ID Consult

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.

Do the right thing: Immunize yourself and your office staff!

With the recent licensure of a new acellular pertussis vaccine for adults, now is a good time to review the immunization status of heath care workers in your setting. We should protect ourselves against vaccine-preventable diseases such as pertussis, influenza, varicella, and hepatitis A so that our patients will be protected as well.

Indeed, the federal government has prioritized immunization of health care workers in its pandemic influenza preparedness plan. Without the personnel to care for affected individuals in the event of a human H5N1 outbreak, we would be risking a greater disaster.

Health care workers who treat children have a particular responsibility to protect themselves. As we know, children less than 6 months of age are vulnerable to a wide variety of infections for which they have not yet been fully immunized. Infants born prematurely—more of whom are surviving today—also remain at high risk for infection during the first year of life.

We also are seeing increasing numbers of older children with chronic diseases such as asthma, as well as more of those left immunosuppressed from formerly fatal diseases such as cancer and HIV. We simply cannot allow ourselves to become the agents for transmission to these vulnerable patients.

I want to touch on four adult vaccines in particular:

Pertussis

Earlier this year, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) recommended that health care workers in hospitals or ambulatory care settings and those who have direct patient contact should receive the recently licensed adult formulation of the tetanus-diphtheria-acellular pertussis vaccine (Adacel, Sanofi Pasteur). Priority should be given to providers who have direct contact with infants who are less than 12 months of age.

Because the efficacy of routine childhood pertussis immunization decays after about 10 years, most adults are currently susceptible to pertussis. Although the disease is rarely fatal in adults (as it can be in infants), it does cause prolonged cough lasting for 3 or more weeks in 80%–100% of adults, and posttussive vomiting in 50%. Missed work for illness or medical care occurs in 78% of adults for a mean of 9.8 days, according to data from the CDC.

Transmission of pertussis is most likely to occur during the early phase of disease (catarrhal stage), when cough and coryza are unlikely to be recognized as anything other than a cold. Now that there's a licensed vaccine that will prevent pertussis transmission—not to mention updating our tetanus and diphtheria immunity—it's in everybody's best interest for health care workers to just get vaccinated.

Influenza

Protection against annual influenza also is essential for health care workers who see children. Both the ACIP and the American Academy of Pediatrics now recommend that all children aged 6–59 months receive an annual influenza vaccination. However, children under 6 months of age remain susceptible. Moreover, any child who has not previously received an influenza vaccine needs two doses over a 6-week period, and remains susceptible for several weeks after receiving the second dose.

Health care workers who are younger than 50 years of age and don't have high-risk chronic conditions have the option of choosing the live attenuated virus influenza vaccine (FluMist, MedImmune Inc.) as an alternative to the inactivated injectable vaccine.

For the vast majority of health care workers, there is no need to refrain from working after receipt of the live virus vaccine.

The only exception is those who have direct contact with severely immunosuppressed patients, such as bone marrow recipients.

Varicella

Although the routine childhood vaccine has dramatically reduced its incidence and severity, varicella still persists in the community. When it does occur in adults, it tends to be far more serious than it is in children.

The importance of immunity to varicella is even more critical now that varicella zoster immune globulin—previously given following a known exposure to varicella—is no longer being manufactured in the United States. It's available as an experimental product from Canada, but even if you were able to obtain a supply, it would not likely be in enough time to avert the full-blown clinical picture. You can still take acyclovir prophylactically, but only if you know you've been exposed.

Most pediatricians practicing today have already had chickenpox and are, therefore, immune.

However, that may not be true much longer. Every year my hospital tests incoming medical students for antibodies to varicella, and this past year we found that 10% of these young adults lacked immunity.

Hepatitis A

Last fall, ACIP recommended that all children at least 1 year of age receive the hepatitis A vaccine. Typically, children with hepatitis A infection are either asymptomatic or have nonspecific symptoms such as fever and gastroenteritis. Jaundice is uncommon. If you are treating a child with hepatitis A, you are at high risk for clinically significant illness, including jaundice.

While there is no specific recommendation for hepatitis A vaccination of health care workers, the CDC does state that the vaccine can be given to “any person wishing to obtain immunity.” For those of us whose job is to protect our patients and ourselves, I think it's a good idea.

For more on adult immunization, go to www.cdc.gov/nip/recs/adult-schedule.htm

Do the right thing: Immunize yourself and your office staff!

With the recent licensure of a new acellular pertussis vaccine for adults, now is a good time to review the immunization status of heath care workers in your setting. We should protect ourselves against vaccine-preventable diseases such as pertussis, influenza, varicella, and hepatitis A so that our patients will be protected as well.

Indeed, the federal government has prioritized immunization of health care workers in its pandemic influenza preparedness plan. Without the personnel to care for affected individuals in the event of a human H5N1 outbreak, we would be risking a greater disaster.

Health care workers who treat children have a particular responsibility to protect themselves. As we know, children less than 6 months of age are vulnerable to a wide variety of infections for which they have not yet been fully immunized. Infants born prematurely—more of whom are surviving today—also remain at high risk for infection during the first year of life.

We also are seeing increasing numbers of older children with chronic diseases such as asthma, as well as more of those left immunosuppressed from formerly fatal diseases such as cancer and HIV. We simply cannot allow ourselves to become the agents for transmission to these vulnerable patients.

I want to touch on four adult vaccines in particular:

Pertussis

Earlier this year, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) recommended that health care workers in hospitals or ambulatory care settings and those who have direct patient contact should receive the recently licensed adult formulation of the tetanus-diphtheria-acellular pertussis vaccine (Adacel, Sanofi Pasteur). Priority should be given to providers who have direct contact with infants who are less than 12 months of age.

Because the efficacy of routine childhood pertussis immunization decays after about 10 years, most adults are currently susceptible to pertussis. Although the disease is rarely fatal in adults (as it can be in infants), it does cause prolonged cough lasting for 3 or more weeks in 80%–100% of adults, and posttussive vomiting in 50%. Missed work for illness or medical care occurs in 78% of adults for a mean of 9.8 days, according to data from the CDC.

Transmission of pertussis is most likely to occur during the early phase of disease (catarrhal stage), when cough and coryza are unlikely to be recognized as anything other than a cold. Now that there's a licensed vaccine that will prevent pertussis transmission—not to mention updating our tetanus and diphtheria immunity—it's in everybody's best interest for health care workers to just get vaccinated.

Influenza

Protection against annual influenza also is essential for health care workers who see children. Both the ACIP and the American Academy of Pediatrics now recommend that all children aged 6–59 months receive an annual influenza vaccination. However, children under 6 months of age remain susceptible. Moreover, any child who has not previously received an influenza vaccine needs two doses over a 6-week period, and remains susceptible for several weeks after receiving the second dose.

Health care workers who are younger than 50 years of age and don't have high-risk chronic conditions have the option of choosing the live attenuated virus influenza vaccine (FluMist, MedImmune Inc.) as an alternative to the inactivated injectable vaccine.

For the vast majority of health care workers, there is no need to refrain from working after receipt of the live virus vaccine.

The only exception is those who have direct contact with severely immunosuppressed patients, such as bone marrow recipients.

Varicella

Although the routine childhood vaccine has dramatically reduced its incidence and severity, varicella still persists in the community. When it does occur in adults, it tends to be far more serious than it is in children.

The importance of immunity to varicella is even more critical now that varicella zoster immune globulin—previously given following a known exposure to varicella—is no longer being manufactured in the United States. It's available as an experimental product from Canada, but even if you were able to obtain a supply, it would not likely be in enough time to avert the full-blown clinical picture. You can still take acyclovir prophylactically, but only if you know you've been exposed.

Most pediatricians practicing today have already had chickenpox and are, therefore, immune.

However, that may not be true much longer. Every year my hospital tests incoming medical students for antibodies to varicella, and this past year we found that 10% of these young adults lacked immunity.

Hepatitis A

Last fall, ACIP recommended that all children at least 1 year of age receive the hepatitis A vaccine. Typically, children with hepatitis A infection are either asymptomatic or have nonspecific symptoms such as fever and gastroenteritis. Jaundice is uncommon. If you are treating a child with hepatitis A, you are at high risk for clinically significant illness, including jaundice.

While there is no specific recommendation for hepatitis A vaccination of health care workers, the CDC does state that the vaccine can be given to “any person wishing to obtain immunity.” For those of us whose job is to protect our patients and ourselves, I think it's a good idea.

For more on adult immunization, go to www.cdc.gov/nip/recs/adult-schedule.htm

Do the right thing: Immunize yourself and your office staff!

With the recent licensure of a new acellular pertussis vaccine for adults, now is a good time to review the immunization status of heath care workers in your setting. We should protect ourselves against vaccine-preventable diseases such as pertussis, influenza, varicella, and hepatitis A so that our patients will be protected as well.

Indeed, the federal government has prioritized immunization of health care workers in its pandemic influenza preparedness plan. Without the personnel to care for affected individuals in the event of a human H5N1 outbreak, we would be risking a greater disaster.

Health care workers who treat children have a particular responsibility to protect themselves. As we know, children less than 6 months of age are vulnerable to a wide variety of infections for which they have not yet been fully immunized. Infants born prematurely—more of whom are surviving today—also remain at high risk for infection during the first year of life.

We also are seeing increasing numbers of older children with chronic diseases such as asthma, as well as more of those left immunosuppressed from formerly fatal diseases such as cancer and HIV. We simply cannot allow ourselves to become the agents for transmission to these vulnerable patients.

I want to touch on four adult vaccines in particular:

Pertussis

Earlier this year, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) recommended that health care workers in hospitals or ambulatory care settings and those who have direct patient contact should receive the recently licensed adult formulation of the tetanus-diphtheria-acellular pertussis vaccine (Adacel, Sanofi Pasteur). Priority should be given to providers who have direct contact with infants who are less than 12 months of age.

Because the efficacy of routine childhood pertussis immunization decays after about 10 years, most adults are currently susceptible to pertussis. Although the disease is rarely fatal in adults (as it can be in infants), it does cause prolonged cough lasting for 3 or more weeks in 80%–100% of adults, and posttussive vomiting in 50%. Missed work for illness or medical care occurs in 78% of adults for a mean of 9.8 days, according to data from the CDC.

Transmission of pertussis is most likely to occur during the early phase of disease (catarrhal stage), when cough and coryza are unlikely to be recognized as anything other than a cold. Now that there's a licensed vaccine that will prevent pertussis transmission—not to mention updating our tetanus and diphtheria immunity—it's in everybody's best interest for health care workers to just get vaccinated.

Influenza

Protection against annual influenza also is essential for health care workers who see children. Both the ACIP and the American Academy of Pediatrics now recommend that all children aged 6–59 months receive an annual influenza vaccination. However, children under 6 months of age remain susceptible. Moreover, any child who has not previously received an influenza vaccine needs two doses over a 6-week period, and remains susceptible for several weeks after receiving the second dose.

Health care workers who are younger than 50 years of age and don't have high-risk chronic conditions have the option of choosing the live attenuated virus influenza vaccine (FluMist, MedImmune Inc.) as an alternative to the inactivated injectable vaccine.

For the vast majority of health care workers, there is no need to refrain from working after receipt of the live virus vaccine.

The only exception is those who have direct contact with severely immunosuppressed patients, such as bone marrow recipients.

Varicella

Although the routine childhood vaccine has dramatically reduced its incidence and severity, varicella still persists in the community. When it does occur in adults, it tends to be far more serious than it is in children.

The importance of immunity to varicella is even more critical now that varicella zoster immune globulin—previously given following a known exposure to varicella—is no longer being manufactured in the United States. It's available as an experimental product from Canada, but even if you were able to obtain a supply, it would not likely be in enough time to avert the full-blown clinical picture. You can still take acyclovir prophylactically, but only if you know you've been exposed.

Most pediatricians practicing today have already had chickenpox and are, therefore, immune.

However, that may not be true much longer. Every year my hospital tests incoming medical students for antibodies to varicella, and this past year we found that 10% of these young adults lacked immunity.

Hepatitis A

Last fall, ACIP recommended that all children at least 1 year of age receive the hepatitis A vaccine. Typically, children with hepatitis A infection are either asymptomatic or have nonspecific symptoms such as fever and gastroenteritis. Jaundice is uncommon. If you are treating a child with hepatitis A, you are at high risk for clinically significant illness, including jaundice.

While there is no specific recommendation for hepatitis A vaccination of health care workers, the CDC does state that the vaccine can be given to “any person wishing to obtain immunity.” For those of us whose job is to protect our patients and ourselves, I think it's a good idea.

For more on adult immunization, go to www.cdc.gov/nip/recs/adult-schedule.htm

You may actually see cases of mumps in the coming year. It's time to get reacquainted with what it looks like, what the complications are, and what the control measures are.

As of the first week of May, a mumps outbreak that began in December 2005 with a few reported cases at a university in eastern Iowa had grown to more than 1,500 confirmed, probable, and suspected cases in Iowa, along with several hundred additional cases reported in Illinois, Indiana, Kansas, Michigan, Minnesota, Missouri, Nebraska, and Wisconsin.

Compare that with an average of just 5 mumps cases per year in Iowa since 1996 and 265 cases annually for the entire country since 2001, and it's obvious we've got a problem that could stay with us for a while.

Mumps is an acute viral illness, first described by Hippocrates in the 5th century. Approximately 40%–50% of patients present with unilateral or bilateral parotitis and fever, while another 20%–30% are asymptomatic.

Before the measles-mumps-rubella (MMR) vaccine entered the U.S. market in 1967, a physician who saw a child with parotitis would automatically think of mumps.

Today, we're more likely to suspect that submaxillary/sublingual swelling is related to lymphadenitis, and a sore throat with fever to strep throat.

Some patients complain of pain in the corner of the jaw and/or an earache, which can be confused with otitis.

For the time being at least, we need to resurrect our clinical suspicion for mumps in order to avoid giving unnecessary antibiotics.

Once you suspect mumps, you can culture the nasopharynx, throat, or urine or do a serology looking for IgM antibodies. Check with your laboratory to make sure that the viral culture they perform will identify mumps because standard shell vial culture could miss it.

Although usually self-limited, mumps can cause complications such as meningitis, encephalitis, inflammation of the testes or ovaries, myocarditis, arthritis, and deafness.

Any of these can occur in the absence of parotitis.

Symptomatic meningitis occurs in up to 15% of cases. In fact, mumps was the most common cause of viral meningitis in the prevaccine era.

Interestingly enough—and this is a clinical pearl—mumps meningitis is associated with a lymphocytic pleocytosis (inflammatory cells in the cerebrospinal fluid) that is typical of viral meningitis, but with a low glucose level.

Most children with typical summertime enterovirus meningitis have normal or low-normal CSF glucose levels, typically around 40%–50% of peripheral glucose.

In contrast, those levels might be somewhere between 10% and 25% with mumps meningitis. A low CSF glucose level might make you think of bacterial meningitis, so again, it's important to rule that out in order to treat appropriately.

In Iowa thus far, the median patient age at onset is 22 years. About one-fifth of all the patients are currently attending college.

Of 1,201 patients for whom vaccine history was investigated, 51% had documentation of receiving two MMR doses, 12% one dose, and 6% no doses. (Information was not available for the other 31%.)

It's not clear why immunized individuals would be contracting mumps. Although waning immunity may be a factor, in highly vaccinated populations a majority of individuals affected by a typical measles outbreak may represent vaccine nonresponders. This observation in the past led to the recommendation for two doses of MMR to be given.

Although a second dose can be given 30 days after the first, we currently give the second dose when a child starts school, potentially leaving the 1- to 5-year-old population vulnerable. Time will tell whether this age group emerges as a high-risk group.

In Iowa, the most common symptoms were parotitis in 60%, sore throat in 50%, submaxillary/maxillary gland swelling in 41%, and fever in 31%. Another 27% had headache, 9% cough, and 6% orchitis; 0.2% (3 patients) had encephalitis. Average duration of symptoms was 5 days.

In the prevaccine era, as many as 50% of postpubertal males with mumps developed testicular inflammation and 5% of postpubertal females developed ovarian inflammation, which may be confused with appendicitis. It's not clear why more cases of those complications haven't been reported in Iowa, although it's possible the information simply hasn't been sought.

Since mumps is self-limited, there's not much we can do as clinicians other than to make sure that our patients—as well as ourselves and our staffs—have received two doses of the MMR vaccine.

One dose of MMR is said to be 97% effective against mumps, but immunogenicity studies vary and some suggest that a single dose may protect 85%. A second dose may bring the protection rate to 90% or more. Vaccine immunity probably doesn't last more than 25 years. Mumps is similar in transmissibility to influenza and rubella, but less so than either measles or varicella.

Individuals born before 1957 are believed to be immune because they were exposed, but we're not sure about the status of those born between 1957 and the time the vaccine came into widespread use, in the mid-1970s.

The CDC has advised that the vaccine be offered to these individuals living in affected areas.

Suspected cases should be reported immediately to local public health officials, and those individuals should be isolated for 9 days after symptom onset. It is possible the CDC will make further recommendations after this column goes to press.

MMR vaccine has a good safety profile, but adult women may develop a transient arthritis/arthralgia following vaccination. Studies show that 12%–26% of adult female vaccine recipients, compared with 0%–3% of children, will have arthralgia; the rate in adolescent girls falls somewhere in between.

The majority of cases are mild and don't interfere with normal activity.

More information and updates are available from the CDC at www.cdc.gov/nip/diseases/mumps/mumps-outbreak.htm

CDC/NIP/Barbara Rice

You may actually see cases of mumps in the coming year. It's time to get reacquainted with what it looks like, what the complications are, and what the control measures are.

As of the first week of May, a mumps outbreak that began in December 2005 with a few reported cases at a university in eastern Iowa had grown to more than 1,500 confirmed, probable, and suspected cases in Iowa, along with several hundred additional cases reported in Illinois, Indiana, Kansas, Michigan, Minnesota, Missouri, Nebraska, and Wisconsin.

Compare that with an average of just 5 mumps cases per year in Iowa since 1996 and 265 cases annually for the entire country since 2001, and it's obvious we've got a problem that could stay with us for a while.

Mumps is an acute viral illness, first described by Hippocrates in the 5th century. Approximately 40%–50% of patients present with unilateral or bilateral parotitis and fever, while another 20%–30% are asymptomatic.

Before the measles-mumps-rubella (MMR) vaccine entered the U.S. market in 1967, a physician who saw a child with parotitis would automatically think of mumps.

Today, we're more likely to suspect that submaxillary/sublingual swelling is related to lymphadenitis, and a sore throat with fever to strep throat.

Some patients complain of pain in the corner of the jaw and/or an earache, which can be confused with otitis.

For the time being at least, we need to resurrect our clinical suspicion for mumps in order to avoid giving unnecessary antibiotics.

Once you suspect mumps, you can culture the nasopharynx, throat, or urine or do a serology looking for IgM antibodies. Check with your laboratory to make sure that the viral culture they perform will identify mumps because standard shell vial culture could miss it.

Although usually self-limited, mumps can cause complications such as meningitis, encephalitis, inflammation of the testes or ovaries, myocarditis, arthritis, and deafness.

Any of these can occur in the absence of parotitis.

Symptomatic meningitis occurs in up to 15% of cases. In fact, mumps was the most common cause of viral meningitis in the prevaccine era.

Interestingly enough—and this is a clinical pearl—mumps meningitis is associated with a lymphocytic pleocytosis (inflammatory cells in the cerebrospinal fluid) that is typical of viral meningitis, but with a low glucose level.

Most children with typical summertime enterovirus meningitis have normal or low-normal CSF glucose levels, typically around 40%–50% of peripheral glucose.

In contrast, those levels might be somewhere between 10% and 25% with mumps meningitis. A low CSF glucose level might make you think of bacterial meningitis, so again, it's important to rule that out in order to treat appropriately.

In Iowa thus far, the median patient age at onset is 22 years. About one-fifth of all the patients are currently attending college.

Of 1,201 patients for whom vaccine history was investigated, 51% had documentation of receiving two MMR doses, 12% one dose, and 6% no doses. (Information was not available for the other 31%.)

It's not clear why immunized individuals would be contracting mumps. Although waning immunity may be a factor, in highly vaccinated populations a majority of individuals affected by a typical measles outbreak may represent vaccine nonresponders. This observation in the past led to the recommendation for two doses of MMR to be given.

Although a second dose can be given 30 days after the first, we currently give the second dose when a child starts school, potentially leaving the 1- to 5-year-old population vulnerable. Time will tell whether this age group emerges as a high-risk group.

In Iowa, the most common symptoms were parotitis in 60%, sore throat in 50%, submaxillary/maxillary gland swelling in 41%, and fever in 31%. Another 27% had headache, 9% cough, and 6% orchitis; 0.2% (3 patients) had encephalitis. Average duration of symptoms was 5 days.

In the prevaccine era, as many as 50% of postpubertal males with mumps developed testicular inflammation and 5% of postpubertal females developed ovarian inflammation, which may be confused with appendicitis. It's not clear why more cases of those complications haven't been reported in Iowa, although it's possible the information simply hasn't been sought.

Since mumps is self-limited, there's not much we can do as clinicians other than to make sure that our patients—as well as ourselves and our staffs—have received two doses of the MMR vaccine.

One dose of MMR is said to be 97% effective against mumps, but immunogenicity studies vary and some suggest that a single dose may protect 85%. A second dose may bring the protection rate to 90% or more. Vaccine immunity probably doesn't last more than 25 years. Mumps is similar in transmissibility to influenza and rubella, but less so than either measles or varicella.

Individuals born before 1957 are believed to be immune because they were exposed, but we're not sure about the status of those born between 1957 and the time the vaccine came into widespread use, in the mid-1970s.

The CDC has advised that the vaccine be offered to these individuals living in affected areas.

Suspected cases should be reported immediately to local public health officials, and those individuals should be isolated for 9 days after symptom onset. It is possible the CDC will make further recommendations after this column goes to press.

MMR vaccine has a good safety profile, but adult women may develop a transient arthritis/arthralgia following vaccination. Studies show that 12%–26% of adult female vaccine recipients, compared with 0%–3% of children, will have arthralgia; the rate in adolescent girls falls somewhere in between.

The majority of cases are mild and don't interfere with normal activity.

More information and updates are available from the CDC at www.cdc.gov/nip/diseases/mumps/mumps-outbreak.htm

CDC/NIP/Barbara Rice

You may actually see cases of mumps in the coming year. It's time to get reacquainted with what it looks like, what the complications are, and what the control measures are.

As of the first week of May, a mumps outbreak that began in December 2005 with a few reported cases at a university in eastern Iowa had grown to more than 1,500 confirmed, probable, and suspected cases in Iowa, along with several hundred additional cases reported in Illinois, Indiana, Kansas, Michigan, Minnesota, Missouri, Nebraska, and Wisconsin.

Compare that with an average of just 5 mumps cases per year in Iowa since 1996 and 265 cases annually for the entire country since 2001, and it's obvious we've got a problem that could stay with us for a while.

Mumps is an acute viral illness, first described by Hippocrates in the 5th century. Approximately 40%–50% of patients present with unilateral or bilateral parotitis and fever, while another 20%–30% are asymptomatic.

Before the measles-mumps-rubella (MMR) vaccine entered the U.S. market in 1967, a physician who saw a child with parotitis would automatically think of mumps.

Today, we're more likely to suspect that submaxillary/sublingual swelling is related to lymphadenitis, and a sore throat with fever to strep throat.

Some patients complain of pain in the corner of the jaw and/or an earache, which can be confused with otitis.

For the time being at least, we need to resurrect our clinical suspicion for mumps in order to avoid giving unnecessary antibiotics.

Once you suspect mumps, you can culture the nasopharynx, throat, or urine or do a serology looking for IgM antibodies. Check with your laboratory to make sure that the viral culture they perform will identify mumps because standard shell vial culture could miss it.

Although usually self-limited, mumps can cause complications such as meningitis, encephalitis, inflammation of the testes or ovaries, myocarditis, arthritis, and deafness.

Any of these can occur in the absence of parotitis.

Symptomatic meningitis occurs in up to 15% of cases. In fact, mumps was the most common cause of viral meningitis in the prevaccine era.

Interestingly enough—and this is a clinical pearl—mumps meningitis is associated with a lymphocytic pleocytosis (inflammatory cells in the cerebrospinal fluid) that is typical of viral meningitis, but with a low glucose level.

Most children with typical summertime enterovirus meningitis have normal or low-normal CSF glucose levels, typically around 40%–50% of peripheral glucose.

In contrast, those levels might be somewhere between 10% and 25% with mumps meningitis. A low CSF glucose level might make you think of bacterial meningitis, so again, it's important to rule that out in order to treat appropriately.

In Iowa thus far, the median patient age at onset is 22 years. About one-fifth of all the patients are currently attending college.

Of 1,201 patients for whom vaccine history was investigated, 51% had documentation of receiving two MMR doses, 12% one dose, and 6% no doses. (Information was not available for the other 31%.)

It's not clear why immunized individuals would be contracting mumps. Although waning immunity may be a factor, in highly vaccinated populations a majority of individuals affected by a typical measles outbreak may represent vaccine nonresponders. This observation in the past led to the recommendation for two doses of MMR to be given.

Although a second dose can be given 30 days after the first, we currently give the second dose when a child starts school, potentially leaving the 1- to 5-year-old population vulnerable. Time will tell whether this age group emerges as a high-risk group.

In Iowa, the most common symptoms were parotitis in 60%, sore throat in 50%, submaxillary/maxillary gland swelling in 41%, and fever in 31%. Another 27% had headache, 9% cough, and 6% orchitis; 0.2% (3 patients) had encephalitis. Average duration of symptoms was 5 days.

In the prevaccine era, as many as 50% of postpubertal males with mumps developed testicular inflammation and 5% of postpubertal females developed ovarian inflammation, which may be confused with appendicitis. It's not clear why more cases of those complications haven't been reported in Iowa, although it's possible the information simply hasn't been sought.

Since mumps is self-limited, there's not much we can do as clinicians other than to make sure that our patients—as well as ourselves and our staffs—have received two doses of the MMR vaccine.

One dose of MMR is said to be 97% effective against mumps, but immunogenicity studies vary and some suggest that a single dose may protect 85%. A second dose may bring the protection rate to 90% or more. Vaccine immunity probably doesn't last more than 25 years. Mumps is similar in transmissibility to influenza and rubella, but less so than either measles or varicella.

Individuals born before 1957 are believed to be immune because they were exposed, but we're not sure about the status of those born between 1957 and the time the vaccine came into widespread use, in the mid-1970s.

The CDC has advised that the vaccine be offered to these individuals living in affected areas.

Suspected cases should be reported immediately to local public health officials, and those individuals should be isolated for 9 days after symptom onset. It is possible the CDC will make further recommendations after this column goes to press.

MMR vaccine has a good safety profile, but adult women may develop a transient arthritis/arthralgia following vaccination. Studies show that 12%–26% of adult female vaccine recipients, compared with 0%–3% of children, will have arthralgia; the rate in adolescent girls falls somewhere in between.

The majority of cases are mild and don't interfere with normal activity.

More information and updates are available from the CDC at www.cdc.gov/nip/diseases/mumps/mumps-outbreak.htm

CDC/NIP/Barbara Rice

Novel approaches are necessary to address the emerging problem of the child who fails conventional therapy for acute otorrhea following tympanostomy tube insertion.

We've seen an increase in the number of children with otorrhea through a tympanostomy tube lasting more than 10 days in the past few years, primarily due to the emergence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). Another contributing factor is the increased use of quinolone ear drops, which are thought to promote the occurrence of fungal infections.

Approximately 30% of children who undergo tube placement develop acute otorrhea. Haemophilus influenzae and Streptococcus pneumoniae are responsible for 40%–45% of these cases, particularly in children under 2 years of age and in those who develop symptoms during the winter months. It's hypothesized that these children have ongoing eustachian tube dysfunction that permits nasopharyngeal pathogens to ascend to the middle ear, resulting in acute otorrhea through the tympanostomy tube.

The other 55%–60% of cases are caused by pathogens from the external canal, most commonly Staphylococcus aureus and Pseudomonas aeruginosa. These patients tend to be older, to develop symptoms during the warmer months, and to have a malodorous discharge (in contrast to the nasopharyngeal pathogens, which are odorless).

There appears to be a contribution from water in the ear, which triggers an inflammatory response.

In the past, standard treatment for ear drainage in children was oral antibiotics aimed at H. influenzae and pneumococcus, such as amoxicillin, amoxicillin-clavulanate, or a cephalosporin.

More recently, there has been a shift to greater use of topical fluoroquinolones—particularly ofloxacin and ciprofloxacin—with the increased recognition that the staphylococcus and pseudomonas pathogens also contribute to the microbiology of this disease.

Even in young children, otic preparations are often considered superior to oral antibiotics because they are active against all four of the main pathogens, safely achieve high concentrations in the middle ear, and are less likely to contribute to the emergence of resistance because they are not given systemically.

And of course, they eliminate the bad taste problem.

Now, however, we're starting to see clinical failures with both oral and topical antibiotics, primarily due to CA-MRSA. Among otherwise healthy children, the risk for the development of otorrhea due to MRSA appears to increase with the number of acute otitis media episodes prior to tube placement, as well as with the number of courses and duration of treatment prior to tube placement (Arch. Otolaryngol. Head Neck Surg. 2005;131:868–73).

For MRSA-associated skin and soft tissue infections, drugs such as trimethoprim-sulfamethoxazole, linezolid, or even intravenous vancomycin are usually effective. However, these agents are often ineffective or associated with relapse as soon as therapy is discontinued when a foreign body such as a tympanostomy tube is involved, because of the lack of blood supply and the formation of biofilm.

What does appear to work, at least in small case reports, is the use of either topical vancomycin or combination topical plus oral treatment.

In one report, a group in Thailand combined a 500-mg vial of vancomycin powder with 20 mL of sterile distilled water to create a 25-mg/mL vancomycin solution. Two 0.8-mg drops were placed into the ear three times daily for 10 days in 35 patients with MRSA otorrhea. A control group of 20 patients was treated with the same regimen of gentamycin 0.3% drops (J. Laryngol. Otol. 2004;118:645–7).

Clinical cure was achieved in 30 (86%) of the vancomycin recipients, compared with 2 (10%) of those treated with gentamycin. Failures occurred in just 2 (6%) patients given vancomycin versus 16 (80%) given gentamycin.

Of course, this is a small study, but it is based on sound biologic principles and there appear to be no adverse effects. We certainly need more long-term data, but I think topical vancomycin may represent a good alternative to removal of the tubes in some patients. If your pharmacy is able to make this formulation, I think it offers an option to tube removal if CA-MRSA is cultured and the child fails initial oral or topical therapy.

In another small study, successful eradication of MRSA was achieved using a combination of oral trimethoprim-sulfamethoxazole plus topical gentamycin sulfate or polymyxin B sulfate-neomycin sulfate-hydrocortisone (Cortisporin) in six children (five with prior tympanostomy tube placement and one with perforation of the tympanic membrane) who had failed either oral antibiotics or fluoroquinolone ear drops alone (Arch. Otolaryngol. Head Neck Surg. 2005;131:782–4). However, I'd be less apt to use this approach because of concerns about potential ototoxicity of the gentamycin/neomycin on the vestibular system.

In addition to CA-MRSA, otorrhea due to fungal organisms is now being seen increasingly in children who have been treated previously for bacterial infections following tube placement.

In a retrospective review conducted at a pediatric otolaryngology clinic, out of a total 1,242 patients who underwent ear culture between 1996 and 2003, 166 patients (119 with otitis media, 41 with otitis externa, and 6 with both) aged 16 days to 18 years (mean 4 years) were found to have fungal organisms. The proportion of fungus-positive cultures increased dramatically in the years following the availability of the fluoroquinolone drops, from just 4.2% of 356 cultures obtained during 1996–1998 to 18.2% of the 457 cultures done during 1999–2001 (Int. J. Pediatr. Otorhinolaryngol. 2005;69:1503–8).

The most common of the fungi were Candida albicans (43% of the 166), Candida parapsilosis (23.5%), and Aspergillus fumigatus (21%). Although reporting of medications was inconsistent, the authors estimated that the patients had previously received an average of 1.7 oral antibiotics and 1.1 ototopical agents before the culture was taken. Infection resolved in all the patients with treatment, which included clotrimazole topical and tolnaftate topical in 27 patients each, fluconazole in 25, acetic acid alone in 14, and topical plus fluconazole in 10. The thinking is that the use of broad-spectrum quinolone drops may be promoting the emergence of fungus by eliminating the colonizers in the external ear canal, thereby allowing the fungus to grow. This doesn't imply we should stop using quinolone-containing otic solutions, but I do think we need to be aware of the possibility and culture the middle ear in a child who still has otorrhea after 5–7 days of treatment.

Of course, we all know that prevention is the best medicine.

A group from Turkey recently published a comparison of 1 mL intraoperative isotonic saline irrigation, postoperative antibiotic treatment (sulbactam/ampicillin 25 mg/kg for 5 days), postoperative ofloxacin drops (twice a day for 5 days), or placebo in 280 children (mean age 5.9 years) undergoing bilateral ventilation tube insertion because of serous otitis media during 2000–2004 (Am. J. Otolaryngol. 2005;26:123–7).

At 2 weeks post surgery, purulent otorrhea was observed in 15.7% of the saline group, 14.2% of those who received prophylactic oral antibiotics, and 8.6% of the topical antibiotic group, all significantly lower than the 30% rate among the controls. It appears that saline irrigation of the middle ear prior to tube placement offers a low-cost intervention for reducing early post-tympanostomy tube otorrhea.

Novel approaches are necessary to address the emerging problem of the child who fails conventional therapy for acute otorrhea following tympanostomy tube insertion.

We've seen an increase in the number of children with otorrhea through a tympanostomy tube lasting more than 10 days in the past few years, primarily due to the emergence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). Another contributing factor is the increased use of quinolone ear drops, which are thought to promote the occurrence of fungal infections.

Approximately 30% of children who undergo tube placement develop acute otorrhea. Haemophilus influenzae and Streptococcus pneumoniae are responsible for 40%–45% of these cases, particularly in children under 2 years of age and in those who develop symptoms during the winter months. It's hypothesized that these children have ongoing eustachian tube dysfunction that permits nasopharyngeal pathogens to ascend to the middle ear, resulting in acute otorrhea through the tympanostomy tube.

The other 55%–60% of cases are caused by pathogens from the external canal, most commonly Staphylococcus aureus and Pseudomonas aeruginosa. These patients tend to be older, to develop symptoms during the warmer months, and to have a malodorous discharge (in contrast to the nasopharyngeal pathogens, which are odorless).

There appears to be a contribution from water in the ear, which triggers an inflammatory response.

In the past, standard treatment for ear drainage in children was oral antibiotics aimed at H. influenzae and pneumococcus, such as amoxicillin, amoxicillin-clavulanate, or a cephalosporin.

More recently, there has been a shift to greater use of topical fluoroquinolones—particularly ofloxacin and ciprofloxacin—with the increased recognition that the staphylococcus and pseudomonas pathogens also contribute to the microbiology of this disease.

Even in young children, otic preparations are often considered superior to oral antibiotics because they are active against all four of the main pathogens, safely achieve high concentrations in the middle ear, and are less likely to contribute to the emergence of resistance because they are not given systemically.

And of course, they eliminate the bad taste problem.

Now, however, we're starting to see clinical failures with both oral and topical antibiotics, primarily due to CA-MRSA. Among otherwise healthy children, the risk for the development of otorrhea due to MRSA appears to increase with the number of acute otitis media episodes prior to tube placement, as well as with the number of courses and duration of treatment prior to tube placement (Arch. Otolaryngol. Head Neck Surg. 2005;131:868–73).

For MRSA-associated skin and soft tissue infections, drugs such as trimethoprim-sulfamethoxazole, linezolid, or even intravenous vancomycin are usually effective. However, these agents are often ineffective or associated with relapse as soon as therapy is discontinued when a foreign body such as a tympanostomy tube is involved, because of the lack of blood supply and the formation of biofilm.

What does appear to work, at least in small case reports, is the use of either topical vancomycin or combination topical plus oral treatment.

In one report, a group in Thailand combined a 500-mg vial of vancomycin powder with 20 mL of sterile distilled water to create a 25-mg/mL vancomycin solution. Two 0.8-mg drops were placed into the ear three times daily for 10 days in 35 patients with MRSA otorrhea. A control group of 20 patients was treated with the same regimen of gentamycin 0.3% drops (J. Laryngol. Otol. 2004;118:645–7).

Clinical cure was achieved in 30 (86%) of the vancomycin recipients, compared with 2 (10%) of those treated with gentamycin. Failures occurred in just 2 (6%) patients given vancomycin versus 16 (80%) given gentamycin.

Of course, this is a small study, but it is based on sound biologic principles and there appear to be no adverse effects. We certainly need more long-term data, but I think topical vancomycin may represent a good alternative to removal of the tubes in some patients. If your pharmacy is able to make this formulation, I think it offers an option to tube removal if CA-MRSA is cultured and the child fails initial oral or topical therapy.

In another small study, successful eradication of MRSA was achieved using a combination of oral trimethoprim-sulfamethoxazole plus topical gentamycin sulfate or polymyxin B sulfate-neomycin sulfate-hydrocortisone (Cortisporin) in six children (five with prior tympanostomy tube placement and one with perforation of the tympanic membrane) who had failed either oral antibiotics or fluoroquinolone ear drops alone (Arch. Otolaryngol. Head Neck Surg. 2005;131:782–4). However, I'd be less apt to use this approach because of concerns about potential ototoxicity of the gentamycin/neomycin on the vestibular system.

In addition to CA-MRSA, otorrhea due to fungal organisms is now being seen increasingly in children who have been treated previously for bacterial infections following tube placement.

In a retrospective review conducted at a pediatric otolaryngology clinic, out of a total 1,242 patients who underwent ear culture between 1996 and 2003, 166 patients (119 with otitis media, 41 with otitis externa, and 6 with both) aged 16 days to 18 years (mean 4 years) were found to have fungal organisms. The proportion of fungus-positive cultures increased dramatically in the years following the availability of the fluoroquinolone drops, from just 4.2% of 356 cultures obtained during 1996–1998 to 18.2% of the 457 cultures done during 1999–2001 (Int. J. Pediatr. Otorhinolaryngol. 2005;69:1503–8).

The most common of the fungi were Candida albicans (43% of the 166), Candida parapsilosis (23.5%), and Aspergillus fumigatus (21%). Although reporting of medications was inconsistent, the authors estimated that the patients had previously received an average of 1.7 oral antibiotics and 1.1 ototopical agents before the culture was taken. Infection resolved in all the patients with treatment, which included clotrimazole topical and tolnaftate topical in 27 patients each, fluconazole in 25, acetic acid alone in 14, and topical plus fluconazole in 10. The thinking is that the use of broad-spectrum quinolone drops may be promoting the emergence of fungus by eliminating the colonizers in the external ear canal, thereby allowing the fungus to grow. This doesn't imply we should stop using quinolone-containing otic solutions, but I do think we need to be aware of the possibility and culture the middle ear in a child who still has otorrhea after 5–7 days of treatment.

Of course, we all know that prevention is the best medicine.

A group from Turkey recently published a comparison of 1 mL intraoperative isotonic saline irrigation, postoperative antibiotic treatment (sulbactam/ampicillin 25 mg/kg for 5 days), postoperative ofloxacin drops (twice a day for 5 days), or placebo in 280 children (mean age 5.9 years) undergoing bilateral ventilation tube insertion because of serous otitis media during 2000–2004 (Am. J. Otolaryngol. 2005;26:123–7).

At 2 weeks post surgery, purulent otorrhea was observed in 15.7% of the saline group, 14.2% of those who received prophylactic oral antibiotics, and 8.6% of the topical antibiotic group, all significantly lower than the 30% rate among the controls. It appears that saline irrigation of the middle ear prior to tube placement offers a low-cost intervention for reducing early post-tympanostomy tube otorrhea.

Novel approaches are necessary to address the emerging problem of the child who fails conventional therapy for acute otorrhea following tympanostomy tube insertion.

We've seen an increase in the number of children with otorrhea through a tympanostomy tube lasting more than 10 days in the past few years, primarily due to the emergence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). Another contributing factor is the increased use of quinolone ear drops, which are thought to promote the occurrence of fungal infections.

Approximately 30% of children who undergo tube placement develop acute otorrhea. Haemophilus influenzae and Streptococcus pneumoniae are responsible for 40%–45% of these cases, particularly in children under 2 years of age and in those who develop symptoms during the winter months. It's hypothesized that these children have ongoing eustachian tube dysfunction that permits nasopharyngeal pathogens to ascend to the middle ear, resulting in acute otorrhea through the tympanostomy tube.

The other 55%–60% of cases are caused by pathogens from the external canal, most commonly Staphylococcus aureus and Pseudomonas aeruginosa. These patients tend to be older, to develop symptoms during the warmer months, and to have a malodorous discharge (in contrast to the nasopharyngeal pathogens, which are odorless).

There appears to be a contribution from water in the ear, which triggers an inflammatory response.

In the past, standard treatment for ear drainage in children was oral antibiotics aimed at H. influenzae and pneumococcus, such as amoxicillin, amoxicillin-clavulanate, or a cephalosporin.

More recently, there has been a shift to greater use of topical fluoroquinolones—particularly ofloxacin and ciprofloxacin—with the increased recognition that the staphylococcus and pseudomonas pathogens also contribute to the microbiology of this disease.

Even in young children, otic preparations are often considered superior to oral antibiotics because they are active against all four of the main pathogens, safely achieve high concentrations in the middle ear, and are less likely to contribute to the emergence of resistance because they are not given systemically.

And of course, they eliminate the bad taste problem.

Now, however, we're starting to see clinical failures with both oral and topical antibiotics, primarily due to CA-MRSA. Among otherwise healthy children, the risk for the development of otorrhea due to MRSA appears to increase with the number of acute otitis media episodes prior to tube placement, as well as with the number of courses and duration of treatment prior to tube placement (Arch. Otolaryngol. Head Neck Surg. 2005;131:868–73).

For MRSA-associated skin and soft tissue infections, drugs such as trimethoprim-sulfamethoxazole, linezolid, or even intravenous vancomycin are usually effective. However, these agents are often ineffective or associated with relapse as soon as therapy is discontinued when a foreign body such as a tympanostomy tube is involved, because of the lack of blood supply and the formation of biofilm.

What does appear to work, at least in small case reports, is the use of either topical vancomycin or combination topical plus oral treatment.

In one report, a group in Thailand combined a 500-mg vial of vancomycin powder with 20 mL of sterile distilled water to create a 25-mg/mL vancomycin solution. Two 0.8-mg drops were placed into the ear three times daily for 10 days in 35 patients with MRSA otorrhea. A control group of 20 patients was treated with the same regimen of gentamycin 0.3% drops (J. Laryngol. Otol. 2004;118:645–7).

Clinical cure was achieved in 30 (86%) of the vancomycin recipients, compared with 2 (10%) of those treated with gentamycin. Failures occurred in just 2 (6%) patients given vancomycin versus 16 (80%) given gentamycin.

Of course, this is a small study, but it is based on sound biologic principles and there appear to be no adverse effects. We certainly need more long-term data, but I think topical vancomycin may represent a good alternative to removal of the tubes in some patients. If your pharmacy is able to make this formulation, I think it offers an option to tube removal if CA-MRSA is cultured and the child fails initial oral or topical therapy.

In another small study, successful eradication of MRSA was achieved using a combination of oral trimethoprim-sulfamethoxazole plus topical gentamycin sulfate or polymyxin B sulfate-neomycin sulfate-hydrocortisone (Cortisporin) in six children (five with prior tympanostomy tube placement and one with perforation of the tympanic membrane) who had failed either oral antibiotics or fluoroquinolone ear drops alone (Arch. Otolaryngol. Head Neck Surg. 2005;131:782–4). However, I'd be less apt to use this approach because of concerns about potential ototoxicity of the gentamycin/neomycin on the vestibular system.

In addition to CA-MRSA, otorrhea due to fungal organisms is now being seen increasingly in children who have been treated previously for bacterial infections following tube placement.

In a retrospective review conducted at a pediatric otolaryngology clinic, out of a total 1,242 patients who underwent ear culture between 1996 and 2003, 166 patients (119 with otitis media, 41 with otitis externa, and 6 with both) aged 16 days to 18 years (mean 4 years) were found to have fungal organisms. The proportion of fungus-positive cultures increased dramatically in the years following the availability of the fluoroquinolone drops, from just 4.2% of 356 cultures obtained during 1996–1998 to 18.2% of the 457 cultures done during 1999–2001 (Int. J. Pediatr. Otorhinolaryngol. 2005;69:1503–8).

The most common of the fungi were Candida albicans (43% of the 166), Candida parapsilosis (23.5%), and Aspergillus fumigatus (21%). Although reporting of medications was inconsistent, the authors estimated that the patients had previously received an average of 1.7 oral antibiotics and 1.1 ototopical agents before the culture was taken. Infection resolved in all the patients with treatment, which included clotrimazole topical and tolnaftate topical in 27 patients each, fluconazole in 25, acetic acid alone in 14, and topical plus fluconazole in 10. The thinking is that the use of broad-spectrum quinolone drops may be promoting the emergence of fungus by eliminating the colonizers in the external ear canal, thereby allowing the fungus to grow. This doesn't imply we should stop using quinolone-containing otic solutions, but I do think we need to be aware of the possibility and culture the middle ear in a child who still has otorrhea after 5–7 days of treatment.

Of course, we all know that prevention is the best medicine.

A group from Turkey recently published a comparison of 1 mL intraoperative isotonic saline irrigation, postoperative antibiotic treatment (sulbactam/ampicillin 25 mg/kg for 5 days), postoperative ofloxacin drops (twice a day for 5 days), or placebo in 280 children (mean age 5.9 years) undergoing bilateral ventilation tube insertion because of serous otitis media during 2000–2004 (Am. J. Otolaryngol. 2005;26:123–7).

At 2 weeks post surgery, purulent otorrhea was observed in 15.7% of the saline group, 14.2% of those who received prophylactic oral antibiotics, and 8.6% of the topical antibiotic group, all significantly lower than the 30% rate among the controls. It appears that saline irrigation of the middle ear prior to tube placement offers a low-cost intervention for reducing early post-tympanostomy tube otorrhea.