephalosporin or amoxicillin for treating strep throat is currently under discussion. It stands to reason: The only way to prevent rheumatic fever is to eradicate strep, and these drugs do that better than penicillin!

Keep in mind too that at the time those old studies were done, penicillin cured 95% of strep bacteria. Today that number is just 65%, because of the bombardment of antimicrobials we've been using for the last several decades. The newer literature suggests it's time for change.

I have performed clinical trials, received honoraria, and/or served as a consultant for Abbott Laboratories and Pfizer Inc.

www.pediatricnews.com

I'd like to clear up some of the controversy regarding short-course antibiotic therapy for streptococcal tonsillopharyngitis versus longer-term therapy.

A meta-analysis published this summer from a group in Athens is the latest to call into question the wisdom of using antibiotics for less than 10 days in the treatment of group A β-hemolytic streptococcal (GABHS) tonsillopharyngitis. They examined 11 randomized controlled trials (including one of mine) comparing short-course (7 days or less) versus long-course (at least 2 days longer than short course) treatment.

The investigators concluded that short-course therapy produced inferior bacteriologic cure rates, even though the results were only statistically significant among the studies that compared short vs. long courses of penicillin (Mayo Clin. Proc. 2008;83:880–9).

In fact, in the study from my group that they included, 5 days of twice-daily treatment with cefpodoxime was as efficacious in bacteriologic eradication and clinical response (defined as cure plus improvement) as 10 days of cefpodoxime therapy, and both regimens produced superior bacteriologic efficacy, compared with a 10-day regimen of penicillin V three times daily in the treatment of GABHS tonsillopharyngitis in children (Arch. Pediatr. Adolesc. Med. 1994;148:1053–60).

Indeed, the Food and Drug Administration has approved three oral antibiotics for 5-day strep throat treatment in both children and adults: cefdinir (Omnicef), cefpodoxime (Vantin), and azithromycin (Zithromax). With the FDA approval, use of these three agents is considered a standard of care and therefore medicolegally safe. Nonetheless, the American Academy of Pediatrics continues to recommend 10 days of penicillin as the treatment of choice, and many practitioners are reluctant to embrace the short-course concept.

When I advocate in favor of short-course therapy, I'm speaking only of those that have the FDA labeling to back it up. I wouldn't use first-generation cephalosporins such as cephalexin (Keflex) or cefadroxil (Duricef) in short course, for example, even though those generics are nearly as cheap as penicillin and might be more effective than 10 days of penicillin or as effective as 5 days of one of the approved agents (although they probably aren't). Without the FDA indication for 5-day use, the medicolegal risk is too great.

But with cefdinir, cefpodoxime, and azithromycin, the literature clearly supports 5-day efficacy—defined by the FDA as 85% or better bacterial eradication at the end of treatment—in treating strep throat. Cefdinir and cefpodoxime have recently become available as generics and thus are less costly than they were before, although they are still more expensive than the first-generation cephalosporins.

In a meta-analysis Dr. Janet Casey and I conducted of 22 trials involving a total of 7,470 patients, short-course second- and third-generation cephalosporins produced a bacterial cure rate superior to 10 days of penicillin, with an odds ratio of 1.47 and cure rates of 90% vs. 70%. On the other hand, we found that 5 days of penicillin is inferior to 10 days of penicillin, just as the Mayo group did (Pediatr. Infect. Dis. J. 2005;24:909–17).

The Athens group lumped together studies using different types of comparisons in making their overall conclusion, which I don't think is a helpful way of reporting meta-analysis data. Moreover, as Dr. Casey and I pointed out in our article, in the real world few children complete 10 days of treatment anyway. When you factor that in, the 5-day option looks even better.

Another important issue affecting the results of these studies is whether strep carriers were excluded. Penicillin does not do a good job of eradicating carrier status, whereas cephalosporins do. In addition, a strep carrier who has symptoms caused by a virus would be mistakenly recorded as a clinical failure.

We separately analyzed the nine studies that excluded strep carriers in our 2005 meta-analysis, as well as in another meta-analysis that we published in 2004 in which we showed that the likelihood of bacteriologic and clinical failure of GABHS tonsillopharyngitis in children is significantly less with 10 days of treatment with an oral cephalosporin than with oral penicillin for 10 days (Pediatrics 2004;113:866–82). In both analyses, the cephalosporins still came out ahead.

Finally, cure rates for azithromycin should not be lumped into the same category as rates for the cephalosporins, because azithromycin has a half-life of about 96 hours, compared with 2–4 hours with the cephalosporins. Thus, when you give azithromycin for 5 days, it stays in the body as long as 10 days of another antibiotic.

The issue here is in the dosing, which often causes confusion among practitioners. For strep throat, the 5-day dose of azithromycin for children is a single 10- to 12-mg/kg per day dose for each of the 5 days. This is different from the dosage given for otitis media or sinusitis, which is 10–12 mg/kg per day for just the first day, followed by 5 mg/kg per day for the next 4 days. It's easy to forget that, because we write far more prescriptions for ear and sinus infections.

Dr. Casey and I have shown that the otitis media dose of azithromycin is inferior for the treatment of strep throat (Clin. Infect. Dis. 2005;40:1748–55). If you accidentally prescribe the lower dose for strep throat and the child develops rheumatic fever, you may have a lawsuit on your hands.

In adolescents and adults with strep throat, this means that you need two of the standard “Z-PAKs” in order to give a high enough dose for eradication. The Z-PAKs label doesn't say this because our data showing inferiority weren't published until after the product was approved for treating strep throat. Thus, in this case you won't get sued if you just prescribe one pack, … but there's a better chance the patient will be cured if you prescribe two.

I hope I've convinced you that 5-day treatment is a viable option for strep throat, because the guidelines from AAP and other organizations aren't likely to change any time soon. Guidelines should be based on data, but the current guideline writers prefer to harken back to penicillin studies done in the 1940s and 1950s, when rheumatic fever was still prevalent. However, a recommendation for 10 days of cephalosporin or amoxicillin for treating strep throat is currently under discussion. It stands to reason: The only way to prevent rheumatic fever is to eradicate strep, and these drugs do that better than penicillin!

Keep in mind too that at the time those old studies were done, penicillin cured 95% of strep bacteria. Today that number is just 65%, because of the bombardment of antimicrobials we've been using for the last several decades. The newer literature suggests it's time for change.

I have performed clinical trials, received honoraria, and/or served as a consultant for Abbott Laboratories and Pfizer Inc.

www.pediatricnews.com

I'd like to clear up some of the controversy regarding short-course antibiotic therapy for streptococcal tonsillopharyngitis versus longer-term therapy.

A meta-analysis published this summer from a group in Athens is the latest to call into question the wisdom of using antibiotics for less than 10 days in the treatment of group A β-hemolytic streptococcal (GABHS) tonsillopharyngitis. They examined 11 randomized controlled trials (including one of mine) comparing short-course (7 days or less) versus long-course (at least 2 days longer than short course) treatment.

The investigators concluded that short-course therapy produced inferior bacteriologic cure rates, even though the results were only statistically significant among the studies that compared short vs. long courses of penicillin (Mayo Clin. Proc. 2008;83:880–9).

In fact, in the study from my group that they included, 5 days of twice-daily treatment with cefpodoxime was as efficacious in bacteriologic eradication and clinical response (defined as cure plus improvement) as 10 days of cefpodoxime therapy, and both regimens produced superior bacteriologic efficacy, compared with a 10-day regimen of penicillin V three times daily in the treatment of GABHS tonsillopharyngitis in children (Arch. Pediatr. Adolesc. Med. 1994;148:1053–60).

Indeed, the Food and Drug Administration has approved three oral antibiotics for 5-day strep throat treatment in both children and adults: cefdinir (Omnicef), cefpodoxime (Vantin), and azithromycin (Zithromax). With the FDA approval, use of these three agents is considered a standard of care and therefore medicolegally safe. Nonetheless, the American Academy of Pediatrics continues to recommend 10 days of penicillin as the treatment of choice, and many practitioners are reluctant to embrace the short-course concept.

When I advocate in favor of short-course therapy, I'm speaking only of those that have the FDA labeling to back it up. I wouldn't use first-generation cephalosporins such as cephalexin (Keflex) or cefadroxil (Duricef) in short course, for example, even though those generics are nearly as cheap as penicillin and might be more effective than 10 days of penicillin or as effective as 5 days of one of the approved agents (although they probably aren't). Without the FDA indication for 5-day use, the medicolegal risk is too great.

But with cefdinir, cefpodoxime, and azithromycin, the literature clearly supports 5-day efficacy—defined by the FDA as 85% or better bacterial eradication at the end of treatment—in treating strep throat. Cefdinir and cefpodoxime have recently become available as generics and thus are less costly than they were before, although they are still more expensive than the first-generation cephalosporins.

In a meta-analysis Dr. Janet Casey and I conducted of 22 trials involving a total of 7,470 patients, short-course second- and third-generation cephalosporins produced a bacterial cure rate superior to 10 days of penicillin, with an odds ratio of 1.47 and cure rates of 90% vs. 70%. On the other hand, we found that 5 days of penicillin is inferior to 10 days of penicillin, just as the Mayo group did (Pediatr. Infect. Dis. J. 2005;24:909–17).

The Athens group lumped together studies using different types of comparisons in making their overall conclusion, which I don't think is a helpful way of reporting meta-analysis data. Moreover, as Dr. Casey and I pointed out in our article, in the real world few children complete 10 days of treatment anyway. When you factor that in, the 5-day option looks even better.

Another important issue affecting the results of these studies is whether strep carriers were excluded. Penicillin does not do a good job of eradicating carrier status, whereas cephalosporins do. In addition, a strep carrier who has symptoms caused by a virus would be mistakenly recorded as a clinical failure.

We separately analyzed the nine studies that excluded strep carriers in our 2005 meta-analysis, as well as in another meta-analysis that we published in 2004 in which we showed that the likelihood of bacteriologic and clinical failure of GABHS tonsillopharyngitis in children is significantly less with 10 days of treatment with an oral cephalosporin than with oral penicillin for 10 days (Pediatrics 2004;113:866–82). In both analyses, the cephalosporins still came out ahead.

Finally, cure rates for azithromycin should not be lumped into the same category as rates for the cephalosporins, because azithromycin has a half-life of about 96 hours, compared with 2–4 hours with the cephalosporins. Thus, when you give azithromycin for 5 days, it stays in the body as long as 10 days of another antibiotic.

The issue here is in the dosing, which often causes confusion among practitioners. For strep throat, the 5-day dose of azithromycin for children is a single 10- to 12-mg/kg per day dose for each of the 5 days. This is different from the dosage given for otitis media or sinusitis, which is 10–12 mg/kg per day for just the first day, followed by 5 mg/kg per day for the next 4 days. It's easy to forget that, because we write far more prescriptions for ear and sinus infections.

Dr. Casey and I have shown that the otitis media dose of azithromycin is inferior for the treatment of strep throat (Clin. Infect. Dis. 2005;40:1748–55). If you accidentally prescribe the lower dose for strep throat and the child develops rheumatic fever, you may have a lawsuit on your hands.

In adolescents and adults with strep throat, this means that you need two of the standard “Z-PAKs” in order to give a high enough dose for eradication. The Z-PAKs label doesn't say this because our data showing inferiority weren't published until after the product was approved for treating strep throat. Thus, in this case you won't get sued if you just prescribe one pack, … but there's a better chance the patient will be cured if you prescribe two.

I hope I've convinced you that 5-day treatment is a viable option for strep throat, because the guidelines from AAP and other organizations aren't likely to change any time soon. Guidelines should be based on data, but the current guideline writers prefer to harken back to penicillin studies done in the 1940s and 1950s, when rheumatic fever was still prevalent. However, a recommendation for 10 days of cephalosporin or amoxicillin for treating strep throat is currently under discussion. It stands to reason: The only way to prevent rheumatic fever is to eradicate strep, and these drugs do that better than penicillin!

Keep in mind too that at the time those old studies were done, penicillin cured 95% of strep bacteria. Today that number is just 65%, because of the bombardment of antimicrobials we've been using for the last several decades. The newer literature suggests it's time for change.

I have performed clinical trials, received honoraria, and/or served as a consultant for Abbott Laboratories and Pfizer Inc.

[email protected]

Innovative vaccines in the pipeline offer needleless alternatives that will help alleviate the human pincushion problem as well as facilitate immunization in the developing world.

Transdermal patches, oral administration via food or drink, and new intranasal vaccines are three exciting technologies that I foresee becoming available within the next 2-5 years.

Such alternative vaccine delivery systems are particularly critical in the developing world, where shortages of needles, contamination problems, and lack of trained personnel often make injections risky or impossible.

And of course, injections are uncomfortable no matter where in the world you happen to be.

It's logical to assume that one would target an infection that enters the body through the respiratory tract by an intranasal vaccine, while gastrointestinal pathogens would be more amenable to vaccines delivered orally.

However, that's not necessarily the case. Intranasal vaccine administration could be used for gastrointestinal pathogens, and oral administration for respiratory ones, because the process proceeds in the same fashion once the antigen gains access to the antigen-presenting cells and is taken to the B cells and T cells in the lymph nodes and spleen. And of course, antigens delivered via patch can go anywhere once they are delivered to the regional lymph nodes draining the skin.

Typically, these new technologies are developed with venture capital by small firms and, if successful, get picked up by the larger vaccine manufacturers.

The latest buzz has come from a recent phase II randomized, double-blind, placebo-controlled field trial of a traveler's diarrhea vaccine skin patch that contains heat-labile enterotoxin (LT) from Escherichia coli.

Of 201 healthy adults who were planning trips to either Mexico or Guatemala, 67 were randomized to receive the LT patch and 134 assigned placebo. A total of 59 received a second LT patch and completed in-country surveillance, as did 111 who received a second placebo patch. Patches were worn for about 6 hours and then discarded, at 3 weeks and 1 week prior to travel. The average stay in Mexico or Guatemala was 12.4 days (Lancet 2008;371:2019-25).

The results were promising: The proportion of individuals with diarrhea of any cause–as recorded in diary cards–was 15% with the LT patch, compared with 22% with placebo. Severe diarrhea occurred in 2% vs. 11%. The proportions with diarrhea caused by enterotoxigenic Escherichia coli (ETEC) were 5% with the LT vaccine patch vs. 10% with placebo, for a protective efficacy of 49%. For severe diarrhea, those proportions were 5% vs. 2%, translating to 62% protective efficacy.

Moreover, those who did develop diarrhea with the LT patch had a milder course of disease, with a mean stool frequency of 3.7 per episode, compared with 10.5 with placebo. Duration of diarrhea was also much less, 0.5 vs. 2.1 days. For ETEC diarrhea, the frequencies were 4.3 vs. 10.5 per episode, and the duration 0.4 vs. 2.2 days.

As it turns out, patches are very attractive delivery systems for vaccines because they introduce the antigens just below the epidermis. This local epidermal delivery appears to produce a more robust immune response than does an intramuscular injection.

On the downside, patches do involve greater potential for local site irritation. In the ETEC patch trial, application of the patch–which involves scraping the skin with a mild abrasive prior to affixing the patch–caused local pruritus in 67% vs. 4% with placebo, rash in 61% vs. 1%, respectively, and pigmentation changes in 7% vs. 0. However, there were no significant differences in systemic events such as fever, malaise, or headache. In my view, the local irritation is minor, compared with the benefits of needleless technology.

Patch technology also is being studied for the prevention of disease caused by a variety of other pathogens, including tetanus and Helicobacter pylori.

I'm also excited about the use of transgenic plants such as potatoes and corn as another alternative vaccine delivery method. Thus far in early human trials of diarrheal diseases, transgenic plant-derived vaccines appear to be safe and immunogenic without the need for a buffer or vehicle other than the plant cell.

Among these are transgenic potatoes and corn that express the B subunit of the ETEC toxin, another transgenic potato that expresses the hepatitis B surface antigen, and a third, the capsid protein of norovirus (NV).

In a study of the last, 24 healthy adult volunteers were randomly assigned to one of three regimens: Three doses of transgenic potato expressing NV capsid protein on days 0, 7, and 21, two doses of the transgenic potato on days 0 and 21 plus a dose of wild-type potato on day 7, or three doses of wild-type potato on days 0, 7, and 21. The potatoes were peeled and diced and ingested raw on the day of vaccination.

The volunteers in all three studies completed a diary each day for 7 days after ingesting each dose to record the occurrence of nausea, vomiting, cramps, diarrhea, or other symptoms. Blood was collected before and at 7, 14, 21, 28, and 60 days after the first dose of transgenic plant for measurement of serum antibodies to LT or NV capsid protein. Whole blood was collected for antibody-secreting cell assays on days 0, 7, 14, 21, and 28 (J. Infect. Dis. 2000;182:302-5).

Nineteen of the 20 subjects who ingested transgenic potatoes developed significant increases in the numbers of specific IgA antibody-secreting cells, 4 developed specific serum IgG, and 6 developed specific stool IgA.

Overall, 19 of 20 subjects developed an immune response of some kind, although the level of serum antibody increases was modest.

As for the intranasal route, my lab under National Institutes of Health-funded grants is working on anthrax, botulism, and tularemia in the bioterrorism arena.

Others are investigating intranasal vaccines against respiratory syncytial virus.

I doubt that companies will attempt to transition already-existing injectable vaccines to other modes of delivery, with a few exceptions like those for tetanus and hepatitis B. Rather, I think that much of this work will apply to the prevention of diseases that we currently are unable to prevent, both here and in the developing world.

I have no financial relationships with any of the companies developing these alternative vaccines.

[email protected]

Innovative vaccines in the pipeline offer needleless alternatives that will help alleviate the human pincushion problem as well as facilitate immunization in the developing world.

Transdermal patches, oral administration via food or drink, and new intranasal vaccines are three exciting technologies that I foresee becoming available within the next 2-5 years.

Such alternative vaccine delivery systems are particularly critical in the developing world, where shortages of needles, contamination problems, and lack of trained personnel often make injections risky or impossible.

And of course, injections are uncomfortable no matter where in the world you happen to be.

It's logical to assume that one would target an infection that enters the body through the respiratory tract by an intranasal vaccine, while gastrointestinal pathogens would be more amenable to vaccines delivered orally.

However, that's not necessarily the case. Intranasal vaccine administration could be used for gastrointestinal pathogens, and oral administration for respiratory ones, because the process proceeds in the same fashion once the antigen gains access to the antigen-presenting cells and is taken to the B cells and T cells in the lymph nodes and spleen. And of course, antigens delivered via patch can go anywhere once they are delivered to the regional lymph nodes draining the skin.

Typically, these new technologies are developed with venture capital by small firms and, if successful, get picked up by the larger vaccine manufacturers.

The latest buzz has come from a recent phase II randomized, double-blind, placebo-controlled field trial of a traveler's diarrhea vaccine skin patch that contains heat-labile enterotoxin (LT) from Escherichia coli.

Of 201 healthy adults who were planning trips to either Mexico or Guatemala, 67 were randomized to receive the LT patch and 134 assigned placebo. A total of 59 received a second LT patch and completed in-country surveillance, as did 111 who received a second placebo patch. Patches were worn for about 6 hours and then discarded, at 3 weeks and 1 week prior to travel. The average stay in Mexico or Guatemala was 12.4 days (Lancet 2008;371:2019-25).

The results were promising: The proportion of individuals with diarrhea of any cause–as recorded in diary cards–was 15% with the LT patch, compared with 22% with placebo. Severe diarrhea occurred in 2% vs. 11%. The proportions with diarrhea caused by enterotoxigenic Escherichia coli (ETEC) were 5% with the LT vaccine patch vs. 10% with placebo, for a protective efficacy of 49%. For severe diarrhea, those proportions were 5% vs. 2%, translating to 62% protective efficacy.

Moreover, those who did develop diarrhea with the LT patch had a milder course of disease, with a mean stool frequency of 3.7 per episode, compared with 10.5 with placebo. Duration of diarrhea was also much less, 0.5 vs. 2.1 days. For ETEC diarrhea, the frequencies were 4.3 vs. 10.5 per episode, and the duration 0.4 vs. 2.2 days.

As it turns out, patches are very attractive delivery systems for vaccines because they introduce the antigens just below the epidermis. This local epidermal delivery appears to produce a more robust immune response than does an intramuscular injection.

On the downside, patches do involve greater potential for local site irritation. In the ETEC patch trial, application of the patch–which involves scraping the skin with a mild abrasive prior to affixing the patch–caused local pruritus in 67% vs. 4% with placebo, rash in 61% vs. 1%, respectively, and pigmentation changes in 7% vs. 0. However, there were no significant differences in systemic events such as fever, malaise, or headache. In my view, the local irritation is minor, compared with the benefits of needleless technology.

Patch technology also is being studied for the prevention of disease caused by a variety of other pathogens, including tetanus and Helicobacter pylori.

I'm also excited about the use of transgenic plants such as potatoes and corn as another alternative vaccine delivery method. Thus far in early human trials of diarrheal diseases, transgenic plant-derived vaccines appear to be safe and immunogenic without the need for a buffer or vehicle other than the plant cell.

Among these are transgenic potatoes and corn that express the B subunit of the ETEC toxin, another transgenic potato that expresses the hepatitis B surface antigen, and a third, the capsid protein of norovirus (NV).

In a study of the last, 24 healthy adult volunteers were randomly assigned to one of three regimens: Three doses of transgenic potato expressing NV capsid protein on days 0, 7, and 21, two doses of the transgenic potato on days 0 and 21 plus a dose of wild-type potato on day 7, or three doses of wild-type potato on days 0, 7, and 21. The potatoes were peeled and diced and ingested raw on the day of vaccination.

The volunteers in all three studies completed a diary each day for 7 days after ingesting each dose to record the occurrence of nausea, vomiting, cramps, diarrhea, or other symptoms. Blood was collected before and at 7, 14, 21, 28, and 60 days after the first dose of transgenic plant for measurement of serum antibodies to LT or NV capsid protein. Whole blood was collected for antibody-secreting cell assays on days 0, 7, 14, 21, and 28 (J. Infect. Dis. 2000;182:302-5).

Nineteen of the 20 subjects who ingested transgenic potatoes developed significant increases in the numbers of specific IgA antibody-secreting cells, 4 developed specific serum IgG, and 6 developed specific stool IgA.

Overall, 19 of 20 subjects developed an immune response of some kind, although the level of serum antibody increases was modest.

As for the intranasal route, my lab under National Institutes of Health-funded grants is working on anthrax, botulism, and tularemia in the bioterrorism arena.

Others are investigating intranasal vaccines against respiratory syncytial virus.

I doubt that companies will attempt to transition already-existing injectable vaccines to other modes of delivery, with a few exceptions like those for tetanus and hepatitis B. Rather, I think that much of this work will apply to the prevention of diseases that we currently are unable to prevent, both here and in the developing world.

I have no financial relationships with any of the companies developing these alternative vaccines.

[email protected]

Innovative vaccines in the pipeline offer needleless alternatives that will help alleviate the human pincushion problem as well as facilitate immunization in the developing world.

Transdermal patches, oral administration via food or drink, and new intranasal vaccines are three exciting technologies that I foresee becoming available within the next 2-5 years.

Such alternative vaccine delivery systems are particularly critical in the developing world, where shortages of needles, contamination problems, and lack of trained personnel often make injections risky or impossible.

And of course, injections are uncomfortable no matter where in the world you happen to be.

It's logical to assume that one would target an infection that enters the body through the respiratory tract by an intranasal vaccine, while gastrointestinal pathogens would be more amenable to vaccines delivered orally.

However, that's not necessarily the case. Intranasal vaccine administration could be used for gastrointestinal pathogens, and oral administration for respiratory ones, because the process proceeds in the same fashion once the antigen gains access to the antigen-presenting cells and is taken to the B cells and T cells in the lymph nodes and spleen. And of course, antigens delivered via patch can go anywhere once they are delivered to the regional lymph nodes draining the skin.

Typically, these new technologies are developed with venture capital by small firms and, if successful, get picked up by the larger vaccine manufacturers.

The latest buzz has come from a recent phase II randomized, double-blind, placebo-controlled field trial of a traveler's diarrhea vaccine skin patch that contains heat-labile enterotoxin (LT) from Escherichia coli.

Of 201 healthy adults who were planning trips to either Mexico or Guatemala, 67 were randomized to receive the LT patch and 134 assigned placebo. A total of 59 received a second LT patch and completed in-country surveillance, as did 111 who received a second placebo patch. Patches were worn for about 6 hours and then discarded, at 3 weeks and 1 week prior to travel. The average stay in Mexico or Guatemala was 12.4 days (Lancet 2008;371:2019-25).

The results were promising: The proportion of individuals with diarrhea of any cause–as recorded in diary cards–was 15% with the LT patch, compared with 22% with placebo. Severe diarrhea occurred in 2% vs. 11%. The proportions with diarrhea caused by enterotoxigenic Escherichia coli (ETEC) were 5% with the LT vaccine patch vs. 10% with placebo, for a protective efficacy of 49%. For severe diarrhea, those proportions were 5% vs. 2%, translating to 62% protective efficacy.

Moreover, those who did develop diarrhea with the LT patch had a milder course of disease, with a mean stool frequency of 3.7 per episode, compared with 10.5 with placebo. Duration of diarrhea was also much less, 0.5 vs. 2.1 days. For ETEC diarrhea, the frequencies were 4.3 vs. 10.5 per episode, and the duration 0.4 vs. 2.2 days.

As it turns out, patches are very attractive delivery systems for vaccines because they introduce the antigens just below the epidermis. This local epidermal delivery appears to produce a more robust immune response than does an intramuscular injection.

On the downside, patches do involve greater potential for local site irritation. In the ETEC patch trial, application of the patch–which involves scraping the skin with a mild abrasive prior to affixing the patch–caused local pruritus in 67% vs. 4% with placebo, rash in 61% vs. 1%, respectively, and pigmentation changes in 7% vs. 0. However, there were no significant differences in systemic events such as fever, malaise, or headache. In my view, the local irritation is minor, compared with the benefits of needleless technology.

Patch technology also is being studied for the prevention of disease caused by a variety of other pathogens, including tetanus and Helicobacter pylori.

I'm also excited about the use of transgenic plants such as potatoes and corn as another alternative vaccine delivery method. Thus far in early human trials of diarrheal diseases, transgenic plant-derived vaccines appear to be safe and immunogenic without the need for a buffer or vehicle other than the plant cell.

Among these are transgenic potatoes and corn that express the B subunit of the ETEC toxin, another transgenic potato that expresses the hepatitis B surface antigen, and a third, the capsid protein of norovirus (NV).

In a study of the last, 24 healthy adult volunteers were randomly assigned to one of three regimens: Three doses of transgenic potato expressing NV capsid protein on days 0, 7, and 21, two doses of the transgenic potato on days 0 and 21 plus a dose of wild-type potato on day 7, or three doses of wild-type potato on days 0, 7, and 21. The potatoes were peeled and diced and ingested raw on the day of vaccination.

The volunteers in all three studies completed a diary each day for 7 days after ingesting each dose to record the occurrence of nausea, vomiting, cramps, diarrhea, or other symptoms. Blood was collected before and at 7, 14, 21, 28, and 60 days after the first dose of transgenic plant for measurement of serum antibodies to LT or NV capsid protein. Whole blood was collected for antibody-secreting cell assays on days 0, 7, 14, 21, and 28 (J. Infect. Dis. 2000;182:302-5).

Nineteen of the 20 subjects who ingested transgenic potatoes developed significant increases in the numbers of specific IgA antibody-secreting cells, 4 developed specific serum IgG, and 6 developed specific stool IgA.

Overall, 19 of 20 subjects developed an immune response of some kind, although the level of serum antibody increases was modest.

As for the intranasal route, my lab under National Institutes of Health-funded grants is working on anthrax, botulism, and tularemia in the bioterrorism arena.

Others are investigating intranasal vaccines against respiratory syncytial virus.

I doubt that companies will attempt to transition already-existing injectable vaccines to other modes of delivery, with a few exceptions like those for tetanus and hepatitis B. Rather, I think that much of this work will apply to the prevention of diseases that we currently are unable to prevent, both here and in the developing world.

I have no financial relationships with any of the companies developing these alternative vaccines.