ID Consult

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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.

The evolving picture of Clostridium difficile-associated disease suggests that we may need to revise our traditional approach to the child with persistent diarrhea.

The increase in frequency and severity of health care-associated Clostridium difficile-associated disease (CDAD) in North America over the last several years is believed to be due in large part to a newer, more virulent strain first reported a little over a year ago (N. Engl. J. Med. 2005;353:2433–41, 2442–9)

At the same time, we've been seeing previously healthy patients without prior antimicrobial use, including children, become infected in the community. Of 23 community-acquired cases reported to the CDC from four states during May and June of 2005, 11 were in children less than 18 years of age (MMWR 2005;54:1201–5).

In a 3-year prospective study published in the fall of 2006, 7% of 1,626 stool samples from children who presented to an emergency department with diarrhea were positive for C. difficile toxin (Clin. Infect. Dis. 2006;43:807–13). It's not clear from the data whether this represents an increase, but we do know that it's a problem.

I think we need to consider the possibility of CDAD in any child—even those without prior antibiotic use—who has persistent diarrhea lasting more than 5 days, or very severe diarrhea of more than 8–10 stools a day. The data suggest that about 1 in 10 of these children will have stool assays positive for C. difficile toxin.

Some children with CDAD—perhaps 25%–35%—improve on their own within a week and may not need treatment. The ones whose condition does not resolve in a week are candidates for metronidazole therapy. About 15%–20% of those treated will fail. For them, the American Academy of Pediatrics advises a second course of metronidazole. For the 15%–20% who will fail or relapse a second time, oral vancomycin is recommended.

While you're waiting for the toxin assay to come back, I think it's a good idea to use probiotics such as Lactobacillus GG species or Saccharomyces boulardii as a preemptive strike, even before you know the pathogen. Data suggest that those “good bacteria” might be helpful in restoring balance in the flora and thus reduce symptoms due to a variety of diarrhea-causing organisms, including rotavirus and other viral agents as well as C. difficile (Am. J. Gastroenterol. 2006;101:812–22).

Because alcohol-based hand sanitizers aren't as effective at removing infectious C. difficile spores from contaminated hands, it's important to wash your hands with soap and water after examining children with prolonged diarrhea. However, until you know what the pathogen is, use of alcohol-based products also is recommended because they're better at eliminating other GI pathogens including the usual virus suspects. I will typically wash with soap and water first, dry my hands, then rub in the sanitizer as I'm walking away from the sink after seeing children with persistent diarrhea and an as-yet undefined pathogen.

The appearance of CDAD in previously healthy, community-dwelling individuals is a new and worrisome change. Until recently, antibiotic use was believed to be the nearly universal culprit that disrupted the natural gut flora and allowed C. difficile to flourish, leading to the presentations ranging from frequent diarrhea to the characteristic pseudomembranous colitis.

Now, however, it appears that in some children CDAD may be initially triggered by a common viral gastroenteritis—such as rotavirus, norovirus, or adenovirus—which lowers the colonic pH enough to prompt the normally-quiescent C. difficile to begin overproducing toxin.

This recent shift may be related to the newly described strain, which not only produces many times the usual amount of C. difficile toxins A and B, but also contains a mutation that leads to the production of an additional binary toxin that appears to be even more toxic to gut mucosa than are A and B. We don't fully understand the implications of this new strain. It is becoming clear, though, that it's not a temporary situation as we had hoped.

On the positive side, several ongoing trials offer some reason for optimism. A group at Baylor College of Medicine in Houston is now conducting National Institutes of Health-funded phase III trials of nitazoxanide in adults with CDAD. Nitazoxanide (Alinia, manufactured by Romark Laboratories L.C., Tampa, Fla.), which acts by interfering with anaerobic metabolic pathways, is already licensed for the treatment of parasitic diseases of the gastrointestinal tract, such as giardiasis, and has been used in millions of children worldwide. So far, the CDAD data look good.

A totally different approach to CDAD treatment is with a nonabsorbable polymer called tolevamer, manufactured by Genzyme Corp., Cambridge, Mass. It works by binding C. difficile toxins A and B. Because it's not an antibiotic, tolevamer would be expected to avoid the problems associated with antimicrobial treatment, including resistance. Phase II data suggested that it worked at least as well as vancomycin and was associated with less recurrence of diarrhea, although there was an increased risk for hyperkalemia (Clin. Infect. Dis. 2006;43:411–20). Genzyme expects to complete phase III trials this year. The agent has been given fast-track designation by the Food and Drug Administration, and the company anticipates commercial approval in 2008.

The evolving picture of Clostridium difficile-associated disease suggests that we may need to revise our traditional approach to the child with persistent diarrhea.

The increase in frequency and severity of health care-associated Clostridium difficile-associated disease (CDAD) in North America over the last several years is believed to be due in large part to a newer, more virulent strain first reported a little over a year ago (N. Engl. J. Med. 2005;353:2433–41, 2442–9)

At the same time, we've been seeing previously healthy patients without prior antimicrobial use, including children, become infected in the community. Of 23 community-acquired cases reported to the CDC from four states during May and June of 2005, 11 were in children less than 18 years of age (MMWR 2005;54:1201–5).

In a 3-year prospective study published in the fall of 2006, 7% of 1,626 stool samples from children who presented to an emergency department with diarrhea were positive for C. difficile toxin (Clin. Infect. Dis. 2006;43:807–13). It's not clear from the data whether this represents an increase, but we do know that it's a problem.

I think we need to consider the possibility of CDAD in any child—even those without prior antibiotic use—who has persistent diarrhea lasting more than 5 days, or very severe diarrhea of more than 8–10 stools a day. The data suggest that about 1 in 10 of these children will have stool assays positive for C. difficile toxin.

Some children with CDAD—perhaps 25%–35%—improve on their own within a week and may not need treatment. The ones whose condition does not resolve in a week are candidates for metronidazole therapy. About 15%–20% of those treated will fail. For them, the American Academy of Pediatrics advises a second course of metronidazole. For the 15%–20% who will fail or relapse a second time, oral vancomycin is recommended.

While you're waiting for the toxin assay to come back, I think it's a good idea to use probiotics such as Lactobacillus GG species or Saccharomyces boulardii as a preemptive strike, even before you know the pathogen. Data suggest that those “good bacteria” might be helpful in restoring balance in the flora and thus reduce symptoms due to a variety of diarrhea-causing organisms, including rotavirus and other viral agents as well as C. difficile (Am. J. Gastroenterol. 2006;101:812–22).

Because alcohol-based hand sanitizers aren't as effective at removing infectious C. difficile spores from contaminated hands, it's important to wash your hands with soap and water after examining children with prolonged diarrhea. However, until you know what the pathogen is, use of alcohol-based products also is recommended because they're better at eliminating other GI pathogens including the usual virus suspects. I will typically wash with soap and water first, dry my hands, then rub in the sanitizer as I'm walking away from the sink after seeing children with persistent diarrhea and an as-yet undefined pathogen.

The appearance of CDAD in previously healthy, community-dwelling individuals is a new and worrisome change. Until recently, antibiotic use was believed to be the nearly universal culprit that disrupted the natural gut flora and allowed C. difficile to flourish, leading to the presentations ranging from frequent diarrhea to the characteristic pseudomembranous colitis.

Now, however, it appears that in some children CDAD may be initially triggered by a common viral gastroenteritis—such as rotavirus, norovirus, or adenovirus—which lowers the colonic pH enough to prompt the normally-quiescent C. difficile to begin overproducing toxin.

This recent shift may be related to the newly described strain, which not only produces many times the usual amount of C. difficile toxins A and B, but also contains a mutation that leads to the production of an additional binary toxin that appears to be even more toxic to gut mucosa than are A and B. We don't fully understand the implications of this new strain. It is becoming clear, though, that it's not a temporary situation as we had hoped.

On the positive side, several ongoing trials offer some reason for optimism. A group at Baylor College of Medicine in Houston is now conducting National Institutes of Health-funded phase III trials of nitazoxanide in adults with CDAD. Nitazoxanide (Alinia, manufactured by Romark Laboratories L.C., Tampa, Fla.), which acts by interfering with anaerobic metabolic pathways, is already licensed for the treatment of parasitic diseases of the gastrointestinal tract, such as giardiasis, and has been used in millions of children worldwide. So far, the CDAD data look good.

A totally different approach to CDAD treatment is with a nonabsorbable polymer called tolevamer, manufactured by Genzyme Corp., Cambridge, Mass. It works by binding C. difficile toxins A and B. Because it's not an antibiotic, tolevamer would be expected to avoid the problems associated with antimicrobial treatment, including resistance. Phase II data suggested that it worked at least as well as vancomycin and was associated with less recurrence of diarrhea, although there was an increased risk for hyperkalemia (Clin. Infect. Dis. 2006;43:411–20). Genzyme expects to complete phase III trials this year. The agent has been given fast-track designation by the Food and Drug Administration, and the company anticipates commercial approval in 2008.

The evolving picture of Clostridium difficile-associated disease suggests that we may need to revise our traditional approach to the child with persistent diarrhea.

The increase in frequency and severity of health care-associated Clostridium difficile-associated disease (CDAD) in North America over the last several years is believed to be due in large part to a newer, more virulent strain first reported a little over a year ago (N. Engl. J. Med. 2005;353:2433–41, 2442–9)

At the same time, we've been seeing previously healthy patients without prior antimicrobial use, including children, become infected in the community. Of 23 community-acquired cases reported to the CDC from four states during May and June of 2005, 11 were in children less than 18 years of age (MMWR 2005;54:1201–5).

In a 3-year prospective study published in the fall of 2006, 7% of 1,626 stool samples from children who presented to an emergency department with diarrhea were positive for C. difficile toxin (Clin. Infect. Dis. 2006;43:807–13). It's not clear from the data whether this represents an increase, but we do know that it's a problem.

I think we need to consider the possibility of CDAD in any child—even those without prior antibiotic use—who has persistent diarrhea lasting more than 5 days, or very severe diarrhea of more than 8–10 stools a day. The data suggest that about 1 in 10 of these children will have stool assays positive for C. difficile toxin.

Some children with CDAD—perhaps 25%–35%—improve on their own within a week and may not need treatment. The ones whose condition does not resolve in a week are candidates for metronidazole therapy. About 15%–20% of those treated will fail. For them, the American Academy of Pediatrics advises a second course of metronidazole. For the 15%–20% who will fail or relapse a second time, oral vancomycin is recommended.

While you're waiting for the toxin assay to come back, I think it's a good idea to use probiotics such as Lactobacillus GG species or Saccharomyces boulardii as a preemptive strike, even before you know the pathogen. Data suggest that those “good bacteria” might be helpful in restoring balance in the flora and thus reduce symptoms due to a variety of diarrhea-causing organisms, including rotavirus and other viral agents as well as C. difficile (Am. J. Gastroenterol. 2006;101:812–22).

Because alcohol-based hand sanitizers aren't as effective at removing infectious C. difficile spores from contaminated hands, it's important to wash your hands with soap and water after examining children with prolonged diarrhea. However, until you know what the pathogen is, use of alcohol-based products also is recommended because they're better at eliminating other GI pathogens including the usual virus suspects. I will typically wash with soap and water first, dry my hands, then rub in the sanitizer as I'm walking away from the sink after seeing children with persistent diarrhea and an as-yet undefined pathogen.

The appearance of CDAD in previously healthy, community-dwelling individuals is a new and worrisome change. Until recently, antibiotic use was believed to be the nearly universal culprit that disrupted the natural gut flora and allowed C. difficile to flourish, leading to the presentations ranging from frequent diarrhea to the characteristic pseudomembranous colitis.

Now, however, it appears that in some children CDAD may be initially triggered by a common viral gastroenteritis—such as rotavirus, norovirus, or adenovirus—which lowers the colonic pH enough to prompt the normally-quiescent C. difficile to begin overproducing toxin.

This recent shift may be related to the newly described strain, which not only produces many times the usual amount of C. difficile toxins A and B, but also contains a mutation that leads to the production of an additional binary toxin that appears to be even more toxic to gut mucosa than are A and B. We don't fully understand the implications of this new strain. It is becoming clear, though, that it's not a temporary situation as we had hoped.

On the positive side, several ongoing trials offer some reason for optimism. A group at Baylor College of Medicine in Houston is now conducting National Institutes of Health-funded phase III trials of nitazoxanide in adults with CDAD. Nitazoxanide (Alinia, manufactured by Romark Laboratories L.C., Tampa, Fla.), which acts by interfering with anaerobic metabolic pathways, is already licensed for the treatment of parasitic diseases of the gastrointestinal tract, such as giardiasis, and has been used in millions of children worldwide. So far, the CDAD data look good.

A totally different approach to CDAD treatment is with a nonabsorbable polymer called tolevamer, manufactured by Genzyme Corp., Cambridge, Mass. It works by binding C. difficile toxins A and B. Because it's not an antibiotic, tolevamer would be expected to avoid the problems associated with antimicrobial treatment, including resistance. Phase II data suggested that it worked at least as well as vancomycin and was associated with less recurrence of diarrhea, although there was an increased risk for hyperkalemia (Clin. Infect. Dis. 2006;43:411–20). Genzyme expects to complete phase III trials this year. The agent has been given fast-track designation by the Food and Drug Administration, and the company anticipates commercial approval in 2008.

[email protected]

Screening for HIV should be routine for all sexually active adolescents.

In September 2006, the Centers for Disease Control and Prevention issued new recommendations calling for annual routine HIV screening in health care settings for all patients aged 13–64 years, regardless of perceived risk status. The guidelines are notable in that they call for a policy of “opt-out” screening rather than requiring written informed consent, and they allow for screening to occur without pre-test counseling in situations where such a requirement would present a barrier (MMWR 2006;55:RR-14).

The CDC believes—and I agree—that these changes are necessary. Our current practice of screening only those individuals perceived to be at high risk isn't working. There are about 1 million HIV-infected people in the United States, as many as 25% of whom are undiagnosed. Not only are they missing out on the potential benefits of antiretroviral therapy, but their sexual activity represents a threat for transmission to others. Current HIV testing programs identify approximately 40,000 new cases every year, a number that has not changed in nearly a decade.

Teenagers are among those at risk. The CDC guidelines note that in the 2005 national Youth Risk Behavior Survey, 47% of high school students reported having had sexual intercourse at least once, and 37% of those who were sexually active had not used a condom during their most recent act of sexual intercourse. In 2005, according to the CDC, heterosexual intercourse overall accounted for 15% of HIV transmission in males and 80% in females. (Male-to-male sexual contact made up 67% of transmission among males.)

I strongly support routine screening for our adolescent patients but with certain modifications to the CDC's stated policy. While the idea of eliminating all risk profiling makes sense for the adult community, in adolescents I think it boils down to one question: Are you sexually active? If the answer is yes, no matter what the circumstances, screening is indicated. Clearly, this is an issue for every physician who treats adolescents.

I also think that, contrary to the guideline for adults, adolescents do need counseling about HIV before and after testing. Simply telling a teenager that you plan to test them for HIV unless they opt out is not adequate. At a minimum, we need to tell teens that sexual activity is a risk factor for the transmission of HIV, and for that reason we believe they should be tested. Just because a teen is monogamous doesn't mean her or his partner is. We must impress upon them that even if they're sure their partner is “safe,” they can't be confident that the same applied to their partner's previous partners.

We also should explain that the testing is a two-step process. The initial step (ELISA) identifies HIV-specific antibodies but sometimes is falsely positive. If the ELISA is positive, a Western blot test is done for confirmation. No matter what the result, a second visit is highly recommended. If the adolescent is HIV positive, this visit should be used to assess how the teen is handling the diagnosis emotionally, to determine the best course of action for treatment and to refer the teen for other support services.

If the test comes back negative, the primary care physician should still use the opportunity to remind teens that if they're sexually active and not using condoms, they're always at risk. The test was only a snapshot in time.

It's also important to explain beforehand what a positive test means: It indicates that there is an HIV infection, but it gives no information about what stage of the disease they're in. They could be very early in the course of disease, or very late in the course of disease and already have AIDS.

Just as the CDC recommends for adults, I believe that physicians should use every medical encounter with an adolescent, be it a sports physical or an acute illness visit, to do HIV counseling and screening.

The issue of parental consent is still problematic and a potential barrier. Ideally, of course, the teenager is willing to have his or her parent or guardian consent to testing. But if not, the laws concerning consent and confidentiality vary by state. In general, public health statute and legal precedent allow for evaluation and treatment of minors for sexually transmitted diseases without parental knowledge or consent. The Guttmacher Institute's Web site is an excellent resource for specific state-by-state information on laws governing minors' consent to medical care, access to STD services, and sex and STD/HIV education (www.guttmacher.org

Most state laws, however, don't yet address the issue of consent for screening for HIV in asymptomatic adolescents. The American Academy of Pediatrics advises that physicians obtain advice regarding the disposition of laws in their state addressing consent or other legal obligations from their attorney or another trusted local source, such as their hospital's office of legal compliance. The AAP Committee on Pediatric AIDS is expected to issue a statement in response to the CDC guidelines sometime in 2007.

[email protected]

Screening for HIV should be routine for all sexually active adolescents.

In September 2006, the Centers for Disease Control and Prevention issued new recommendations calling for annual routine HIV screening in health care settings for all patients aged 13–64 years, regardless of perceived risk status. The guidelines are notable in that they call for a policy of “opt-out” screening rather than requiring written informed consent, and they allow for screening to occur without pre-test counseling in situations where such a requirement would present a barrier (MMWR 2006;55:RR-14).

The CDC believes—and I agree—that these changes are necessary. Our current practice of screening only those individuals perceived to be at high risk isn't working. There are about 1 million HIV-infected people in the United States, as many as 25% of whom are undiagnosed. Not only are they missing out on the potential benefits of antiretroviral therapy, but their sexual activity represents a threat for transmission to others. Current HIV testing programs identify approximately 40,000 new cases every year, a number that has not changed in nearly a decade.

Teenagers are among those at risk. The CDC guidelines note that in the 2005 national Youth Risk Behavior Survey, 47% of high school students reported having had sexual intercourse at least once, and 37% of those who were sexually active had not used a condom during their most recent act of sexual intercourse. In 2005, according to the CDC, heterosexual intercourse overall accounted for 15% of HIV transmission in males and 80% in females. (Male-to-male sexual contact made up 67% of transmission among males.)

I strongly support routine screening for our adolescent patients but with certain modifications to the CDC's stated policy. While the idea of eliminating all risk profiling makes sense for the adult community, in adolescents I think it boils down to one question: Are you sexually active? If the answer is yes, no matter what the circumstances, screening is indicated. Clearly, this is an issue for every physician who treats adolescents.

I also think that, contrary to the guideline for adults, adolescents do need counseling about HIV before and after testing. Simply telling a teenager that you plan to test them for HIV unless they opt out is not adequate. At a minimum, we need to tell teens that sexual activity is a risk factor for the transmission of HIV, and for that reason we believe they should be tested. Just because a teen is monogamous doesn't mean her or his partner is. We must impress upon them that even if they're sure their partner is “safe,” they can't be confident that the same applied to their partner's previous partners.

We also should explain that the testing is a two-step process. The initial step (ELISA) identifies HIV-specific antibodies but sometimes is falsely positive. If the ELISA is positive, a Western blot test is done for confirmation. No matter what the result, a second visit is highly recommended. If the adolescent is HIV positive, this visit should be used to assess how the teen is handling the diagnosis emotionally, to determine the best course of action for treatment and to refer the teen for other support services.

If the test comes back negative, the primary care physician should still use the opportunity to remind teens that if they're sexually active and not using condoms, they're always at risk. The test was only a snapshot in time.

It's also important to explain beforehand what a positive test means: It indicates that there is an HIV infection, but it gives no information about what stage of the disease they're in. They could be very early in the course of disease, or very late in the course of disease and already have AIDS.

Just as the CDC recommends for adults, I believe that physicians should use every medical encounter with an adolescent, be it a sports physical or an acute illness visit, to do HIV counseling and screening.

The issue of parental consent is still problematic and a potential barrier. Ideally, of course, the teenager is willing to have his or her parent or guardian consent to testing. But if not, the laws concerning consent and confidentiality vary by state. In general, public health statute and legal precedent allow for evaluation and treatment of minors for sexually transmitted diseases without parental knowledge or consent. The Guttmacher Institute's Web site is an excellent resource for specific state-by-state information on laws governing minors' consent to medical care, access to STD services, and sex and STD/HIV education (www.guttmacher.org

Most state laws, however, don't yet address the issue of consent for screening for HIV in asymptomatic adolescents. The American Academy of Pediatrics advises that physicians obtain advice regarding the disposition of laws in their state addressing consent or other legal obligations from their attorney or another trusted local source, such as their hospital's office of legal compliance. The AAP Committee on Pediatric AIDS is expected to issue a statement in response to the CDC guidelines sometime in 2007.

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Screening for HIV should be routine for all sexually active adolescents.

In September 2006, the Centers for Disease Control and Prevention issued new recommendations calling for annual routine HIV screening in health care settings for all patients aged 13–64 years, regardless of perceived risk status. The guidelines are notable in that they call for a policy of “opt-out” screening rather than requiring written informed consent, and they allow for screening to occur without pre-test counseling in situations where such a requirement would present a barrier (MMWR 2006;55:RR-14).

The CDC believes—and I agree—that these changes are necessary. Our current practice of screening only those individuals perceived to be at high risk isn't working. There are about 1 million HIV-infected people in the United States, as many as 25% of whom are undiagnosed. Not only are they missing out on the potential benefits of antiretroviral therapy, but their sexual activity represents a threat for transmission to others. Current HIV testing programs identify approximately 40,000 new cases every year, a number that has not changed in nearly a decade.

Teenagers are among those at risk. The CDC guidelines note that in the 2005 national Youth Risk Behavior Survey, 47% of high school students reported having had sexual intercourse at least once, and 37% of those who were sexually active had not used a condom during their most recent act of sexual intercourse. In 2005, according to the CDC, heterosexual intercourse overall accounted for 15% of HIV transmission in males and 80% in females. (Male-to-male sexual contact made up 67% of transmission among males.)

I strongly support routine screening for our adolescent patients but with certain modifications to the CDC's stated policy. While the idea of eliminating all risk profiling makes sense for the adult community, in adolescents I think it boils down to one question: Are you sexually active? If the answer is yes, no matter what the circumstances, screening is indicated. Clearly, this is an issue for every physician who treats adolescents.

I also think that, contrary to the guideline for adults, adolescents do need counseling about HIV before and after testing. Simply telling a teenager that you plan to test them for HIV unless they opt out is not adequate. At a minimum, we need to tell teens that sexual activity is a risk factor for the transmission of HIV, and for that reason we believe they should be tested. Just because a teen is monogamous doesn't mean her or his partner is. We must impress upon them that even if they're sure their partner is “safe,” they can't be confident that the same applied to their partner's previous partners.

We also should explain that the testing is a two-step process. The initial step (ELISA) identifies HIV-specific antibodies but sometimes is falsely positive. If the ELISA is positive, a Western blot test is done for confirmation. No matter what the result, a second visit is highly recommended. If the adolescent is HIV positive, this visit should be used to assess how the teen is handling the diagnosis emotionally, to determine the best course of action for treatment and to refer the teen for other support services.

If the test comes back negative, the primary care physician should still use the opportunity to remind teens that if they're sexually active and not using condoms, they're always at risk. The test was only a snapshot in time.

It's also important to explain beforehand what a positive test means: It indicates that there is an HIV infection, but it gives no information about what stage of the disease they're in. They could be very early in the course of disease, or very late in the course of disease and already have AIDS.

Just as the CDC recommends for adults, I believe that physicians should use every medical encounter with an adolescent, be it a sports physical or an acute illness visit, to do HIV counseling and screening.

The issue of parental consent is still problematic and a potential barrier. Ideally, of course, the teenager is willing to have his or her parent or guardian consent to testing. But if not, the laws concerning consent and confidentiality vary by state. In general, public health statute and legal precedent allow for evaluation and treatment of minors for sexually transmitted diseases without parental knowledge or consent. The Guttmacher Institute's Web site is an excellent resource for specific state-by-state information on laws governing minors' consent to medical care, access to STD services, and sex and STD/HIV education (www.guttmacher.org

Most state laws, however, don't yet address the issue of consent for screening for HIV in asymptomatic adolescents. The American Academy of Pediatrics advises that physicians obtain advice regarding the disposition of laws in their state addressing consent or other legal obligations from their attorney or another trusted local source, such as their hospital's office of legal compliance. The AAP Committee on Pediatric AIDS is expected to issue a statement in response to the CDC guidelines sometime in 2007.

The future is here. It's just not widely distributed yet.

—William Gibson

To answer the question of what's going to be hot in 2007, we need only look at the important advances in 2006.

Listed below are my top infectious disease developments from the prior year, which may have an impact on our practice in the coming year:

▸ Should we still be concerned about meningitis in the infant aged 2–24 months who has fever without a source? The good news is that overall rates of pneumococcal invasive disease are reduced compared to the pre-pneumococcal vaccine era, with the most significant reduction in the number of cases of occult bacteremia. However, we saw more cases of pneumococcal meningitis last year than in any other year in the last decade in our institution, almost all caused by nonvaccine serotypes. Continue to be vigilant in assessing the febrile infant without localizing findings, and carefully document immunization status to identify the underimmunized.

▸ Have we come to a new era in evaluation and management of pediatric urinary tract infection? For about 25 years, the recommendation has been that a voiding cystourethrogram be done after the first febrile UTI, but this has not been substantiated by current studies. Who should have imaging? Those who fail to respond after 72 hours of effective antibiotics, those infected with an unusual organism, those in whom close follow-up of the patient is not possible, those with abnormal urine stream or abdominal mass, and those with recurrence of a febrile UTI. The utility of prophylactic antibiotics to prevent recurrence of a febrile UTI or renal scarring is not known; some data suggest prophylaxis is not necessary. The knowledge that the risk of urosepsis is highest in youngest infants and recurrence is highest in the first 6 months after a UTI should be factored in when making the decision concerning prophylaxis. Look for the upcoming American Academy of Pediatrics policy, which will fully delineate these guidelines.

▸ Will rotavirus epidemiology change, now that the new vaccine has been implemented? Virtually every child is infected with rotavirus by 24 months of age; two-thirds of children are infected more than once. It is estimated that approximately 1 in 17 children will require an emergency department visit and approximately 1 in 65 children will require hospitalization. If the vaccine successfully eliminates 98% of severe cases, the impact on hospitalizations should be dramatic. The vaccine is given orally, with the first dose given between 6 and 12 weeks of age and two additional doses administered at 4- to 10-week intervals. All three doses should be completed before a child reaches 32 weeks of age. This restrictive timing of the immunization schedule has proved problematic, however, and full implementation may take another year or more.

▸ Should we remove a vaccine-preventable infection from the eradicated list? The resurgence of mumps in 2006 was unexpected. Approximately 5,000 cases were reported starting in December 2005, many occurring in individuals with a history of two doses of vaccine. This would not be unexpected in a highly immunized population, but the percentage of such cases still seems high to me and is not totally explained. The Advisory Committee on Immunization Practices now has redefined evidence of mumps immunity. Practitioners should ensure that preschool children and adults not at high risk have had one dose of a live mumps virus vaccine, and that two doses have been given for children in grades K-12 and adults at high risk (for example, persons who work in health care facilities, international travelers, and students at post-high school educational institutions). Immunity can be assumed for those who were born before 1957, have documentation of physician-diagnosed mumps, or laboratory evidence of immunity.

▸ What's new in influenza immunization? Those of you in practice who have struggled with obtaining influenza vaccine for your at-risk pediatric patients are probably wondering how we will ever improve the current distribution system and whether school-based immunization programs will be feasible in the future. A recent New England Journal of Medicine article sheds some light on the matter. (See story, page 4.) Investigators at the University of Maryland in Baltimore used intranasal live attenuated virus vaccine in a school-based immunization strategy to see if it reduced outcomes related to influenzalike illness (ILI). Vaccinated children were less likely to become ill, and ILI in adults in the same household also was reduced. There were lower absentee rates for flulike illness among the children, fewer lost workdays among parents, and a reduced rate of use of health care. Sounds good, but we may still be some years away from a universal program targeting flu in school-age children.

▸ Have we forgotten chickenpox? The average pediatric resident (as well as many young attendings) has never seen clinical varicella. Cases have steadily declined 80%–85% in surveillance sites since licensure of the vaccine. From 1995 to 2001, varicella hospitalizations declined by 72%, and deaths among those 50 years old and younger decreased by 75% or more. A second dose of varicella vaccine is recommended at 4–6 years of age since we learned that 15%–24% of children who have received one dose are not fully protected. Additionally, one dose of the vaccine may not provide immunity into adulthood, when chickenpox is more severe. The Advisory Committee on Immunization Practices also recommends that children, adolescents, and adults who previously received one dose receive a second. The future epidemiologic impact of this disease is not entirely clear.

▸ How is the new vaccine to prevent cervical cancer being received? The licensure and implementation of the human papillomavirus vaccine has challenged pediatricians to educate themselves and their families about the importance of adolescent immunization programs. The Infectious Diseases Society of America is working on a document delineating the working principles and actions needed to strengthen U.S. adult and adolescent immunization coverage. Pediatricians are encouraged to offer immunization at all encounters with teens, and financial structures to ensure opportunities for immunization in nontraditional settings (school-based clinics) are being discussed. Getting public and private payers to provide coverage for vaccines is key, and is a current barrier for some physicians to providing immunizations.

▸ Speaking of adolescent immunization, is eradication of whooping cough achievable now that the adolescent/adult formulation of tetanus-diphtheria-acellular pertussis vaccine (Tdap) has been licensed? Although the incidence of pertussis in North America declined by more than 90% during the last half century as a result of universal childhood pertussis immunization, there has been a steady increase in cases during the last decade, particularly among adolescents and adults. One study found that universal immunization of adolescents 10–19 years old would be expected to prevent between 400,000 and 1.8 million cases and would save between $1.3 billion and 1.6 billion. Pediatricians should also encourage the use of Tdap vaccine for adults (including themselves) who will have close contact with an infant less than 12 months old, ideally at least 1 month before beginning such contact.

▸ What is the risk of Guillain-Barré syndrome in adolescents who receive meningococcal conjugate vaccine? As of September 2006, 17 cases of GBS had been confirmed within 1 month of vaccination. Based on current data, the number of excess cases of GBS for every 1 million doses distributed to persons aged 11–19 years is approximately 1.25 (CI = 0.058–5.99). Although a surge of cases following vaccine licensure has not been noted, the timing issue is interesting in that most cases occurred 2 weeks after the patient received the vaccine.

The future is here. It's just not widely distributed yet.

—William Gibson

To answer the question of what's going to be hot in 2007, we need only look at the important advances in 2006.

Listed below are my top infectious disease developments from the prior year, which may have an impact on our practice in the coming year:

▸ Should we still be concerned about meningitis in the infant aged 2–24 months who has fever without a source? The good news is that overall rates of pneumococcal invasive disease are reduced compared to the pre-pneumococcal vaccine era, with the most significant reduction in the number of cases of occult bacteremia. However, we saw more cases of pneumococcal meningitis last year than in any other year in the last decade in our institution, almost all caused by nonvaccine serotypes. Continue to be vigilant in assessing the febrile infant without localizing findings, and carefully document immunization status to identify the underimmunized.

▸ Have we come to a new era in evaluation and management of pediatric urinary tract infection? For about 25 years, the recommendation has been that a voiding cystourethrogram be done after the first febrile UTI, but this has not been substantiated by current studies. Who should have imaging? Those who fail to respond after 72 hours of effective antibiotics, those infected with an unusual organism, those in whom close follow-up of the patient is not possible, those with abnormal urine stream or abdominal mass, and those with recurrence of a febrile UTI. The utility of prophylactic antibiotics to prevent recurrence of a febrile UTI or renal scarring is not known; some data suggest prophylaxis is not necessary. The knowledge that the risk of urosepsis is highest in youngest infants and recurrence is highest in the first 6 months after a UTI should be factored in when making the decision concerning prophylaxis. Look for the upcoming American Academy of Pediatrics policy, which will fully delineate these guidelines.

▸ Will rotavirus epidemiology change, now that the new vaccine has been implemented? Virtually every child is infected with rotavirus by 24 months of age; two-thirds of children are infected more than once. It is estimated that approximately 1 in 17 children will require an emergency department visit and approximately 1 in 65 children will require hospitalization. If the vaccine successfully eliminates 98% of severe cases, the impact on hospitalizations should be dramatic. The vaccine is given orally, with the first dose given between 6 and 12 weeks of age and two additional doses administered at 4- to 10-week intervals. All three doses should be completed before a child reaches 32 weeks of age. This restrictive timing of the immunization schedule has proved problematic, however, and full implementation may take another year or more.

▸ Should we remove a vaccine-preventable infection from the eradicated list? The resurgence of mumps in 2006 was unexpected. Approximately 5,000 cases were reported starting in December 2005, many occurring in individuals with a history of two doses of vaccine. This would not be unexpected in a highly immunized population, but the percentage of such cases still seems high to me and is not totally explained. The Advisory Committee on Immunization Practices now has redefined evidence of mumps immunity. Practitioners should ensure that preschool children and adults not at high risk have had one dose of a live mumps virus vaccine, and that two doses have been given for children in grades K-12 and adults at high risk (for example, persons who work in health care facilities, international travelers, and students at post-high school educational institutions). Immunity can be assumed for those who were born before 1957, have documentation of physician-diagnosed mumps, or laboratory evidence of immunity.

▸ What's new in influenza immunization? Those of you in practice who have struggled with obtaining influenza vaccine for your at-risk pediatric patients are probably wondering how we will ever improve the current distribution system and whether school-based immunization programs will be feasible in the future. A recent New England Journal of Medicine article sheds some light on the matter. (See story, page 4.) Investigators at the University of Maryland in Baltimore used intranasal live attenuated virus vaccine in a school-based immunization strategy to see if it reduced outcomes related to influenzalike illness (ILI). Vaccinated children were less likely to become ill, and ILI in adults in the same household also was reduced. There were lower absentee rates for flulike illness among the children, fewer lost workdays among parents, and a reduced rate of use of health care. Sounds good, but we may still be some years away from a universal program targeting flu in school-age children.

▸ Have we forgotten chickenpox? The average pediatric resident (as well as many young attendings) has never seen clinical varicella. Cases have steadily declined 80%–85% in surveillance sites since licensure of the vaccine. From 1995 to 2001, varicella hospitalizations declined by 72%, and deaths among those 50 years old and younger decreased by 75% or more. A second dose of varicella vaccine is recommended at 4–6 years of age since we learned that 15%–24% of children who have received one dose are not fully protected. Additionally, one dose of the vaccine may not provide immunity into adulthood, when chickenpox is more severe. The Advisory Committee on Immunization Practices also recommends that children, adolescents, and adults who previously received one dose receive a second. The future epidemiologic impact of this disease is not entirely clear.

▸ How is the new vaccine to prevent cervical cancer being received? The licensure and implementation of the human papillomavirus vaccine has challenged pediatricians to educate themselves and their families about the importance of adolescent immunization programs. The Infectious Diseases Society of America is working on a document delineating the working principles and actions needed to strengthen U.S. adult and adolescent immunization coverage. Pediatricians are encouraged to offer immunization at all encounters with teens, and financial structures to ensure opportunities for immunization in nontraditional settings (school-based clinics) are being discussed. Getting public and private payers to provide coverage for vaccines is key, and is a current barrier for some physicians to providing immunizations.

▸ Speaking of adolescent immunization, is eradication of whooping cough achievable now that the adolescent/adult formulation of tetanus-diphtheria-acellular pertussis vaccine (Tdap) has been licensed? Although the incidence of pertussis in North America declined by more than 90% during the last half century as a result of universal childhood pertussis immunization, there has been a steady increase in cases during the last decade, particularly among adolescents and adults. One study found that universal immunization of adolescents 10–19 years old would be expected to prevent between 400,000 and 1.8 million cases and would save between $1.3 billion and 1.6 billion. Pediatricians should also encourage the use of Tdap vaccine for adults (including themselves) who will have close contact with an infant less than 12 months old, ideally at least 1 month before beginning such contact.

▸ What is the risk of Guillain-Barré syndrome in adolescents who receive meningococcal conjugate vaccine? As of September 2006, 17 cases of GBS had been confirmed within 1 month of vaccination. Based on current data, the number of excess cases of GBS for every 1 million doses distributed to persons aged 11–19 years is approximately 1.25 (CI = 0.058–5.99). Although a surge of cases following vaccine licensure has not been noted, the timing issue is interesting in that most cases occurred 2 weeks after the patient received the vaccine.

The future is here. It's just not widely distributed yet.

—William Gibson

To answer the question of what's going to be hot in 2007, we need only look at the important advances in 2006.

Listed below are my top infectious disease developments from the prior year, which may have an impact on our practice in the coming year:

▸ Should we still be concerned about meningitis in the infant aged 2–24 months who has fever without a source? The good news is that overall rates of pneumococcal invasive disease are reduced compared to the pre-pneumococcal vaccine era, with the most significant reduction in the number of cases of occult bacteremia. However, we saw more cases of pneumococcal meningitis last year than in any other year in the last decade in our institution, almost all caused by nonvaccine serotypes. Continue to be vigilant in assessing the febrile infant without localizing findings, and carefully document immunization status to identify the underimmunized.

▸ Have we come to a new era in evaluation and management of pediatric urinary tract infection? For about 25 years, the recommendation has been that a voiding cystourethrogram be done after the first febrile UTI, but this has not been substantiated by current studies. Who should have imaging? Those who fail to respond after 72 hours of effective antibiotics, those infected with an unusual organism, those in whom close follow-up of the patient is not possible, those with abnormal urine stream or abdominal mass, and those with recurrence of a febrile UTI. The utility of prophylactic antibiotics to prevent recurrence of a febrile UTI or renal scarring is not known; some data suggest prophylaxis is not necessary. The knowledge that the risk of urosepsis is highest in youngest infants and recurrence is highest in the first 6 months after a UTI should be factored in when making the decision concerning prophylaxis. Look for the upcoming American Academy of Pediatrics policy, which will fully delineate these guidelines.

▸ Will rotavirus epidemiology change, now that the new vaccine has been implemented? Virtually every child is infected with rotavirus by 24 months of age; two-thirds of children are infected more than once. It is estimated that approximately 1 in 17 children will require an emergency department visit and approximately 1 in 65 children will require hospitalization. If the vaccine successfully eliminates 98% of severe cases, the impact on hospitalizations should be dramatic. The vaccine is given orally, with the first dose given between 6 and 12 weeks of age and two additional doses administered at 4- to 10-week intervals. All three doses should be completed before a child reaches 32 weeks of age. This restrictive timing of the immunization schedule has proved problematic, however, and full implementation may take another year or more.

▸ Should we remove a vaccine-preventable infection from the eradicated list? The resurgence of mumps in 2006 was unexpected. Approximately 5,000 cases were reported starting in December 2005, many occurring in individuals with a history of two doses of vaccine. This would not be unexpected in a highly immunized population, but the percentage of such cases still seems high to me and is not totally explained. The Advisory Committee on Immunization Practices now has redefined evidence of mumps immunity. Practitioners should ensure that preschool children and adults not at high risk have had one dose of a live mumps virus vaccine, and that two doses have been given for children in grades K-12 and adults at high risk (for example, persons who work in health care facilities, international travelers, and students at post-high school educational institutions). Immunity can be assumed for those who were born before 1957, have documentation of physician-diagnosed mumps, or laboratory evidence of immunity.

▸ What's new in influenza immunization? Those of you in practice who have struggled with obtaining influenza vaccine for your at-risk pediatric patients are probably wondering how we will ever improve the current distribution system and whether school-based immunization programs will be feasible in the future. A recent New England Journal of Medicine article sheds some light on the matter. (See story, page 4.) Investigators at the University of Maryland in Baltimore used intranasal live attenuated virus vaccine in a school-based immunization strategy to see if it reduced outcomes related to influenzalike illness (ILI). Vaccinated children were less likely to become ill, and ILI in adults in the same household also was reduced. There were lower absentee rates for flulike illness among the children, fewer lost workdays among parents, and a reduced rate of use of health care. Sounds good, but we may still be some years away from a universal program targeting flu in school-age children.

▸ Have we forgotten chickenpox? The average pediatric resident (as well as many young attendings) has never seen clinical varicella. Cases have steadily declined 80%–85% in surveillance sites since licensure of the vaccine. From 1995 to 2001, varicella hospitalizations declined by 72%, and deaths among those 50 years old and younger decreased by 75% or more. A second dose of varicella vaccine is recommended at 4–6 years of age since we learned that 15%–24% of children who have received one dose are not fully protected. Additionally, one dose of the vaccine may not provide immunity into adulthood, when chickenpox is more severe. The Advisory Committee on Immunization Practices also recommends that children, adolescents, and adults who previously received one dose receive a second. The future epidemiologic impact of this disease is not entirely clear.

▸ How is the new vaccine to prevent cervical cancer being received? The licensure and implementation of the human papillomavirus vaccine has challenged pediatricians to educate themselves and their families about the importance of adolescent immunization programs. The Infectious Diseases Society of America is working on a document delineating the working principles and actions needed to strengthen U.S. adult and adolescent immunization coverage. Pediatricians are encouraged to offer immunization at all encounters with teens, and financial structures to ensure opportunities for immunization in nontraditional settings (school-based clinics) are being discussed. Getting public and private payers to provide coverage for vaccines is key, and is a current barrier for some physicians to providing immunizations.

▸ Speaking of adolescent immunization, is eradication of whooping cough achievable now that the adolescent/adult formulation of tetanus-diphtheria-acellular pertussis vaccine (Tdap) has been licensed? Although the incidence of pertussis in North America declined by more than 90% during the last half century as a result of universal childhood pertussis immunization, there has been a steady increase in cases during the last decade, particularly among adolescents and adults. One study found that universal immunization of adolescents 10–19 years old would be expected to prevent between 400,000 and 1.8 million cases and would save between $1.3 billion and 1.6 billion. Pediatricians should also encourage the use of Tdap vaccine for adults (including themselves) who will have close contact with an infant less than 12 months old, ideally at least 1 month before beginning such contact.

▸ What is the risk of Guillain-Barré syndrome in adolescents who receive meningococcal conjugate vaccine? As of September 2006, 17 cases of GBS had been confirmed within 1 month of vaccination. Based on current data, the number of excess cases of GBS for every 1 million doses distributed to persons aged 11–19 years is approximately 1.25 (CI = 0.058–5.99). Although a surge of cases following vaccine licensure has not been noted, the timing issue is interesting in that most cases occurred 2 weeks after the patient received the vaccine.

Prebiotics and probiotics might offer a way to both prevent and treat disease by enhancing the body's natural immune defense mechanisms.

Recognition that certain naturally occurring bacteria in the gut might be beneficial to health dates back to the early 1900s, when Nobel laureate Dr. Eli Metchnikoff reported that peasants who consumed sour milk with live Lactobacillus bulgaricus lived longer than other people. Now, emerging data suggest that supplementation with health-associated bacteria, also known as “probiotics,” can prevent or reduce diarrhea caused by altered gut flora from antibiotics or rotavirus.

In addition, “prebiotics,” the nondigestible oligosaccharides that stimulate growth of existing probiotic bacteria, also have drawn interest. Prebiotic supplements that do not contain added probiotics could avoid some of the problems associated with probiotics, such as difficulty maintaining live organisms until administration and potential bacteremia in immunosuppressed individuals.

Present in breast milk, prebiotics enhance the growth of existing probiotic bacteria strains Bifidobacteria and Lactobacillus, which predominate in the guts of breast-fed infants. The gut flora of bottle-fed infants, in contrast, tend to comprise primarily Enterobacteriaceae and Clostridia.

Several studies—some supported by infant formula manufacturers—show that adding prebiotic galacto-oligosaccharides and fructo-oligosaccharides to cow's milk formula can result in intestinal flora in bottle-fed infants similar to that in breast-fed infants. This, in turn, results in a reduced intestinal load of more pathogenic bacteria in the infant.

Mucosal and systemic immunity also appear to be enhanced with prebiotic supplementation, possibly reducing subsequent immune-mediated disease such as asthma and allergies. In one prospective, placebo-controlled study, 102 infants at high risk for atopy were fed prebiotic-containing formula (galacto- and long-chain fructo-oligosaccharides) or formula with a placebo (maltodextrin). The atopic dermatitis rate was 9.8% for infants receiving prebiotics, compared with 23.1% for placebo (Arch. Dis. Child. 2006;91:814–9).

A growing data set suggests that pre- and probiotic supplementation in infancy can enhance IgA responses to antigenic challenge, and favorably influence T-helper cell balance, thus reducing inflammatory and/or allergic responses. One prebiotic, lactulose, is commercially available in liquid form under various brand names and is approved for treating constipation.

Whether to routinely prescribe lactulose or other prebiotics for non-breast-fed infants remains an unanswered question. Stay tuned for more data.

Meantime, I believe the data on probiotics are sufficient to support several clinical uses. I advise using a product called Lactinex, which contains both Lactobacillus acidophilus and Lactobacillus bulgaricus, as antidiarrheal prophylaxis during prolonged antimicrobial therapy, particularly with broad-spectrum agents. I also recommend it during shorter antibiotic courses if mom says that her child always develops diarrhea while on antibiotics.

Lactinex comes in tablet or packet form, with 1 million colony-forming units per tablet or 100 million per packet. The granules can be mixed with food or formula. I advise one packet per day for all ages. Older children can take two to three tablets, three to four times a day.

In the 1990s, my colleagues and I conducted a study in children on a broad-spectrum antibiotic where a 30% reduction in daily stool number and 50% fewer diarrhea days occurred with Lactinex, compared with placebo supplements. The study, funded by an antibiotic manufacturer, was not published because of higher-than-expected diarrhea rates in controls. But, it encouraged me about the potential benefit of probiotics.

Another option for acute diarrhea is Lactobacillus GG, a widely studied probiotic strain sold commercially under the brand name Culturelle. A 2001 literature review revealed that probiotics significantly lowered the risk (odds ratio 0.43) of diarrhea lasting more than 3 days, particularly with rotavirus. Of individual strains, only Lactobacillus GG showed consistent effect (J. Pediatr. Gastroenterol. Nutr. 2001;33[suppl. 2]:S17–25).

But other data suggest benefit for other probiotic organisms. A randomized study of 201 healthy, non-breast-fed day care infants aged 4–10 months compared Lactobacillus reuteri or Bifidobacterium lactis with placebo, revealing significantly fewer episodes of fever (11%, 27%, and 41%, respectively) and diarrhea (13%, 2%, 31%). Duration of diarrhea was also shorter with the probiotics (Pediatrics 2005;115:5–9).

Other exciting data include reductions in atopic disease among children whose mothers took prenatal Lactobacillus GG (Lancet 2001;357:1076–9), enhanced immune response to typhoid immunization in adults given Lactobacilli (FASEB J 1999;13:A872 [abstr]), and reduced incidence/severity of necrotizing enterocolitis in very-low-birth-weight newborns receiving Lactobacillus acidophilus plus Bifidobacterium infantis (Infloran) (Pediatrics 2005;115:1–4).

To be sure, not all pre- and probiotic studies have had positive outcomes. But, excluding immunosuppressed individuals, risk is minimal from these naturally occurring organisms, so why not use them? I predict that we'll be hearing more about this in the future.

Prebiotics and probiotics might offer a way to both prevent and treat disease by enhancing the body's natural immune defense mechanisms.

Recognition that certain naturally occurring bacteria in the gut might be beneficial to health dates back to the early 1900s, when Nobel laureate Dr. Eli Metchnikoff reported that peasants who consumed sour milk with live Lactobacillus bulgaricus lived longer than other people. Now, emerging data suggest that supplementation with health-associated bacteria, also known as “probiotics,” can prevent or reduce diarrhea caused by altered gut flora from antibiotics or rotavirus.

In addition, “prebiotics,” the nondigestible oligosaccharides that stimulate growth of existing probiotic bacteria, also have drawn interest. Prebiotic supplements that do not contain added probiotics could avoid some of the problems associated with probiotics, such as difficulty maintaining live organisms until administration and potential bacteremia in immunosuppressed individuals.

Present in breast milk, prebiotics enhance the growth of existing probiotic bacteria strains Bifidobacteria and Lactobacillus, which predominate in the guts of breast-fed infants. The gut flora of bottle-fed infants, in contrast, tend to comprise primarily Enterobacteriaceae and Clostridia.

Several studies—some supported by infant formula manufacturers—show that adding prebiotic galacto-oligosaccharides and fructo-oligosaccharides to cow's milk formula can result in intestinal flora in bottle-fed infants similar to that in breast-fed infants. This, in turn, results in a reduced intestinal load of more pathogenic bacteria in the infant.

Mucosal and systemic immunity also appear to be enhanced with prebiotic supplementation, possibly reducing subsequent immune-mediated disease such as asthma and allergies. In one prospective, placebo-controlled study, 102 infants at high risk for atopy were fed prebiotic-containing formula (galacto- and long-chain fructo-oligosaccharides) or formula with a placebo (maltodextrin). The atopic dermatitis rate was 9.8% for infants receiving prebiotics, compared with 23.1% for placebo (Arch. Dis. Child. 2006;91:814–9).

A growing data set suggests that pre- and probiotic supplementation in infancy can enhance IgA responses to antigenic challenge, and favorably influence T-helper cell balance, thus reducing inflammatory and/or allergic responses. One prebiotic, lactulose, is commercially available in liquid form under various brand names and is approved for treating constipation.

Whether to routinely prescribe lactulose or other prebiotics for non-breast-fed infants remains an unanswered question. Stay tuned for more data.

Meantime, I believe the data on probiotics are sufficient to support several clinical uses. I advise using a product called Lactinex, which contains both Lactobacillus acidophilus and Lactobacillus bulgaricus, as antidiarrheal prophylaxis during prolonged antimicrobial therapy, particularly with broad-spectrum agents. I also recommend it during shorter antibiotic courses if mom says that her child always develops diarrhea while on antibiotics.

Lactinex comes in tablet or packet form, with 1 million colony-forming units per tablet or 100 million per packet. The granules can be mixed with food or formula. I advise one packet per day for all ages. Older children can take two to three tablets, three to four times a day.

In the 1990s, my colleagues and I conducted a study in children on a broad-spectrum antibiotic where a 30% reduction in daily stool number and 50% fewer diarrhea days occurred with Lactinex, compared with placebo supplements. The study, funded by an antibiotic manufacturer, was not published because of higher-than-expected diarrhea rates in controls. But, it encouraged me about the potential benefit of probiotics.

Another option for acute diarrhea is Lactobacillus GG, a widely studied probiotic strain sold commercially under the brand name Culturelle. A 2001 literature review revealed that probiotics significantly lowered the risk (odds ratio 0.43) of diarrhea lasting more than 3 days, particularly with rotavirus. Of individual strains, only Lactobacillus GG showed consistent effect (J. Pediatr. Gastroenterol. Nutr. 2001;33[suppl. 2]:S17–25).

But other data suggest benefit for other probiotic organisms. A randomized study of 201 healthy, non-breast-fed day care infants aged 4–10 months compared Lactobacillus reuteri or Bifidobacterium lactis with placebo, revealing significantly fewer episodes of fever (11%, 27%, and 41%, respectively) and diarrhea (13%, 2%, 31%). Duration of diarrhea was also shorter with the probiotics (Pediatrics 2005;115:5–9).

Other exciting data include reductions in atopic disease among children whose mothers took prenatal Lactobacillus GG (Lancet 2001;357:1076–9), enhanced immune response to typhoid immunization in adults given Lactobacilli (FASEB J 1999;13:A872 [abstr]), and reduced incidence/severity of necrotizing enterocolitis in very-low-birth-weight newborns receiving Lactobacillus acidophilus plus Bifidobacterium infantis (Infloran) (Pediatrics 2005;115:1–4).

To be sure, not all pre- and probiotic studies have had positive outcomes. But, excluding immunosuppressed individuals, risk is minimal from these naturally occurring organisms, so why not use them? I predict that we'll be hearing more about this in the future.

Prebiotics and probiotics might offer a way to both prevent and treat disease by enhancing the body's natural immune defense mechanisms.

Recognition that certain naturally occurring bacteria in the gut might be beneficial to health dates back to the early 1900s, when Nobel laureate Dr. Eli Metchnikoff reported that peasants who consumed sour milk with live Lactobacillus bulgaricus lived longer than other people. Now, emerging data suggest that supplementation with health-associated bacteria, also known as “probiotics,” can prevent or reduce diarrhea caused by altered gut flora from antibiotics or rotavirus.

In addition, “prebiotics,” the nondigestible oligosaccharides that stimulate growth of existing probiotic bacteria, also have drawn interest. Prebiotic supplements that do not contain added probiotics could avoid some of the problems associated with probiotics, such as difficulty maintaining live organisms until administration and potential bacteremia in immunosuppressed individuals.

Present in breast milk, prebiotics enhance the growth of existing probiotic bacteria strains Bifidobacteria and Lactobacillus, which predominate in the guts of breast-fed infants. The gut flora of bottle-fed infants, in contrast, tend to comprise primarily Enterobacteriaceae and Clostridia.

Several studies—some supported by infant formula manufacturers—show that adding prebiotic galacto-oligosaccharides and fructo-oligosaccharides to cow's milk formula can result in intestinal flora in bottle-fed infants similar to that in breast-fed infants. This, in turn, results in a reduced intestinal load of more pathogenic bacteria in the infant.

Mucosal and systemic immunity also appear to be enhanced with prebiotic supplementation, possibly reducing subsequent immune-mediated disease such as asthma and allergies. In one prospective, placebo-controlled study, 102 infants at high risk for atopy were fed prebiotic-containing formula (galacto- and long-chain fructo-oligosaccharides) or formula with a placebo (maltodextrin). The atopic dermatitis rate was 9.8% for infants receiving prebiotics, compared with 23.1% for placebo (Arch. Dis. Child. 2006;91:814–9).

A growing data set suggests that pre- and probiotic supplementation in infancy can enhance IgA responses to antigenic challenge, and favorably influence T-helper cell balance, thus reducing inflammatory and/or allergic responses. One prebiotic, lactulose, is commercially available in liquid form under various brand names and is approved for treating constipation.

Whether to routinely prescribe lactulose or other prebiotics for non-breast-fed infants remains an unanswered question. Stay tuned for more data.

Meantime, I believe the data on probiotics are sufficient to support several clinical uses. I advise using a product called Lactinex, which contains both Lactobacillus acidophilus and Lactobacillus bulgaricus, as antidiarrheal prophylaxis during prolonged antimicrobial therapy, particularly with broad-spectrum agents. I also recommend it during shorter antibiotic courses if mom says that her child always develops diarrhea while on antibiotics.

Lactinex comes in tablet or packet form, with 1 million colony-forming units per tablet or 100 million per packet. The granules can be mixed with food or formula. I advise one packet per day for all ages. Older children can take two to three tablets, three to four times a day.

In the 1990s, my colleagues and I conducted a study in children on a broad-spectrum antibiotic where a 30% reduction in daily stool number and 50% fewer diarrhea days occurred with Lactinex, compared with placebo supplements. The study, funded by an antibiotic manufacturer, was not published because of higher-than-expected diarrhea rates in controls. But, it encouraged me about the potential benefit of probiotics.

Another option for acute diarrhea is Lactobacillus GG, a widely studied probiotic strain sold commercially under the brand name Culturelle. A 2001 literature review revealed that probiotics significantly lowered the risk (odds ratio 0.43) of diarrhea lasting more than 3 days, particularly with rotavirus. Of individual strains, only Lactobacillus GG showed consistent effect (J. Pediatr. Gastroenterol. Nutr. 2001;33[suppl. 2]:S17–25).

But other data suggest benefit for other probiotic organisms. A randomized study of 201 healthy, non-breast-fed day care infants aged 4–10 months compared Lactobacillus reuteri or Bifidobacterium lactis with placebo, revealing significantly fewer episodes of fever (11%, 27%, and 41%, respectively) and diarrhea (13%, 2%, 31%). Duration of diarrhea was also shorter with the probiotics (Pediatrics 2005;115:5–9).

Other exciting data include reductions in atopic disease among children whose mothers took prenatal Lactobacillus GG (Lancet 2001;357:1076–9), enhanced immune response to typhoid immunization in adults given Lactobacilli (FASEB J 1999;13:A872 [abstr]), and reduced incidence/severity of necrotizing enterocolitis in very-low-birth-weight newborns receiving Lactobacillus acidophilus plus Bifidobacterium infantis (Infloran) (Pediatrics 2005;115:1–4).

To be sure, not all pre- and probiotic studies have had positive outcomes. But, excluding immunosuppressed individuals, risk is minimal from these naturally occurring organisms, so why not use them? I predict that we'll be hearing more about this in the future.

[email protected]

The recent outbreaks of Escherichia coli O157:H7 linked to spinach and lettuce remind us yet again how limited our tools are when it comes to treating this infection and its sequelae. Focusing our efforts on prevention is by far the best medicine.

As of Oct. 6, a total of 199 people infected with the outbreak strain of E. coli serotype 0157:H7 had been reported to the Centers for Disease Control and Prevention from 26 states, including 22 cases in children younger than 5 years of age. Of the total group, 51% were hospitalized and 16% developed hemolytic uremic syndrome (HUS). Twenty-nine percent of children younger than 18 years developed HUS, compared with 8% of adults aged 18–59 years and 14% of those aged 60 years and older, confirming the increased risk for HUS in children and the elderly.

There were three deaths, including a 2-year-old child with HUS whose stool sample contained evidence of the outbreak strain confirmed by “DNA fingerprinting.”

About 73,000 infections with E. coli 0157:H7 occur annually in the United States. Such infections are reportable nationally as well as in most states. In most states, HUS is reportable to departments of public health as well. The CDC investigates all reported cases to ascertain whether they are outbreak-associated or isolated. Most are the latter. Half of all cases occur between June and September.

Produce was the source in the recent outbreak, but in the past we've seen disease in children associated with undercooked meat, nonpasteurized milk products, and even water. Petting zoos are a major hazard.

During 2004–2005, a total of 173 cases of E. coli 0157:H7 were reported from outbreaks in Arizona, Florida, and North Carolina. Illnesses primarily affected children who had visited petting zoos at agricultural fairs or festivals. There were 22 cases of HUS, but fortunately no fatalities (MMWR 2005;54:1277–80).

In a study the CDC conducted at a petting zoo, illness was associated with touching or stepping in manure, falling or sitting on the ground, using a pacifier or “sippy” cup, and thumb-sucking. Use of alcohol-based sanitizer was not protective, but reported awareness by the accompanying adults of the risk for disease from contact with livestock was. We should counsel parents about the potential risk and the preventive strategies such as avoidance of manure and of the use of a pacifier or eating while at the petting zoo.

Direct human-to-human contact is a rarer source of E. coli infection, but it's important to keep in mind when we see a child with bloody diarrhea, particularly if that child is in day care.

Unfortunately, we don't have a way to interrupt the progression from colitis to HUS. The role of antibiotics in children with E. coli gastrointestinal infection remains controversial. Epidemiologic data have suggested that antibiotics may increase the risk for HUS, perhaps by increased toxin exposure to the kidneys following bacteriolysis in the gut. A meta-analysis of 26 studies conducted between January 1983 and February 2001 did not show a higher risk of HUS due to antibiotic use. However, the authors concluded that a randomized trial of adequate power is needed to conclusively answer the question (JAMA 2002;288:996–1001).

Until then, the potential benefit of antimicrobial therapy in a specific patient presenting with gastroenteritis must be weighed against the potential risk. Stool cultures should be obtained from any child who presents with bloody diarrhea and abdominal pain. If the child is afebrile and otherwise does not appear ill, supportive care is advised. But of course, a child with gastroenteritis who is hypotensive and appears septic requires urgent intervention that may include antimicrobial therapy.

Although we don't know which children with E. coli-associated diarrhea will progress to HUS, we do know that certain risk factors, such as young age, long duration of diarrhea, elevated leukocyte count, and proteinuria, are predictive (Emerg. Infect. Dis. 2005;11:1955–7). Fortunately, there is usually a lag time of several days to a week between the onset of bloody diarrhea and renal failure. If we see the child soon enough, we can intervene with fluid replacement and close monitoring.

At the time of progression to HUS, stool cultures often are negative. The diagnosis is made clinically, on the basis of renal failure and hemolytic anemia, with or without thrombocytopenia. Treatment is supportive: Dialysis has dramatically reduced HUS mortality from about 21% before 1974 to about 4% today.

Intriguing early work is now being done looking at treating HUS with infusion of the human plasma protein serum amyloid P component (J. Infect. Dis. 2006;193:1120–4) and use of specific neutralizing antibodies directed against the A subunit of the toxin (Clin. Microbiol. Rev. 2004;17:926–41). Clinical use is probably years away, however.

For now, we need to continue to educate our patients about thoroughly cooking meat, washing produce, and exercising caution around farm animals and in petting zoos.

[email protected]

The recent outbreaks of Escherichia coli O157:H7 linked to spinach and lettuce remind us yet again how limited our tools are when it comes to treating this infection and its sequelae. Focusing our efforts on prevention is by far the best medicine.

As of Oct. 6, a total of 199 people infected with the outbreak strain of E. coli serotype 0157:H7 had been reported to the Centers for Disease Control and Prevention from 26 states, including 22 cases in children younger than 5 years of age. Of the total group, 51% were hospitalized and 16% developed hemolytic uremic syndrome (HUS). Twenty-nine percent of children younger than 18 years developed HUS, compared with 8% of adults aged 18–59 years and 14% of those aged 60 years and older, confirming the increased risk for HUS in children and the elderly.

There were three deaths, including a 2-year-old child with HUS whose stool sample contained evidence of the outbreak strain confirmed by “DNA fingerprinting.”

About 73,000 infections with E. coli 0157:H7 occur annually in the United States. Such infections are reportable nationally as well as in most states. In most states, HUS is reportable to departments of public health as well. The CDC investigates all reported cases to ascertain whether they are outbreak-associated or isolated. Most are the latter. Half of all cases occur between June and September.

Produce was the source in the recent outbreak, but in the past we've seen disease in children associated with undercooked meat, nonpasteurized milk products, and even water. Petting zoos are a major hazard.

During 2004–2005, a total of 173 cases of E. coli 0157:H7 were reported from outbreaks in Arizona, Florida, and North Carolina. Illnesses primarily affected children who had visited petting zoos at agricultural fairs or festivals. There were 22 cases of HUS, but fortunately no fatalities (MMWR 2005;54:1277–80).

In a study the CDC conducted at a petting zoo, illness was associated with touching or stepping in manure, falling or sitting on the ground, using a pacifier or “sippy” cup, and thumb-sucking. Use of alcohol-based sanitizer was not protective, but reported awareness by the accompanying adults of the risk for disease from contact with livestock was. We should counsel parents about the potential risk and the preventive strategies such as avoidance of manure and of the use of a pacifier or eating while at the petting zoo.

Direct human-to-human contact is a rarer source of E. coli infection, but it's important to keep in mind when we see a child with bloody diarrhea, particularly if that child is in day care.

Unfortunately, we don't have a way to interrupt the progression from colitis to HUS. The role of antibiotics in children with E. coli gastrointestinal infection remains controversial. Epidemiologic data have suggested that antibiotics may increase the risk for HUS, perhaps by increased toxin exposure to the kidneys following bacteriolysis in the gut. A meta-analysis of 26 studies conducted between January 1983 and February 2001 did not show a higher risk of HUS due to antibiotic use. However, the authors concluded that a randomized trial of adequate power is needed to conclusively answer the question (JAMA 2002;288:996–1001).

Until then, the potential benefit of antimicrobial therapy in a specific patient presenting with gastroenteritis must be weighed against the potential risk. Stool cultures should be obtained from any child who presents with bloody diarrhea and abdominal pain. If the child is afebrile and otherwise does not appear ill, supportive care is advised. But of course, a child with gastroenteritis who is hypotensive and appears septic requires urgent intervention that may include antimicrobial therapy.

Although we don't know which children with E. coli-associated diarrhea will progress to HUS, we do know that certain risk factors, such as young age, long duration of diarrhea, elevated leukocyte count, and proteinuria, are predictive (Emerg. Infect. Dis. 2005;11:1955–7). Fortunately, there is usually a lag time of several days to a week between the onset of bloody diarrhea and renal failure. If we see the child soon enough, we can intervene with fluid replacement and close monitoring.

At the time of progression to HUS, stool cultures often are negative. The diagnosis is made clinically, on the basis of renal failure and hemolytic anemia, with or without thrombocytopenia. Treatment is supportive: Dialysis has dramatically reduced HUS mortality from about 21% before 1974 to about 4% today.

Intriguing early work is now being done looking at treating HUS with infusion of the human plasma protein serum amyloid P component (J. Infect. Dis. 2006;193:1120–4) and use of specific neutralizing antibodies directed against the A subunit of the toxin (Clin. Microbiol. Rev. 2004;17:926–41). Clinical use is probably years away, however.

For now, we need to continue to educate our patients about thoroughly cooking meat, washing produce, and exercising caution around farm animals and in petting zoos.

[email protected]

The recent outbreaks of Escherichia coli O157:H7 linked to spinach and lettuce remind us yet again how limited our tools are when it comes to treating this infection and its sequelae. Focusing our efforts on prevention is by far the best medicine.

As of Oct. 6, a total of 199 people infected with the outbreak strain of E. coli serotype 0157:H7 had been reported to the Centers for Disease Control and Prevention from 26 states, including 22 cases in children younger than 5 years of age. Of the total group, 51% were hospitalized and 16% developed hemolytic uremic syndrome (HUS). Twenty-nine percent of children younger than 18 years developed HUS, compared with 8% of adults aged 18–59 years and 14% of those aged 60 years and older, confirming the increased risk for HUS in children and the elderly.

There were three deaths, including a 2-year-old child with HUS whose stool sample contained evidence of the outbreak strain confirmed by “DNA fingerprinting.”

About 73,000 infections with E. coli 0157:H7 occur annually in the United States. Such infections are reportable nationally as well as in most states. In most states, HUS is reportable to departments of public health as well. The CDC investigates all reported cases to ascertain whether they are outbreak-associated or isolated. Most are the latter. Half of all cases occur between June and September.

Produce was the source in the recent outbreak, but in the past we've seen disease in children associated with undercooked meat, nonpasteurized milk products, and even water. Petting zoos are a major hazard.

During 2004–2005, a total of 173 cases of E. coli 0157:H7 were reported from outbreaks in Arizona, Florida, and North Carolina. Illnesses primarily affected children who had visited petting zoos at agricultural fairs or festivals. There were 22 cases of HUS, but fortunately no fatalities (MMWR 2005;54:1277–80).

In a study the CDC conducted at a petting zoo, illness was associated with touching or stepping in manure, falling or sitting on the ground, using a pacifier or “sippy” cup, and thumb-sucking. Use of alcohol-based sanitizer was not protective, but reported awareness by the accompanying adults of the risk for disease from contact with livestock was. We should counsel parents about the potential risk and the preventive strategies such as avoidance of manure and of the use of a pacifier or eating while at the petting zoo.

Direct human-to-human contact is a rarer source of E. coli infection, but it's important to keep in mind when we see a child with bloody diarrhea, particularly if that child is in day care.

Unfortunately, we don't have a way to interrupt the progression from colitis to HUS. The role of antibiotics in children with E. coli gastrointestinal infection remains controversial. Epidemiologic data have suggested that antibiotics may increase the risk for HUS, perhaps by increased toxin exposure to the kidneys following bacteriolysis in the gut. A meta-analysis of 26 studies conducted between January 1983 and February 2001 did not show a higher risk of HUS due to antibiotic use. However, the authors concluded that a randomized trial of adequate power is needed to conclusively answer the question (JAMA 2002;288:996–1001).

Until then, the potential benefit of antimicrobial therapy in a specific patient presenting with gastroenteritis must be weighed against the potential risk. Stool cultures should be obtained from any child who presents with bloody diarrhea and abdominal pain. If the child is afebrile and otherwise does not appear ill, supportive care is advised. But of course, a child with gastroenteritis who is hypotensive and appears septic requires urgent intervention that may include antimicrobial therapy.

Although we don't know which children with E. coli-associated diarrhea will progress to HUS, we do know that certain risk factors, such as young age, long duration of diarrhea, elevated leukocyte count, and proteinuria, are predictive (Emerg. Infect. Dis. 2005;11:1955–7). Fortunately, there is usually a lag time of several days to a week between the onset of bloody diarrhea and renal failure. If we see the child soon enough, we can intervene with fluid replacement and close monitoring.

At the time of progression to HUS, stool cultures often are negative. The diagnosis is made clinically, on the basis of renal failure and hemolytic anemia, with or without thrombocytopenia. Treatment is supportive: Dialysis has dramatically reduced HUS mortality from about 21% before 1974 to about 4% today.

Intriguing early work is now being done looking at treating HUS with infusion of the human plasma protein serum amyloid P component (J. Infect. Dis. 2006;193:1120–4) and use of specific neutralizing antibodies directed against the A subunit of the toxin (Clin. Microbiol. Rev. 2004;17:926–41). Clinical use is probably years away, however.

For now, we need to continue to educate our patients about thoroughly cooking meat, washing produce, and exercising caution around farm animals and in petting zoos.

[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.

When the 7-valent pneumococcal conjugate vaccine was first introduced in 2000, many of us had high hopes that it would bring with it a new era in which we could leave invasive pneumococcal disease out of the equation and not have to worry that we might be missing a case of meningitis.

Indeed, the vaccine has resulted in an impressive overall reduction in pediatric invasive pneumococcal infection.

Unfortunately, emerging data now suggest that rates of invasive disease caused by nonvaccine serotypes are rising and that the overall disease reduction seen in the first 5 years since licensure of the vaccine may have leveled off.

With Haemophilus influenzae type b (Hib), all invasive disease was caused by a single strain. Following the universal implementation of the Hib vaccine in the 1990s, invasive Hib disease has virtually disappeared.

In contrast, pneumococcal infection involves multiple serotypes. This alone inherently limits the success that the 7-valent pneumococcal conjugate vaccine (PCV7) may have and explains part of the changing epidemiology.

Ongoing surveillance is extremely important now, and will continue to be as we move forward with new vaccines containing additional serotypes.

Here at Children's Mercy Hospital, my colleagues Dr. Douglas S. Swanson and Dr. Christopher J. Harrison compared data from patients with invasive pneumococcal disease in the pre-PCV7 era of 1998–2000 with data from 2001 through March 2006. They found that the total number of invasive pneumococcal infections in Kansas City children has decreased from prevaccine years, with the average annual number of invasive pneumococcal disease cases declining by about 50%, from 43 cases/year during 1998–2000 to 21 cases/year from 2001 through March 2006. This is remarkable and consistent with data from other pediatric hospitals.

Steenhoff et al. recently compared data on pneumococcal bacteremia from the pre-PCV7 era in Philadelphia with data from 2001 through May 2005, and found that the incidence decreased by 57% (CID 2006;42:907–14).

Schutze et al. similarly noted a decrease in disease incidence of invasive disease in Arkansas from a high of 5.78/100,000 population to 3.02/100,000 population in the postvaccine era (Pediatr. Infect. Dis. J. 2004;23:1125–9).

Occult pneumococcal bacteremia has been by far the most common of the invasive infections that pediatricians have encountered in the past and appears to be the most common invasive infection impacted by PCV7. This entity, which traditionally occurs in infants from 6 to 36 months of age with high fever and no localizing findings, generally has a benign outcome. Complications, including meningitis, occur rarely.

Reduction of more virulent diseases like empyema and meningitis with PCV7 has been clearly demonstrated. However, data suggest that pneumococcus continues to play an important role in complicated pneumonia with empyema.

In a study from the United Kingdom published earlier this summer, locally presenting pleural empyema cases in children increased threefold during 2003–2004. Antigen analysis of empyema fluid identified Streptococcus pneumoniae in 27 of 29 cases for whom samples were available, and capsular polysaccharide type 1 was confirmed in 18 of those (Pediatr. Infect. Dis. J. 2006;25:559–60).

The authors, Fletcher et al. of the South West of England Invasive Community Acquired Infection Study Group, concluded that “use of a conjugate vaccine without serotype 1 antigen would have had limited impact on this morbidity in our region.”

Postvaccine licensure studies have shown a decline in incidence of pneumococcal meningitis cases. In our review, this was less remarkable, with an average of 6.7 cases/year in 1998–2000 and 4.8 cases/year from 2001 through March 2006. This year alone we have treated eight patients with pneumococcal meningitis.

Serotype replacement is a major issue. In our institution since 2001, only 2 of the 20 isolates that have been serotyped are vaccine-specific serotypes. The apparent failure of the vaccine to impact 19A disease is notable, because it was hoped that cross-protection with vaccine serotype 19F would occur.

Kaplan et al. of the U.S. Pediatric Multicenter Pneumococcal Surveillance Group recently examined this issue. Investigators from eight children's hospitals have been prospectively identifying children in their centers with invasive infections caused by S. pneumoniae for the last 9 years. They found that serotypes 15, 19A, and 33 were the most common nonvaccine serotypes and accounted for almost half of nonvaccine isolates recovered from vaccinated patients in the postvaccine era (Pediatrics 2004;113:443–9).

The vaccine's impact on antimicrobial resistance is less clear. Schutze et al. noted that 44% of isolates were nonsusceptible to penicillin in 1998–2000, not significantly different from the 46% seen in the postvaccine era of 2001–2003.

In our institution, 34% of the invasive isolates in 1998–2000 were penicillin nonsusceptible, compared with 42% in 2001 through March 2006. The latter finding was not statistically significant, but it does support data from other studies suggesting that the vaccine's impact on cases of invasive disease caused by penicillin nonsusceptible pneumococcal strains warrants continued monitoring.

In a study that was funded in part by Wyeth et al. of Kaiser Permanente, Oakland, Calif., found that the herd immunity conferred by individuals vaccinated with PCV7 resulted in significant savings in cost per life-year saved during the first 5 years following introduction of the vaccine.

However, they acknowledged, “if serotype replacement increases over time, it is possible that the efficacy of the vaccine—both for the vaccinated and nonvaccinated populations—could decline in the future” (Pediatr. Infect. Dis. J. 2006;25:494–501).

Current efforts to develop new multivalent pneumococcal conjugate vaccines will pay off in the long run. As we turn our attention to the next phase of development, we also must keep in mind and prioritize the needs in the developing world.

According to the World Health Organization, as many as 1 million children under 5 years of age die every year of pneumococcal pneumonia, meningitis, and sepsis. In populations with high child mortality rates, pneumonia is the leading infectious cause of mortality, accounting for about 20%–25% of all deaths in children.

Clinical trials now underway in Africa and elsewhere are utilizing conjugate pneumococcal vaccines containing between 7 and 13 serotypes. While serotype replacement could eventually occur in the developing world as well, the immediate impact in reducing disease and death would be enormous and undeniably worthwhile.

Phase III studies are ongoing with one prototype that contains 13 serotypes including 19A, 1, 3, 5, 6A, and 7V. Investigators estimate that in the United States, the 13-valent vaccine will cover around 60% of the remaining disease in children and expand coverage for strains prevalent in developing countries.

Despite the success of conjugate pneumococcal vaccine, it is clear that it will not be associated with the type of triumph we achieved with the Hib vaccine.

For the near future at least, we will need to remain vigilant when evaluating febrile children, understanding the clinical setting in which pneumococcal infection may occur. As the epidemiology of pneumococcal infection evolves, it is important for clinicians to continue to stay abreast of data regarding disease incidence, emerging serotypes, bacterial resistance, and future advances.

When the 7-valent pneumococcal conjugate vaccine was first introduced in 2000, many of us had high hopes that it would bring with it a new era in which we could leave invasive pneumococcal disease out of the equation and not have to worry that we might be missing a case of meningitis.

Indeed, the vaccine has resulted in an impressive overall reduction in pediatric invasive pneumococcal infection.

Unfortunately, emerging data now suggest that rates of invasive disease caused by nonvaccine serotypes are rising and that the overall disease reduction seen in the first 5 years since licensure of the vaccine may have leveled off.

With Haemophilus influenzae type b (Hib), all invasive disease was caused by a single strain. Following the universal implementation of the Hib vaccine in the 1990s, invasive Hib disease has virtually disappeared.

In contrast, pneumococcal infection involves multiple serotypes. This alone inherently limits the success that the 7-valent pneumococcal conjugate vaccine (PCV7) may have and explains part of the changing epidemiology.

Ongoing surveillance is extremely important now, and will continue to be as we move forward with new vaccines containing additional serotypes.

Here at Children's Mercy Hospital, my colleagues Dr. Douglas S. Swanson and Dr. Christopher J. Harrison compared data from patients with invasive pneumococcal disease in the pre-PCV7 era of 1998–2000 with data from 2001 through March 2006. They found that the total number of invasive pneumococcal infections in Kansas City children has decreased from prevaccine years, with the average annual number of invasive pneumococcal disease cases declining by about 50%, from 43 cases/year during 1998–2000 to 21 cases/year from 2001 through March 2006. This is remarkable and consistent with data from other pediatric hospitals.

Steenhoff et al. recently compared data on pneumococcal bacteremia from the pre-PCV7 era in Philadelphia with data from 2001 through May 2005, and found that the incidence decreased by 57% (CID 2006;42:907–14).

Schutze et al. similarly noted a decrease in disease incidence of invasive disease in Arkansas from a high of 5.78/100,000 population to 3.02/100,000 population in the postvaccine era (Pediatr. Infect. Dis. J. 2004;23:1125–9).

Occult pneumococcal bacteremia has been by far the most common of the invasive infections that pediatricians have encountered in the past and appears to be the most common invasive infection impacted by PCV7. This entity, which traditionally occurs in infants from 6 to 36 months of age with high fever and no localizing findings, generally has a benign outcome. Complications, including meningitis, occur rarely.

Reduction of more virulent diseases like empyema and meningitis with PCV7 has been clearly demonstrated. However, data suggest that pneumococcus continues to play an important role in complicated pneumonia with empyema.

In a study from the United Kingdom published earlier this summer, locally presenting pleural empyema cases in children increased threefold during 2003–2004. Antigen analysis of empyema fluid identified Streptococcus pneumoniae in 27 of 29 cases for whom samples were available, and capsular polysaccharide type 1 was confirmed in 18 of those (Pediatr. Infect. Dis. J. 2006;25:559–60).

The authors, Fletcher et al. of the South West of England Invasive Community Acquired Infection Study Group, concluded that “use of a conjugate vaccine without serotype 1 antigen would have had limited impact on this morbidity in our region.”

Postvaccine licensure studies have shown a decline in incidence of pneumococcal meningitis cases. In our review, this was less remarkable, with an average of 6.7 cases/year in 1998–2000 and 4.8 cases/year from 2001 through March 2006. This year alone we have treated eight patients with pneumococcal meningitis.

Serotype replacement is a major issue. In our institution since 2001, only 2 of the 20 isolates that have been serotyped are vaccine-specific serotypes. The apparent failure of the vaccine to impact 19A disease is notable, because it was hoped that cross-protection with vaccine serotype 19F would occur.

Kaplan et al. of the U.S. Pediatric Multicenter Pneumococcal Surveillance Group recently examined this issue. Investigators from eight children's hospitals have been prospectively identifying children in their centers with invasive infections caused by S. pneumoniae for the last 9 years. They found that serotypes 15, 19A, and 33 were the most common nonvaccine serotypes and accounted for almost half of nonvaccine isolates recovered from vaccinated patients in the postvaccine era (Pediatrics 2004;113:443–9).

The vaccine's impact on antimicrobial resistance is less clear. Schutze et al. noted that 44% of isolates were nonsusceptible to penicillin in 1998–2000, not significantly different from the 46% seen in the postvaccine era of 2001–2003.

In our institution, 34% of the invasive isolates in 1998–2000 were penicillin nonsusceptible, compared with 42% in 2001 through March 2006. The latter finding was not statistically significant, but it does support data from other studies suggesting that the vaccine's impact on cases of invasive disease caused by penicillin nonsusceptible pneumococcal strains warrants continued monitoring.

In a study that was funded in part by Wyeth et al. of Kaiser Permanente, Oakland, Calif., found that the herd immunity conferred by individuals vaccinated with PCV7 resulted in significant savings in cost per life-year saved during the first 5 years following introduction of the vaccine.

However, they acknowledged, “if serotype replacement increases over time, it is possible that the efficacy of the vaccine—both for the vaccinated and nonvaccinated populations—could decline in the future” (Pediatr. Infect. Dis. J. 2006;25:494–501).

Current efforts to develop new multivalent pneumococcal conjugate vaccines will pay off in the long run. As we turn our attention to the next phase of development, we also must keep in mind and prioritize the needs in the developing world.

According to the World Health Organization, as many as 1 million children under 5 years of age die every year of pneumococcal pneumonia, meningitis, and sepsis. In populations with high child mortality rates, pneumonia is the leading infectious cause of mortality, accounting for about 20%–25% of all deaths in children.

Clinical trials now underway in Africa and elsewhere are utilizing conjugate pneumococcal vaccines containing between 7 and 13 serotypes. While serotype replacement could eventually occur in the developing world as well, the immediate impact in reducing disease and death would be enormous and undeniably worthwhile.

Phase III studies are ongoing with one prototype that contains 13 serotypes including 19A, 1, 3, 5, 6A, and 7V. Investigators estimate that in the United States, the 13-valent vaccine will cover around 60% of the remaining disease in children and expand coverage for strains prevalent in developing countries.

Despite the success of conjugate pneumococcal vaccine, it is clear that it will not be associated with the type of triumph we achieved with the Hib vaccine.

For the near future at least, we will need to remain vigilant when evaluating febrile children, understanding the clinical setting in which pneumococcal infection may occur. As the epidemiology of pneumococcal infection evolves, it is important for clinicians to continue to stay abreast of data regarding disease incidence, emerging serotypes, bacterial resistance, and future advances.

When the 7-valent pneumococcal conjugate vaccine was first introduced in 2000, many of us had high hopes that it would bring with it a new era in which we could leave invasive pneumococcal disease out of the equation and not have to worry that we might be missing a case of meningitis.

Indeed, the vaccine has resulted in an impressive overall reduction in pediatric invasive pneumococcal infection.

Unfortunately, emerging data now suggest that rates of invasive disease caused by nonvaccine serotypes are rising and that the overall disease reduction seen in the first 5 years since licensure of the vaccine may have leveled off.

With Haemophilus influenzae type b (Hib), all invasive disease was caused by a single strain. Following the universal implementation of the Hib vaccine in the 1990s, invasive Hib disease has virtually disappeared.

In contrast, pneumococcal infection involves multiple serotypes. This alone inherently limits the success that the 7-valent pneumococcal conjugate vaccine (PCV7) may have and explains part of the changing epidemiology.

Ongoing surveillance is extremely important now, and will continue to be as we move forward with new vaccines containing additional serotypes.

Here at Children's Mercy Hospital, my colleagues Dr. Douglas S. Swanson and Dr. Christopher J. Harrison compared data from patients with invasive pneumococcal disease in the pre-PCV7 era of 1998–2000 with data from 2001 through March 2006. They found that the total number of invasive pneumococcal infections in Kansas City children has decreased from prevaccine years, with the average annual number of invasive pneumococcal disease cases declining by about 50%, from 43 cases/year during 1998–2000 to 21 cases/year from 2001 through March 2006. This is remarkable and consistent with data from other pediatric hospitals.

Steenhoff et al. recently compared data on pneumococcal bacteremia from the pre-PCV7 era in Philadelphia with data from 2001 through May 2005, and found that the incidence decreased by 57% (CID 2006;42:907–14).

Schutze et al. similarly noted a decrease in disease incidence of invasive disease in Arkansas from a high of 5.78/100,000 population to 3.02/100,000 population in the postvaccine era (Pediatr. Infect. Dis. J. 2004;23:1125–9).

Occult pneumococcal bacteremia has been by far the most common of the invasive infections that pediatricians have encountered in the past and appears to be the most common invasive infection impacted by PCV7. This entity, which traditionally occurs in infants from 6 to 36 months of age with high fever and no localizing findings, generally has a benign outcome. Complications, including meningitis, occur rarely.

Reduction of more virulent diseases like empyema and meningitis with PCV7 has been clearly demonstrated. However, data suggest that pneumococcus continues to play an important role in complicated pneumonia with empyema.

In a study from the United Kingdom published earlier this summer, locally presenting pleural empyema cases in children increased threefold during 2003–2004. Antigen analysis of empyema fluid identified Streptococcus pneumoniae in 27 of 29 cases for whom samples were available, and capsular polysaccharide type 1 was confirmed in 18 of those (Pediatr. Infect. Dis. J. 2006;25:559–60).

The authors, Fletcher et al. of the South West of England Invasive Community Acquired Infection Study Group, concluded that “use of a conjugate vaccine without serotype 1 antigen would have had limited impact on this morbidity in our region.”

Postvaccine licensure studies have shown a decline in incidence of pneumococcal meningitis cases. In our review, this was less remarkable, with an average of 6.7 cases/year in 1998–2000 and 4.8 cases/year from 2001 through March 2006. This year alone we have treated eight patients with pneumococcal meningitis.

Serotype replacement is a major issue. In our institution since 2001, only 2 of the 20 isolates that have been serotyped are vaccine-specific serotypes. The apparent failure of the vaccine to impact 19A disease is notable, because it was hoped that cross-protection with vaccine serotype 19F would occur.

Kaplan et al. of the U.S. Pediatric Multicenter Pneumococcal Surveillance Group recently examined this issue. Investigators from eight children's hospitals have been prospectively identifying children in their centers with invasive infections caused by S. pneumoniae for the last 9 years. They found that serotypes 15, 19A, and 33 were the most common nonvaccine serotypes and accounted for almost half of nonvaccine isolates recovered from vaccinated patients in the postvaccine era (Pediatrics 2004;113:443–9).

The vaccine's impact on antimicrobial resistance is less clear. Schutze et al. noted that 44% of isolates were nonsusceptible to penicillin in 1998–2000, not significantly different from the 46% seen in the postvaccine era of 2001–2003.

In our institution, 34% of the invasive isolates in 1998–2000 were penicillin nonsusceptible, compared with 42% in 2001 through March 2006. The latter finding was not statistically significant, but it does support data from other studies suggesting that the vaccine's impact on cases of invasive disease caused by penicillin nonsusceptible pneumococcal strains warrants continued monitoring.

In a study that was funded in part by Wyeth et al. of Kaiser Permanente, Oakland, Calif., found that the herd immunity conferred by individuals vaccinated with PCV7 resulted in significant savings in cost per life-year saved during the first 5 years following introduction of the vaccine.

However, they acknowledged, “if serotype replacement increases over time, it is possible that the efficacy of the vaccine—both for the vaccinated and nonvaccinated populations—could decline in the future” (Pediatr. Infect. Dis. J. 2006;25:494–501).

Current efforts to develop new multivalent pneumococcal conjugate vaccines will pay off in the long run. As we turn our attention to the next phase of development, we also must keep in mind and prioritize the needs in the developing world.

According to the World Health Organization, as many as 1 million children under 5 years of age die every year of pneumococcal pneumonia, meningitis, and sepsis. In populations with high child mortality rates, pneumonia is the leading infectious cause of mortality, accounting for about 20%–25% of all deaths in children.

Clinical trials now underway in Africa and elsewhere are utilizing conjugate pneumococcal vaccines containing between 7 and 13 serotypes. While serotype replacement could eventually occur in the developing world as well, the immediate impact in reducing disease and death would be enormous and undeniably worthwhile.

Phase III studies are ongoing with one prototype that contains 13 serotypes including 19A, 1, 3, 5, 6A, and 7V. Investigators estimate that in the United States, the 13-valent vaccine will cover around 60% of the remaining disease in children and expand coverage for strains prevalent in developing countries.

Despite the success of conjugate pneumococcal vaccine, it is clear that it will not be associated with the type of triumph we achieved with the Hib vaccine.

For the near future at least, we will need to remain vigilant when evaluating febrile children, understanding the clinical setting in which pneumococcal infection may occur. As the epidemiology of pneumococcal infection evolves, it is important for clinicians to continue to stay abreast of data regarding disease incidence, emerging serotypes, bacterial resistance, and future advances.

A debate in the vaccine community currently revolves around the wisdom of recommending universal influenza vaccine administration, rather than continuing the current strategy of focusing on high-risk individuals. I come down solidly on the side of universal immunization.

The influenza-related death toll—36,000 annually in the United States—is greater than that from all other vaccine-preventable diseases combined. Influenza also results in an average of 150,000 hospitalizations and millions of physician visits each year. Among children aged less than 5 years, hospitalization rates are nearly 500/100,000 in children with high-risk medical conditions, but still are robust at 100/100,000 even in children without high-risk conditions (MMWR 2006;55[early release]:1–41).

Given those numbers, it seems to me that we're tying one hand behind our backs when trying to defend against influenza by not immunizing all our patients.

Even the current guidelines from the Centers for Disease Control and Prevention say that “physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza or transmitting influenza to others should they become infected.” To me, that makes everyone a potential candidate. The real sticking points at present in implementing universal influenza immunization are the limitations of our infrastructure for producing, distributing, and administering the vaccine.

I practiced primary care for 8 years in the 1970s and ′80s before specializing in infectious disease. Even then, I recommended influenza vaccine to everyone who came to the office in the time leading up to influenza season. It seemed illogical to protect only a select few of my patients.

The piecemeal approach we follow now is confusing and a headache for practitioners—things are never the same from year to year. For example, this year for the first time we'll need to order enough vaccine for 24- to 59-month-olds as well as 6- to 23-month-olds, plus our older patients with high-risk medical conditions and all of their household contacts. Wouldn't it be a lot simpler just to count how many children are in our practices and order that number?

If vaccine manufacturers could be assured that we would order a certain number of doses each year, they would gear up and make them. So far, they haven't been willing to do this because it's too much of a gamble—during some seasons, as much as two-thirds of their doses have gone unused. If there were a universal recommendation with consistent year-to-year utilization, it should remove their reticence.

Manufacturers also would be aided a great deal if there were a way to make influenza vaccine without having to grow the virus in thousands of fertilized chicken eggs. In June of this year, a Canadian company called Hepalife Technologies Inc. licensed technology from researchers at Michigan State University in East Lansing for the development of new cell culture-based influenza vaccines, including one for the potential pandemic-causing strain H5N1. If the cell line is able to grow influenza virus reliably—preliminary data indicate that it is—it would greatly facilitate the manufacturing process by enabling influenza vaccine to be grown more efficiently and less expensively. It also would eliminate the egg allergy problem. I don't own stock in the company, but I am excited about this product's potential.

Of course, immunizing all of our patients within a 6-week period during October and November would be a huge challenge. It wouldn't be practical for the primary care office to be the only avenue for distribution. Grocery and drugstore chains have become major influenza vaccine vendors for adults, but generally not for children because of liability concerns. I think the effort will need to utilize public health departments to extend the infrastructure, and perhaps coordinate with schools for the older children.

There has been precedent for this. During the influenza season 2 years ago that killed several children in Colorado and in this year's Midwest mumps outbreak, county health departments moved their mobile units to schools and managed to immunize large numbers of children. Documentation may be a bit of a problem, but this can be worked out. We just need the go-ahead of a universal recommendation to get the ball rolling.

A universal immunization recommendation for routine influenza seasons would also prepare us for a pandemic situation. We currently have incomplete logistical support for potential intervention involving the entire U.S. population. This would be excellent training for our health care system, and would provide templates upon which to build. If we had 2 or 3 years of practice in immunizing everyone prior to a pandemic, we'd all be much more expert when a pandemic arrived.

Obviously, a universal recommendation doesn't mean that everyone will be immunized. But, we would be far more likely to achieve herd immunity than with what we do now. We should see fewer hospitalizations in the very old and the very young, the two groups that utilize the greatest amount of health care resources.

We know that the severe complications of influenza—invasive bacterial infections such as empyemas, bacteremias, and meningococcemia—tend to peak during and just after each influenza season because bacterial pathogens more readily invade the mucosa of influenza-damaged respiratory tracts, which are still healing for weeks after the patient's influenza infection has resolved. In a bad influenza season, emergency departments are bombarded with influenza cases and patients with sequelae during January-April. Reducing that enormous utilization of medical resources should be worth every bit of effort we'd put into getting everyone immunized in the fall.

A debate in the vaccine community currently revolves around the wisdom of recommending universal influenza vaccine administration, rather than continuing the current strategy of focusing on high-risk individuals. I come down solidly on the side of universal immunization.

The influenza-related death toll—36,000 annually in the United States—is greater than that from all other vaccine-preventable diseases combined. Influenza also results in an average of 150,000 hospitalizations and millions of physician visits each year. Among children aged less than 5 years, hospitalization rates are nearly 500/100,000 in children with high-risk medical conditions, but still are robust at 100/100,000 even in children without high-risk conditions (MMWR 2006;55[early release]:1–41).

Given those numbers, it seems to me that we're tying one hand behind our backs when trying to defend against influenza by not immunizing all our patients.

Even the current guidelines from the Centers for Disease Control and Prevention say that “physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza or transmitting influenza to others should they become infected.” To me, that makes everyone a potential candidate. The real sticking points at present in implementing universal influenza immunization are the limitations of our infrastructure for producing, distributing, and administering the vaccine.

I practiced primary care for 8 years in the 1970s and ′80s before specializing in infectious disease. Even then, I recommended influenza vaccine to everyone who came to the office in the time leading up to influenza season. It seemed illogical to protect only a select few of my patients.

The piecemeal approach we follow now is confusing and a headache for practitioners—things are never the same from year to year. For example, this year for the first time we'll need to order enough vaccine for 24- to 59-month-olds as well as 6- to 23-month-olds, plus our older patients with high-risk medical conditions and all of their household contacts. Wouldn't it be a lot simpler just to count how many children are in our practices and order that number?

If vaccine manufacturers could be assured that we would order a certain number of doses each year, they would gear up and make them. So far, they haven't been willing to do this because it's too much of a gamble—during some seasons, as much as two-thirds of their doses have gone unused. If there were a universal recommendation with consistent year-to-year utilization, it should remove their reticence.

Manufacturers also would be aided a great deal if there were a way to make influenza vaccine without having to grow the virus in thousands of fertilized chicken eggs. In June of this year, a Canadian company called Hepalife Technologies Inc. licensed technology from researchers at Michigan State University in East Lansing for the development of new cell culture-based influenza vaccines, including one for the potential pandemic-causing strain H5N1. If the cell line is able to grow influenza virus reliably—preliminary data indicate that it is—it would greatly facilitate the manufacturing process by enabling influenza vaccine to be grown more efficiently and less expensively. It also would eliminate the egg allergy problem. I don't own stock in the company, but I am excited about this product's potential.

Of course, immunizing all of our patients within a 6-week period during October and November would be a huge challenge. It wouldn't be practical for the primary care office to be the only avenue for distribution. Grocery and drugstore chains have become major influenza vaccine vendors for adults, but generally not for children because of liability concerns. I think the effort will need to utilize public health departments to extend the infrastructure, and perhaps coordinate with schools for the older children.

There has been precedent for this. During the influenza season 2 years ago that killed several children in Colorado and in this year's Midwest mumps outbreak, county health departments moved their mobile units to schools and managed to immunize large numbers of children. Documentation may be a bit of a problem, but this can be worked out. We just need the go-ahead of a universal recommendation to get the ball rolling.

A universal immunization recommendation for routine influenza seasons would also prepare us for a pandemic situation. We currently have incomplete logistical support for potential intervention involving the entire U.S. population. This would be excellent training for our health care system, and would provide templates upon which to build. If we had 2 or 3 years of practice in immunizing everyone prior to a pandemic, we'd all be much more expert when a pandemic arrived.

Obviously, a universal recommendation doesn't mean that everyone will be immunized. But, we would be far more likely to achieve herd immunity than with what we do now. We should see fewer hospitalizations in the very old and the very young, the two groups that utilize the greatest amount of health care resources.

We know that the severe complications of influenza—invasive bacterial infections such as empyemas, bacteremias, and meningococcemia—tend to peak during and just after each influenza season because bacterial pathogens more readily invade the mucosa of influenza-damaged respiratory tracts, which are still healing for weeks after the patient's influenza infection has resolved. In a bad influenza season, emergency departments are bombarded with influenza cases and patients with sequelae during January-April. Reducing that enormous utilization of medical resources should be worth every bit of effort we'd put into getting everyone immunized in the fall.

A debate in the vaccine community currently revolves around the wisdom of recommending universal influenza vaccine administration, rather than continuing the current strategy of focusing on high-risk individuals. I come down solidly on the side of universal immunization.

The influenza-related death toll—36,000 annually in the United States—is greater than that from all other vaccine-preventable diseases combined. Influenza also results in an average of 150,000 hospitalizations and millions of physician visits each year. Among children aged less than 5 years, hospitalization rates are nearly 500/100,000 in children with high-risk medical conditions, but still are robust at 100/100,000 even in children without high-risk conditions (MMWR 2006;55[early release]:1–41).

Given those numbers, it seems to me that we're tying one hand behind our backs when trying to defend against influenza by not immunizing all our patients.

Even the current guidelines from the Centers for Disease Control and Prevention say that “physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza or transmitting influenza to others should they become infected.” To me, that makes everyone a potential candidate. The real sticking points at present in implementing universal influenza immunization are the limitations of our infrastructure for producing, distributing, and administering the vaccine.

I practiced primary care for 8 years in the 1970s and ′80s before specializing in infectious disease. Even then, I recommended influenza vaccine to everyone who came to the office in the time leading up to influenza season. It seemed illogical to protect only a select few of my patients.

The piecemeal approach we follow now is confusing and a headache for practitioners—things are never the same from year to year. For example, this year for the first time we'll need to order enough vaccine for 24- to 59-month-olds as well as 6- to 23-month-olds, plus our older patients with high-risk medical conditions and all of their household contacts. Wouldn't it be a lot simpler just to count how many children are in our practices and order that number?

If vaccine manufacturers could be assured that we would order a certain number of doses each year, they would gear up and make them. So far, they haven't been willing to do this because it's too much of a gamble—during some seasons, as much as two-thirds of their doses have gone unused. If there were a universal recommendation with consistent year-to-year utilization, it should remove their reticence.

Manufacturers also would be aided a great deal if there were a way to make influenza vaccine without having to grow the virus in thousands of fertilized chicken eggs. In June of this year, a Canadian company called Hepalife Technologies Inc. licensed technology from researchers at Michigan State University in East Lansing for the development of new cell culture-based influenza vaccines, including one for the potential pandemic-causing strain H5N1. If the cell line is able to grow influenza virus reliably—preliminary data indicate that it is—it would greatly facilitate the manufacturing process by enabling influenza vaccine to be grown more efficiently and less expensively. It also would eliminate the egg allergy problem. I don't own stock in the company, but I am excited about this product's potential.

Of course, immunizing all of our patients within a 6-week period during October and November would be a huge challenge. It wouldn't be practical for the primary care office to be the only avenue for distribution. Grocery and drugstore chains have become major influenza vaccine vendors for adults, but generally not for children because of liability concerns. I think the effort will need to utilize public health departments to extend the infrastructure, and perhaps coordinate with schools for the older children.

There has been precedent for this. During the influenza season 2 years ago that killed several children in Colorado and in this year's Midwest mumps outbreak, county health departments moved their mobile units to schools and managed to immunize large numbers of children. Documentation may be a bit of a problem, but this can be worked out. We just need the go-ahead of a universal recommendation to get the ball rolling.

A universal immunization recommendation for routine influenza seasons would also prepare us for a pandemic situation. We currently have incomplete logistical support for potential intervention involving the entire U.S. population. This would be excellent training for our health care system, and would provide templates upon which to build. If we had 2 or 3 years of practice in immunizing everyone prior to a pandemic, we'd all be much more expert when a pandemic arrived.

Obviously, a universal recommendation doesn't mean that everyone will be immunized. But, we would be far more likely to achieve herd immunity than with what we do now. We should see fewer hospitalizations in the very old and the very young, the two groups that utilize the greatest amount of health care resources.

We know that the severe complications of influenza—invasive bacterial infections such as empyemas, bacteremias, and meningococcemia—tend to peak during and just after each influenza season because bacterial pathogens more readily invade the mucosa of influenza-damaged respiratory tracts, which are still healing for weeks after the patient's influenza infection has resolved. In a bad influenza season, emergency departments are bombarded with influenza cases and patients with sequelae during January-April. Reducing that enormous utilization of medical resources should be worth every bit of effort we'd put into getting everyone immunized in the fall.

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.