Michael E. Pichichero

[email protected]

I would like to clear up some of the confusion surrounding a recent federal government ruling that vaccines might have contributed to autismlike symptoms in a child with underlying mitochondrial disorder. The media have portrayed this as an acknowledgment of a link between vaccines and autism, and that simply isn't the case.

The story broke on the Internet blog of journalist David Kirby, the author of a book promoting the theory that the thimerosal preservative in vaccines is linked with autism. He obtained a copy of the ruling from an unnamed source and posted it on the Internet. The family of the child then spoke publicly about the case at a press briefing sponsored by an autism advocacy group.

The document was evidently issued last November by an official in the Department of Justice who wrote that medical personnel at the Department of Health and Human Services' Division of Vaccine Injury Compensation (DVIC) had reviewed the case and “concluded that compensation is appropriate.”

The case involves a 9-year-old girl who, at 18 months of age, received five different vaccines on the same day and in the following months began exhibiting abnormal symptoms deemed to be “regressive encephalopathy with features consistent with an autism spectrum disorder.” Subsequent evaluation led to the diagnosis of a previously unrecognized underlying mitochondrial disorder.

At this writing, the federal Health Resources and Services Administration (HRSA), which administers the Vaccine Injury Compensation Program through which this case was reportedly filed, could not confirm any of the information reported because the agency had not yet received written consent from the family to do so.

However, HRSA said in a statement that “HRSA has maintained and continues to maintain the position that vaccines do not cause autism, and has never concluded in any case that autism was caused by vaccination.”

But that hasn't stopped the media reports, which have caused a great deal of concern and confusion among the public and the medical community. According to the document, “DVIC has concluded that the facts of this case meet the statutory criteria for demonstrating that the vaccinations [the child] received on July 19, 2000, significantly aggravated an underlying mitochondrial disorder, which predisposed her to deficits in cellular energy metabolism, and manifested as a regressive encephalopathy with features of autism spectrum disorder.”

First of all, note that this report is not talking about the disorder “autism.” Indeed, children with mitochondrial disorders, which produce severe deficits in cellular energy metabolism, often develop regressive encephalopathy and features of autism spectrum disorder such as loss of language skills and impaired motor coordination.

Such manifestations are more likely to occur in those with mitochondrial disorders when there is a physiological stressor such as a viral or bacterial illness. Therefore, it is plausible that receiving five vaccines in 1 day also could provoke the same outcome.

Is that stress equivalent to influenza or a cold? We don't know, but anything that perturbs the balance of energy metabolism in these children is likely to have an adverse impact. Therefore, we could argue that these children should be vaccinated to prevent more severe illness.

Note, too, that the ruling does not mention thimerosal, the vaccine ingredient—now removed from nearly all childhood vaccines—that many activists have claimed causes autism.

In February, my colleagues and I published a study in which we showed that the measurement of blood levels of methylmercury from fish used to make nearly all recommendations pertaining to safe levels of mercury exposure were completely inaccurate for risk assessments of children who received vaccines containing thimerosal.

The recommendations in 1999 by the American Academy of Pediatrics and others were based on toxicology data in adults regarding the oral consumption of methylmercury, as would occur from eating fish. Compared with the blood half-life of about 45 days associated with methylmercury from fish consumption, the half-life of intramuscular ethyl mercury from thimerosal in vaccines in infants is substantially shorter, at a mean of 3.7 days with a return to baseline by 30 days post vaccination (Pediatrics 2008;121:e208–14).

Unfortunately, the antivaccine claims are unlikely to abate until more is known about what really does cause autism. Several reports in the literature have documented an association between mitochondrial disorders and similarities to autism spectrum disorders, but none have shown a direct connection.

On the other hand, there is increasing evidence that autism is an inherited disorder. In one interesting example, new data from 751 families with autism participating in the Autism Genetic Resource Exchange point to a novel, recurrent gene microdeletion and a reciprocal microduplication that are associated with substantial susceptibility to autism, and appear to account for approximately 1% of cases (N. Engl. J. Med. 2008;358:667–75).

I suspect we will see more evidence of genetic markers for autism in the future.

In the meantime, I hope that clinicians will view the situation of this particular child as a sad but isolated case. Mitochondrial disorders are extremely rare—I have never seen one in my 20-plus years of practicing general pediatrics. And even among these patients, the benefits of vaccination still likely outweigh the risks.

Thimerosal has now been removed from all childhood vaccines except for multidose influenza vaccines, but the rates of autism have not abated, thus providing very strong epidemiologic evidence that thimerosal did not cause the upswing in autism spectrum disorder diagnoses that began in the 1990s and still continues. The antivaccine folks have begun switching their argument to say that it is multiple vaccines that cause autism and other neurodevelopmental problems by “overwhelming” the immune system.

In an effort to quantitate that, current research is looking at the effect on the immune system when a healthy child becomes colonized with common bacteria such as Streptococcus pneumoniae. Thus far, we know that the immune “stress” associated with asymptomatic nasal colonization is quite a bit greater than that of the purified vaccines given to children today.

Infectious diseases are “stressful” to the immune system. Vaccines are not risk free, but they induce far less “stress.” We need to inform our patients and their families that while everything has some risk, the real question is risk versus benefit. From that perspective, vaccines are the clear winners.

[email protected]

I would like to clear up some of the confusion surrounding a recent federal government ruling that vaccines might have contributed to autismlike symptoms in a child with underlying mitochondrial disorder. The media have portrayed this as an acknowledgment of a link between vaccines and autism, and that simply isn't the case.

The story broke on the Internet blog of journalist David Kirby, the author of a book promoting the theory that the thimerosal preservative in vaccines is linked with autism. He obtained a copy of the ruling from an unnamed source and posted it on the Internet. The family of the child then spoke publicly about the case at a press briefing sponsored by an autism advocacy group.

The document was evidently issued last November by an official in the Department of Justice who wrote that medical personnel at the Department of Health and Human Services' Division of Vaccine Injury Compensation (DVIC) had reviewed the case and “concluded that compensation is appropriate.”

The case involves a 9-year-old girl who, at 18 months of age, received five different vaccines on the same day and in the following months began exhibiting abnormal symptoms deemed to be “regressive encephalopathy with features consistent with an autism spectrum disorder.” Subsequent evaluation led to the diagnosis of a previously unrecognized underlying mitochondrial disorder.

At this writing, the federal Health Resources and Services Administration (HRSA), which administers the Vaccine Injury Compensation Program through which this case was reportedly filed, could not confirm any of the information reported because the agency had not yet received written consent from the family to do so.

However, HRSA said in a statement that “HRSA has maintained and continues to maintain the position that vaccines do not cause autism, and has never concluded in any case that autism was caused by vaccination.”

But that hasn't stopped the media reports, which have caused a great deal of concern and confusion among the public and the medical community. According to the document, “DVIC has concluded that the facts of this case meet the statutory criteria for demonstrating that the vaccinations [the child] received on July 19, 2000, significantly aggravated an underlying mitochondrial disorder, which predisposed her to deficits in cellular energy metabolism, and manifested as a regressive encephalopathy with features of autism spectrum disorder.”

First of all, note that this report is not talking about the disorder “autism.” Indeed, children with mitochondrial disorders, which produce severe deficits in cellular energy metabolism, often develop regressive encephalopathy and features of autism spectrum disorder such as loss of language skills and impaired motor coordination.

Such manifestations are more likely to occur in those with mitochondrial disorders when there is a physiological stressor such as a viral or bacterial illness. Therefore, it is plausible that receiving five vaccines in 1 day also could provoke the same outcome.

Is that stress equivalent to influenza or a cold? We don't know, but anything that perturbs the balance of energy metabolism in these children is likely to have an adverse impact. Therefore, we could argue that these children should be vaccinated to prevent more severe illness.

Note, too, that the ruling does not mention thimerosal, the vaccine ingredient—now removed from nearly all childhood vaccines—that many activists have claimed causes autism.

In February, my colleagues and I published a study in which we showed that the measurement of blood levels of methylmercury from fish used to make nearly all recommendations pertaining to safe levels of mercury exposure were completely inaccurate for risk assessments of children who received vaccines containing thimerosal.

The recommendations in 1999 by the American Academy of Pediatrics and others were based on toxicology data in adults regarding the oral consumption of methylmercury, as would occur from eating fish. Compared with the blood half-life of about 45 days associated with methylmercury from fish consumption, the half-life of intramuscular ethyl mercury from thimerosal in vaccines in infants is substantially shorter, at a mean of 3.7 days with a return to baseline by 30 days post vaccination (Pediatrics 2008;121:e208–14).

Unfortunately, the antivaccine claims are unlikely to abate until more is known about what really does cause autism. Several reports in the literature have documented an association between mitochondrial disorders and similarities to autism spectrum disorders, but none have shown a direct connection.

On the other hand, there is increasing evidence that autism is an inherited disorder. In one interesting example, new data from 751 families with autism participating in the Autism Genetic Resource Exchange point to a novel, recurrent gene microdeletion and a reciprocal microduplication that are associated with substantial susceptibility to autism, and appear to account for approximately 1% of cases (N. Engl. J. Med. 2008;358:667–75).

I suspect we will see more evidence of genetic markers for autism in the future.

In the meantime, I hope that clinicians will view the situation of this particular child as a sad but isolated case. Mitochondrial disorders are extremely rare—I have never seen one in my 20-plus years of practicing general pediatrics. And even among these patients, the benefits of vaccination still likely outweigh the risks.

Thimerosal has now been removed from all childhood vaccines except for multidose influenza vaccines, but the rates of autism have not abated, thus providing very strong epidemiologic evidence that thimerosal did not cause the upswing in autism spectrum disorder diagnoses that began in the 1990s and still continues. The antivaccine folks have begun switching their argument to say that it is multiple vaccines that cause autism and other neurodevelopmental problems by “overwhelming” the immune system.

In an effort to quantitate that, current research is looking at the effect on the immune system when a healthy child becomes colonized with common bacteria such as Streptococcus pneumoniae. Thus far, we know that the immune “stress” associated with asymptomatic nasal colonization is quite a bit greater than that of the purified vaccines given to children today.

Infectious diseases are “stressful” to the immune system. Vaccines are not risk free, but they induce far less “stress.” We need to inform our patients and their families that while everything has some risk, the real question is risk versus benefit. From that perspective, vaccines are the clear winners.

[email protected]

I would like to clear up some of the confusion surrounding a recent federal government ruling that vaccines might have contributed to autismlike symptoms in a child with underlying mitochondrial disorder. The media have portrayed this as an acknowledgment of a link between vaccines and autism, and that simply isn't the case.

The story broke on the Internet blog of journalist David Kirby, the author of a book promoting the theory that the thimerosal preservative in vaccines is linked with autism. He obtained a copy of the ruling from an unnamed source and posted it on the Internet. The family of the child then spoke publicly about the case at a press briefing sponsored by an autism advocacy group.

The document was evidently issued last November by an official in the Department of Justice who wrote that medical personnel at the Department of Health and Human Services' Division of Vaccine Injury Compensation (DVIC) had reviewed the case and “concluded that compensation is appropriate.”

The case involves a 9-year-old girl who, at 18 months of age, received five different vaccines on the same day and in the following months began exhibiting abnormal symptoms deemed to be “regressive encephalopathy with features consistent with an autism spectrum disorder.” Subsequent evaluation led to the diagnosis of a previously unrecognized underlying mitochondrial disorder.

At this writing, the federal Health Resources and Services Administration (HRSA), which administers the Vaccine Injury Compensation Program through which this case was reportedly filed, could not confirm any of the information reported because the agency had not yet received written consent from the family to do so.

However, HRSA said in a statement that “HRSA has maintained and continues to maintain the position that vaccines do not cause autism, and has never concluded in any case that autism was caused by vaccination.”

But that hasn't stopped the media reports, which have caused a great deal of concern and confusion among the public and the medical community. According to the document, “DVIC has concluded that the facts of this case meet the statutory criteria for demonstrating that the vaccinations [the child] received on July 19, 2000, significantly aggravated an underlying mitochondrial disorder, which predisposed her to deficits in cellular energy metabolism, and manifested as a regressive encephalopathy with features of autism spectrum disorder.”

First of all, note that this report is not talking about the disorder “autism.” Indeed, children with mitochondrial disorders, which produce severe deficits in cellular energy metabolism, often develop regressive encephalopathy and features of autism spectrum disorder such as loss of language skills and impaired motor coordination.

Such manifestations are more likely to occur in those with mitochondrial disorders when there is a physiological stressor such as a viral or bacterial illness. Therefore, it is plausible that receiving five vaccines in 1 day also could provoke the same outcome.

Is that stress equivalent to influenza or a cold? We don't know, but anything that perturbs the balance of energy metabolism in these children is likely to have an adverse impact. Therefore, we could argue that these children should be vaccinated to prevent more severe illness.

Note, too, that the ruling does not mention thimerosal, the vaccine ingredient—now removed from nearly all childhood vaccines—that many activists have claimed causes autism.

In February, my colleagues and I published a study in which we showed that the measurement of blood levels of methylmercury from fish used to make nearly all recommendations pertaining to safe levels of mercury exposure were completely inaccurate for risk assessments of children who received vaccines containing thimerosal.

The recommendations in 1999 by the American Academy of Pediatrics and others were based on toxicology data in adults regarding the oral consumption of methylmercury, as would occur from eating fish. Compared with the blood half-life of about 45 days associated with methylmercury from fish consumption, the half-life of intramuscular ethyl mercury from thimerosal in vaccines in infants is substantially shorter, at a mean of 3.7 days with a return to baseline by 30 days post vaccination (Pediatrics 2008;121:e208–14).

Unfortunately, the antivaccine claims are unlikely to abate until more is known about what really does cause autism. Several reports in the literature have documented an association between mitochondrial disorders and similarities to autism spectrum disorders, but none have shown a direct connection.

On the other hand, there is increasing evidence that autism is an inherited disorder. In one interesting example, new data from 751 families with autism participating in the Autism Genetic Resource Exchange point to a novel, recurrent gene microdeletion and a reciprocal microduplication that are associated with substantial susceptibility to autism, and appear to account for approximately 1% of cases (N. Engl. J. Med. 2008;358:667–75).

I suspect we will see more evidence of genetic markers for autism in the future.

In the meantime, I hope that clinicians will view the situation of this particular child as a sad but isolated case. Mitochondrial disorders are extremely rare—I have never seen one in my 20-plus years of practicing general pediatrics. And even among these patients, the benefits of vaccination still likely outweigh the risks.

Thimerosal has now been removed from all childhood vaccines except for multidose influenza vaccines, but the rates of autism have not abated, thus providing very strong epidemiologic evidence that thimerosal did not cause the upswing in autism spectrum disorder diagnoses that began in the 1990s and still continues. The antivaccine folks have begun switching their argument to say that it is multiple vaccines that cause autism and other neurodevelopmental problems by “overwhelming” the immune system.

In an effort to quantitate that, current research is looking at the effect on the immune system when a healthy child becomes colonized with common bacteria such as Streptococcus pneumoniae. Thus far, we know that the immune “stress” associated with asymptomatic nasal colonization is quite a bit greater than that of the purified vaccines given to children today.

Infectious diseases are “stressful” to the immune system. Vaccines are not risk free, but they induce far less “stress.” We need to inform our patients and their families that while everything has some risk, the real question is risk versus benefit. From that perspective, vaccines are the clear winners.

[email protected]

Vaccine shortages have become all too common in the United States, with no end in sight. In my view, the best solution would be for the federal government to step in and provide incentives to vaccine manufacturers to bring more products to the U.S. market.

The current situation with Haemophilus influenzae type b (Hib) vaccine is just the latest in a string of vaccine production problems that has been causing major headaches for physicians and patients over the past several years.

As you know, on Dec. 13, 2007, Merck & Co. announced a voluntary recall of certain lots of both of its Hib conjugate vaccines, PedvaxHIB (monovalent) and Comvax (combined Hib/hepatitis B), because of concerns about contamination. Merck does not anticipate resumption of distribution until the fourth quarter of 2008. Sanofi Pasteur, the other company that makes Hib vaccines that are licensed for the U.S. market (ActHIB and TriHIBit), won't be able to produce enough to cover all the remaining children for whom the vaccine is recommended. We've also seen recent supply problems with measles-mumps-rubella-varicella (MMRV) and hepatitis A vaccines.

In 2004 there were major shortages of influenza vaccine and of pneumococcal conjugate vaccine because of various production problems. And any pediatrician who was practicing in 2001-2002 will remember the nightmare when five different vaccines that protect against eight different diseases–diphtheria, tetanus, pertussis, measles, mumps, rubella, pneumococcus, and varicella–all fell into short supply simultaneously. There was no single reason for those shortages; rather, they were due to a combination of factors: manufacturing and compliance problems; vaccine manufacturers' leaving the market for business reasons; supply and demand issues; and the removal of thimerosal from vaccines, which led to a lower yield.

Each time a shortage occurs, we're handed yet another set of interim guidelines for prioritization that means more paperwork; more hassles for us, our staffs, and our patients; plus the ongoing concern that at some point these shortages will result in true resurgence of disease. That hasn't happened yet, but I worry that it's right around the corner–herd immunity can take us only so far.

The Centers for Disease Control and Prevention maintains a stockpile of routine pediatric vaccines, which is a good safety net in case of a disease outbreak or a short-term production problem. However, not all pediatric vaccines are included in the stockpile, and it contains only a 6-month supply. Some of the recent shortages have lasted longer than that. Moreover, that stockpile competes for government dollars with vaccines devoted to bioterrorism and pandemic flu vaccines.

Some of my colleagues have talked about stockpiling their own vaccines. I don't think that is a viable solution, given the short shelf life of vaccines and the high cost that would be involved. In my practice, vaccines now are the second most expensive item on my balance sheet–second only to my staff payroll. My rent comes in third.

Of course, this is primarily because the newer vaccines–Prevnar, Menactra, Gardasil, etc.–are still patent protected and cost around $80-$120 per dose. For an average pediatrician, even a short-term supply would end up totaling around $40,000-$50,000. Multiply that by the number of partners in a group practice, and you'd easily be up to a quarter of a million dollars' worth of vaccine in your refrigerators and freezers. It's not a long-term solution to the shortage problem.

I believe the real answer is to ensure an adequate number of products from an adequate number of manufacturers. In 1967 there were 26 licensed vaccine manufacturers in the United States. By 2005, only six U.S. manufacturers with licensed products remained. What's worse, for several vaccines–including inactivated polio virus, MMR, and pneumococcal conjugate vaccines–there is only one manufacturer (Pediatrics 2006;6:2269-75).

This isn't good news. Just as they do after mergers in the airline industry, consumers end up with fewer choices and higher prices. The consolidation we've seen in the vaccine industry–brought on by increased regulatory demands for licensure; the high risk involved in developing a product, and competition with products like Lipitor, which patients take for a lifetime and generate billion-dollar profits–is really the core of the problem. Vaccine companies must be given incentives to compete.

How? The National Institute of Allergy and Infectious Diseases (NIAID) maintains nine Vaccine Treatment and Evaluation Units (VTEUs) around the country. Funded by the National Institutes of Health, these centers have stepped in at various times to conduct phase I and phase II testing on vaccines when there was critical need, such as the 2005 influenza vaccine shortage.

At that time, the NIAID worked closely with the Food and Drug Administration to conduct a clinical trial of GlaxoSmithKline's Fluarix–which was already available in Europe–to rapidly demonstrate sufficient safety and immunogenicity for the FDA to approve it in less than a year, in time for that year's influenza season. “The Fluarix study is an excellent example of what government and industry can accomplish in a short time frame, when faced with a serious public health need,” NIH Director Elias A. Zerhouni said at the time.

The VTEUs played a role in testing acellular pertussis vaccines in the late 1980s, when pressure from activist groups led to congressional demands for a safer alternative to whole-cell pertussis vaccines, and again in the 1990s, when the United States initiated the transition from oral to inactivated poliovirus vaccines. In each case, the FDA has been in the loop to ensure that adequate testing takes place. And importantly, the government also has promised to purchase a certain number of vaccine doses from the companies, thereby further ensuring economic feasibility.

Thus far the VTEUs have been brought into use on a case-by-case basis. I think their use should become a routine mechanism in shortage situations. For example, GlaxoSmithKline (GSK) currently has another Hib vaccine on the market in Europe called Hiberix. It's virtually identical to Sanofi Pasteur's ACTHib, yet it is not licensed in the United States. Why? My guess is that GSK has determined that the large investment it would take to satisfy FDA's stringent safety and immunogenicity requirements wouldn't be worthwhile simply to bring a third Hib vaccine to market.

In the interest of public health, I believe the FDA should ask the VTEUs to conduct those studies in order to bring Hiberix here to help alleviate our current Hib vaccine shortage. The same goes for an MMRV vaccine that GSK also makes for the European market. Both are “mature” vaccines that can't command the kind of prices that the newer vaccines like Prevnar and Menactra can. I believe these are cases where the government must step in and help. We should not have to rely on a single source for these products. It's unsafe for the public.

[email protected]

Vaccine shortages have become all too common in the United States, with no end in sight. In my view, the best solution would be for the federal government to step in and provide incentives to vaccine manufacturers to bring more products to the U.S. market.

The current situation with Haemophilus influenzae type b (Hib) vaccine is just the latest in a string of vaccine production problems that has been causing major headaches for physicians and patients over the past several years.

As you know, on Dec. 13, 2007, Merck & Co. announced a voluntary recall of certain lots of both of its Hib conjugate vaccines, PedvaxHIB (monovalent) and Comvax (combined Hib/hepatitis B), because of concerns about contamination. Merck does not anticipate resumption of distribution until the fourth quarter of 2008. Sanofi Pasteur, the other company that makes Hib vaccines that are licensed for the U.S. market (ActHIB and TriHIBit), won't be able to produce enough to cover all the remaining children for whom the vaccine is recommended. We've also seen recent supply problems with measles-mumps-rubella-varicella (MMRV) and hepatitis A vaccines.

In 2004 there were major shortages of influenza vaccine and of pneumococcal conjugate vaccine because of various production problems. And any pediatrician who was practicing in 2001-2002 will remember the nightmare when five different vaccines that protect against eight different diseases–diphtheria, tetanus, pertussis, measles, mumps, rubella, pneumococcus, and varicella–all fell into short supply simultaneously. There was no single reason for those shortages; rather, they were due to a combination of factors: manufacturing and compliance problems; vaccine manufacturers' leaving the market for business reasons; supply and demand issues; and the removal of thimerosal from vaccines, which led to a lower yield.

Each time a shortage occurs, we're handed yet another set of interim guidelines for prioritization that means more paperwork; more hassles for us, our staffs, and our patients; plus the ongoing concern that at some point these shortages will result in true resurgence of disease. That hasn't happened yet, but I worry that it's right around the corner–herd immunity can take us only so far.

The Centers for Disease Control and Prevention maintains a stockpile of routine pediatric vaccines, which is a good safety net in case of a disease outbreak or a short-term production problem. However, not all pediatric vaccines are included in the stockpile, and it contains only a 6-month supply. Some of the recent shortages have lasted longer than that. Moreover, that stockpile competes for government dollars with vaccines devoted to bioterrorism and pandemic flu vaccines.

Some of my colleagues have talked about stockpiling their own vaccines. I don't think that is a viable solution, given the short shelf life of vaccines and the high cost that would be involved. In my practice, vaccines now are the second most expensive item on my balance sheet–second only to my staff payroll. My rent comes in third.

Of course, this is primarily because the newer vaccines–Prevnar, Menactra, Gardasil, etc.–are still patent protected and cost around $80-$120 per dose. For an average pediatrician, even a short-term supply would end up totaling around $40,000-$50,000. Multiply that by the number of partners in a group practice, and you'd easily be up to a quarter of a million dollars' worth of vaccine in your refrigerators and freezers. It's not a long-term solution to the shortage problem.

I believe the real answer is to ensure an adequate number of products from an adequate number of manufacturers. In 1967 there were 26 licensed vaccine manufacturers in the United States. By 2005, only six U.S. manufacturers with licensed products remained. What's worse, for several vaccines–including inactivated polio virus, MMR, and pneumococcal conjugate vaccines–there is only one manufacturer (Pediatrics 2006;6:2269-75).

This isn't good news. Just as they do after mergers in the airline industry, consumers end up with fewer choices and higher prices. The consolidation we've seen in the vaccine industry–brought on by increased regulatory demands for licensure; the high risk involved in developing a product, and competition with products like Lipitor, which patients take for a lifetime and generate billion-dollar profits–is really the core of the problem. Vaccine companies must be given incentives to compete.

How? The National Institute of Allergy and Infectious Diseases (NIAID) maintains nine Vaccine Treatment and Evaluation Units (VTEUs) around the country. Funded by the National Institutes of Health, these centers have stepped in at various times to conduct phase I and phase II testing on vaccines when there was critical need, such as the 2005 influenza vaccine shortage.

At that time, the NIAID worked closely with the Food and Drug Administration to conduct a clinical trial of GlaxoSmithKline's Fluarix–which was already available in Europe–to rapidly demonstrate sufficient safety and immunogenicity for the FDA to approve it in less than a year, in time for that year's influenza season. “The Fluarix study is an excellent example of what government and industry can accomplish in a short time frame, when faced with a serious public health need,” NIH Director Elias A. Zerhouni said at the time.

The VTEUs played a role in testing acellular pertussis vaccines in the late 1980s, when pressure from activist groups led to congressional demands for a safer alternative to whole-cell pertussis vaccines, and again in the 1990s, when the United States initiated the transition from oral to inactivated poliovirus vaccines. In each case, the FDA has been in the loop to ensure that adequate testing takes place. And importantly, the government also has promised to purchase a certain number of vaccine doses from the companies, thereby further ensuring economic feasibility.

Thus far the VTEUs have been brought into use on a case-by-case basis. I think their use should become a routine mechanism in shortage situations. For example, GlaxoSmithKline (GSK) currently has another Hib vaccine on the market in Europe called Hiberix. It's virtually identical to Sanofi Pasteur's ACTHib, yet it is not licensed in the United States. Why? My guess is that GSK has determined that the large investment it would take to satisfy FDA's stringent safety and immunogenicity requirements wouldn't be worthwhile simply to bring a third Hib vaccine to market.

In the interest of public health, I believe the FDA should ask the VTEUs to conduct those studies in order to bring Hiberix here to help alleviate our current Hib vaccine shortage. The same goes for an MMRV vaccine that GSK also makes for the European market. Both are “mature” vaccines that can't command the kind of prices that the newer vaccines like Prevnar and Menactra can. I believe these are cases where the government must step in and help. We should not have to rely on a single source for these products. It's unsafe for the public.

[email protected]

Vaccine shortages have become all too common in the United States, with no end in sight. In my view, the best solution would be for the federal government to step in and provide incentives to vaccine manufacturers to bring more products to the U.S. market.

The current situation with Haemophilus influenzae type b (Hib) vaccine is just the latest in a string of vaccine production problems that has been causing major headaches for physicians and patients over the past several years.

As you know, on Dec. 13, 2007, Merck & Co. announced a voluntary recall of certain lots of both of its Hib conjugate vaccines, PedvaxHIB (monovalent) and Comvax (combined Hib/hepatitis B), because of concerns about contamination. Merck does not anticipate resumption of distribution until the fourth quarter of 2008. Sanofi Pasteur, the other company that makes Hib vaccines that are licensed for the U.S. market (ActHIB and TriHIBit), won't be able to produce enough to cover all the remaining children for whom the vaccine is recommended. We've also seen recent supply problems with measles-mumps-rubella-varicella (MMRV) and hepatitis A vaccines.

In 2004 there were major shortages of influenza vaccine and of pneumococcal conjugate vaccine because of various production problems. And any pediatrician who was practicing in 2001-2002 will remember the nightmare when five different vaccines that protect against eight different diseases–diphtheria, tetanus, pertussis, measles, mumps, rubella, pneumococcus, and varicella–all fell into short supply simultaneously. There was no single reason for those shortages; rather, they were due to a combination of factors: manufacturing and compliance problems; vaccine manufacturers' leaving the market for business reasons; supply and demand issues; and the removal of thimerosal from vaccines, which led to a lower yield.

Each time a shortage occurs, we're handed yet another set of interim guidelines for prioritization that means more paperwork; more hassles for us, our staffs, and our patients; plus the ongoing concern that at some point these shortages will result in true resurgence of disease. That hasn't happened yet, but I worry that it's right around the corner–herd immunity can take us only so far.

The Centers for Disease Control and Prevention maintains a stockpile of routine pediatric vaccines, which is a good safety net in case of a disease outbreak or a short-term production problem. However, not all pediatric vaccines are included in the stockpile, and it contains only a 6-month supply. Some of the recent shortages have lasted longer than that. Moreover, that stockpile competes for government dollars with vaccines devoted to bioterrorism and pandemic flu vaccines.

Some of my colleagues have talked about stockpiling their own vaccines. I don't think that is a viable solution, given the short shelf life of vaccines and the high cost that would be involved. In my practice, vaccines now are the second most expensive item on my balance sheet–second only to my staff payroll. My rent comes in third.

Of course, this is primarily because the newer vaccines–Prevnar, Menactra, Gardasil, etc.–are still patent protected and cost around $80-$120 per dose. For an average pediatrician, even a short-term supply would end up totaling around $40,000-$50,000. Multiply that by the number of partners in a group practice, and you'd easily be up to a quarter of a million dollars' worth of vaccine in your refrigerators and freezers. It's not a long-term solution to the shortage problem.

I believe the real answer is to ensure an adequate number of products from an adequate number of manufacturers. In 1967 there were 26 licensed vaccine manufacturers in the United States. By 2005, only six U.S. manufacturers with licensed products remained. What's worse, for several vaccines–including inactivated polio virus, MMR, and pneumococcal conjugate vaccines–there is only one manufacturer (Pediatrics 2006;6:2269-75).

This isn't good news. Just as they do after mergers in the airline industry, consumers end up with fewer choices and higher prices. The consolidation we've seen in the vaccine industry–brought on by increased regulatory demands for licensure; the high risk involved in developing a product, and competition with products like Lipitor, which patients take for a lifetime and generate billion-dollar profits–is really the core of the problem. Vaccine companies must be given incentives to compete.

How? The National Institute of Allergy and Infectious Diseases (NIAID) maintains nine Vaccine Treatment and Evaluation Units (VTEUs) around the country. Funded by the National Institutes of Health, these centers have stepped in at various times to conduct phase I and phase II testing on vaccines when there was critical need, such as the 2005 influenza vaccine shortage.

At that time, the NIAID worked closely with the Food and Drug Administration to conduct a clinical trial of GlaxoSmithKline's Fluarix–which was already available in Europe–to rapidly demonstrate sufficient safety and immunogenicity for the FDA to approve it in less than a year, in time for that year's influenza season. “The Fluarix study is an excellent example of what government and industry can accomplish in a short time frame, when faced with a serious public health need,” NIH Director Elias A. Zerhouni said at the time.

The VTEUs played a role in testing acellular pertussis vaccines in the late 1980s, when pressure from activist groups led to congressional demands for a safer alternative to whole-cell pertussis vaccines, and again in the 1990s, when the United States initiated the transition from oral to inactivated poliovirus vaccines. In each case, the FDA has been in the loop to ensure that adequate testing takes place. And importantly, the government also has promised to purchase a certain number of vaccine doses from the companies, thereby further ensuring economic feasibility.

Thus far the VTEUs have been brought into use on a case-by-case basis. I think their use should become a routine mechanism in shortage situations. For example, GlaxoSmithKline (GSK) currently has another Hib vaccine on the market in Europe called Hiberix. It's virtually identical to Sanofi Pasteur's ACTHib, yet it is not licensed in the United States. Why? My guess is that GSK has determined that the large investment it would take to satisfy FDA's stringent safety and immunogenicity requirements wouldn't be worthwhile simply to bring a third Hib vaccine to market.

In the interest of public health, I believe the FDA should ask the VTEUs to conduct those studies in order to bring Hiberix here to help alleviate our current Hib vaccine shortage. The same goes for an MMRV vaccine that GSK also makes for the European market. Both are “mature” vaccines that can't command the kind of prices that the newer vaccines like Prevnar and Menactra can. I believe these are cases where the government must step in and help. We should not have to rely on a single source for these products. It's unsafe for the public.

[email protected]

Apair of newly detected actions of Group A streptococci may offer clues as to why penicillin and amoxicillin often fail to eradicate streptococcal pharyngitis in children and adults, and why cephalosporins or macrolides may be better treatment options.

Penicillin failure in eradicating strep throat has been increasingly documented beginning in the 1980s, rising from just 5% in the 1950s to approximately 35% today. My colleague Dr. Janet R. Casey and I have published a series of articles over the years documenting this phenomenon, as have other researchers worldwide. In 2004, Dr. Casey and I conducted two separate meta-analyses demonstrating the clear superiority of cephalosporins—mainly azithromycin and clarithromycin—over penicillin in treating strep throat, both in children (Pediatrics 2004;113:866–82) and adults (Clin. Infect. Dis. 2004;38:1526–34).

Traditional antibiotic resistance does not appear to be the reason. In fact, there is absolutely no in vitro resistance of group A streptococci (GAS) to penicillin or amoxicillin (or cephalosporins).

Some people have theorized that the inadvertent inclusion of strep carriers in many of the studies explains the eradication failure with penicillin, but that has never made sense to me. Why would such inclusion have increased since the 1950s? In fact, the opposite has happened: Efforts have been made in more recent studies to exclude carriers. Our meta-analyses showed that the failure rate remained pretty much rocksolid at 35%, even when we looked at only the 12 most recent studies that did a fantastic job of excluding carriers.

I think the answer lies in considering mechanisms of “resistance” beyond those involving a particular bacterium resisting a particular drug in a test tube. There are two newly appreciated phenomena that I categorize as “in vivo resistance” because they result from a fundamental interaction with the host and can't be measured by a lab test.

About 5 years ago, several researchers published studies showing that streptococci were capable of entering and living inside the epithelial cells of the upper respiratory tract, a process dubbed “internalization.” Prior to that time, GAS was thought to be a strictly extracellular pathogen.

Then, just last year, Dr. Edward L. Kaplan of the University of Minnesota and his associates showed for the first time that internalization was a likely explanation for the treatment failure of penicillin and amoxicillin, which are incapable of penetrating the cell wall. In contrast, erythromycin and azithromycin, which enter cells easily, were the most effective at GAS eradication while the first-generation cephalosporin cephalothin and clindamycin had intermediate efficacy (Clin. Infect. Dis. 2006;43:1398–406).

A second mechanism of in vivo resistance, known as “coaggregation,” was first described in 2004 by Dr. Eric R. LaFontaine and his associates at the University of Toledo (Ohio). They found that the pathogens Streptococcus pyogenes and Moraxella catarrhalis colonize overlapping regions of the human nasopharynx, and that M. catarrhalis can dramatically increase the adherence of S. pyogenes to human epithelial cells (Infect. Immun. 2004;72:6689–93).

Subsequent to that paper, my laboratory group completed a study in which we confirmed Dr. LaFontaine's finding regarding coaggregation of S. pyogenes with M. catarrhalis, and also for the first time demonstrated the same phenomenon with S. pyogenes and Haemophilus influenzae.

With coaggregation, the GAS bacteria acquire the ability to attach themselves to the M. catarrhalis or H. influenzae that already colonize the throat at various times during childhood and adulthood (H. influenzae is about 5–6 times more common than M. catarrhalis). While these two organisms have long been known to become pathogenic in certain settings, we are now realizing that they also may serve to enhance the attachment of GAS to throat cells.

Indeed, coaggregation is a likely explanation for why some children—such as those more frequently colonized with M. catarrhalis or H. influenzae—are more vulnerable to strep throat than others. Moreover, it also explains our finding that an individual who is colonized with one of those two organisms and then is exposed to streptococcus has a 10-fold increased likelihood of developing strep throat.

It also helps explain the differential treatment effect of penicillin/amoxicillin versus other antibiotic classes. Both M. catarrhalis and H. influenzae produce beta-lactamase, which inactivates penicillin and amoxicillin. Cephalosporins, on the other hand, have greater activity in the presence of beta-lactamase, while macrolides such as azithromycin are completely immune to the enzyme.

Thus, it appears that beta-lactamase production, a well-described mechanism for in vitro antimicrobial resistance, is being enhanced by this additional coaggregation mechanism.

Based on this new information, my practice now uses cephalosporins as first-line treatment for strep throat. Cephalexin is a good option because it's generic, and it's first-generation, so it is not as broad-spectrum. We prescribe it twice daily for 10 days.

Second choice would be either a second- or third-generation cephalosporin or azithromycin, depending upon the degree of macrolide resistance in your community. Here in Rochester, where macrolide resistance is about 8%, we normally go with cefprozil, cefdinir, or cefpodoxime. All three are generic, although they're still not cheap— there's currently only one distributor. Cefprozil is the least expensive of the three, and there also is evidence that it eradicates the strep carrier state as well as the active infection (Clin.Ther. 2001;23:1889–900).

The Infectious Diseases Society of America is planning to issue new guidelines for the treatment of streptococcal pharyngitis sometime in 2008. Dr. Kaplan is the chairman of the writing committee, and Dr. Casey is a member. The American Academy of Pediatrics' 2006 Red Book still recommends amoxicillin as first-line therapy, but I'm guessing that will not be the case in the next edition, due out in 2009.

I have no financial conflicts that are relevant to this article.

[email protected]

Apair of newly detected actions of Group A streptococci may offer clues as to why penicillin and amoxicillin often fail to eradicate streptococcal pharyngitis in children and adults, and why cephalosporins or macrolides may be better treatment options.

Penicillin failure in eradicating strep throat has been increasingly documented beginning in the 1980s, rising from just 5% in the 1950s to approximately 35% today. My colleague Dr. Janet R. Casey and I have published a series of articles over the years documenting this phenomenon, as have other researchers worldwide. In 2004, Dr. Casey and I conducted two separate meta-analyses demonstrating the clear superiority of cephalosporins—mainly azithromycin and clarithromycin—over penicillin in treating strep throat, both in children (Pediatrics 2004;113:866–82) and adults (Clin. Infect. Dis. 2004;38:1526–34).

Traditional antibiotic resistance does not appear to be the reason. In fact, there is absolutely no in vitro resistance of group A streptococci (GAS) to penicillin or amoxicillin (or cephalosporins).

Some people have theorized that the inadvertent inclusion of strep carriers in many of the studies explains the eradication failure with penicillin, but that has never made sense to me. Why would such inclusion have increased since the 1950s? In fact, the opposite has happened: Efforts have been made in more recent studies to exclude carriers. Our meta-analyses showed that the failure rate remained pretty much rocksolid at 35%, even when we looked at only the 12 most recent studies that did a fantastic job of excluding carriers.

I think the answer lies in considering mechanisms of “resistance” beyond those involving a particular bacterium resisting a particular drug in a test tube. There are two newly appreciated phenomena that I categorize as “in vivo resistance” because they result from a fundamental interaction with the host and can't be measured by a lab test.

About 5 years ago, several researchers published studies showing that streptococci were capable of entering and living inside the epithelial cells of the upper respiratory tract, a process dubbed “internalization.” Prior to that time, GAS was thought to be a strictly extracellular pathogen.

Then, just last year, Dr. Edward L. Kaplan of the University of Minnesota and his associates showed for the first time that internalization was a likely explanation for the treatment failure of penicillin and amoxicillin, which are incapable of penetrating the cell wall. In contrast, erythromycin and azithromycin, which enter cells easily, were the most effective at GAS eradication while the first-generation cephalosporin cephalothin and clindamycin had intermediate efficacy (Clin. Infect. Dis. 2006;43:1398–406).

A second mechanism of in vivo resistance, known as “coaggregation,” was first described in 2004 by Dr. Eric R. LaFontaine and his associates at the University of Toledo (Ohio). They found that the pathogens Streptococcus pyogenes and Moraxella catarrhalis colonize overlapping regions of the human nasopharynx, and that M. catarrhalis can dramatically increase the adherence of S. pyogenes to human epithelial cells (Infect. Immun. 2004;72:6689–93).

Subsequent to that paper, my laboratory group completed a study in which we confirmed Dr. LaFontaine's finding regarding coaggregation of S. pyogenes with M. catarrhalis, and also for the first time demonstrated the same phenomenon with S. pyogenes and Haemophilus influenzae.

With coaggregation, the GAS bacteria acquire the ability to attach themselves to the M. catarrhalis or H. influenzae that already colonize the throat at various times during childhood and adulthood (H. influenzae is about 5–6 times more common than M. catarrhalis). While these two organisms have long been known to become pathogenic in certain settings, we are now realizing that they also may serve to enhance the attachment of GAS to throat cells.

Indeed, coaggregation is a likely explanation for why some children—such as those more frequently colonized with M. catarrhalis or H. influenzae—are more vulnerable to strep throat than others. Moreover, it also explains our finding that an individual who is colonized with one of those two organisms and then is exposed to streptococcus has a 10-fold increased likelihood of developing strep throat.

It also helps explain the differential treatment effect of penicillin/amoxicillin versus other antibiotic classes. Both M. catarrhalis and H. influenzae produce beta-lactamase, which inactivates penicillin and amoxicillin. Cephalosporins, on the other hand, have greater activity in the presence of beta-lactamase, while macrolides such as azithromycin are completely immune to the enzyme.

Thus, it appears that beta-lactamase production, a well-described mechanism for in vitro antimicrobial resistance, is being enhanced by this additional coaggregation mechanism.

Based on this new information, my practice now uses cephalosporins as first-line treatment for strep throat. Cephalexin is a good option because it's generic, and it's first-generation, so it is not as broad-spectrum. We prescribe it twice daily for 10 days.

Second choice would be either a second- or third-generation cephalosporin or azithromycin, depending upon the degree of macrolide resistance in your community. Here in Rochester, where macrolide resistance is about 8%, we normally go with cefprozil, cefdinir, or cefpodoxime. All three are generic, although they're still not cheap— there's currently only one distributor. Cefprozil is the least expensive of the three, and there also is evidence that it eradicates the strep carrier state as well as the active infection (Clin.Ther. 2001;23:1889–900).

The Infectious Diseases Society of America is planning to issue new guidelines for the treatment of streptococcal pharyngitis sometime in 2008. Dr. Kaplan is the chairman of the writing committee, and Dr. Casey is a member. The American Academy of Pediatrics' 2006 Red Book still recommends amoxicillin as first-line therapy, but I'm guessing that will not be the case in the next edition, due out in 2009.

I have no financial conflicts that are relevant to this article.

[email protected]

Apair of newly detected actions of Group A streptococci may offer clues as to why penicillin and amoxicillin often fail to eradicate streptococcal pharyngitis in children and adults, and why cephalosporins or macrolides may be better treatment options.

Penicillin failure in eradicating strep throat has been increasingly documented beginning in the 1980s, rising from just 5% in the 1950s to approximately 35% today. My colleague Dr. Janet R. Casey and I have published a series of articles over the years documenting this phenomenon, as have other researchers worldwide. In 2004, Dr. Casey and I conducted two separate meta-analyses demonstrating the clear superiority of cephalosporins—mainly azithromycin and clarithromycin—over penicillin in treating strep throat, both in children (Pediatrics 2004;113:866–82) and adults (Clin. Infect. Dis. 2004;38:1526–34).

Traditional antibiotic resistance does not appear to be the reason. In fact, there is absolutely no in vitro resistance of group A streptococci (GAS) to penicillin or amoxicillin (or cephalosporins).

Some people have theorized that the inadvertent inclusion of strep carriers in many of the studies explains the eradication failure with penicillin, but that has never made sense to me. Why would such inclusion have increased since the 1950s? In fact, the opposite has happened: Efforts have been made in more recent studies to exclude carriers. Our meta-analyses showed that the failure rate remained pretty much rocksolid at 35%, even when we looked at only the 12 most recent studies that did a fantastic job of excluding carriers.

I think the answer lies in considering mechanisms of “resistance” beyond those involving a particular bacterium resisting a particular drug in a test tube. There are two newly appreciated phenomena that I categorize as “in vivo resistance” because they result from a fundamental interaction with the host and can't be measured by a lab test.

About 5 years ago, several researchers published studies showing that streptococci were capable of entering and living inside the epithelial cells of the upper respiratory tract, a process dubbed “internalization.” Prior to that time, GAS was thought to be a strictly extracellular pathogen.

Then, just last year, Dr. Edward L. Kaplan of the University of Minnesota and his associates showed for the first time that internalization was a likely explanation for the treatment failure of penicillin and amoxicillin, which are incapable of penetrating the cell wall. In contrast, erythromycin and azithromycin, which enter cells easily, were the most effective at GAS eradication while the first-generation cephalosporin cephalothin and clindamycin had intermediate efficacy (Clin. Infect. Dis. 2006;43:1398–406).

A second mechanism of in vivo resistance, known as “coaggregation,” was first described in 2004 by Dr. Eric R. LaFontaine and his associates at the University of Toledo (Ohio). They found that the pathogens Streptococcus pyogenes and Moraxella catarrhalis colonize overlapping regions of the human nasopharynx, and that M. catarrhalis can dramatically increase the adherence of S. pyogenes to human epithelial cells (Infect. Immun. 2004;72:6689–93).

Subsequent to that paper, my laboratory group completed a study in which we confirmed Dr. LaFontaine's finding regarding coaggregation of S. pyogenes with M. catarrhalis, and also for the first time demonstrated the same phenomenon with S. pyogenes and Haemophilus influenzae.

With coaggregation, the GAS bacteria acquire the ability to attach themselves to the M. catarrhalis or H. influenzae that already colonize the throat at various times during childhood and adulthood (H. influenzae is about 5–6 times more common than M. catarrhalis). While these two organisms have long been known to become pathogenic in certain settings, we are now realizing that they also may serve to enhance the attachment of GAS to throat cells.

Indeed, coaggregation is a likely explanation for why some children—such as those more frequently colonized with M. catarrhalis or H. influenzae—are more vulnerable to strep throat than others. Moreover, it also explains our finding that an individual who is colonized with one of those two organisms and then is exposed to streptococcus has a 10-fold increased likelihood of developing strep throat.

It also helps explain the differential treatment effect of penicillin/amoxicillin versus other antibiotic classes. Both M. catarrhalis and H. influenzae produce beta-lactamase, which inactivates penicillin and amoxicillin. Cephalosporins, on the other hand, have greater activity in the presence of beta-lactamase, while macrolides such as azithromycin are completely immune to the enzyme.

Thus, it appears that beta-lactamase production, a well-described mechanism for in vitro antimicrobial resistance, is being enhanced by this additional coaggregation mechanism.

Based on this new information, my practice now uses cephalosporins as first-line treatment for strep throat. Cephalexin is a good option because it's generic, and it's first-generation, so it is not as broad-spectrum. We prescribe it twice daily for 10 days.

Second choice would be either a second- or third-generation cephalosporin or azithromycin, depending upon the degree of macrolide resistance in your community. Here in Rochester, where macrolide resistance is about 8%, we normally go with cefprozil, cefdinir, or cefpodoxime. All three are generic, although they're still not cheap— there's currently only one distributor. Cefprozil is the least expensive of the three, and there also is evidence that it eradicates the strep carrier state as well as the active infection (Clin.Ther. 2001;23:1889–900).

The Infectious Diseases Society of America is planning to issue new guidelines for the treatment of streptococcal pharyngitis sometime in 2008. Dr. Kaplan is the chairman of the writing committee, and Dr. Casey is a member. The American Academy of Pediatrics' 2006 Red Book still recommends amoxicillin as first-line therapy, but I'm guessing that will not be the case in the next edition, due out in 2009.

I have no financial conflicts that are relevant to this article.

[email protected]

Combination vaccines make life easier for our patients. But until the payment and regulatory issues are resolved, the same is not true for us.

In January, the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee endorsed the overall safety and efficacy of Sanofi Pasteur's Pentacel, a combination vaccine containing diphtheria, tetanus toxoid, and acellular pertussis (DTaP), inactivated polio (IPV), and Haemophilus influenzae type b (Hib). If approved, that vaccine will compete with GlaxoSmithKline's Pediarix, which contains DTaP, IPV, and hepatitis B antigens.

Infants given a dose of hepatitis B (HB) vaccine at birth and then Pentacel at 2, 4, and 6 months of age would not be receiving an extra dose of HB vaccine, as they would with Pediarix. Some see this as an advantage to Pentacel, but my colleagues and I showed that the extra HB dose was not a problem in terms of reactogenicity or immunogenicity, even though it resulted in considerably higher anti-HB levels (Pediatr. Infect. Dis. J. 2002;21:854–9).

Pediarix is now widely used in the public sector through the Vaccines for Children Program. In that setting, it has resulted in improved immunization rates and reduced errors. But the private sector has been slower to adopt Pediarix, and I predict that the same will be true of Pentacel for the same reason: The current lack of appropriate administration fees continues to present a huge barrier to the use of all combination vaccines.

Of course, we all want to minimize pain for our patients by reducing the total number of injections we give them at any one visit. However, because most insurers will only pay one administration fee per injection—no matter how many antigens it contains—the loss of income incurred by switching from separate vaccines to combinations is an unacceptable burden for many practitioners.

Here in Rochester, N.Y., for example, physicians charge a $12 administration fee to cover the informed consent process, record keeping, storage, and wastage for each vaccine. The use of either Pediarix or Pentacel (if licensed), results in a loss of $24 per visit per child.

In my mind, it's absolutely wrong to view vaccine “administration” as simply putting a needle into a child's leg. The American Academy of Pediatrics and the vaccine manufacturers have been working to change this system. We can only hope that the anticipated licensure of Pentacel—which has the advantage of fitting better into the current immunization schedule—will add momentum to those efforts. With even more combination vaccines in the pipeline, the issue of loss of income will need to be resolved.

Another complex problem regarding combination vaccines, this one regulatory, now faces the FDA as it decides whether to follow the advisory panel's advice on licensing Pentacel. At the January hearing, the panel debated a great deal about the importance of a slight diminution in immunogenicity to the vaccine's Hib component in some of Sanofi Pasteur's studies (PEDIATRIC NEWS, “FDA Panel Backs Five-in-One Combination Vaccine,” February 2007, p. 18).

Since 1997, the FDA has required that all components of a vaccine be noninferior to those of the separately administered antigens. The regulation has been widely interpreted to mean that a combination vaccine containing a Hib component must elicit an antibody response of at least 90% of the response to the separate Hib antigen; Pentacel technically did not meet all the criteria with regard to absolute antibody levels.

In contrast, European and Canadian licensing boards have decided that immunologic memory is more important than absolute antibody levels. Thus, a combination vaccine containing Hib conjugate has been licensed in many European countries because it establishes immunologic memory, even though the antibody response is more than 10% lower. Pentacel itself has been licensed in Canada since 1997 and used exclusively there since 1998, with more than 12 million doses distributed. It also is used in several European countries.

In Canada and in Germany, rates of Hib disease have remained very low or nondetectable since Hib-containing combination vaccines were introduced. Seems to me the Europeans got it right.

To resolve this discrepancy in regulatory policy, I think that the FDA needs to look at one more piece of the clinical trial data that it is not currently considering: Among vaccine recipients who don't meet the absolute noninferior antibody level, what is the proportion of nonresponders, compared with the proportion whose titers are just beneath the threshold? I'm not worried about the child whose level is at 89%. Thanks to immunologic memory, that child will be protected.

Rather, the important question is whether there is a large proportion with little or no anti-Hib antibody following immunization. Having participated in many of these trials, I can tell you the answer is no. The manufacturers have those data. The FDA needs to start considering them, in order to bring to the market more combination vaccines that could improve the health and well-being of our patients.

[email protected]

Combination vaccines make life easier for our patients. But until the payment and regulatory issues are resolved, the same is not true for us.

In January, the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee endorsed the overall safety and efficacy of Sanofi Pasteur's Pentacel, a combination vaccine containing diphtheria, tetanus toxoid, and acellular pertussis (DTaP), inactivated polio (IPV), and Haemophilus influenzae type b (Hib). If approved, that vaccine will compete with GlaxoSmithKline's Pediarix, which contains DTaP, IPV, and hepatitis B antigens.

Infants given a dose of hepatitis B (HB) vaccine at birth and then Pentacel at 2, 4, and 6 months of age would not be receiving an extra dose of HB vaccine, as they would with Pediarix. Some see this as an advantage to Pentacel, but my colleagues and I showed that the extra HB dose was not a problem in terms of reactogenicity or immunogenicity, even though it resulted in considerably higher anti-HB levels (Pediatr. Infect. Dis. J. 2002;21:854–9).

Pediarix is now widely used in the public sector through the Vaccines for Children Program. In that setting, it has resulted in improved immunization rates and reduced errors. But the private sector has been slower to adopt Pediarix, and I predict that the same will be true of Pentacel for the same reason: The current lack of appropriate administration fees continues to present a huge barrier to the use of all combination vaccines.

Of course, we all want to minimize pain for our patients by reducing the total number of injections we give them at any one visit. However, because most insurers will only pay one administration fee per injection—no matter how many antigens it contains—the loss of income incurred by switching from separate vaccines to combinations is an unacceptable burden for many practitioners.

Here in Rochester, N.Y., for example, physicians charge a $12 administration fee to cover the informed consent process, record keeping, storage, and wastage for each vaccine. The use of either Pediarix or Pentacel (if licensed), results in a loss of $24 per visit per child.

In my mind, it's absolutely wrong to view vaccine “administration” as simply putting a needle into a child's leg. The American Academy of Pediatrics and the vaccine manufacturers have been working to change this system. We can only hope that the anticipated licensure of Pentacel—which has the advantage of fitting better into the current immunization schedule—will add momentum to those efforts. With even more combination vaccines in the pipeline, the issue of loss of income will need to be resolved.

Another complex problem regarding combination vaccines, this one regulatory, now faces the FDA as it decides whether to follow the advisory panel's advice on licensing Pentacel. At the January hearing, the panel debated a great deal about the importance of a slight diminution in immunogenicity to the vaccine's Hib component in some of Sanofi Pasteur's studies (PEDIATRIC NEWS, “FDA Panel Backs Five-in-One Combination Vaccine,” February 2007, p. 18).

Since 1997, the FDA has required that all components of a vaccine be noninferior to those of the separately administered antigens. The regulation has been widely interpreted to mean that a combination vaccine containing a Hib component must elicit an antibody response of at least 90% of the response to the separate Hib antigen; Pentacel technically did not meet all the criteria with regard to absolute antibody levels.

In contrast, European and Canadian licensing boards have decided that immunologic memory is more important than absolute antibody levels. Thus, a combination vaccine containing Hib conjugate has been licensed in many European countries because it establishes immunologic memory, even though the antibody response is more than 10% lower. Pentacel itself has been licensed in Canada since 1997 and used exclusively there since 1998, with more than 12 million doses distributed. It also is used in several European countries.

In Canada and in Germany, rates of Hib disease have remained very low or nondetectable since Hib-containing combination vaccines were introduced. Seems to me the Europeans got it right.

To resolve this discrepancy in regulatory policy, I think that the FDA needs to look at one more piece of the clinical trial data that it is not currently considering: Among vaccine recipients who don't meet the absolute noninferior antibody level, what is the proportion of nonresponders, compared with the proportion whose titers are just beneath the threshold? I'm not worried about the child whose level is at 89%. Thanks to immunologic memory, that child will be protected.

Rather, the important question is whether there is a large proportion with little or no anti-Hib antibody following immunization. Having participated in many of these trials, I can tell you the answer is no. The manufacturers have those data. The FDA needs to start considering them, in order to bring to the market more combination vaccines that could improve the health and well-being of our patients.

[email protected]

Combination vaccines make life easier for our patients. But until the payment and regulatory issues are resolved, the same is not true for us.

In January, the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee endorsed the overall safety and efficacy of Sanofi Pasteur's Pentacel, a combination vaccine containing diphtheria, tetanus toxoid, and acellular pertussis (DTaP), inactivated polio (IPV), and Haemophilus influenzae type b (Hib). If approved, that vaccine will compete with GlaxoSmithKline's Pediarix, which contains DTaP, IPV, and hepatitis B antigens.

Infants given a dose of hepatitis B (HB) vaccine at birth and then Pentacel at 2, 4, and 6 months of age would not be receiving an extra dose of HB vaccine, as they would with Pediarix. Some see this as an advantage to Pentacel, but my colleagues and I showed that the extra HB dose was not a problem in terms of reactogenicity or immunogenicity, even though it resulted in considerably higher anti-HB levels (Pediatr. Infect. Dis. J. 2002;21:854–9).

Pediarix is now widely used in the public sector through the Vaccines for Children Program. In that setting, it has resulted in improved immunization rates and reduced errors. But the private sector has been slower to adopt Pediarix, and I predict that the same will be true of Pentacel for the same reason: The current lack of appropriate administration fees continues to present a huge barrier to the use of all combination vaccines.

Of course, we all want to minimize pain for our patients by reducing the total number of injections we give them at any one visit. However, because most insurers will only pay one administration fee per injection—no matter how many antigens it contains—the loss of income incurred by switching from separate vaccines to combinations is an unacceptable burden for many practitioners.

Here in Rochester, N.Y., for example, physicians charge a $12 administration fee to cover the informed consent process, record keeping, storage, and wastage for each vaccine. The use of either Pediarix or Pentacel (if licensed), results in a loss of $24 per visit per child.

In my mind, it's absolutely wrong to view vaccine “administration” as simply putting a needle into a child's leg. The American Academy of Pediatrics and the vaccine manufacturers have been working to change this system. We can only hope that the anticipated licensure of Pentacel—which has the advantage of fitting better into the current immunization schedule—will add momentum to those efforts. With even more combination vaccines in the pipeline, the issue of loss of income will need to be resolved.

Another complex problem regarding combination vaccines, this one regulatory, now faces the FDA as it decides whether to follow the advisory panel's advice on licensing Pentacel. At the January hearing, the panel debated a great deal about the importance of a slight diminution in immunogenicity to the vaccine's Hib component in some of Sanofi Pasteur's studies (PEDIATRIC NEWS, “FDA Panel Backs Five-in-One Combination Vaccine,” February 2007, p. 18).

Since 1997, the FDA has required that all components of a vaccine be noninferior to those of the separately administered antigens. The regulation has been widely interpreted to mean that a combination vaccine containing a Hib component must elicit an antibody response of at least 90% of the response to the separate Hib antigen; Pentacel technically did not meet all the criteria with regard to absolute antibody levels.

In contrast, European and Canadian licensing boards have decided that immunologic memory is more important than absolute antibody levels. Thus, a combination vaccine containing Hib conjugate has been licensed in many European countries because it establishes immunologic memory, even though the antibody response is more than 10% lower. Pentacel itself has been licensed in Canada since 1997 and used exclusively there since 1998, with more than 12 million doses distributed. It also is used in several European countries.

In Canada and in Germany, rates of Hib disease have remained very low or nondetectable since Hib-containing combination vaccines were introduced. Seems to me the Europeans got it right.

To resolve this discrepancy in regulatory policy, I think that the FDA needs to look at one more piece of the clinical trial data that it is not currently considering: Among vaccine recipients who don't meet the absolute noninferior antibody level, what is the proportion of nonresponders, compared with the proportion whose titers are just beneath the threshold? I'm not worried about the child whose level is at 89%. Thanks to immunologic memory, that child will be protected.

Rather, the important question is whether there is a large proportion with little or no anti-Hib antibody following immunization. Having participated in many of these trials, I can tell you the answer is no. The manufacturers have those data. The FDA needs to start considering them, in order to bring to the market more combination vaccines that could improve the health and well-being of our patients.

[email protected]

The American Academy of Pediatrics' new policy statement on fluoroquinolone use in children is a thoughtful, measured step in the right direction. As we await the availability of new agents in this class, as well as new pediatric indications for those already licensed, it's very helpful to have a document that will help guide our judicious use of these potent antimicrobials.

I agree with the statement's overall message, that in order to minimize the chance of antimicrobial resistance, use of fluoroquinolones should be restricted to situations in which infection is caused by multidrug-resistant pathogens for which no other effective oral agent is available, or when parenteral therapy is not feasible and no other effective oral agent is available (Pediatrics 2006;118:1287–92).

The statement provides a list of specific clinical scenarios that qualify, including urinary tract infections caused by Pseudomonas aeruginosa or other multidrug-resistant gram-negative bacteria, chronic suppurative otitis media or malignant otitis externa caused by P. aeruginosa, chronic or acute osteomyelitis or osteochondritis caused by P. aeruginosa (often associated with foot puncture), and for exacerbation of pulmonary disease in patients with cystic fibrosis who are colonized with P. aeruginosa.

Unfortunately, though, the document is already somewhat out of date. Most of the data cited in it were published prior to 2004.

One important change that has occurred since then is the resurgence of difficult-to-treat ear infections in children due to multidrug-resistant Streptococcus pneumoniae.

We've had 4 or 5 years following the introduction of Prevnar when the rate of those infections were plummeting. Now, however, we're increasingly seeing cases of otitis media caused by the nonvaccine serotype 19A, a particularly nasty clonal strain that is resistant to amoxicillin, amoxicillin-clavulanate, and all the cephalosporins including intramuscular ceftriaxone.

In our practice, these children are relapsing even after tympanocentesis and following tube placement. The ear just keeps draining.

I suggest that this is an appropriate indication for a quinolone.

Such a scenario isn't spelled out in the AAP statement, but recurrent otitis media due to pneumococcal serotype 19A certainly does qualify under the general heading of a “multidrug-resistant pathogen for which there is no safe and effective alternative.”

I think we can lay to rest the safety concerns regarding several of the fluoroquinolones in children.

In 2005, my colleagues and I published an article in which we summarized the available data on the use of gatifloxacin in children with recurrent ear infections and ear infection treatment failure (CID 2005;41:470–8).

The database wasn't huge—a total of 867 children aged younger than 2 years from four clinical trials—but it was very reassuring in that during a full year of follow-up, we found no evidence of arthrotoxicity, hepatoxicity, or central nervous system toxicity, nor were there the alterations in glucose homeostasis that had occurred in adults.

Earlier this year, gatifloxacin was pulled from the market worldwide because of glucose homeostasis concerns in adults. Prior to that, Bristol-Myers Squibb had withdrawn its application for a pediatric indication for the agent because it couldn't come to an agreement with the Food and Drug Administration about how to limit overprescribing (CID 2005;41:1824–5).

I think we can extrapolate the safety data on gatifloxacin to other fluoroquinolones, with some caution.

I believe we have enough data on ciprofloxacin and levofloxacin to support their use in children.

The only other major systemic fluoroquinolone, moxifloxacin, is probably okay, but I'd hesitate to endorse its use in children because there are no data—and it doesn't come in a liquid formulation, so it's very difficult to give to a young child.

Of course, resistance remains a major concern.

We must continue to be vigilant in reaching for the more narrow-spectrum drugs first, and only advance to more potent agents as the clinical situation demands.

However, even if we restrict our use of fluoroquinolones to the most difficult-to-treat ear infections, that could still mean several hundred thousand prescriptions nationwide.

If these bugs develop resistance to them, we're in trouble.

There is one promising agent in the pipeline called faropenem. It's the first of a new class of beta-lactam antibiotics called the penems, which are essentially structural hybrids between the penicillins and cephalosporins. Faropenem appears to be far less vulnerable to beta-lactamase, compared with other cephalosporins and imipenem, giving it a lower propensity for resistance. It also has very potent activity against gram-positive bacteria, particularly multiresistant S. pneumoniae.

A new drug application for faropenem medoxomil was filed with the FDA in December 2005, with approval and launch expected in late 2006, according to Replidyne, which licensed the agent from Daiichi Suntory Pharmaceuticals in March 2004. Trials in children are set to begin this winter.

[email protected]

The American Academy of Pediatrics' new policy statement on fluoroquinolone use in children is a thoughtful, measured step in the right direction. As we await the availability of new agents in this class, as well as new pediatric indications for those already licensed, it's very helpful to have a document that will help guide our judicious use of these potent antimicrobials.

I agree with the statement's overall message, that in order to minimize the chance of antimicrobial resistance, use of fluoroquinolones should be restricted to situations in which infection is caused by multidrug-resistant pathogens for which no other effective oral agent is available, or when parenteral therapy is not feasible and no other effective oral agent is available (Pediatrics 2006;118:1287–92).

The statement provides a list of specific clinical scenarios that qualify, including urinary tract infections caused by Pseudomonas aeruginosa or other multidrug-resistant gram-negative bacteria, chronic suppurative otitis media or malignant otitis externa caused by P. aeruginosa, chronic or acute osteomyelitis or osteochondritis caused by P. aeruginosa (often associated with foot puncture), and for exacerbation of pulmonary disease in patients with cystic fibrosis who are colonized with P. aeruginosa.

Unfortunately, though, the document is already somewhat out of date. Most of the data cited in it were published prior to 2004.

One important change that has occurred since then is the resurgence of difficult-to-treat ear infections in children due to multidrug-resistant Streptococcus pneumoniae.

We've had 4 or 5 years following the introduction of Prevnar when the rate of those infections were plummeting. Now, however, we're increasingly seeing cases of otitis media caused by the nonvaccine serotype 19A, a particularly nasty clonal strain that is resistant to amoxicillin, amoxicillin-clavulanate, and all the cephalosporins including intramuscular ceftriaxone.

In our practice, these children are relapsing even after tympanocentesis and following tube placement. The ear just keeps draining.

I suggest that this is an appropriate indication for a quinolone.

Such a scenario isn't spelled out in the AAP statement, but recurrent otitis media due to pneumococcal serotype 19A certainly does qualify under the general heading of a “multidrug-resistant pathogen for which there is no safe and effective alternative.”

I think we can lay to rest the safety concerns regarding several of the fluoroquinolones in children.

In 2005, my colleagues and I published an article in which we summarized the available data on the use of gatifloxacin in children with recurrent ear infections and ear infection treatment failure (CID 2005;41:470–8).

The database wasn't huge—a total of 867 children aged younger than 2 years from four clinical trials—but it was very reassuring in that during a full year of follow-up, we found no evidence of arthrotoxicity, hepatoxicity, or central nervous system toxicity, nor were there the alterations in glucose homeostasis that had occurred in adults.

Earlier this year, gatifloxacin was pulled from the market worldwide because of glucose homeostasis concerns in adults. Prior to that, Bristol-Myers Squibb had withdrawn its application for a pediatric indication for the agent because it couldn't come to an agreement with the Food and Drug Administration about how to limit overprescribing (CID 2005;41:1824–5).

I think we can extrapolate the safety data on gatifloxacin to other fluoroquinolones, with some caution.

I believe we have enough data on ciprofloxacin and levofloxacin to support their use in children.

The only other major systemic fluoroquinolone, moxifloxacin, is probably okay, but I'd hesitate to endorse its use in children because there are no data—and it doesn't come in a liquid formulation, so it's very difficult to give to a young child.

Of course, resistance remains a major concern.

We must continue to be vigilant in reaching for the more narrow-spectrum drugs first, and only advance to more potent agents as the clinical situation demands.

However, even if we restrict our use of fluoroquinolones to the most difficult-to-treat ear infections, that could still mean several hundred thousand prescriptions nationwide.

If these bugs develop resistance to them, we're in trouble.

There is one promising agent in the pipeline called faropenem. It's the first of a new class of beta-lactam antibiotics called the penems, which are essentially structural hybrids between the penicillins and cephalosporins. Faropenem appears to be far less vulnerable to beta-lactamase, compared with other cephalosporins and imipenem, giving it a lower propensity for resistance. It also has very potent activity against gram-positive bacteria, particularly multiresistant S. pneumoniae.

A new drug application for faropenem medoxomil was filed with the FDA in December 2005, with approval and launch expected in late 2006, according to Replidyne, which licensed the agent from Daiichi Suntory Pharmaceuticals in March 2004. Trials in children are set to begin this winter.

[email protected]

The American Academy of Pediatrics' new policy statement on fluoroquinolone use in children is a thoughtful, measured step in the right direction. As we await the availability of new agents in this class, as well as new pediatric indications for those already licensed, it's very helpful to have a document that will help guide our judicious use of these potent antimicrobials.

I agree with the statement's overall message, that in order to minimize the chance of antimicrobial resistance, use of fluoroquinolones should be restricted to situations in which infection is caused by multidrug-resistant pathogens for which no other effective oral agent is available, or when parenteral therapy is not feasible and no other effective oral agent is available (Pediatrics 2006;118:1287–92).

The statement provides a list of specific clinical scenarios that qualify, including urinary tract infections caused by Pseudomonas aeruginosa or other multidrug-resistant gram-negative bacteria, chronic suppurative otitis media or malignant otitis externa caused by P. aeruginosa, chronic or acute osteomyelitis or osteochondritis caused by P. aeruginosa (often associated with foot puncture), and for exacerbation of pulmonary disease in patients with cystic fibrosis who are colonized with P. aeruginosa.

Unfortunately, though, the document is already somewhat out of date. Most of the data cited in it were published prior to 2004.

One important change that has occurred since then is the resurgence of difficult-to-treat ear infections in children due to multidrug-resistant Streptococcus pneumoniae.

We've had 4 or 5 years following the introduction of Prevnar when the rate of those infections were plummeting. Now, however, we're increasingly seeing cases of otitis media caused by the nonvaccine serotype 19A, a particularly nasty clonal strain that is resistant to amoxicillin, amoxicillin-clavulanate, and all the cephalosporins including intramuscular ceftriaxone.

In our practice, these children are relapsing even after tympanocentesis and following tube placement. The ear just keeps draining.

I suggest that this is an appropriate indication for a quinolone.

Such a scenario isn't spelled out in the AAP statement, but recurrent otitis media due to pneumococcal serotype 19A certainly does qualify under the general heading of a “multidrug-resistant pathogen for which there is no safe and effective alternative.”

I think we can lay to rest the safety concerns regarding several of the fluoroquinolones in children.

In 2005, my colleagues and I published an article in which we summarized the available data on the use of gatifloxacin in children with recurrent ear infections and ear infection treatment failure (CID 2005;41:470–8).

The database wasn't huge—a total of 867 children aged younger than 2 years from four clinical trials—but it was very reassuring in that during a full year of follow-up, we found no evidence of arthrotoxicity, hepatoxicity, or central nervous system toxicity, nor were there the alterations in glucose homeostasis that had occurred in adults.

Earlier this year, gatifloxacin was pulled from the market worldwide because of glucose homeostasis concerns in adults. Prior to that, Bristol-Myers Squibb had withdrawn its application for a pediatric indication for the agent because it couldn't come to an agreement with the Food and Drug Administration about how to limit overprescribing (CID 2005;41:1824–5).

I think we can extrapolate the safety data on gatifloxacin to other fluoroquinolones, with some caution.

I believe we have enough data on ciprofloxacin and levofloxacin to support their use in children.

The only other major systemic fluoroquinolone, moxifloxacin, is probably okay, but I'd hesitate to endorse its use in children because there are no data—and it doesn't come in a liquid formulation, so it's very difficult to give to a young child.

Of course, resistance remains a major concern.

We must continue to be vigilant in reaching for the more narrow-spectrum drugs first, and only advance to more potent agents as the clinical situation demands.

However, even if we restrict our use of fluoroquinolones to the most difficult-to-treat ear infections, that could still mean several hundred thousand prescriptions nationwide.

If these bugs develop resistance to them, we're in trouble.

There is one promising agent in the pipeline called faropenem. It's the first of a new class of beta-lactam antibiotics called the penems, which are essentially structural hybrids between the penicillins and cephalosporins. Faropenem appears to be far less vulnerable to beta-lactamase, compared with other cephalosporins and imipenem, giving it a lower propensity for resistance. It also has very potent activity against gram-positive bacteria, particularly multiresistant S. pneumoniae.

A new drug application for faropenem medoxomil was filed with the FDA in December 2005, with approval and launch expected in late 2006, according to Replidyne, which licensed the agent from Daiichi Suntory Pharmaceuticals in March 2004. Trials in children are set to begin this winter.

During the summer and early fall, we should be careful about unnecessary antibiotic use in patients who most likely have enteroviral infections.

Nonpolio enterovirus (NPEV) infections are amazingly diverse in their range of clinical manifestations. While most of these infections are self-limited and nonserious, NPEV can turn serious and even fatal in newborns and immunosuppressed individuals. Of course, the diagnosis is easy when we see a child with the classic hand-foot-and-mouth (HFM) blister presentation. But that happens in only a small proportion of cases.

More commonly, we see a child with a high fever, sore throat, a slightly stiff neck, and a very worried mother. Even with a negative strep test, sometimes we retreat to our comfort zone and prescribe amoxicillin. While understandable, we should try to avoid this practice.

In a study my colleagues and I conducted a few years ago, only 8% of 372 children with a clinical diagnosis of systemic NPEV syndrome presented with HFM blisters. More common were stomatitis in 58%, and fever with myalgias and malaise in 28%. Another 3% had pleurodynia, 3% had fever with rash, and 1% had aseptic meningitis. Most patients had four to seven symptoms at the onset of illness and at the time of presentation (Pediatrics 1998;102:1126–34).

To my knowledge, there have been no other published studies since that one on the epidemiology of enteroviral illness in private clinical practice.

Of the 372 index cases, more than half (53%) also had a family member with an NPEV illness, including 51% of the 105 with myalgia/malaise, 20% of the 10 with rash, 57% of the 214 with stomatitis, and 45% of the 11 with pleurodynia. Interestingly, the illness often presented differently in different family members. It was not uncommon, for example, to see one child with HFM, another with just rash and fever, and the mother with malaise and myalgia, but with the identical virus isolated from all three. We were somewhat surprised by this finding.

Also unexpected was the long duration of illness in many instances. While we typically think of a “summer cold” as lasting no more than 2–3 days, in our study the myalgias and malaise lasted a mean of 9.5 days, stomatitis lasted 7 days, HFM 7.2 days, rash 6 days, pleurodynia 8.8 days, and meningitis 6.5 days. Unless we caution our patients about how long these symptoms can linger, we're sure to see them back in our offices, asking for antibiotics.

Unfortunately, efforts that began a decade or so ago to develop rapid-test enterovirus kits for widespread clinical use fell by the wayside for a variety of reasons. Some tertiary medical centers do have polymerase chain reaction-based rapid tests, but their cost is prohibitive for most community hospitals and private physicians' offices.

What I've found most useful in my practice is a simple white blood cell count. Most of these children will have a drop in their WBC count consistent with a viral infection, and an increase in their lymphocytes (“right shift”). During the summer or early fall, a febrile illness—even a high febrile illness—with no specific signs to indicate bacterial disease is most likely caused by an enterovirus.

That knowledge—coupled with a low WBC count and a right shift—should be sufficient in 90% of cases to ensure that you don't need empiric antibiotic therapy, as long as you have good follow-up with the patient.

The exceptions to that are newborns less than 2 months of age and immunosuppressed patients of any age. In those cases, a sepsis work-up is still advised. Indeed, a recent review paper noted that severe NPEV disease develops in a subset of newborns infected in the first 2 weeks of life, consisting of sepsis, meningoencephalitis, myocarditis, pneumonia, hepatitis, and/or coagulopathy. Substantial mortality has been reported, and long-term sequelae may occur among survivors (Paediatr. Drugs 2004;6:1–10).

The National Institute of Allergy and Infectious Diseases had funded an investigation of pleconaril—an agent that inhibits viral attachment to host cell receptors—for use in infants with enteroviral sepsis.

The study was suspended earlier this year, but NIAID is currently in talks with manufacturer Schering-Plough Corp. to restart the trial.

During the summer and early fall, we should be careful about unnecessary antibiotic use in patients who most likely have enteroviral infections.

Nonpolio enterovirus (NPEV) infections are amazingly diverse in their range of clinical manifestations. While most of these infections are self-limited and nonserious, NPEV can turn serious and even fatal in newborns and immunosuppressed individuals. Of course, the diagnosis is easy when we see a child with the classic hand-foot-and-mouth (HFM) blister presentation. But that happens in only a small proportion of cases.

More commonly, we see a child with a high fever, sore throat, a slightly stiff neck, and a very worried mother. Even with a negative strep test, sometimes we retreat to our comfort zone and prescribe amoxicillin. While understandable, we should try to avoid this practice.

In a study my colleagues and I conducted a few years ago, only 8% of 372 children with a clinical diagnosis of systemic NPEV syndrome presented with HFM blisters. More common were stomatitis in 58%, and fever with myalgias and malaise in 28%. Another 3% had pleurodynia, 3% had fever with rash, and 1% had aseptic meningitis. Most patients had four to seven symptoms at the onset of illness and at the time of presentation (Pediatrics 1998;102:1126–34).

To my knowledge, there have been no other published studies since that one on the epidemiology of enteroviral illness in private clinical practice.

Of the 372 index cases, more than half (53%) also had a family member with an NPEV illness, including 51% of the 105 with myalgia/malaise, 20% of the 10 with rash, 57% of the 214 with stomatitis, and 45% of the 11 with pleurodynia. Interestingly, the illness often presented differently in different family members. It was not uncommon, for example, to see one child with HFM, another with just rash and fever, and the mother with malaise and myalgia, but with the identical virus isolated from all three. We were somewhat surprised by this finding.

Also unexpected was the long duration of illness in many instances. While we typically think of a “summer cold” as lasting no more than 2–3 days, in our study the myalgias and malaise lasted a mean of 9.5 days, stomatitis lasted 7 days, HFM 7.2 days, rash 6 days, pleurodynia 8.8 days, and meningitis 6.5 days. Unless we caution our patients about how long these symptoms can linger, we're sure to see them back in our offices, asking for antibiotics.

Unfortunately, efforts that began a decade or so ago to develop rapid-test enterovirus kits for widespread clinical use fell by the wayside for a variety of reasons. Some tertiary medical centers do have polymerase chain reaction-based rapid tests, but their cost is prohibitive for most community hospitals and private physicians' offices.

What I've found most useful in my practice is a simple white blood cell count. Most of these children will have a drop in their WBC count consistent with a viral infection, and an increase in their lymphocytes (“right shift”). During the summer or early fall, a febrile illness—even a high febrile illness—with no specific signs to indicate bacterial disease is most likely caused by an enterovirus.

That knowledge—coupled with a low WBC count and a right shift—should be sufficient in 90% of cases to ensure that you don't need empiric antibiotic therapy, as long as you have good follow-up with the patient.

The exceptions to that are newborns less than 2 months of age and immunosuppressed patients of any age. In those cases, a sepsis work-up is still advised. Indeed, a recent review paper noted that severe NPEV disease develops in a subset of newborns infected in the first 2 weeks of life, consisting of sepsis, meningoencephalitis, myocarditis, pneumonia, hepatitis, and/or coagulopathy. Substantial mortality has been reported, and long-term sequelae may occur among survivors (Paediatr. Drugs 2004;6:1–10).

The National Institute of Allergy and Infectious Diseases had funded an investigation of pleconaril—an agent that inhibits viral attachment to host cell receptors—for use in infants with enteroviral sepsis.

The study was suspended earlier this year, but NIAID is currently in talks with manufacturer Schering-Plough Corp. to restart the trial.

During the summer and early fall, we should be careful about unnecessary antibiotic use in patients who most likely have enteroviral infections.

Nonpolio enterovirus (NPEV) infections are amazingly diverse in their range of clinical manifestations. While most of these infections are self-limited and nonserious, NPEV can turn serious and even fatal in newborns and immunosuppressed individuals. Of course, the diagnosis is easy when we see a child with the classic hand-foot-and-mouth (HFM) blister presentation. But that happens in only a small proportion of cases.

More commonly, we see a child with a high fever, sore throat, a slightly stiff neck, and a very worried mother. Even with a negative strep test, sometimes we retreat to our comfort zone and prescribe amoxicillin. While understandable, we should try to avoid this practice.

In a study my colleagues and I conducted a few years ago, only 8% of 372 children with a clinical diagnosis of systemic NPEV syndrome presented with HFM blisters. More common were stomatitis in 58%, and fever with myalgias and malaise in 28%. Another 3% had pleurodynia, 3% had fever with rash, and 1% had aseptic meningitis. Most patients had four to seven symptoms at the onset of illness and at the time of presentation (Pediatrics 1998;102:1126–34).

To my knowledge, there have been no other published studies since that one on the epidemiology of enteroviral illness in private clinical practice.

Of the 372 index cases, more than half (53%) also had a family member with an NPEV illness, including 51% of the 105 with myalgia/malaise, 20% of the 10 with rash, 57% of the 214 with stomatitis, and 45% of the 11 with pleurodynia. Interestingly, the illness often presented differently in different family members. It was not uncommon, for example, to see one child with HFM, another with just rash and fever, and the mother with malaise and myalgia, but with the identical virus isolated from all three. We were somewhat surprised by this finding.

Also unexpected was the long duration of illness in many instances. While we typically think of a “summer cold” as lasting no more than 2–3 days, in our study the myalgias and malaise lasted a mean of 9.5 days, stomatitis lasted 7 days, HFM 7.2 days, rash 6 days, pleurodynia 8.8 days, and meningitis 6.5 days. Unless we caution our patients about how long these symptoms can linger, we're sure to see them back in our offices, asking for antibiotics.

Unfortunately, efforts that began a decade or so ago to develop rapid-test enterovirus kits for widespread clinical use fell by the wayside for a variety of reasons. Some tertiary medical centers do have polymerase chain reaction-based rapid tests, but their cost is prohibitive for most community hospitals and private physicians' offices.

What I've found most useful in my practice is a simple white blood cell count. Most of these children will have a drop in their WBC count consistent with a viral infection, and an increase in their lymphocytes (“right shift”). During the summer or early fall, a febrile illness—even a high febrile illness—with no specific signs to indicate bacterial disease is most likely caused by an enterovirus.

That knowledge—coupled with a low WBC count and a right shift—should be sufficient in 90% of cases to ensure that you don't need empiric antibiotic therapy, as long as you have good follow-up with the patient.

The exceptions to that are newborns less than 2 months of age and immunosuppressed patients of any age. In those cases, a sepsis work-up is still advised. Indeed, a recent review paper noted that severe NPEV disease develops in a subset of newborns infected in the first 2 weeks of life, consisting of sepsis, meningoencephalitis, myocarditis, pneumonia, hepatitis, and/or coagulopathy. Substantial mortality has been reported, and long-term sequelae may occur among survivors (Paediatr. Drugs 2004;6:1–10).

The National Institute of Allergy and Infectious Diseases had funded an investigation of pleconaril—an agent that inhibits viral attachment to host cell receptors—for use in infants with enteroviral sepsis.

The study was suspended earlier this year, but NIAID is currently in talks with manufacturer Schering-Plough Corp. to restart the trial.

Upon returning from the annual Interscience Conference on Antimicrobial Agents and Chemotherapy, I wanted to share my view of what seemed to emerge as a theme from the many papers published on ear infection treatment.

First, consensus exists on the importance of a bulging tympanic membrane in the diagnosis of acute otitis media (AOM) and its differentiation from otitis media with effusion (OME). Most AOM experts appear to agree that antibiotic treatment is warranted and recommended for children with clear-cut AOM as distinguished by a bulging eardrum.

Watchful observation or placebo treatment should involve less ill, older children who are verbal enough to describe their pain accurately.

Second, in children with a bulging tympanic membrane, the chances for bacterial infection are high, probably around 90%–98%. These children are not the ones with an 80% or greater likelihood of “spontaneous resolution” of their ear infections at the same speed as those who receive antibiotics.

Third, the spontaneous resolution rate of bacterial otitis media depends on when you ask the question: 1–2 days into treatment, on days 3–5, on days 10–14, or on day 28.

Most of the symptomatic benefit of antibiotics occurs during the early days of treatment.

The rates of persistent effusion, measured later, will be lower if appropriate antibiotics are used.

Fourth, the effectiveness of antibiotic therapy should be gauged against the likelihood of resolution that would accompany placebo treatment of otitis media.

Research in this area involves ethical, medicolegal, and practical concerns. The patient populations who enroll in trials in which children could be receiving antibiotic, placebo, or possibly one or two tympanocenteses (ear taps) are almost certainly different from each other and different from what we see in everyday practice.

The situation is dynamic in terms of study populations, investigative sites, causative bacteria, and antibiotic resistance.

Thus, comparisons across studies and across time should be made with extreme caution; frankly, I don't think they should be made at all.

Absent new data to the contrary—and I know of none—among children who have AOM of sufficient severity to receive an ear tap, bacterial eradication by natural host defense occurs 3–5 days after the onset of symptoms in 20% of these patients with Streptococcus pneumoniae, in 50% of those with Haemophilus influenzae, and in 70% with Moraxella catarrhalis. These numbers have been confirmed in multiple studies.

The bacterial profile for AOM in the United States has changed significantly because of the conjugate pneumococcal vaccine (Prevnar).

In vaccinated children, the No. 1 bacterial species is now H. influenzae, and more than half of those organisms make β-lactamase, rendering them resistant to the current first-line antibiotic choice, amoxicillin.

In fact, it appears that about 60% of AOM in Prevnar-vaccinated children involve H. influenzae.

But we can't ignore S. pneumoniae, which makes up about 30% of the total bacterial burden.

Although most of those strains are now penicillin susceptible because of the vaccine, the resistant strains are still around. The ratios may change with time, but S. pneumoniae is more worrisome because of its invasiveness and suppurative complications.

Finally, at least for the moment, we see a clearer distinction emerging among antibiotics as “good, better, and best” for anticipated effectiveness and for tolerability in the current U.S. pathogen mix. (See table below.)

Of course, there are caveats to these distinctions.

Measures of efficacy include bacterial cure (by double tympanocentesis study designs) and pharmacokinetic/pharmacodynamic antibiotic measurements of the key pathogens in middle-ear fluids.

Although I'm tempted to add “tolerability to the pocketbook (monetary cost)” and “annoyance cost of phone calls from the managed care policy police” as measures of tolerability and adherence to the prescribed regimen, the tolerability measurements in the table refer to taste, the number of doses per day, the duration of treatment, and the number of office visits involved.

Not included in the table are cefixime and ceftibuten because these agents are not satisfactorily effective against penicillin-nonsusceptible S. pneumoniae. (Combined with high-dose amoxicillin, however, such a combination would be expected to work very well.)

Also not listed are cefaclor and loracarbef because their efficacy, by current standards, has not been tested and they are anticipated not to be that good, although the tolerability is excellent.

Now the debate will continue around what to do in practice: Do we start with a good antibiotic, then go to a better one? Or start with a better one, and then jump to the best? Or start with the best and go to other “bests”—or to ear taps or tubes?

The best antibiotics in efficacy are not the same as the best in tolerability, so which one takes precedence? The most effective antibiotic won't work if it is not taken, and the most tolerable antibiotic won't work if it is not effective.

Stay tuned for the next chapter.

Upon returning from the annual Interscience Conference on Antimicrobial Agents and Chemotherapy, I wanted to share my view of what seemed to emerge as a theme from the many papers published on ear infection treatment.

First, consensus exists on the importance of a bulging tympanic membrane in the diagnosis of acute otitis media (AOM) and its differentiation from otitis media with effusion (OME). Most AOM experts appear to agree that antibiotic treatment is warranted and recommended for children with clear-cut AOM as distinguished by a bulging eardrum.

Watchful observation or placebo treatment should involve less ill, older children who are verbal enough to describe their pain accurately.

Second, in children with a bulging tympanic membrane, the chances for bacterial infection are high, probably around 90%–98%. These children are not the ones with an 80% or greater likelihood of “spontaneous resolution” of their ear infections at the same speed as those who receive antibiotics.

Third, the spontaneous resolution rate of bacterial otitis media depends on when you ask the question: 1–2 days into treatment, on days 3–5, on days 10–14, or on day 28.

Most of the symptomatic benefit of antibiotics occurs during the early days of treatment.

The rates of persistent effusion, measured later, will be lower if appropriate antibiotics are used.

Fourth, the effectiveness of antibiotic therapy should be gauged against the likelihood of resolution that would accompany placebo treatment of otitis media.

Research in this area involves ethical, medicolegal, and practical concerns. The patient populations who enroll in trials in which children could be receiving antibiotic, placebo, or possibly one or two tympanocenteses (ear taps) are almost certainly different from each other and different from what we see in everyday practice.

The situation is dynamic in terms of study populations, investigative sites, causative bacteria, and antibiotic resistance.

Thus, comparisons across studies and across time should be made with extreme caution; frankly, I don't think they should be made at all.

Absent new data to the contrary—and I know of none—among children who have AOM of sufficient severity to receive an ear tap, bacterial eradication by natural host defense occurs 3–5 days after the onset of symptoms in 20% of these patients with Streptococcus pneumoniae, in 50% of those with Haemophilus influenzae, and in 70% with Moraxella catarrhalis. These numbers have been confirmed in multiple studies.

The bacterial profile for AOM in the United States has changed significantly because of the conjugate pneumococcal vaccine (Prevnar).

In vaccinated children, the No. 1 bacterial species is now H. influenzae, and more than half of those organisms make β-lactamase, rendering them resistant to the current first-line antibiotic choice, amoxicillin.

In fact, it appears that about 60% of AOM in Prevnar-vaccinated children involve H. influenzae.

But we can't ignore S. pneumoniae, which makes up about 30% of the total bacterial burden.

Although most of those strains are now penicillin susceptible because of the vaccine, the resistant strains are still around. The ratios may change with time, but S. pneumoniae is more worrisome because of its invasiveness and suppurative complications.

Finally, at least for the moment, we see a clearer distinction emerging among antibiotics as “good, better, and best” for anticipated effectiveness and for tolerability in the current U.S. pathogen mix. (See table below.)

Of course, there are caveats to these distinctions.

Measures of efficacy include bacterial cure (by double tympanocentesis study designs) and pharmacokinetic/pharmacodynamic antibiotic measurements of the key pathogens in middle-ear fluids.

Although I'm tempted to add “tolerability to the pocketbook (monetary cost)” and “annoyance cost of phone calls from the managed care policy police” as measures of tolerability and adherence to the prescribed regimen, the tolerability measurements in the table refer to taste, the number of doses per day, the duration of treatment, and the number of office visits involved.

Not included in the table are cefixime and ceftibuten because these agents are not satisfactorily effective against penicillin-nonsusceptible S. pneumoniae. (Combined with high-dose amoxicillin, however, such a combination would be expected to work very well.)

Also not listed are cefaclor and loracarbef because their efficacy, by current standards, has not been tested and they are anticipated not to be that good, although the tolerability is excellent.

Now the debate will continue around what to do in practice: Do we start with a good antibiotic, then go to a better one? Or start with a better one, and then jump to the best? Or start with the best and go to other “bests”—or to ear taps or tubes?

The best antibiotics in efficacy are not the same as the best in tolerability, so which one takes precedence? The most effective antibiotic won't work if it is not taken, and the most tolerable antibiotic won't work if it is not effective.

Stay tuned for the next chapter.

Upon returning from the annual Interscience Conference on Antimicrobial Agents and Chemotherapy, I wanted to share my view of what seemed to emerge as a theme from the many papers published on ear infection treatment.

First, consensus exists on the importance of a bulging tympanic membrane in the diagnosis of acute otitis media (AOM) and its differentiation from otitis media with effusion (OME). Most AOM experts appear to agree that antibiotic treatment is warranted and recommended for children with clear-cut AOM as distinguished by a bulging eardrum.

Watchful observation or placebo treatment should involve less ill, older children who are verbal enough to describe their pain accurately.

Second, in children with a bulging tympanic membrane, the chances for bacterial infection are high, probably around 90%–98%. These children are not the ones with an 80% or greater likelihood of “spontaneous resolution” of their ear infections at the same speed as those who receive antibiotics.

Third, the spontaneous resolution rate of bacterial otitis media depends on when you ask the question: 1–2 days into treatment, on days 3–5, on days 10–14, or on day 28.

Most of the symptomatic benefit of antibiotics occurs during the early days of treatment.

The rates of persistent effusion, measured later, will be lower if appropriate antibiotics are used.

Fourth, the effectiveness of antibiotic therapy should be gauged against the likelihood of resolution that would accompany placebo treatment of otitis media.

Research in this area involves ethical, medicolegal, and practical concerns. The patient populations who enroll in trials in which children could be receiving antibiotic, placebo, or possibly one or two tympanocenteses (ear taps) are almost certainly different from each other and different from what we see in everyday practice.

The situation is dynamic in terms of study populations, investigative sites, causative bacteria, and antibiotic resistance.

Thus, comparisons across studies and across time should be made with extreme caution; frankly, I don't think they should be made at all.

Absent new data to the contrary—and I know of none—among children who have AOM of sufficient severity to receive an ear tap, bacterial eradication by natural host defense occurs 3–5 days after the onset of symptoms in 20% of these patients with Streptococcus pneumoniae, in 50% of those with Haemophilus influenzae, and in 70% with Moraxella catarrhalis. These numbers have been confirmed in multiple studies.

The bacterial profile for AOM in the United States has changed significantly because of the conjugate pneumococcal vaccine (Prevnar).

In vaccinated children, the No. 1 bacterial species is now H. influenzae, and more than half of those organisms make β-lactamase, rendering them resistant to the current first-line antibiotic choice, amoxicillin.

In fact, it appears that about 60% of AOM in Prevnar-vaccinated children involve H. influenzae.

But we can't ignore S. pneumoniae, which makes up about 30% of the total bacterial burden.

Although most of those strains are now penicillin susceptible because of the vaccine, the resistant strains are still around. The ratios may change with time, but S. pneumoniae is more worrisome because of its invasiveness and suppurative complications.

Finally, at least for the moment, we see a clearer distinction emerging among antibiotics as “good, better, and best” for anticipated effectiveness and for tolerability in the current U.S. pathogen mix. (See table below.)

Of course, there are caveats to these distinctions.

Measures of efficacy include bacterial cure (by double tympanocentesis study designs) and pharmacokinetic/pharmacodynamic antibiotic measurements of the key pathogens in middle-ear fluids.

Although I'm tempted to add “tolerability to the pocketbook (monetary cost)” and “annoyance cost of phone calls from the managed care policy police” as measures of tolerability and adherence to the prescribed regimen, the tolerability measurements in the table refer to taste, the number of doses per day, the duration of treatment, and the number of office visits involved.

Not included in the table are cefixime and ceftibuten because these agents are not satisfactorily effective against penicillin-nonsusceptible S. pneumoniae. (Combined with high-dose amoxicillin, however, such a combination would be expected to work very well.)

Also not listed are cefaclor and loracarbef because their efficacy, by current standards, has not been tested and they are anticipated not to be that good, although the tolerability is excellent.

Now the debate will continue around what to do in practice: Do we start with a good antibiotic, then go to a better one? Or start with a better one, and then jump to the best? Or start with the best and go to other “bests”—or to ear taps or tubes?

The best antibiotics in efficacy are not the same as the best in tolerability, so which one takes precedence? The most effective antibiotic won't work if it is not taken, and the most tolerable antibiotic won't work if it is not effective.

Stay tuned for the next chapter.

We may soon be able to prevent cervical cancer in women by vaccinating preteens against human papillomavirus.

Two candidate HPV vaccines—GlaxoSmithKline's Cervarix and Merck's Gardasil—are expected to be licensed for use in the United States in 2006. Both vaccines are highly effective in preventing infection with both HPV strains 16 and 18, which are responsible for 70%–75% of cervical cancers in women.

The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention is already working on guidelines for their use, as is the American Academy of Pediatrics. Both groups are likely to recommend that the vaccines be given to girls aged 11–12 as part of the adolescent “vaccine platform,” along with the meningococcal conjugate vaccine and the adolescent and adult DTaP vaccine.

I see this as a new frontier. It's a fabulous opportunity for those of us who work in vaccinology to be able to move from the prevention of infectious disease per se to the prevention of cancer. Cervical cancer affects approximately 12,000 women in the United States. And despite advances in Pap screening and treatment, the disease kills more than 4,000 women annually.

Nearly all (99.7%) of cervical cancer cases are caused by HPV infection. Approximately 15–20 of the 30–40 anogenital types of HPV that have been identified are oncogenic: HPV 16 causes about 54% of cases, and HPV 18 about 13%. Among the nononcogenic types, HPV 6 and 11 are most often associated with external genital warts. The Merck vaccine targets those two strains as well.

We know that acquisition of HPV typically occurs very soon after initiation of sexual intercourse. In a study of 608 U.S. college women who were followed at 6-month intervals, 43% had become infected with HPV by the third year. Indeed, nearly three-fourths of new HPV infections occur in sexually active young adults aged 15–24, and the prevalence of infection in women less than 25 years of age ranges from 28% to 46%.

As more vaccines are being added to the already-crowded childhood and adolescent immunization schedules, payers will be looking to prioritize more than they have with vaccines in the past. Some authorities think it makes sense to hold off for now on vaccinating males against HPV, even though they are, of course, the major source of infection for females. But since the majority of females pick up HPV by the time they reach their late 20s or early 30s and are therefore at risk for cervical cancer, how can we justify not vaccinating every girl in America?

At last year's meeting of the Interscience Conference on Antimicrobials and Chemotherapy, data were presented for a monovalent version of the current Merck vaccine containing only strain 16. In that phase II “proof of principle” study involving 1,533 women aged 16–23 years who were initially negative for HPV 16 DNA and antibodies, the vaccine was 94% effective in preventing persistent HPV infection and 100% effective against cervical intraepithelial neoplasia grades 2 and 3, compared with placebo over 3.5 years.

No cases of cervical intraepithelial neoplasia (CIN) were seen among vaccine recipients, compared with CIN 1 in 12 in the placebo group, CIN 2 in 7, and CIN 3 in 6 in the placebo group (PEDIATRIC NEWS, December 2004, p. 10).

Now, phase III data for the current quadrivalent Merck vaccine from a total of 1,529 male and female subjects aged 10–23 show 100% seroconversion at 6 months for HPV types 16, 6, and 11, and 99.9% seroconversion for serotype 18. Antibody levels for all four serotypes were significantly higher among females and males aged 10–15 years than among those aged 16–23. These data were presented earlier this year at the annual meeting of the European Society of Pediatric Infectious Diseases.

The GlaxoSmithKline vaccine also was found highly effective in a multinational randomized, placebo-controlled study of 1,113 women aged 15–25 years who were followed up to 27 months. Vaccine efficacy overall was 91.6% against incident infection and 100% against persistent infection with HPV 16 and/or 18. In the intention-to-treat analysis, vaccine efficacy was 95.1% against persistent cervical infection and 92.9% against cytologic abnormalities associated with HPV 16 and 18 infection (Lancet 2004;364:1731–2).

Merck and GlaxoSmithKline are now each studying the efficacy and safety of their HPV vaccines in more than 20,000 people aged 9–24 years. The results should tell us whether the vaccines have a therapeutic effect in women who are already infected with HPV, perhaps by inducing antibodies to generate an immune response thereby preventing the progression from simple, transient infection to persistent infection to stage 3 (CIN). However, the first order of business is to target girls before they become sexually active.

About a million women per year have an abnormal Pap smear. What follows is a series of costly and anxiety-provoking steps, including colposcopy, cervical scraping, and if abnormal cells are found, cervical biopsy and possible hysterectomy, all at a cost of approximately $2.8 billion. Widespread vaccination against HPV could substantially reduce this burden.

Although the HPV vaccines will not be the first to prevent cancer—the hepatitis B vaccine reduces the likelihood of developing hepatocellular carcinoma—they are the first to be specifically developed and marketed for cancer prevention. As an infectious disease specialist, I see this concept as novel and very, very exciting.

We may soon be able to prevent cervical cancer in women by vaccinating preteens against human papillomavirus.

Two candidate HPV vaccines—GlaxoSmithKline's Cervarix and Merck's Gardasil—are expected to be licensed for use in the United States in 2006. Both vaccines are highly effective in preventing infection with both HPV strains 16 and 18, which are responsible for 70%–75% of cervical cancers in women.

The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention is already working on guidelines for their use, as is the American Academy of Pediatrics. Both groups are likely to recommend that the vaccines be given to girls aged 11–12 as part of the adolescent “vaccine platform,” along with the meningococcal conjugate vaccine and the adolescent and adult DTaP vaccine.

I see this as a new frontier. It's a fabulous opportunity for those of us who work in vaccinology to be able to move from the prevention of infectious disease per se to the prevention of cancer. Cervical cancer affects approximately 12,000 women in the United States. And despite advances in Pap screening and treatment, the disease kills more than 4,000 women annually.

Nearly all (99.7%) of cervical cancer cases are caused by HPV infection. Approximately 15–20 of the 30–40 anogenital types of HPV that have been identified are oncogenic: HPV 16 causes about 54% of cases, and HPV 18 about 13%. Among the nononcogenic types, HPV 6 and 11 are most often associated with external genital warts. The Merck vaccine targets those two strains as well.

We know that acquisition of HPV typically occurs very soon after initiation of sexual intercourse. In a study of 608 U.S. college women who were followed at 6-month intervals, 43% had become infected with HPV by the third year. Indeed, nearly three-fourths of new HPV infections occur in sexually active young adults aged 15–24, and the prevalence of infection in women less than 25 years of age ranges from 28% to 46%.

As more vaccines are being added to the already-crowded childhood and adolescent immunization schedules, payers will be looking to prioritize more than they have with vaccines in the past. Some authorities think it makes sense to hold off for now on vaccinating males against HPV, even though they are, of course, the major source of infection for females. But since the majority of females pick up HPV by the time they reach their late 20s or early 30s and are therefore at risk for cervical cancer, how can we justify not vaccinating every girl in America?

At last year's meeting of the Interscience Conference on Antimicrobials and Chemotherapy, data were presented for a monovalent version of the current Merck vaccine containing only strain 16. In that phase II “proof of principle” study involving 1,533 women aged 16–23 years who were initially negative for HPV 16 DNA and antibodies, the vaccine was 94% effective in preventing persistent HPV infection and 100% effective against cervical intraepithelial neoplasia grades 2 and 3, compared with placebo over 3.5 years.

No cases of cervical intraepithelial neoplasia (CIN) were seen among vaccine recipients, compared with CIN 1 in 12 in the placebo group, CIN 2 in 7, and CIN 3 in 6 in the placebo group (PEDIATRIC NEWS, December 2004, p. 10).

Now, phase III data for the current quadrivalent Merck vaccine from a total of 1,529 male and female subjects aged 10–23 show 100% seroconversion at 6 months for HPV types 16, 6, and 11, and 99.9% seroconversion for serotype 18. Antibody levels for all four serotypes were significantly higher among females and males aged 10–15 years than among those aged 16–23. These data were presented earlier this year at the annual meeting of the European Society of Pediatric Infectious Diseases.

The GlaxoSmithKline vaccine also was found highly effective in a multinational randomized, placebo-controlled study of 1,113 women aged 15–25 years who were followed up to 27 months. Vaccine efficacy overall was 91.6% against incident infection and 100% against persistent infection with HPV 16 and/or 18. In the intention-to-treat analysis, vaccine efficacy was 95.1% against persistent cervical infection and 92.9% against cytologic abnormalities associated with HPV 16 and 18 infection (Lancet 2004;364:1731–2).

Merck and GlaxoSmithKline are now each studying the efficacy and safety of their HPV vaccines in more than 20,000 people aged 9–24 years. The results should tell us whether the vaccines have a therapeutic effect in women who are already infected with HPV, perhaps by inducing antibodies to generate an immune response thereby preventing the progression from simple, transient infection to persistent infection to stage 3 (CIN). However, the first order of business is to target girls before they become sexually active.

About a million women per year have an abnormal Pap smear. What follows is a series of costly and anxiety-provoking steps, including colposcopy, cervical scraping, and if abnormal cells are found, cervical biopsy and possible hysterectomy, all at a cost of approximately $2.8 billion. Widespread vaccination against HPV could substantially reduce this burden.

Although the HPV vaccines will not be the first to prevent cancer—the hepatitis B vaccine reduces the likelihood of developing hepatocellular carcinoma—they are the first to be specifically developed and marketed for cancer prevention. As an infectious disease specialist, I see this concept as novel and very, very exciting.

We may soon be able to prevent cervical cancer in women by vaccinating preteens against human papillomavirus.

Two candidate HPV vaccines—GlaxoSmithKline's Cervarix and Merck's Gardasil—are expected to be licensed for use in the United States in 2006. Both vaccines are highly effective in preventing infection with both HPV strains 16 and 18, which are responsible for 70%–75% of cervical cancers in women.

The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention is already working on guidelines for their use, as is the American Academy of Pediatrics. Both groups are likely to recommend that the vaccines be given to girls aged 11–12 as part of the adolescent “vaccine platform,” along with the meningococcal conjugate vaccine and the adolescent and adult DTaP vaccine.

I see this as a new frontier. It's a fabulous opportunity for those of us who work in vaccinology to be able to move from the prevention of infectious disease per se to the prevention of cancer. Cervical cancer affects approximately 12,000 women in the United States. And despite advances in Pap screening and treatment, the disease kills more than 4,000 women annually.

Nearly all (99.7%) of cervical cancer cases are caused by HPV infection. Approximately 15–20 of the 30–40 anogenital types of HPV that have been identified are oncogenic: HPV 16 causes about 54% of cases, and HPV 18 about 13%. Among the nononcogenic types, HPV 6 and 11 are most often associated with external genital warts. The Merck vaccine targets those two strains as well.

We know that acquisition of HPV typically occurs very soon after initiation of sexual intercourse. In a study of 608 U.S. college women who were followed at 6-month intervals, 43% had become infected with HPV by the third year. Indeed, nearly three-fourths of new HPV infections occur in sexually active young adults aged 15–24, and the prevalence of infection in women less than 25 years of age ranges from 28% to 46%.

As more vaccines are being added to the already-crowded childhood and adolescent immunization schedules, payers will be looking to prioritize more than they have with vaccines in the past. Some authorities think it makes sense to hold off for now on vaccinating males against HPV, even though they are, of course, the major source of infection for females. But since the majority of females pick up HPV by the time they reach their late 20s or early 30s and are therefore at risk for cervical cancer, how can we justify not vaccinating every girl in America?

At last year's meeting of the Interscience Conference on Antimicrobials and Chemotherapy, data were presented for a monovalent version of the current Merck vaccine containing only strain 16. In that phase II “proof of principle” study involving 1,533 women aged 16–23 years who were initially negative for HPV 16 DNA and antibodies, the vaccine was 94% effective in preventing persistent HPV infection and 100% effective against cervical intraepithelial neoplasia grades 2 and 3, compared with placebo over 3.5 years.

No cases of cervical intraepithelial neoplasia (CIN) were seen among vaccine recipients, compared with CIN 1 in 12 in the placebo group, CIN 2 in 7, and CIN 3 in 6 in the placebo group (PEDIATRIC NEWS, December 2004, p. 10).

Now, phase III data for the current quadrivalent Merck vaccine from a total of 1,529 male and female subjects aged 10–23 show 100% seroconversion at 6 months for HPV types 16, 6, and 11, and 99.9% seroconversion for serotype 18. Antibody levels for all four serotypes were significantly higher among females and males aged 10–15 years than among those aged 16–23. These data were presented earlier this year at the annual meeting of the European Society of Pediatric Infectious Diseases.

The GlaxoSmithKline vaccine also was found highly effective in a multinational randomized, placebo-controlled study of 1,113 women aged 15–25 years who were followed up to 27 months. Vaccine efficacy overall was 91.6% against incident infection and 100% against persistent infection with HPV 16 and/or 18. In the intention-to-treat analysis, vaccine efficacy was 95.1% against persistent cervical infection and 92.9% against cytologic abnormalities associated with HPV 16 and 18 infection (Lancet 2004;364:1731–2).

Merck and GlaxoSmithKline are now each studying the efficacy and safety of their HPV vaccines in more than 20,000 people aged 9–24 years. The results should tell us whether the vaccines have a therapeutic effect in women who are already infected with HPV, perhaps by inducing antibodies to generate an immune response thereby preventing the progression from simple, transient infection to persistent infection to stage 3 (CIN). However, the first order of business is to target girls before they become sexually active.

About a million women per year have an abnormal Pap smear. What follows is a series of costly and anxiety-provoking steps, including colposcopy, cervical scraping, and if abnormal cells are found, cervical biopsy and possible hysterectomy, all at a cost of approximately $2.8 billion. Widespread vaccination against HPV could substantially reduce this burden.

Although the HPV vaccines will not be the first to prevent cancer—the hepatitis B vaccine reduces the likelihood of developing hepatocellular carcinoma—they are the first to be specifically developed and marketed for cancer prevention. As an infectious disease specialist, I see this concept as novel and very, very exciting.

Quinolone otic drops may represent a better choice for treating swimmer's ear in children than are the generics that we're accustomed to using.

Both Floxin (ofloxacin otic solution 0.3%) and Ciprodex (ciprofloxacin 0.3% and dexamethasone 0.1% sterile otic suspension) have recently been approved for the treatment of acute otitis externa in children as young as age 6 months. Otolaryngologists are using these drugs extensively in children, but so far, the pediatric community has not embraced them. This lag is due in part to the way these products have been marketed. But I believe that inappropriate concern about fluoroquinolone-associated arthropathy has also impeded use of what appear to be products with greater efficacy and convenience, and possibly even lower cost, in the case of Floxin.

Overall, the data suggest that efficacy of Floxin and Ciprodex drops in treating acute otitis externa in children is greater than 90%, compared with about 80% for the generics such as Cortisporin (neomycin, polymyxin B sulfates, and hydrocortisone otic solution), and about 70% for astringents such as acetic acid, isopropyl alcohol, or hydrogen peroxide.

In an open-label, phase III trial involving 439 children with acute otitis externa in Latin America, a 7-day course of Floxin given once daily—5 drops for children aged 6 months to 12 years, 10 drops for those 13 years and older—produced eradication rates of 96% overall (Clin. Ther. 2004;26:1046–54).

Similar efficacy for Ciprodex was seen in a recent randomized, blinded multicenter trial in 396 otitis externa patients older than 1 year. Clinical cure rates at day 18 were 90.9% after 7 days of Ciprodex (3–4 drops twice daily), compared with 83.9% after 7 days of Cortisporin (3–4 drops three times daily), while microbiologic eradication rates were 94.7% and 86%, respectively (Curr. Med. Res. Opin. 2004;20:1175–83).

Antimicrobial resistance to the older topicals might be one reason for the quinolones' superior efficacy. Data from two multicenter trials conducted by Floxin manufacturer Daiichi Pharmaceuticals Inc. suggested that the two most common organisms associated with otitis externa—Pseudomonas aeruginosa and Staphylococcus aureus—appear to be developing resistance to Cortisporin but not to Floxin (South. Med. J. 2004; 97:465–71).

The quinolones are also more convenient to administer. Floxin is available in 5-mL and 10-mL plastic dropper bottles and as “singles” containing individual once-daily doses (one packet for ages 6 months to 12 years and two for children aged 13 years and older, given for 7 days). The dropper bottles also allow for once-daily dosing (5 drops for ages 6 months to 13 years and 10 drops for ages 13 and older). Ciprodex dosing for patients 6 months and older is four drops twice daily for 7 days.

In contrast, 3 drops of Cortisporin must be administered three or four times daily to children with acute otitis externa.

There is some disagreement about whether a corticosteroid—contained in Ciprodex and Cortisporin but not Floxin—adds significant benefit. While the anti-inflammatory effect does produce greater symptomatic relief, it also may dampen the immune response. Because the data suggest Floxin is just as effective as Ciprodex, and more effective than Cortisporin, the steroid may not be much of an advantage.

Floxin can be slightly cheaper than the generic Cortisporin on a per-treatment basis: Computed with the average wholesale price for a 5-mL bottle, the cost of 5 drops of Floxin daily for 7 days is $17.60, compared with $18.34 for a 10-day treatment of Cortisporin, 4 drops daily. The cost of Ciprodex is somewhat higher than for the generic.

In addition to being more effective and convenient without costing more, quinolone drops are also quite safe. Systemic absorption of these topicals is essentially zero. And even with oral administration, combined data from studies involving approximately 16,000 children and adolescents have not revealed a single case of arthropathy, which has been seen in juvenile animals only. Safety data such as these led to the recent approval of ciprofloxacin for children 1 year and older with complicated urinary tract infections or pyelonephritis.

In four Bristol-Meyers Squibb-sponsored trials analyzed by my group and others, there was no evidence of arthrotoxicity among 867 children with recurrent or acute otitis media who were treated with gatifloxacin. Our results will be published in the August issue of Clinical Infectious Diseases.

Of course, as physicians we should also try to help our patients avoid swimmer's ear in the first place, and especially to prevent recurrence in those who've had the problem in the past. Swimming is the No. 1 cause of otitis externa, with lakes and rivers being the culprit more often than chlorinated swimming pools. Patients who regularly swim in natural bodies of water might be advised to place a couple drops of rubbing alcohol or hydrogen peroxide in each ear after emerging from the water.

In swimmer's ear, the child complains of ear pain, but often you can't see the eardrum because the ear is so swollen.

The second-most frequent cause of otitis externa in children occurs among those with drainage from tympanostomy tubes or a perforated eardrum.

The third is trauma. Children—or their parents—may stick cotton swabs or bobby pins in the child's ear, perhaps in an attempt to remove wax, and end up abrading the canal. This kind of trauma can introduce bacterial contamination. Such practices should be discouraged.

I served as a one-time consultant to Floxin manufacturer Daiichi. I have no affiliation with Bayer Pharmaceuticals Corp. or its subsidiary Alcon Laboratories Inc., the makers of Ciprodex.

Quinolone otic drops may represent a better choice for treating swimmer's ear in children than are the generics that we're accustomed to using.

Both Floxin (ofloxacin otic solution 0.3%) and Ciprodex (ciprofloxacin 0.3% and dexamethasone 0.1% sterile otic suspension) have recently been approved for the treatment of acute otitis externa in children as young as age 6 months. Otolaryngologists are using these drugs extensively in children, but so far, the pediatric community has not embraced them. This lag is due in part to the way these products have been marketed. But I believe that inappropriate concern about fluoroquinolone-associated arthropathy has also impeded use of what appear to be products with greater efficacy and convenience, and possibly even lower cost, in the case of Floxin.

Overall, the data suggest that efficacy of Floxin and Ciprodex drops in treating acute otitis externa in children is greater than 90%, compared with about 80% for the generics such as Cortisporin (neomycin, polymyxin B sulfates, and hydrocortisone otic solution), and about 70% for astringents such as acetic acid, isopropyl alcohol, or hydrogen peroxide.

In an open-label, phase III trial involving 439 children with acute otitis externa in Latin America, a 7-day course of Floxin given once daily—5 drops for children aged 6 months to 12 years, 10 drops for those 13 years and older—produced eradication rates of 96% overall (Clin. Ther. 2004;26:1046–54).

Similar efficacy for Ciprodex was seen in a recent randomized, blinded multicenter trial in 396 otitis externa patients older than 1 year. Clinical cure rates at day 18 were 90.9% after 7 days of Ciprodex (3–4 drops twice daily), compared with 83.9% after 7 days of Cortisporin (3–4 drops three times daily), while microbiologic eradication rates were 94.7% and 86%, respectively (Curr. Med. Res. Opin. 2004;20:1175–83).

Antimicrobial resistance to the older topicals might be one reason for the quinolones' superior efficacy. Data from two multicenter trials conducted by Floxin manufacturer Daiichi Pharmaceuticals Inc. suggested that the two most common organisms associated with otitis externa—Pseudomonas aeruginosa and Staphylococcus aureus—appear to be developing resistance to Cortisporin but not to Floxin (South. Med. J. 2004; 97:465–71).

The quinolones are also more convenient to administer. Floxin is available in 5-mL and 10-mL plastic dropper bottles and as “singles” containing individual once-daily doses (one packet for ages 6 months to 12 years and two for children aged 13 years and older, given for 7 days). The dropper bottles also allow for once-daily dosing (5 drops for ages 6 months to 13 years and 10 drops for ages 13 and older). Ciprodex dosing for patients 6 months and older is four drops twice daily for 7 days.

In contrast, 3 drops of Cortisporin must be administered three or four times daily to children with acute otitis externa.

There is some disagreement about whether a corticosteroid—contained in Ciprodex and Cortisporin but not Floxin—adds significant benefit. While the anti-inflammatory effect does produce greater symptomatic relief, it also may dampen the immune response. Because the data suggest Floxin is just as effective as Ciprodex, and more effective than Cortisporin, the steroid may not be much of an advantage.

Floxin can be slightly cheaper than the generic Cortisporin on a per-treatment basis: Computed with the average wholesale price for a 5-mL bottle, the cost of 5 drops of Floxin daily for 7 days is $17.60, compared with $18.34 for a 10-day treatment of Cortisporin, 4 drops daily. The cost of Ciprodex is somewhat higher than for the generic.

In addition to being more effective and convenient without costing more, quinolone drops are also quite safe. Systemic absorption of these topicals is essentially zero. And even with oral administration, combined data from studies involving approximately 16,000 children and adolescents have not revealed a single case of arthropathy, which has been seen in juvenile animals only. Safety data such as these led to the recent approval of ciprofloxacin for children 1 year and older with complicated urinary tract infections or pyelonephritis.

In four Bristol-Meyers Squibb-sponsored trials analyzed by my group and others, there was no evidence of arthrotoxicity among 867 children with recurrent or acute otitis media who were treated with gatifloxacin. Our results will be published in the August issue of Clinical Infectious Diseases.

Of course, as physicians we should also try to help our patients avoid swimmer's ear in the first place, and especially to prevent recurrence in those who've had the problem in the past. Swimming is the No. 1 cause of otitis externa, with lakes and rivers being the culprit more often than chlorinated swimming pools. Patients who regularly swim in natural bodies of water might be advised to place a couple drops of rubbing alcohol or hydrogen peroxide in each ear after emerging from the water.

In swimmer's ear, the child complains of ear pain, but often you can't see the eardrum because the ear is so swollen.

The second-most frequent cause of otitis externa in children occurs among those with drainage from tympanostomy tubes or a perforated eardrum.

The third is trauma. Children—or their parents—may stick cotton swabs or bobby pins in the child's ear, perhaps in an attempt to remove wax, and end up abrading the canal. This kind of trauma can introduce bacterial contamination. Such practices should be discouraged.

I served as a one-time consultant to Floxin manufacturer Daiichi. I have no affiliation with Bayer Pharmaceuticals Corp. or its subsidiary Alcon Laboratories Inc., the makers of Ciprodex.

Quinolone otic drops may represent a better choice for treating swimmer's ear in children than are the generics that we're accustomed to using.

Both Floxin (ofloxacin otic solution 0.3%) and Ciprodex (ciprofloxacin 0.3% and dexamethasone 0.1% sterile otic suspension) have recently been approved for the treatment of acute otitis externa in children as young as age 6 months. Otolaryngologists are using these drugs extensively in children, but so far, the pediatric community has not embraced them. This lag is due in part to the way these products have been marketed. But I believe that inappropriate concern about fluoroquinolone-associated arthropathy has also impeded use of what appear to be products with greater efficacy and convenience, and possibly even lower cost, in the case of Floxin.

Overall, the data suggest that efficacy of Floxin and Ciprodex drops in treating acute otitis externa in children is greater than 90%, compared with about 80% for the generics such as Cortisporin (neomycin, polymyxin B sulfates, and hydrocortisone otic solution), and about 70% for astringents such as acetic acid, isopropyl alcohol, or hydrogen peroxide.

In an open-label, phase III trial involving 439 children with acute otitis externa in Latin America, a 7-day course of Floxin given once daily—5 drops for children aged 6 months to 12 years, 10 drops for those 13 years and older—produced eradication rates of 96% overall (Clin. Ther. 2004;26:1046–54).

Similar efficacy for Ciprodex was seen in a recent randomized, blinded multicenter trial in 396 otitis externa patients older than 1 year. Clinical cure rates at day 18 were 90.9% after 7 days of Ciprodex (3–4 drops twice daily), compared with 83.9% after 7 days of Cortisporin (3–4 drops three times daily), while microbiologic eradication rates were 94.7% and 86%, respectively (Curr. Med. Res. Opin. 2004;20:1175–83).

Antimicrobial resistance to the older topicals might be one reason for the quinolones' superior efficacy. Data from two multicenter trials conducted by Floxin manufacturer Daiichi Pharmaceuticals Inc. suggested that the two most common organisms associated with otitis externa—Pseudomonas aeruginosa and Staphylococcus aureus—appear to be developing resistance to Cortisporin but not to Floxin (South. Med. J. 2004; 97:465–71).

The quinolones are also more convenient to administer. Floxin is available in 5-mL and 10-mL plastic dropper bottles and as “singles” containing individual once-daily doses (one packet for ages 6 months to 12 years and two for children aged 13 years and older, given for 7 days). The dropper bottles also allow for once-daily dosing (5 drops for ages 6 months to 13 years and 10 drops for ages 13 and older). Ciprodex dosing for patients 6 months and older is four drops twice daily for 7 days.

In contrast, 3 drops of Cortisporin must be administered three or four times daily to children with acute otitis externa.

There is some disagreement about whether a corticosteroid—contained in Ciprodex and Cortisporin but not Floxin—adds significant benefit. While the anti-inflammatory effect does produce greater symptomatic relief, it also may dampen the immune response. Because the data suggest Floxin is just as effective as Ciprodex, and more effective than Cortisporin, the steroid may not be much of an advantage.

Floxin can be slightly cheaper than the generic Cortisporin on a per-treatment basis: Computed with the average wholesale price for a 5-mL bottle, the cost of 5 drops of Floxin daily for 7 days is $17.60, compared with $18.34 for a 10-day treatment of Cortisporin, 4 drops daily. The cost of Ciprodex is somewhat higher than for the generic.

In addition to being more effective and convenient without costing more, quinolone drops are also quite safe. Systemic absorption of these topicals is essentially zero. And even with oral administration, combined data from studies involving approximately 16,000 children and adolescents have not revealed a single case of arthropathy, which has been seen in juvenile animals only. Safety data such as these led to the recent approval of ciprofloxacin for children 1 year and older with complicated urinary tract infections or pyelonephritis.

In four Bristol-Meyers Squibb-sponsored trials analyzed by my group and others, there was no evidence of arthrotoxicity among 867 children with recurrent or acute otitis media who were treated with gatifloxacin. Our results will be published in the August issue of Clinical Infectious Diseases.

Of course, as physicians we should also try to help our patients avoid swimmer's ear in the first place, and especially to prevent recurrence in those who've had the problem in the past. Swimming is the No. 1 cause of otitis externa, with lakes and rivers being the culprit more often than chlorinated swimming pools. Patients who regularly swim in natural bodies of water might be advised to place a couple drops of rubbing alcohol or hydrogen peroxide in each ear after emerging from the water.

In swimmer's ear, the child complains of ear pain, but often you can't see the eardrum because the ear is so swollen.

The second-most frequent cause of otitis externa in children occurs among those with drainage from tympanostomy tubes or a perforated eardrum.

The third is trauma. Children—or their parents—may stick cotton swabs or bobby pins in the child's ear, perhaps in an attempt to remove wax, and end up abrading the canal. This kind of trauma can introduce bacterial contamination. Such practices should be discouraged.

I served as a one-time consultant to Floxin manufacturer Daiichi. I have no affiliation with Bayer Pharmaceuticals Corp. or its subsidiary Alcon Laboratories Inc., the makers of Ciprodex.

Recent guidelines for the treatment of acute bacterial sinusitis and otitis media advise physicians to do something that most of us were taught never to do: Use a cephalosporin in a penicillin-allergic patient. Unfortunately, those documents neglected to explain why this once-taboo practice is now the standard of care.

The American Academy of Pediatrics' clinical practice guidelines for the management of sinusitis endorse the use of cefuroxime, cefpodoxime, ceftriaxone, and cefdinir for penicillin-allergic patients in whom the previous penicillin reaction was not severe (Pediatrics 2001;108:798-808), while the guidelines for the diagnosis and management of acute otitis media support the use of the same three oral cephalosporins in patients with “non-type-1 allergy” and ceftriaxone for type 1 allergy (Pediatrics 2004;113:1451-65).

Although the two documents are evidence based and have been endorsed by several other professional groups including the American Academy of Family Physicians, many clinicians have not embraced the recommendation because of the often-cited yet inaccurate statistic that there is a 10% rate of cross-sensitivity to cephalosporins among penicillin-allergic patients.

In fact, the risk that a patient with a history of penicillin allergy will experience a reaction to a first-generation cephalosporin is not more than 0.5%, to a second-generation cephalosporin, not more than 0.2%, and to a third-generation cephalosporin, practically nil. In at least 25 studies, cephalosporins were actually given to penicillin-allergic patients with reaction rates not greater than in non-allergic patients. I have reviewed this literature in the April issue of Pediatrics (2005;115:1048-57).

The misconception arose out of the belief that the cross-reactivity is to the shared β-lactam ring.

Now, however, we know that the β-lactam ring of cephalosporins—unlike that of penicillin and ampicillin—becomes rapidly degraded, so that antibodies are instead targeted to side chain structures. Therefore, cross-reactivity is only possible with the cephalosporins that share penicillin side chains. (See chart.) And even then, the likelihood of a reaction is still far less than 10%.

Many of the older studies suggesting greater rates of cross-reactivity were conducted with penicillin and/or amoxicillin that had been made with Cephalosporium mold, which of course would have caused cross-contamination. Yet, the caution remains in the package label for most cephalosporins.

Patients and physicians alike tend to use the term “allergy” very loosely. But unless the patient experienced a generalized pruritic skin reaction, hives, or anaphylaxis, it was not an IgE-mediated (type 1) reaction.

For patients who do report a true allergic history—or who have had a positive skin test—it would be prudent to avoid the four cephalosporins with side chains similar to amoxicillin—namely cefaclor, cefprozil, cephalexin, and cefadroxil. All other cephalosporins are acceptable, including the four endorsed in the sinusitis/otitis guidelines.

Consider that a major reason for the new guidelines is the increasing rates of macrolide-resistant Streptococcus pneumoniae. The rate was 35% in 2002, and it has been rising since. Therefore, the old paradigm of simply putting a penicillin-allergic patient on azithromycin or clarithromycin is no longer good medicine—in doing so, you are substantially compromising the anticipated efficacy of the drug.

There has never been a case of fatal anaphylaxis with a cephalosporin reported in a child. From a medicolegal standpoint, if the AAP/AAFP guideline says you can use a cephalosporin in a penicillin-allergic patient—as does my evidence-based peer reviewed article in AAP's journal, Pediatrics—rest assured you can do it.

Cross-Reactivity Between Penicillins and Cephalosporins

Contrary to long-held belief, the risk of cross-reactivity between penicillins and cephalosporins is based on the similarities of their side-chain structures, not of the b-lactam ring they all share. The three lists below are grouped by side-chain similarity (or lack thereof in the third group). However, even within groups with related side chains, the risk that a patient with a history of sensitivity to one drug will have a reaction to another is still no more than 0.5%.

Recent guidelines for the treatment of acute bacterial sinusitis and otitis media advise physicians to do something that most of us were taught never to do: Use a cephalosporin in a penicillin-allergic patient. Unfortunately, those documents neglected to explain why this once-taboo practice is now the standard of care.

The American Academy of Pediatrics' clinical practice guidelines for the management of sinusitis endorse the use of cefuroxime, cefpodoxime, ceftriaxone, and cefdinir for penicillin-allergic patients in whom the previous penicillin reaction was not severe (Pediatrics 2001;108:798-808), while the guidelines for the diagnosis and management of acute otitis media support the use of the same three oral cephalosporins in patients with “non-type-1 allergy” and ceftriaxone for type 1 allergy (Pediatrics 2004;113:1451-65).

Although the two documents are evidence based and have been endorsed by several other professional groups including the American Academy of Family Physicians, many clinicians have not embraced the recommendation because of the often-cited yet inaccurate statistic that there is a 10% rate of cross-sensitivity to cephalosporins among penicillin-allergic patients.

In fact, the risk that a patient with a history of penicillin allergy will experience a reaction to a first-generation cephalosporin is not more than 0.5%, to a second-generation cephalosporin, not more than 0.2%, and to a third-generation cephalosporin, practically nil. In at least 25 studies, cephalosporins were actually given to penicillin-allergic patients with reaction rates not greater than in non-allergic patients. I have reviewed this literature in the April issue of Pediatrics (2005;115:1048-57).

The misconception arose out of the belief that the cross-reactivity is to the shared β-lactam ring.

Now, however, we know that the β-lactam ring of cephalosporins—unlike that of penicillin and ampicillin—becomes rapidly degraded, so that antibodies are instead targeted to side chain structures. Therefore, cross-reactivity is only possible with the cephalosporins that share penicillin side chains. (See chart.) And even then, the likelihood of a reaction is still far less than 10%.

Many of the older studies suggesting greater rates of cross-reactivity were conducted with penicillin and/or amoxicillin that had been made with Cephalosporium mold, which of course would have caused cross-contamination. Yet, the caution remains in the package label for most cephalosporins.

Patients and physicians alike tend to use the term “allergy” very loosely. But unless the patient experienced a generalized pruritic skin reaction, hives, or anaphylaxis, it was not an IgE-mediated (type 1) reaction.

For patients who do report a true allergic history—or who have had a positive skin test—it would be prudent to avoid the four cephalosporins with side chains similar to amoxicillin—namely cefaclor, cefprozil, cephalexin, and cefadroxil. All other cephalosporins are acceptable, including the four endorsed in the sinusitis/otitis guidelines.

Consider that a major reason for the new guidelines is the increasing rates of macrolide-resistant Streptococcus pneumoniae. The rate was 35% in 2002, and it has been rising since. Therefore, the old paradigm of simply putting a penicillin-allergic patient on azithromycin or clarithromycin is no longer good medicine—in doing so, you are substantially compromising the anticipated efficacy of the drug.

There has never been a case of fatal anaphylaxis with a cephalosporin reported in a child. From a medicolegal standpoint, if the AAP/AAFP guideline says you can use a cephalosporin in a penicillin-allergic patient—as does my evidence-based peer reviewed article in AAP's journal, Pediatrics—rest assured you can do it.

Cross-Reactivity Between Penicillins and Cephalosporins

Contrary to long-held belief, the risk of cross-reactivity between penicillins and cephalosporins is based on the similarities of their side-chain structures, not of the b-lactam ring they all share. The three lists below are grouped by side-chain similarity (or lack thereof in the third group). However, even within groups with related side chains, the risk that a patient with a history of sensitivity to one drug will have a reaction to another is still no more than 0.5%.

Recent guidelines for the treatment of acute bacterial sinusitis and otitis media advise physicians to do something that most of us were taught never to do: Use a cephalosporin in a penicillin-allergic patient. Unfortunately, those documents neglected to explain why this once-taboo practice is now the standard of care.

The American Academy of Pediatrics' clinical practice guidelines for the management of sinusitis endorse the use of cefuroxime, cefpodoxime, ceftriaxone, and cefdinir for penicillin-allergic patients in whom the previous penicillin reaction was not severe (Pediatrics 2001;108:798-808), while the guidelines for the diagnosis and management of acute otitis media support the use of the same three oral cephalosporins in patients with “non-type-1 allergy” and ceftriaxone for type 1 allergy (Pediatrics 2004;113:1451-65).

Although the two documents are evidence based and have been endorsed by several other professional groups including the American Academy of Family Physicians, many clinicians have not embraced the recommendation because of the often-cited yet inaccurate statistic that there is a 10% rate of cross-sensitivity to cephalosporins among penicillin-allergic patients.

In fact, the risk that a patient with a history of penicillin allergy will experience a reaction to a first-generation cephalosporin is not more than 0.5%, to a second-generation cephalosporin, not more than 0.2%, and to a third-generation cephalosporin, practically nil. In at least 25 studies, cephalosporins were actually given to penicillin-allergic patients with reaction rates not greater than in non-allergic patients. I have reviewed this literature in the April issue of Pediatrics (2005;115:1048-57).

The misconception arose out of the belief that the cross-reactivity is to the shared β-lactam ring.

Now, however, we know that the β-lactam ring of cephalosporins—unlike that of penicillin and ampicillin—becomes rapidly degraded, so that antibodies are instead targeted to side chain structures. Therefore, cross-reactivity is only possible with the cephalosporins that share penicillin side chains. (See chart.) And even then, the likelihood of a reaction is still far less than 10%.

Many of the older studies suggesting greater rates of cross-reactivity were conducted with penicillin and/or amoxicillin that had been made with Cephalosporium mold, which of course would have caused cross-contamination. Yet, the caution remains in the package label for most cephalosporins.

Patients and physicians alike tend to use the term “allergy” very loosely. But unless the patient experienced a generalized pruritic skin reaction, hives, or anaphylaxis, it was not an IgE-mediated (type 1) reaction.

For patients who do report a true allergic history—or who have had a positive skin test—it would be prudent to avoid the four cephalosporins with side chains similar to amoxicillin—namely cefaclor, cefprozil, cephalexin, and cefadroxil. All other cephalosporins are acceptable, including the four endorsed in the sinusitis/otitis guidelines.

Consider that a major reason for the new guidelines is the increasing rates of macrolide-resistant Streptococcus pneumoniae. The rate was 35% in 2002, and it has been rising since. Therefore, the old paradigm of simply putting a penicillin-allergic patient on azithromycin or clarithromycin is no longer good medicine—in doing so, you are substantially compromising the anticipated efficacy of the drug.

There has never been a case of fatal anaphylaxis with a cephalosporin reported in a child. From a medicolegal standpoint, if the AAP/AAFP guideline says you can use a cephalosporin in a penicillin-allergic patient—as does my evidence-based peer reviewed article in AAP's journal, Pediatrics—rest assured you can do it.

Cross-Reactivity Between Penicillins and Cephalosporins

Contrary to long-held belief, the risk of cross-reactivity between penicillins and cephalosporins is based on the similarities of their side-chain structures, not of the b-lactam ring they all share. The three lists below are grouped by side-chain similarity (or lack thereof in the third group). However, even within groups with related side chains, the risk that a patient with a history of sensitivity to one drug will have a reaction to another is still no more than 0.5%.