ID Consult

[email protected].

The emergence of pneumococcal “replacement” serotype 19A should not lead us to view the seven-valent pneumococcal conjugate vaccine in anything other than an overwhelmingly positive light.

Since the introduction of PCV7 (Prevnar) in the United States in 2000, there has been concern that Streptococcus pneumoniae serotypes other than the seven included in the vaccine (4, 6B, 9V, 14, 18C, 19F, and 23F) could become more prevalent. Now, several recent reports—including one from our group at Boston University—have documented both the relative and absolute increase in the nonvaccine serotype 19A in particular, along with an associated increase in antimicrobial resistance among these isolates.

This emergence suggests that we may need to shift our treatment approach to both invasive pneumococcal disease and noninvasive respiratory tract disease. It also underscores the need for continued surveillance. However, it should not lessen our enthusiasm for immunizing children with PCV7, nor should it lead us to relinquish our embrace of a vaccine that continues to provide enormous benefit for both child and adult health.

Indeed, the most recent data from the Centers for Disease Control and Prevention show that the overall rate of invasive pneumococcal disease (IPD) in the United States dropped by 43%, from 24/100,000 in 1998–1999 to 13/100,000 in 2004 to 14/100,000 in 2005. Between 1998–1999 and 2005, PCV7 prevented approximately 34,900 cases of IPD caused by vaccine serotypes and 24,000 cases overall. The declines in IPD were significant in all age groups, ranging from 17% among 50- to 64-year-olds to 77% among children younger than 5 years of age, Tamara Pilishvili of the CDC reported in October of this year at the annual meeting of the Infectious Diseases Society of America (IDSA).

These data are impressive. Nonetheless, we do need to be attentive to “replacement disease” in general and serotype 19A specifically, particularly when it comes to pneumococcal disease in the most vulnerable patients: those with developing immune systems (infants), those with underlying immune system abnormalities, and those with chronic conditions that put them at increased risk for complicated pneumococcal infections.

Here in Massachusetts, surveillance identified 467 cases of IPD in residents younger than 18 years of age. Annual incidence rates were stable between 2002 and 2006, ranging from 15.9 to 18.6 per 100,000 children younger than 5 years of age. Compared with the pre-PCV7 era (1990–1991), when the annual IPD rate was about 56.9/100,000 in that age group, these numbers represent a major decline of about 70% (MMWR 2007;56:1077–80).

Of 353 isolates available for serotyping during 2001–2006, 27% (97) were serotype 19A. Both the number and proportion of cases caused by that serotype increased from 10% (6) during 2001–2002 to 41% (33) during 2005–2006, while there were no significant changes in the proportions of IPD caused by other PCV7 or PCV7-related serotypes or by non-PCV7 serotypes. Since 2005–2006, 19A has become the most common serotype isolated. The majority of these isolates were nonsusceptible to penicillin, and during 2001–2006 there were significant increases in the proportion that were nonsusceptible to amoxicillin, ceftriaxone, or three or more classes of antimicrobials (multidrug resistant). It was of concern that 14 of 94 (15%) 19A isolates were highly resistant to ceftriaxone. We could not identify any clinical or demographic factor that characterized individuals who developed highly ceftriaxone-resistant 19A IPD.

Similar data from the U.S. Pediatric Multicenter Pneumococcal Surveillance Group were reported at IDSA by Dr. Sheldon L. Kaplan of Baylor College of Medicine, Houston. In eight U.S. children's hospitals, 19A has been the most common serotype causing invasive disease each year since 2003, accounting for 46% of all cases in 2006. Since 2000, penicillin nonsusceptibility and resistance increased—from 38% and 0%, respectively, in 2000, to 75% and 34% in 2006. No 19A isolates were ceftriaxone nonsusceptible or resistant in 2000; in 2006, those numbers had risen to 19% and 3%, respectively.

And the 19A story extends beyond invasive disease. In the widely publicized report last month by Dr. Michael E. Pichichero and Dr. Janet R. Casey, nine children with acute otitis media (AOM) were found to be infected with a 19A pneumococcal serotype that was resistant to all antibiotics approved by the Food and Drug Administration for use in children with the infection. Four of the children were ultimately treated with tympanostomy tube insertion, and the other five with levofloxacin (JAMA 2007;298:1772–8).

Although antimicrobial-resistant 19A has clearly taken hold in the PCV7 era, there is evidence that the vaccine is only one of several reasons for its emergence. In another IDSA abstract, Dr. Eunhwa Choi of Seoul (Republic of Korea) National University Medical College reported that increases in the proportion of 19A among clinical isolates of invasive disease occurred over a 15-year period prior to the introduction of PCV7 in Korea. In children under 5 years of age, 19A increased from 0% in 1991–1994 to 8% in 1995–1997, and to 20%–26% in 2001–2006. All of the 19A isolates were multidrug resistant.

Given these data, vancomycin remains first-line therapy for all suspected cases of pneumococcal meningitis, as well as for those who are severely ill. For the more common respiratory infections, we now need to consider serotype 19A as a potential etiology in a child who does not respond to traditional antibiotic therapy in 48–72 hours. In the case of AOM, tympanocentesis to identify the specific pathogen is the preferred approach. When that is not possible, a nasopharyngeal swab for identification of S. pneumoniae 19A is acceptable to identify children at risk for infection due to this multidrug resistant pathogen.

While waiting for the results in a child with respiratory tract infection who is well enough to be managed as an outpatient, ceftriaxone in doses of 75–100 mg/kg once per day, given either intramuscularly or intravenously for a minimum of 3 days is appropriate. Whether this will work depends on the level of resistance. If cultures reveal S. pneumoniae 19A and either the minimum inhibitory concentration is above 6–8 mg/mL or the child fails to respond to ceftriaxone, an alternative approach is necessary.

In that setting, I would use levofloxacin (the only fluoroquinolone available in a suspension). The American Academy of Pediatrics' recent guidelines on the use of fluoroquinolones in children (Pediatrics 2006;118:1287–92) did not specifically address this particular clinical scenario, but I agree with Dr. Pichichero and Dr. Casey that AOM caused by multidrug-resistant 19A S. pneumoniae is an appropriate off-label use once you have documentation that 19A is the likely pathogen. If the child can't tolerate levofloxacin or has a contraindication to a quinolone, surgical drainage of the ear with tube placement is the only remaining option.

Future vaccines may address the 19A problem. GlaxoSmithKline's 10-valent Synflorix will contain a 19F capsular polysaccharide that results in some functional activity against serotype 19A. Wyeth's 13-valent conjugate pneumococcal vaccine will actually contain serotype 19A capsular polysaccharide. Both vaccines are in phase III clinical trials and could be licensed in 2009–2010. While I don't expect IPD to ever completely disappear from the planet, these second-generation vaccines could further reduce the number of cases of IPD in children and potentially adults.

I am on the advisory board for both the GSK and Wyeth pneumococcal vaccine programs. I also have an investigator-initiated grant from Wyeth for statewide surveillance. I have no current relationship with the makers of levofloxacin.

[email protected].

The emergence of pneumococcal “replacement” serotype 19A should not lead us to view the seven-valent pneumococcal conjugate vaccine in anything other than an overwhelmingly positive light.

Since the introduction of PCV7 (Prevnar) in the United States in 2000, there has been concern that Streptococcus pneumoniae serotypes other than the seven included in the vaccine (4, 6B, 9V, 14, 18C, 19F, and 23F) could become more prevalent. Now, several recent reports—including one from our group at Boston University—have documented both the relative and absolute increase in the nonvaccine serotype 19A in particular, along with an associated increase in antimicrobial resistance among these isolates.

This emergence suggests that we may need to shift our treatment approach to both invasive pneumococcal disease and noninvasive respiratory tract disease. It also underscores the need for continued surveillance. However, it should not lessen our enthusiasm for immunizing children with PCV7, nor should it lead us to relinquish our embrace of a vaccine that continues to provide enormous benefit for both child and adult health.

Indeed, the most recent data from the Centers for Disease Control and Prevention show that the overall rate of invasive pneumococcal disease (IPD) in the United States dropped by 43%, from 24/100,000 in 1998–1999 to 13/100,000 in 2004 to 14/100,000 in 2005. Between 1998–1999 and 2005, PCV7 prevented approximately 34,900 cases of IPD caused by vaccine serotypes and 24,000 cases overall. The declines in IPD were significant in all age groups, ranging from 17% among 50- to 64-year-olds to 77% among children younger than 5 years of age, Tamara Pilishvili of the CDC reported in October of this year at the annual meeting of the Infectious Diseases Society of America (IDSA).

These data are impressive. Nonetheless, we do need to be attentive to “replacement disease” in general and serotype 19A specifically, particularly when it comes to pneumococcal disease in the most vulnerable patients: those with developing immune systems (infants), those with underlying immune system abnormalities, and those with chronic conditions that put them at increased risk for complicated pneumococcal infections.

Here in Massachusetts, surveillance identified 467 cases of IPD in residents younger than 18 years of age. Annual incidence rates were stable between 2002 and 2006, ranging from 15.9 to 18.6 per 100,000 children younger than 5 years of age. Compared with the pre-PCV7 era (1990–1991), when the annual IPD rate was about 56.9/100,000 in that age group, these numbers represent a major decline of about 70% (MMWR 2007;56:1077–80).

Of 353 isolates available for serotyping during 2001–2006, 27% (97) were serotype 19A. Both the number and proportion of cases caused by that serotype increased from 10% (6) during 2001–2002 to 41% (33) during 2005–2006, while there were no significant changes in the proportions of IPD caused by other PCV7 or PCV7-related serotypes or by non-PCV7 serotypes. Since 2005–2006, 19A has become the most common serotype isolated. The majority of these isolates were nonsusceptible to penicillin, and during 2001–2006 there were significant increases in the proportion that were nonsusceptible to amoxicillin, ceftriaxone, or three or more classes of antimicrobials (multidrug resistant). It was of concern that 14 of 94 (15%) 19A isolates were highly resistant to ceftriaxone. We could not identify any clinical or demographic factor that characterized individuals who developed highly ceftriaxone-resistant 19A IPD.

Similar data from the U.S. Pediatric Multicenter Pneumococcal Surveillance Group were reported at IDSA by Dr. Sheldon L. Kaplan of Baylor College of Medicine, Houston. In eight U.S. children's hospitals, 19A has been the most common serotype causing invasive disease each year since 2003, accounting for 46% of all cases in 2006. Since 2000, penicillin nonsusceptibility and resistance increased—from 38% and 0%, respectively, in 2000, to 75% and 34% in 2006. No 19A isolates were ceftriaxone nonsusceptible or resistant in 2000; in 2006, those numbers had risen to 19% and 3%, respectively.

And the 19A story extends beyond invasive disease. In the widely publicized report last month by Dr. Michael E. Pichichero and Dr. Janet R. Casey, nine children with acute otitis media (AOM) were found to be infected with a 19A pneumococcal serotype that was resistant to all antibiotics approved by the Food and Drug Administration for use in children with the infection. Four of the children were ultimately treated with tympanostomy tube insertion, and the other five with levofloxacin (JAMA 2007;298:1772–8).

Although antimicrobial-resistant 19A has clearly taken hold in the PCV7 era, there is evidence that the vaccine is only one of several reasons for its emergence. In another IDSA abstract, Dr. Eunhwa Choi of Seoul (Republic of Korea) National University Medical College reported that increases in the proportion of 19A among clinical isolates of invasive disease occurred over a 15-year period prior to the introduction of PCV7 in Korea. In children under 5 years of age, 19A increased from 0% in 1991–1994 to 8% in 1995–1997, and to 20%–26% in 2001–2006. All of the 19A isolates were multidrug resistant.

Given these data, vancomycin remains first-line therapy for all suspected cases of pneumococcal meningitis, as well as for those who are severely ill. For the more common respiratory infections, we now need to consider serotype 19A as a potential etiology in a child who does not respond to traditional antibiotic therapy in 48–72 hours. In the case of AOM, tympanocentesis to identify the specific pathogen is the preferred approach. When that is not possible, a nasopharyngeal swab for identification of S. pneumoniae 19A is acceptable to identify children at risk for infection due to this multidrug resistant pathogen.

While waiting for the results in a child with respiratory tract infection who is well enough to be managed as an outpatient, ceftriaxone in doses of 75–100 mg/kg once per day, given either intramuscularly or intravenously for a minimum of 3 days is appropriate. Whether this will work depends on the level of resistance. If cultures reveal S. pneumoniae 19A and either the minimum inhibitory concentration is above 6–8 mg/mL or the child fails to respond to ceftriaxone, an alternative approach is necessary.

In that setting, I would use levofloxacin (the only fluoroquinolone available in a suspension). The American Academy of Pediatrics' recent guidelines on the use of fluoroquinolones in children (Pediatrics 2006;118:1287–92) did not specifically address this particular clinical scenario, but I agree with Dr. Pichichero and Dr. Casey that AOM caused by multidrug-resistant 19A S. pneumoniae is an appropriate off-label use once you have documentation that 19A is the likely pathogen. If the child can't tolerate levofloxacin or has a contraindication to a quinolone, surgical drainage of the ear with tube placement is the only remaining option.

Future vaccines may address the 19A problem. GlaxoSmithKline's 10-valent Synflorix will contain a 19F capsular polysaccharide that results in some functional activity against serotype 19A. Wyeth's 13-valent conjugate pneumococcal vaccine will actually contain serotype 19A capsular polysaccharide. Both vaccines are in phase III clinical trials and could be licensed in 2009–2010. While I don't expect IPD to ever completely disappear from the planet, these second-generation vaccines could further reduce the number of cases of IPD in children and potentially adults.

I am on the advisory board for both the GSK and Wyeth pneumococcal vaccine programs. I also have an investigator-initiated grant from Wyeth for statewide surveillance. I have no current relationship with the makers of levofloxacin.

[email protected].

The emergence of pneumococcal “replacement” serotype 19A should not lead us to view the seven-valent pneumococcal conjugate vaccine in anything other than an overwhelmingly positive light.

Since the introduction of PCV7 (Prevnar) in the United States in 2000, there has been concern that Streptococcus pneumoniae serotypes other than the seven included in the vaccine (4, 6B, 9V, 14, 18C, 19F, and 23F) could become more prevalent. Now, several recent reports—including one from our group at Boston University—have documented both the relative and absolute increase in the nonvaccine serotype 19A in particular, along with an associated increase in antimicrobial resistance among these isolates.

This emergence suggests that we may need to shift our treatment approach to both invasive pneumococcal disease and noninvasive respiratory tract disease. It also underscores the need for continued surveillance. However, it should not lessen our enthusiasm for immunizing children with PCV7, nor should it lead us to relinquish our embrace of a vaccine that continues to provide enormous benefit for both child and adult health.

Indeed, the most recent data from the Centers for Disease Control and Prevention show that the overall rate of invasive pneumococcal disease (IPD) in the United States dropped by 43%, from 24/100,000 in 1998–1999 to 13/100,000 in 2004 to 14/100,000 in 2005. Between 1998–1999 and 2005, PCV7 prevented approximately 34,900 cases of IPD caused by vaccine serotypes and 24,000 cases overall. The declines in IPD were significant in all age groups, ranging from 17% among 50- to 64-year-olds to 77% among children younger than 5 years of age, Tamara Pilishvili of the CDC reported in October of this year at the annual meeting of the Infectious Diseases Society of America (IDSA).

These data are impressive. Nonetheless, we do need to be attentive to “replacement disease” in general and serotype 19A specifically, particularly when it comes to pneumococcal disease in the most vulnerable patients: those with developing immune systems (infants), those with underlying immune system abnormalities, and those with chronic conditions that put them at increased risk for complicated pneumococcal infections.

Here in Massachusetts, surveillance identified 467 cases of IPD in residents younger than 18 years of age. Annual incidence rates were stable between 2002 and 2006, ranging from 15.9 to 18.6 per 100,000 children younger than 5 years of age. Compared with the pre-PCV7 era (1990–1991), when the annual IPD rate was about 56.9/100,000 in that age group, these numbers represent a major decline of about 70% (MMWR 2007;56:1077–80).

Of 353 isolates available for serotyping during 2001–2006, 27% (97) were serotype 19A. Both the number and proportion of cases caused by that serotype increased from 10% (6) during 2001–2002 to 41% (33) during 2005–2006, while there were no significant changes in the proportions of IPD caused by other PCV7 or PCV7-related serotypes or by non-PCV7 serotypes. Since 2005–2006, 19A has become the most common serotype isolated. The majority of these isolates were nonsusceptible to penicillin, and during 2001–2006 there were significant increases in the proportion that were nonsusceptible to amoxicillin, ceftriaxone, or three or more classes of antimicrobials (multidrug resistant). It was of concern that 14 of 94 (15%) 19A isolates were highly resistant to ceftriaxone. We could not identify any clinical or demographic factor that characterized individuals who developed highly ceftriaxone-resistant 19A IPD.

Similar data from the U.S. Pediatric Multicenter Pneumococcal Surveillance Group were reported at IDSA by Dr. Sheldon L. Kaplan of Baylor College of Medicine, Houston. In eight U.S. children's hospitals, 19A has been the most common serotype causing invasive disease each year since 2003, accounting for 46% of all cases in 2006. Since 2000, penicillin nonsusceptibility and resistance increased—from 38% and 0%, respectively, in 2000, to 75% and 34% in 2006. No 19A isolates were ceftriaxone nonsusceptible or resistant in 2000; in 2006, those numbers had risen to 19% and 3%, respectively.

And the 19A story extends beyond invasive disease. In the widely publicized report last month by Dr. Michael E. Pichichero and Dr. Janet R. Casey, nine children with acute otitis media (AOM) were found to be infected with a 19A pneumococcal serotype that was resistant to all antibiotics approved by the Food and Drug Administration for use in children with the infection. Four of the children were ultimately treated with tympanostomy tube insertion, and the other five with levofloxacin (JAMA 2007;298:1772–8).

Although antimicrobial-resistant 19A has clearly taken hold in the PCV7 era, there is evidence that the vaccine is only one of several reasons for its emergence. In another IDSA abstract, Dr. Eunhwa Choi of Seoul (Republic of Korea) National University Medical College reported that increases in the proportion of 19A among clinical isolates of invasive disease occurred over a 15-year period prior to the introduction of PCV7 in Korea. In children under 5 years of age, 19A increased from 0% in 1991–1994 to 8% in 1995–1997, and to 20%–26% in 2001–2006. All of the 19A isolates were multidrug resistant.

Given these data, vancomycin remains first-line therapy for all suspected cases of pneumococcal meningitis, as well as for those who are severely ill. For the more common respiratory infections, we now need to consider serotype 19A as a potential etiology in a child who does not respond to traditional antibiotic therapy in 48–72 hours. In the case of AOM, tympanocentesis to identify the specific pathogen is the preferred approach. When that is not possible, a nasopharyngeal swab for identification of S. pneumoniae 19A is acceptable to identify children at risk for infection due to this multidrug resistant pathogen.

While waiting for the results in a child with respiratory tract infection who is well enough to be managed as an outpatient, ceftriaxone in doses of 75–100 mg/kg once per day, given either intramuscularly or intravenously for a minimum of 3 days is appropriate. Whether this will work depends on the level of resistance. If cultures reveal S. pneumoniae 19A and either the minimum inhibitory concentration is above 6–8 mg/mL or the child fails to respond to ceftriaxone, an alternative approach is necessary.

In that setting, I would use levofloxacin (the only fluoroquinolone available in a suspension). The American Academy of Pediatrics' recent guidelines on the use of fluoroquinolones in children (Pediatrics 2006;118:1287–92) did not specifically address this particular clinical scenario, but I agree with Dr. Pichichero and Dr. Casey that AOM caused by multidrug-resistant 19A S. pneumoniae is an appropriate off-label use once you have documentation that 19A is the likely pathogen. If the child can't tolerate levofloxacin or has a contraindication to a quinolone, surgical drainage of the ear with tube placement is the only remaining option.

Future vaccines may address the 19A problem. GlaxoSmithKline's 10-valent Synflorix will contain a 19F capsular polysaccharide that results in some functional activity against serotype 19A. Wyeth's 13-valent conjugate pneumococcal vaccine will actually contain serotype 19A capsular polysaccharide. Both vaccines are in phase III clinical trials and could be licensed in 2009–2010. While I don't expect IPD to ever completely disappear from the planet, these second-generation vaccines could further reduce the number of cases of IPD in children and potentially adults.

I am on the advisory board for both the GSK and Wyeth pneumococcal vaccine programs. I also have an investigator-initiated grant from Wyeth for statewide surveillance. I have no current relationship with the makers of levofloxacin.

[email protected]

Methicillin-resistant Staphylococcus aureus has become the new disease of the moment, with alarming headlines almost daily this autumn about the “killer” bacterium. While of course MRSA is a real concern, we physicians can help by reassuring people that we have tools to deal with this problem.

The media frenzy began early in October 2007, with reports of MRSA-related deaths of high school athletes in at least three states, and numerous other cases of MRSA infection in schools around the country.

Then on Oct. 17, the Centers for Disease Control and Prevention (CDC) reported on the 8,987 cases of invasive MRSA from July 2004 to December 2005 in nine sentinel sites associated with the Active Bacterial Core Surveillance system (JAMA 2007;298:1763-1804).

With headlines like CNN's “Experts: Drug-Resistant Staph Deaths May Surpass AIDS Toll,” it's not surprising that our phone lines became overheated. We received four times the usual number of calls after that item appeared, from both patients and physicians worried about MRSA.

One physician wanted to know how to advise a local high school about the industrial-strength fumigation performed by a hazmat-like team that had been shown on TV. One school proposed bleaching its football field because that's where players' injuries occurred. I suggested that neither procedure was warranted.

The fact is that humans have coexisted with S. aureus for a long time. More persistent MRSA strains appeared about 10 years ago. But both MRSA and methicillin-sensitive S. aureus (MSSA) are capable of causing serious invasive disease. In fact, I recently treated an adolescent with disseminated MSSA disease that included septic thrombophlebitis; abscesses in his lung, spleen and liver; septic arthritis; and sepsis.

On the flip side, the majority of MRSA cases still present as common skin and soft-tissue infections that do not progress to life-threatening illness.

We have long known that S. aureus causes more disease in the warmer months, that it seems to have a male predominance, and that it takes advantage of open wounds, whether surgical or traumatic.

What's new in the last 5-10 years is that more strains are resistant to traditional antistaphylococcal antibiotics, and some (both MRSA and MSSA) have virulence genes that make invasive infections more likely, often in otherwise healthy adolescents.

In our community, about 60% of local disease—furuncles, pyoderma, impetigo—are due to MRSA.

I follow an algorithm that involves incision and drainage as the first step, while obtaining a specimen for culture and stratifying the severity of systemic illness and vulnerability of the infected site(s) (AAP News 2004;25:105).

Antibiotics may not always be necessary with single site infection in a child who is afebrile and previously healthy, while those who are febrile should receive empiric clindamycin or trimethoprim/sulfamethoxazole in mild to moderate disease, or even vancomycin for severe life-threatening disease.

Usually we use clindamycin, which still covers 90% of MRSA strains in Kansas City.

However, if the child is critically ill, we start with vancomycin because we don't want to risk that 10%.

The data reported by the CDC tell us that the majority of cases continue to be health care associated, and the vast majority of cases occur in adults.

Among 5,287 cases from six of the sentinel sites, just 134 were aged 17 and younger.

That small a number makes it difficult to extrapolate meaningfully from the overall epidemiologic data.

An elderly person with underlying chronic illness who dies of MRSA bacteremia is not as striking a story on the evening news as a sudden death in a previously healthy 16-year-old athlete. Death in a healthy child is unexpected these days and raises concern because parents can feel that they have no control, leading to a sense of panic.

And the media don't help matters by using words like “Superbug.”

This term has been used at other recent times to refer to Clostridium difficile, Streptococcus pneumoniae, and a variety of other organisms that are either difficult to treat or that are associated with bad outcome. Will the real “Superbug” please stand up? On second thought, let's just stop using the word altogether.

Another overused phrase is “flesh-eating bacteria.” In fact, most S. aureus can “eat flesh,” using coagulase and other enzymes. That's what helps form boils or carbuncles in pockets within the subcutaneous tissues. Alarming “flesh-eating” strains which can be lethal in a day or 2 have been around for decades, although they are more frequent these days; they can be either MRSA or MSSA.

But in fact, Group A streptococcus was the original bug to be labeled “flesh eating bacteria”—another case of bacterial identity theft.

We physicians can be the voices of reason. We can reassure our patients about MRSA while giving them practical advice on how to avoid it and the danger signs if they do become infected. This includes such common-sense measures as frequent hand washing, which of course helps prevent influenza and other infectious diseases that kill far more people than MRSA does.

Physicians who work with athletes or athletic teams can help by offering players practical advice that includes wiping the last person's sweat off equipment with antiseptic solutions such as diluted Clorox before using it themselves, not sharing towels, giving prompt attention to skin wounds, and practicing general good hygiene. The CDC has an excellent MRSA site that you can recommend to patients: www.cdc.gov/features/mrsainschools

The newly reported CDC data provide us with important benchmark information about the prevalence of MRSA invasive disease in the United States, so that public health professionals can begin making recommendations about how best to minimize recurrent or serious disease using logical and practical tools.

Recognition of the early signs of systemic infection and prompt intervention are the keys.

We have multiple antibiotics that still effectively treat even the scariest strains.

Other simple strategies of infection control and hygiene can reduce risks, too. Rarely if ever will these strategies include fumigating or shutting down schools.

And let's keep in mind: Panic is not a practical tool.

[email protected]

Methicillin-resistant Staphylococcus aureus has become the new disease of the moment, with alarming headlines almost daily this autumn about the “killer” bacterium. While of course MRSA is a real concern, we physicians can help by reassuring people that we have tools to deal with this problem.

The media frenzy began early in October 2007, with reports of MRSA-related deaths of high school athletes in at least three states, and numerous other cases of MRSA infection in schools around the country.

Then on Oct. 17, the Centers for Disease Control and Prevention (CDC) reported on the 8,987 cases of invasive MRSA from July 2004 to December 2005 in nine sentinel sites associated with the Active Bacterial Core Surveillance system (JAMA 2007;298:1763-1804).

With headlines like CNN's “Experts: Drug-Resistant Staph Deaths May Surpass AIDS Toll,” it's not surprising that our phone lines became overheated. We received four times the usual number of calls after that item appeared, from both patients and physicians worried about MRSA.

One physician wanted to know how to advise a local high school about the industrial-strength fumigation performed by a hazmat-like team that had been shown on TV. One school proposed bleaching its football field because that's where players' injuries occurred. I suggested that neither procedure was warranted.

The fact is that humans have coexisted with S. aureus for a long time. More persistent MRSA strains appeared about 10 years ago. But both MRSA and methicillin-sensitive S. aureus (MSSA) are capable of causing serious invasive disease. In fact, I recently treated an adolescent with disseminated MSSA disease that included septic thrombophlebitis; abscesses in his lung, spleen and liver; septic arthritis; and sepsis.

On the flip side, the majority of MRSA cases still present as common skin and soft-tissue infections that do not progress to life-threatening illness.

We have long known that S. aureus causes more disease in the warmer months, that it seems to have a male predominance, and that it takes advantage of open wounds, whether surgical or traumatic.

What's new in the last 5-10 years is that more strains are resistant to traditional antistaphylococcal antibiotics, and some (both MRSA and MSSA) have virulence genes that make invasive infections more likely, often in otherwise healthy adolescents.

In our community, about 60% of local disease—furuncles, pyoderma, impetigo—are due to MRSA.

I follow an algorithm that involves incision and drainage as the first step, while obtaining a specimen for culture and stratifying the severity of systemic illness and vulnerability of the infected site(s) (AAP News 2004;25:105).

Antibiotics may not always be necessary with single site infection in a child who is afebrile and previously healthy, while those who are febrile should receive empiric clindamycin or trimethoprim/sulfamethoxazole in mild to moderate disease, or even vancomycin for severe life-threatening disease.

Usually we use clindamycin, which still covers 90% of MRSA strains in Kansas City.

However, if the child is critically ill, we start with vancomycin because we don't want to risk that 10%.

The data reported by the CDC tell us that the majority of cases continue to be health care associated, and the vast majority of cases occur in adults.

Among 5,287 cases from six of the sentinel sites, just 134 were aged 17 and younger.

That small a number makes it difficult to extrapolate meaningfully from the overall epidemiologic data.

An elderly person with underlying chronic illness who dies of MRSA bacteremia is not as striking a story on the evening news as a sudden death in a previously healthy 16-year-old athlete. Death in a healthy child is unexpected these days and raises concern because parents can feel that they have no control, leading to a sense of panic.

And the media don't help matters by using words like “Superbug.”

This term has been used at other recent times to refer to Clostridium difficile, Streptococcus pneumoniae, and a variety of other organisms that are either difficult to treat or that are associated with bad outcome. Will the real “Superbug” please stand up? On second thought, let's just stop using the word altogether.

Another overused phrase is “flesh-eating bacteria.” In fact, most S. aureus can “eat flesh,” using coagulase and other enzymes. That's what helps form boils or carbuncles in pockets within the subcutaneous tissues. Alarming “flesh-eating” strains which can be lethal in a day or 2 have been around for decades, although they are more frequent these days; they can be either MRSA or MSSA.

But in fact, Group A streptococcus was the original bug to be labeled “flesh eating bacteria”—another case of bacterial identity theft.

We physicians can be the voices of reason. We can reassure our patients about MRSA while giving them practical advice on how to avoid it and the danger signs if they do become infected. This includes such common-sense measures as frequent hand washing, which of course helps prevent influenza and other infectious diseases that kill far more people than MRSA does.

Physicians who work with athletes or athletic teams can help by offering players practical advice that includes wiping the last person's sweat off equipment with antiseptic solutions such as diluted Clorox before using it themselves, not sharing towels, giving prompt attention to skin wounds, and practicing general good hygiene. The CDC has an excellent MRSA site that you can recommend to patients: www.cdc.gov/features/mrsainschools

The newly reported CDC data provide us with important benchmark information about the prevalence of MRSA invasive disease in the United States, so that public health professionals can begin making recommendations about how best to minimize recurrent or serious disease using logical and practical tools.

Recognition of the early signs of systemic infection and prompt intervention are the keys.

We have multiple antibiotics that still effectively treat even the scariest strains.

Other simple strategies of infection control and hygiene can reduce risks, too. Rarely if ever will these strategies include fumigating or shutting down schools.

And let's keep in mind: Panic is not a practical tool.

[email protected]

Methicillin-resistant Staphylococcus aureus has become the new disease of the moment, with alarming headlines almost daily this autumn about the “killer” bacterium. While of course MRSA is a real concern, we physicians can help by reassuring people that we have tools to deal with this problem.

The media frenzy began early in October 2007, with reports of MRSA-related deaths of high school athletes in at least three states, and numerous other cases of MRSA infection in schools around the country.

Then on Oct. 17, the Centers for Disease Control and Prevention (CDC) reported on the 8,987 cases of invasive MRSA from July 2004 to December 2005 in nine sentinel sites associated with the Active Bacterial Core Surveillance system (JAMA 2007;298:1763-1804).

With headlines like CNN's “Experts: Drug-Resistant Staph Deaths May Surpass AIDS Toll,” it's not surprising that our phone lines became overheated. We received four times the usual number of calls after that item appeared, from both patients and physicians worried about MRSA.

One physician wanted to know how to advise a local high school about the industrial-strength fumigation performed by a hazmat-like team that had been shown on TV. One school proposed bleaching its football field because that's where players' injuries occurred. I suggested that neither procedure was warranted.

The fact is that humans have coexisted with S. aureus for a long time. More persistent MRSA strains appeared about 10 years ago. But both MRSA and methicillin-sensitive S. aureus (MSSA) are capable of causing serious invasive disease. In fact, I recently treated an adolescent with disseminated MSSA disease that included septic thrombophlebitis; abscesses in his lung, spleen and liver; septic arthritis; and sepsis.

On the flip side, the majority of MRSA cases still present as common skin and soft-tissue infections that do not progress to life-threatening illness.

We have long known that S. aureus causes more disease in the warmer months, that it seems to have a male predominance, and that it takes advantage of open wounds, whether surgical or traumatic.

What's new in the last 5-10 years is that more strains are resistant to traditional antistaphylococcal antibiotics, and some (both MRSA and MSSA) have virulence genes that make invasive infections more likely, often in otherwise healthy adolescents.

In our community, about 60% of local disease—furuncles, pyoderma, impetigo—are due to MRSA.

I follow an algorithm that involves incision and drainage as the first step, while obtaining a specimen for culture and stratifying the severity of systemic illness and vulnerability of the infected site(s) (AAP News 2004;25:105).

Antibiotics may not always be necessary with single site infection in a child who is afebrile and previously healthy, while those who are febrile should receive empiric clindamycin or trimethoprim/sulfamethoxazole in mild to moderate disease, or even vancomycin for severe life-threatening disease.

Usually we use clindamycin, which still covers 90% of MRSA strains in Kansas City.

However, if the child is critically ill, we start with vancomycin because we don't want to risk that 10%.

The data reported by the CDC tell us that the majority of cases continue to be health care associated, and the vast majority of cases occur in adults.

Among 5,287 cases from six of the sentinel sites, just 134 were aged 17 and younger.

That small a number makes it difficult to extrapolate meaningfully from the overall epidemiologic data.

An elderly person with underlying chronic illness who dies of MRSA bacteremia is not as striking a story on the evening news as a sudden death in a previously healthy 16-year-old athlete. Death in a healthy child is unexpected these days and raises concern because parents can feel that they have no control, leading to a sense of panic.

And the media don't help matters by using words like “Superbug.”

This term has been used at other recent times to refer to Clostridium difficile, Streptococcus pneumoniae, and a variety of other organisms that are either difficult to treat or that are associated with bad outcome. Will the real “Superbug” please stand up? On second thought, let's just stop using the word altogether.

Another overused phrase is “flesh-eating bacteria.” In fact, most S. aureus can “eat flesh,” using coagulase and other enzymes. That's what helps form boils or carbuncles in pockets within the subcutaneous tissues. Alarming “flesh-eating” strains which can be lethal in a day or 2 have been around for decades, although they are more frequent these days; they can be either MRSA or MSSA.

But in fact, Group A streptococcus was the original bug to be labeled “flesh eating bacteria”—another case of bacterial identity theft.

We physicians can be the voices of reason. We can reassure our patients about MRSA while giving them practical advice on how to avoid it and the danger signs if they do become infected. This includes such common-sense measures as frequent hand washing, which of course helps prevent influenza and other infectious diseases that kill far more people than MRSA does.

Physicians who work with athletes or athletic teams can help by offering players practical advice that includes wiping the last person's sweat off equipment with antiseptic solutions such as diluted Clorox before using it themselves, not sharing towels, giving prompt attention to skin wounds, and practicing general good hygiene. The CDC has an excellent MRSA site that you can recommend to patients: www.cdc.gov/features/mrsainschools

The newly reported CDC data provide us with important benchmark information about the prevalence of MRSA invasive disease in the United States, so that public health professionals can begin making recommendations about how best to minimize recurrent or serious disease using logical and practical tools.

Recognition of the early signs of systemic infection and prompt intervention are the keys.

We have multiple antibiotics that still effectively treat even the scariest strains.

Other simple strategies of infection control and hygiene can reduce risks, too. Rarely if ever will these strategies include fumigating or shutting down schools.

And let's keep in mind: Panic is not a practical tool.

[email protected]

It's both surprising and humbling to realize that something we've been doing for the last 50 years appears to have been entirely unnecessary and possibly even harmful.

We now know that's exactly the case when it comes to prescribing prophylactic antibiotics before dental and other invasive procedures for the majority of our patients with benign and even most nonbenign heart conditions. Old habits are hard to break, but we now must do just that.

In September, the American Academy of Pediatrics endorsed the new guidelines from the American Heart Association on the prevention of infective endocarditis, published earlier this year (Circulation 2007 April 19 [Epub ahead of print]). In essence, they whittle down the previous long list of moderate and severe cardiac conditions for which antimicrobial prophylaxis is recommended to just these six highest-risk conditions:

▸ Prosthetic cardiac valve.

▸ Previous infective endocarditis.

▸ Unrepaired cyanotic congenital heart disease, including palliative shunts and conduits.

▸ Completely repaired congenital heart defect with prosthetic material or device, whether placed by surgery or by catheter intervention, during the first 6 months after the procedure (the time in which endothelialization of prosthetic material occurs).

▸ Repaired congenital heart disease with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibit endothelialization).

▸ Cardiac transplantation recipients who develop cardiac valvulopathy.

That's it. No other conditions meet the criteria. In addition, among patients with the conditions listed above, the only procedures that still require prophylaxis are dental procedures that involve manipulation of the gingival tissue or the periapical region of teeth or perforation of the oral mucosa, and respiratory tract procedures for which there is a risk of mucosal perforation. Procedures involving the gastrointestinal and genitourinary tracts are no longer on the list.

The AHA first recommended antibiotics to prevent infective endocarditis back in 1955, and had revised those guidelines frequently thereafter until 1997. The rationale was reasonable enough: Infective endocarditis (IE) is a life-threatening condition. Although rare, there is an increased risk of IE among people with certain underlying heart conditions who developed transient bacteremia as a result of procedures that induce bleeding.

Animal data had suggested that antibiotics could prevent such infections, and it was presumed that the same would be true in humans. There was never any human data, although there were case reports of endocarditis cases that were temporally associated with dental procedures. It just seemed to make sense that “premedication” with antibiotics was the way to safely and effectively prevent IE.

Dentists in particular have felt such a strong sense of responsibility about this, both professionally and legally, that many have refused to perform procedures on any child with even the most benign of heart murmurs without the “protection” of antibiotics.

The development of IE is thought to be a result of turbulent blood flow produced by congenital or acquired heart disease, creating a predisposition for deposition of platelets and fibrin on the endothelial surface, resulting in nonbacterial thrombotic endocarditis. This could lead to subsequent invasion of the bloodstream with certain microbial species—most commonly viridans group streptococci, staphylococci, or enterococci—that have the potential to colonize the site, which then could result in IE.

We know that transient bacteremia is common when you manipulate the teeth in periodontal tissues. It is estimated to occur approximately 10%–100% of the time during tooth extraction, 36%–88% with peridontal surgery, and up to 40% with simple teeth cleaning. But—and here's the kicker—transient bacteremia also occurs at least as often in routine daily activities such as tooth brushing and flossing (20%–68%), use of wooden toothpicks (20%–40%), use of water irrigation devices (7%–50%), and even chewing food (7%–51%)!

When you consider that these activities are performed daily, whereas dental visits occur just once or twice a year, the idea that we can prevent IE by simply giving antibiotics prior to dental procedures seems short-sighted at best.

In fact, one author found that the cumulative risk to a child of transient bacteremia from tooth brushing twice daily for a 1 year was 154,000 times greater than from a single tooth extraction, the dental procedure believed most likely to cause bacteremia. And, the cumulative risk from ALL daily activities may be as high as 5.6 MILLION times greater than that of a single tooth extraction (Pediatr. Cardiol. 1999;20:317-25)!

Even if antimicrobial prophylaxis were 100% effective, and assuming that dental procedures are responsible for 1% of all IE cases, you could only prevent about 1 case for every 14 million dental procedures performed. And of course, we need to consider the risks of antibiotic overuse as well as the cost. No matter how you look at it, there's no bang for your buck in any patients other than those with the most severe cardiac conditions.

Now is the time to begin educating families that antimicrobial prophylaxis for dental procedures is no longer necessary. Admitting we've been wrong all along won't be easy, but I believe patients will understand if we take the time to carefully explain the rationales then and now. With the increasing emphasis on an evidence base for everything we do, this may not be the last time we'll have to revise our thinking.

[email protected]

It's both surprising and humbling to realize that something we've been doing for the last 50 years appears to have been entirely unnecessary and possibly even harmful.

We now know that's exactly the case when it comes to prescribing prophylactic antibiotics before dental and other invasive procedures for the majority of our patients with benign and even most nonbenign heart conditions. Old habits are hard to break, but we now must do just that.

In September, the American Academy of Pediatrics endorsed the new guidelines from the American Heart Association on the prevention of infective endocarditis, published earlier this year (Circulation 2007 April 19 [Epub ahead of print]). In essence, they whittle down the previous long list of moderate and severe cardiac conditions for which antimicrobial prophylaxis is recommended to just these six highest-risk conditions:

▸ Prosthetic cardiac valve.

▸ Previous infective endocarditis.

▸ Unrepaired cyanotic congenital heart disease, including palliative shunts and conduits.

▸ Completely repaired congenital heart defect with prosthetic material or device, whether placed by surgery or by catheter intervention, during the first 6 months after the procedure (the time in which endothelialization of prosthetic material occurs).

▸ Repaired congenital heart disease with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibit endothelialization).

▸ Cardiac transplantation recipients who develop cardiac valvulopathy.

That's it. No other conditions meet the criteria. In addition, among patients with the conditions listed above, the only procedures that still require prophylaxis are dental procedures that involve manipulation of the gingival tissue or the periapical region of teeth or perforation of the oral mucosa, and respiratory tract procedures for which there is a risk of mucosal perforation. Procedures involving the gastrointestinal and genitourinary tracts are no longer on the list.

The AHA first recommended antibiotics to prevent infective endocarditis back in 1955, and had revised those guidelines frequently thereafter until 1997. The rationale was reasonable enough: Infective endocarditis (IE) is a life-threatening condition. Although rare, there is an increased risk of IE among people with certain underlying heart conditions who developed transient bacteremia as a result of procedures that induce bleeding.

Animal data had suggested that antibiotics could prevent such infections, and it was presumed that the same would be true in humans. There was never any human data, although there were case reports of endocarditis cases that were temporally associated with dental procedures. It just seemed to make sense that “premedication” with antibiotics was the way to safely and effectively prevent IE.

Dentists in particular have felt such a strong sense of responsibility about this, both professionally and legally, that many have refused to perform procedures on any child with even the most benign of heart murmurs without the “protection” of antibiotics.

The development of IE is thought to be a result of turbulent blood flow produced by congenital or acquired heart disease, creating a predisposition for deposition of platelets and fibrin on the endothelial surface, resulting in nonbacterial thrombotic endocarditis. This could lead to subsequent invasion of the bloodstream with certain microbial species—most commonly viridans group streptococci, staphylococci, or enterococci—that have the potential to colonize the site, which then could result in IE.

We know that transient bacteremia is common when you manipulate the teeth in periodontal tissues. It is estimated to occur approximately 10%–100% of the time during tooth extraction, 36%–88% with peridontal surgery, and up to 40% with simple teeth cleaning. But—and here's the kicker—transient bacteremia also occurs at least as often in routine daily activities such as tooth brushing and flossing (20%–68%), use of wooden toothpicks (20%–40%), use of water irrigation devices (7%–50%), and even chewing food (7%–51%)!

When you consider that these activities are performed daily, whereas dental visits occur just once or twice a year, the idea that we can prevent IE by simply giving antibiotics prior to dental procedures seems short-sighted at best.

In fact, one author found that the cumulative risk to a child of transient bacteremia from tooth brushing twice daily for a 1 year was 154,000 times greater than from a single tooth extraction, the dental procedure believed most likely to cause bacteremia. And, the cumulative risk from ALL daily activities may be as high as 5.6 MILLION times greater than that of a single tooth extraction (Pediatr. Cardiol. 1999;20:317-25)!

Even if antimicrobial prophylaxis were 100% effective, and assuming that dental procedures are responsible for 1% of all IE cases, you could only prevent about 1 case for every 14 million dental procedures performed. And of course, we need to consider the risks of antibiotic overuse as well as the cost. No matter how you look at it, there's no bang for your buck in any patients other than those with the most severe cardiac conditions.

Now is the time to begin educating families that antimicrobial prophylaxis for dental procedures is no longer necessary. Admitting we've been wrong all along won't be easy, but I believe patients will understand if we take the time to carefully explain the rationales then and now. With the increasing emphasis on an evidence base for everything we do, this may not be the last time we'll have to revise our thinking.

[email protected]

It's both surprising and humbling to realize that something we've been doing for the last 50 years appears to have been entirely unnecessary and possibly even harmful.

We now know that's exactly the case when it comes to prescribing prophylactic antibiotics before dental and other invasive procedures for the majority of our patients with benign and even most nonbenign heart conditions. Old habits are hard to break, but we now must do just that.

In September, the American Academy of Pediatrics endorsed the new guidelines from the American Heart Association on the prevention of infective endocarditis, published earlier this year (Circulation 2007 April 19 [Epub ahead of print]). In essence, they whittle down the previous long list of moderate and severe cardiac conditions for which antimicrobial prophylaxis is recommended to just these six highest-risk conditions:

▸ Prosthetic cardiac valve.

▸ Previous infective endocarditis.

▸ Unrepaired cyanotic congenital heart disease, including palliative shunts and conduits.

▸ Completely repaired congenital heart defect with prosthetic material or device, whether placed by surgery or by catheter intervention, during the first 6 months after the procedure (the time in which endothelialization of prosthetic material occurs).

▸ Repaired congenital heart disease with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibit endothelialization).

▸ Cardiac transplantation recipients who develop cardiac valvulopathy.

That's it. No other conditions meet the criteria. In addition, among patients with the conditions listed above, the only procedures that still require prophylaxis are dental procedures that involve manipulation of the gingival tissue or the periapical region of teeth or perforation of the oral mucosa, and respiratory tract procedures for which there is a risk of mucosal perforation. Procedures involving the gastrointestinal and genitourinary tracts are no longer on the list.

The AHA first recommended antibiotics to prevent infective endocarditis back in 1955, and had revised those guidelines frequently thereafter until 1997. The rationale was reasonable enough: Infective endocarditis (IE) is a life-threatening condition. Although rare, there is an increased risk of IE among people with certain underlying heart conditions who developed transient bacteremia as a result of procedures that induce bleeding.

Animal data had suggested that antibiotics could prevent such infections, and it was presumed that the same would be true in humans. There was never any human data, although there were case reports of endocarditis cases that were temporally associated with dental procedures. It just seemed to make sense that “premedication” with antibiotics was the way to safely and effectively prevent IE.

Dentists in particular have felt such a strong sense of responsibility about this, both professionally and legally, that many have refused to perform procedures on any child with even the most benign of heart murmurs without the “protection” of antibiotics.

The development of IE is thought to be a result of turbulent blood flow produced by congenital or acquired heart disease, creating a predisposition for deposition of platelets and fibrin on the endothelial surface, resulting in nonbacterial thrombotic endocarditis. This could lead to subsequent invasion of the bloodstream with certain microbial species—most commonly viridans group streptococci, staphylococci, or enterococci—that have the potential to colonize the site, which then could result in IE.

We know that transient bacteremia is common when you manipulate the teeth in periodontal tissues. It is estimated to occur approximately 10%–100% of the time during tooth extraction, 36%–88% with peridontal surgery, and up to 40% with simple teeth cleaning. But—and here's the kicker—transient bacteremia also occurs at least as often in routine daily activities such as tooth brushing and flossing (20%–68%), use of wooden toothpicks (20%–40%), use of water irrigation devices (7%–50%), and even chewing food (7%–51%)!

When you consider that these activities are performed daily, whereas dental visits occur just once or twice a year, the idea that we can prevent IE by simply giving antibiotics prior to dental procedures seems short-sighted at best.

In fact, one author found that the cumulative risk to a child of transient bacteremia from tooth brushing twice daily for a 1 year was 154,000 times greater than from a single tooth extraction, the dental procedure believed most likely to cause bacteremia. And, the cumulative risk from ALL daily activities may be as high as 5.6 MILLION times greater than that of a single tooth extraction (Pediatr. Cardiol. 1999;20:317-25)!

Even if antimicrobial prophylaxis were 100% effective, and assuming that dental procedures are responsible for 1% of all IE cases, you could only prevent about 1 case for every 14 million dental procedures performed. And of course, we need to consider the risks of antibiotic overuse as well as the cost. No matter how you look at it, there's no bang for your buck in any patients other than those with the most severe cardiac conditions.

Now is the time to begin educating families that antimicrobial prophylaxis for dental procedures is no longer necessary. Admitting we've been wrong all along won't be easy, but I believe patients will understand if we take the time to carefully explain the rationales then and now. With the increasing emphasis on an evidence base for everything we do, this may not be the last time we'll have to revise our thinking.

[email protected]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

Emerging evidence suggests that we shouldn't be prescribing prophylactic antibiotics for every child with recurrent urinary tract infection, even when vesicoureteral reflux is present.

Just as the pendulum has swung over the last decade away from universal use of antibiotics with acute otitis media toward selective use of “watchful waiting,” data on recurrent urinary tract infection (UTI) suggest that children with lower grades of reflux may not benefit from long-term prophylactic antibiotics. These children may in fact be disadvantaged by prophylaxis's selecting for increased antimicrobial resistance. Therefore, even when we decide to use antimicrobial prophylaxis in selected children with both recurrent UTI plus high-grade vesicoureteral reflux (VUR), we need to consider carefully whether the traditional prophylactic drugs are really the best choice.

The latest evidence comes from a large database study published by Dr. Patrick Conway of the University of Pennsylvania, Philadelphia, and his associates. They retrospectively analyzed the electronic health records of 74,974 children aged 6 years and younger in 27 primary care practices in Delaware, New Jersey, and Pennsylvania over a 5-year period, and identified 666 who had been diagnosed with a first UTI; 611 had at least 24 days of observation. There were 83 with recurrent UTIs, 51 (61%) of which were caused by a resistant pathogen (JAMA 2007;298:179-86).

Significant predictors of recurrence included age 3-4 years (not the toddler in diapers as we might have suspected), white race, and grades 4-5 VUR. Factors that did not affect the risk of recurrent infection included sex, grades 1-3 VUR, and antimicrobial exposure. Because children had different lengths of follow-up (mean 408 days), time to recurrence was used as the primary outcome measure. Use of antimicrobial prophylaxis had no significant overall effect on time between the initial UTI and the first recurrent UTI, even when the children were stratified by age, race, sex, or VUR grade.

Importantly, despite the lack of effect on time to recurrent UTI, prophylaxis was associated with a 7.5-fold increased likelihood of a resistant pathogen causing the recurrence. In the overall group of 611 children with UTI, trimethoprim-sulfamethoxazole was prescribed for 61%, amoxicillin for 29%, nitrofurantoin for 7%, and other antimicrobials including first-generation cephalosporins for the other 3%. Although the investigators didn't report which antibiotics were used in the 83 children with recurrent UTI, they did note that none of the 9 children who received nitrofurantoin had a recurrence.

This study follows last year's publication of a Cochrane review comprising data for 406 children from five randomized studies in which antibiotic prophylaxis was compared with placebo or no treatment (Cochrane Database Syst. Rev. 2006;3:CD001534).

The results were not conclusive. Antibiotics were found to reduce the risk of repeated positive urine culture (relative risk 0.44), but there was no information about rates of symptomatic recurrent infection or long-term renal sequelae. In one study, nitrofurantoin was more effective than trimethoprim in preventing recurrent UTI over a 6-month period (RR 0.48), but patients were more likely to discontinue nitrofurantoin because of side effects. In another study, cefixime was more effective than nitrofurantoin in preventing recurrent UTI during the first 6 months (RR 0.74), but adverse reactions were more common with cefixime than with nitrofurantoin (63% vs. 26%).

Historically, the use of antimicrobial prophylaxis in all children with UTIs–in the 1970s–was based on studies that included asymptomatic bacteriuria as well as the more important symptomatic UTIs. The '70s data suggested that prophylaxis prevented recurrent positive urine cultures, many of which were from asymptomatic children. There also were insufficient data to prove that prophylaxis prevented renal scarring or the need for kidney transplantation. People had presumed that asymptomatic bacteriuria was as important as symptomatic UTI in leading to long-term kidney issues, but there was no definitive evidence for this.

Later imaging results indicated that VUR was associated with more frequent UTI, although we still didn't have proof of their association with long-term renal damage. Recent data indicate that lower grades of reflux are not statistically associated with long-term kidney injury or renal scarring, and now we see that the first recurrent UTI occurs just as soon, whether children are on or off prophylaxis. At the same time, we are increasingly concerned about antimicrobial resistance. The drugs typically used for prophylaxis–amoxicillin, trimethoprim-sulfamethoxazole, and first-generation cephalosporins–have become less and less active in vitro against the most common UTI pathogen, Escherichia coli.

Until we get more definitive data, I think that we can be more selective in deciding which patients with a first UTI should receive antimicrobial prophylaxis without exposing these children to extra risks. My personal bias is to limit prophylaxis to those in whom imaging shows either grade 4 or 5 VUR or other obstructive anatomic abnormalities. For children with lower grades of reflux, I would simply observe them for a recurrence pattern, keeping in mind that some may show more frequent recurrences than expected. This subset might need urologic referral to look for more subtle problems that can benefit from intervention. Given what we know about the risk of antimicrobial resistance, my advice would be to avoid 365 days per year of antibiotic exposure (prophylaxis) with low-grade VUR unless there were more than three UTI recurrences per year.

For children with high degrees of reflux (4 and 5), in vitro resistance data and hints from recent studies suggest that nitrofurantoin may currently be our best bet for prophylaxis. The micronized formulation (Macrobid) appears to have the fewest gastrointestinal side effects, so I'd use it as a first choice.

If patients don't tolerate nitrofurantoin, we should look at local resistance patterns, or perhaps a first-generation cephalosporin might be the next best choice. It's possible that broader-spectrum antimicrobials may work well in certain patients, but we don't have enough data on the prevalence of mechanisms of resistance, and tendencies to induce resistance, to comfortably use them empirically.

And, of course, we need to remember that when we do decide to prescribe long-term daily antibiotics, we can't assume for a minute that adherence will be complete. As the old saying goes, “Two-thirds of patients take two-thirds of the antibiotic two-thirds of the days prescribed.” One thing for which we have definitive proof is that nobody takes a drug every single day.

[email protected]

Emerging evidence suggests that we shouldn't be prescribing prophylactic antibiotics for every child with recurrent urinary tract infection, even when vesicoureteral reflux is present.

Just as the pendulum has swung over the last decade away from universal use of antibiotics with acute otitis media toward selective use of “watchful waiting,” data on recurrent urinary tract infection (UTI) suggest that children with lower grades of reflux may not benefit from long-term prophylactic antibiotics. These children may in fact be disadvantaged by prophylaxis's selecting for increased antimicrobial resistance. Therefore, even when we decide to use antimicrobial prophylaxis in selected children with both recurrent UTI plus high-grade vesicoureteral reflux (VUR), we need to consider carefully whether the traditional prophylactic drugs are really the best choice.

The latest evidence comes from a large database study published by Dr. Patrick Conway of the University of Pennsylvania, Philadelphia, and his associates. They retrospectively analyzed the electronic health records of 74,974 children aged 6 years and younger in 27 primary care practices in Delaware, New Jersey, and Pennsylvania over a 5-year period, and identified 666 who had been diagnosed with a first UTI; 611 had at least 24 days of observation. There were 83 with recurrent UTIs, 51 (61%) of which were caused by a resistant pathogen (JAMA 2007;298:179-86).

Significant predictors of recurrence included age 3-4 years (not the toddler in diapers as we might have suspected), white race, and grades 4-5 VUR. Factors that did not affect the risk of recurrent infection included sex, grades 1-3 VUR, and antimicrobial exposure. Because children had different lengths of follow-up (mean 408 days), time to recurrence was used as the primary outcome measure. Use of antimicrobial prophylaxis had no significant overall effect on time between the initial UTI and the first recurrent UTI, even when the children were stratified by age, race, sex, or VUR grade.

Importantly, despite the lack of effect on time to recurrent UTI, prophylaxis was associated with a 7.5-fold increased likelihood of a resistant pathogen causing the recurrence. In the overall group of 611 children with UTI, trimethoprim-sulfamethoxazole was prescribed for 61%, amoxicillin for 29%, nitrofurantoin for 7%, and other antimicrobials including first-generation cephalosporins for the other 3%. Although the investigators didn't report which antibiotics were used in the 83 children with recurrent UTI, they did note that none of the 9 children who received nitrofurantoin had a recurrence.

This study follows last year's publication of a Cochrane review comprising data for 406 children from five randomized studies in which antibiotic prophylaxis was compared with placebo or no treatment (Cochrane Database Syst. Rev. 2006;3:CD001534).

The results were not conclusive. Antibiotics were found to reduce the risk of repeated positive urine culture (relative risk 0.44), but there was no information about rates of symptomatic recurrent infection or long-term renal sequelae. In one study, nitrofurantoin was more effective than trimethoprim in preventing recurrent UTI over a 6-month period (RR 0.48), but patients were more likely to discontinue nitrofurantoin because of side effects. In another study, cefixime was more effective than nitrofurantoin in preventing recurrent UTI during the first 6 months (RR 0.74), but adverse reactions were more common with cefixime than with nitrofurantoin (63% vs. 26%).

Historically, the use of antimicrobial prophylaxis in all children with UTIs–in the 1970s–was based on studies that included asymptomatic bacteriuria as well as the more important symptomatic UTIs. The '70s data suggested that prophylaxis prevented recurrent positive urine cultures, many of which were from asymptomatic children. There also were insufficient data to prove that prophylaxis prevented renal scarring or the need for kidney transplantation. People had presumed that asymptomatic bacteriuria was as important as symptomatic UTI in leading to long-term kidney issues, but there was no definitive evidence for this.

Later imaging results indicated that VUR was associated with more frequent UTI, although we still didn't have proof of their association with long-term renal damage. Recent data indicate that lower grades of reflux are not statistically associated with long-term kidney injury or renal scarring, and now we see that the first recurrent UTI occurs just as soon, whether children are on or off prophylaxis. At the same time, we are increasingly concerned about antimicrobial resistance. The drugs typically used for prophylaxis–amoxicillin, trimethoprim-sulfamethoxazole, and first-generation cephalosporins–have become less and less active in vitro against the most common UTI pathogen, Escherichia coli.

Until we get more definitive data, I think that we can be more selective in deciding which patients with a first UTI should receive antimicrobial prophylaxis without exposing these children to extra risks. My personal bias is to limit prophylaxis to those in whom imaging shows either grade 4 or 5 VUR or other obstructive anatomic abnormalities. For children with lower grades of reflux, I would simply observe them for a recurrence pattern, keeping in mind that some may show more frequent recurrences than expected. This subset might need urologic referral to look for more subtle problems that can benefit from intervention. Given what we know about the risk of antimicrobial resistance, my advice would be to avoid 365 days per year of antibiotic exposure (prophylaxis) with low-grade VUR unless there were more than three UTI recurrences per year.

For children with high degrees of reflux (4 and 5), in vitro resistance data and hints from recent studies suggest that nitrofurantoin may currently be our best bet for prophylaxis. The micronized formulation (Macrobid) appears to have the fewest gastrointestinal side effects, so I'd use it as a first choice.

If patients don't tolerate nitrofurantoin, we should look at local resistance patterns, or perhaps a first-generation cephalosporin might be the next best choice. It's possible that broader-spectrum antimicrobials may work well in certain patients, but we don't have enough data on the prevalence of mechanisms of resistance, and tendencies to induce resistance, to comfortably use them empirically.

And, of course, we need to remember that when we do decide to prescribe long-term daily antibiotics, we can't assume for a minute that adherence will be complete. As the old saying goes, “Two-thirds of patients take two-thirds of the antibiotic two-thirds of the days prescribed.” One thing for which we have definitive proof is that nobody takes a drug every single day.

[email protected]

Emerging evidence suggests that we shouldn't be prescribing prophylactic antibiotics for every child with recurrent urinary tract infection, even when vesicoureteral reflux is present.

Just as the pendulum has swung over the last decade away from universal use of antibiotics with acute otitis media toward selective use of “watchful waiting,” data on recurrent urinary tract infection (UTI) suggest that children with lower grades of reflux may not benefit from long-term prophylactic antibiotics. These children may in fact be disadvantaged by prophylaxis's selecting for increased antimicrobial resistance. Therefore, even when we decide to use antimicrobial prophylaxis in selected children with both recurrent UTI plus high-grade vesicoureteral reflux (VUR), we need to consider carefully whether the traditional prophylactic drugs are really the best choice.

The latest evidence comes from a large database study published by Dr. Patrick Conway of the University of Pennsylvania, Philadelphia, and his associates. They retrospectively analyzed the electronic health records of 74,974 children aged 6 years and younger in 27 primary care practices in Delaware, New Jersey, and Pennsylvania over a 5-year period, and identified 666 who had been diagnosed with a first UTI; 611 had at least 24 days of observation. There were 83 with recurrent UTIs, 51 (61%) of which were caused by a resistant pathogen (JAMA 2007;298:179-86).

Significant predictors of recurrence included age 3-4 years (not the toddler in diapers as we might have suspected), white race, and grades 4-5 VUR. Factors that did not affect the risk of recurrent infection included sex, grades 1-3 VUR, and antimicrobial exposure. Because children had different lengths of follow-up (mean 408 days), time to recurrence was used as the primary outcome measure. Use of antimicrobial prophylaxis had no significant overall effect on time between the initial UTI and the first recurrent UTI, even when the children were stratified by age, race, sex, or VUR grade.

Importantly, despite the lack of effect on time to recurrent UTI, prophylaxis was associated with a 7.5-fold increased likelihood of a resistant pathogen causing the recurrence. In the overall group of 611 children with UTI, trimethoprim-sulfamethoxazole was prescribed for 61%, amoxicillin for 29%, nitrofurantoin for 7%, and other antimicrobials including first-generation cephalosporins for the other 3%. Although the investigators didn't report which antibiotics were used in the 83 children with recurrent UTI, they did note that none of the 9 children who received nitrofurantoin had a recurrence.

This study follows last year's publication of a Cochrane review comprising data for 406 children from five randomized studies in which antibiotic prophylaxis was compared with placebo or no treatment (Cochrane Database Syst. Rev. 2006;3:CD001534).

The results were not conclusive. Antibiotics were found to reduce the risk of repeated positive urine culture (relative risk 0.44), but there was no information about rates of symptomatic recurrent infection or long-term renal sequelae. In one study, nitrofurantoin was more effective than trimethoprim in preventing recurrent UTI over a 6-month period (RR 0.48), but patients were more likely to discontinue nitrofurantoin because of side effects. In another study, cefixime was more effective than nitrofurantoin in preventing recurrent UTI during the first 6 months (RR 0.74), but adverse reactions were more common with cefixime than with nitrofurantoin (63% vs. 26%).

Historically, the use of antimicrobial prophylaxis in all children with UTIs–in the 1970s–was based on studies that included asymptomatic bacteriuria as well as the more important symptomatic UTIs. The '70s data suggested that prophylaxis prevented recurrent positive urine cultures, many of which were from asymptomatic children. There also were insufficient data to prove that prophylaxis prevented renal scarring or the need for kidney transplantation. People had presumed that asymptomatic bacteriuria was as important as symptomatic UTI in leading to long-term kidney issues, but there was no definitive evidence for this.

Later imaging results indicated that VUR was associated with more frequent UTI, although we still didn't have proof of their association with long-term renal damage. Recent data indicate that lower grades of reflux are not statistically associated with long-term kidney injury or renal scarring, and now we see that the first recurrent UTI occurs just as soon, whether children are on or off prophylaxis. At the same time, we are increasingly concerned about antimicrobial resistance. The drugs typically used for prophylaxis–amoxicillin, trimethoprim-sulfamethoxazole, and first-generation cephalosporins–have become less and less active in vitro against the most common UTI pathogen, Escherichia coli.

Until we get more definitive data, I think that we can be more selective in deciding which patients with a first UTI should receive antimicrobial prophylaxis without exposing these children to extra risks. My personal bias is to limit prophylaxis to those in whom imaging shows either grade 4 or 5 VUR or other obstructive anatomic abnormalities. For children with lower grades of reflux, I would simply observe them for a recurrence pattern, keeping in mind that some may show more frequent recurrences than expected. This subset might need urologic referral to look for more subtle problems that can benefit from intervention. Given what we know about the risk of antimicrobial resistance, my advice would be to avoid 365 days per year of antibiotic exposure (prophylaxis) with low-grade VUR unless there were more than three UTI recurrences per year.

For children with high degrees of reflux (4 and 5), in vitro resistance data and hints from recent studies suggest that nitrofurantoin may currently be our best bet for prophylaxis. The micronized formulation (Macrobid) appears to have the fewest gastrointestinal side effects, so I'd use it as a first choice.

If patients don't tolerate nitrofurantoin, we should look at local resistance patterns, or perhaps a first-generation cephalosporin might be the next best choice. It's possible that broader-spectrum antimicrobials may work well in certain patients, but we don't have enough data on the prevalence of mechanisms of resistance, and tendencies to induce resistance, to comfortably use them empirically.

And, of course, we need to remember that when we do decide to prescribe long-term daily antibiotics, we can't assume for a minute that adherence will be complete. As the old saying goes, “Two-thirds of patients take two-thirds of the antibiotic two-thirds of the days prescribed.” One thing for which we have definitive proof is that nobody takes a drug every single day.

Two new studies may help identify the pathogen for cervical adenopathy in children, an often frustrating condition with numerous and divergent potential causes.

Most of us are comfortable treating certain presentations, such as tender, erythematous, anterior cervical lymphadenitis, for which the cause should be Staphylococcus aureus or Group A streptococci (GAS). We usually prescribe antibiotics and expect improvement within 10 days. A second presentation with a simple disposition is the nontender, unilateral, submandibular node with a purplish color and thinning of the skin over it. Usually, swelling has been present for weeks but has only recently developed the new color and thinning skin. This latter condition is usually nontuberculous mycobacterium (NTM) and is cause for referral to a surgical colleague.

But we have less certainty when predicting the cause of firm, unilateral, nontender adenopathy persisting after the usual 10-day course of antibiotics for initially tender adenitis, or when the child presents initially with nontender, unilateral, soft, mobile cervical adenopathy. Such nodes will often resolve spontaneously if we simply observe them for another 2–3 weeks. Those that don't are often the result of NTM. During the added observation, we often begin a diagnostic quest for such diverse causes as Epstein-Barr virus, Bartonella species, tuberculosis, NTM, Toxoplasma, or in some areas Histoplasma.

If our diagnostic quest is unrevealing and the node persists beyond 4–6 weeks, we usually refer for surgical excision to obtain histopathologic evaluation, plus cultures for mycobacteria, fungi, and conventional bacteria. Where available, fine-needle aspiration can fulfill the same objective. However, parents may become frustrated with the “tincture of time” approach and the slow pace before deciding on surgical referral. Two recent studies offer hope that we can make more rapid and accurate decisions.

A Dutch group reviewed the sensitivity and specificity of tuberculin skin testing (TST) in identifying NTM in Netherlands-born children (median age 48 months) with cervicofacial lymphadenopathy. Of these, 15 had immigrant parents, but none had traveled to TB-endemic areas (Clin. Infect. Dis. 2006;43:1547–51).

A total of 112 received a diagnosis of an NTM, confirmed by culture, polymerase chain reaction testing, or both. The infections were caused by Mycobacterium avium-intracellulare in 83 patients, by M. haemophilum in 21, and by other NTM species in eight. Nonmycobacterial lymphadenopathies were present in 46 of the children, including Bartonella henselae in 20, streptococcal infections in 14, staphylococcal infections in 11, and tuberculosis in one.

Using a cutoff of 5 mm of induration to define a “positive” NTM result, the TST's overall accuracy in detecting NTM was 0.84 (sensitivity, 70%; specificity, 98%; positive predictive value, 98%; and negative predictive value, 64%). Although 10-mm induration is the usual cutoff for M. tuberculosis, this study's data suggest that a 5–10-mm cutoff can predict NTM in previously healthy children with cervical lymphadenopathy, particularly where endemic TB is not common.

In my practice, I have used 5–10 mm of TST induration to strengthen my sense that NTM was the agent for nontender, unilateral cervical adenopathy of greater than 2 weeks' duration. This study increases my confidence with this approach.

In general, because community-acquired methicillin-resistant S. aureus has become more common, my algorithm is to first use 10 days of clindamycin, for antistaphylococcal and -GAS coverage. If the node persists but is asymptomatic and stable in size, I begin a work-up during a 2–4-week observation period before considering surgical referral. Unlike adults, in whom nonpainful neck masses are cancer until proven otherwise, prepubertal children rarely have this presentation for cancer, and so we can wait to see if slow resolution occurs.

My work-up includes serology, TST, and a chest x-ray (CXR). The CXR might show hilar adenopathy, histoplasmosis, or—rarely—tumor. Serology seems helpful only in the approximately 10% of these cases that turn out to be something other than NTM, such as Toxoplasma, Bartonella, or Histoplasma. Unfortunately, this work-up plus observation usually adds up to 6–8 weeks before surgical referral.

Clinical clues can sometimes hasten this process. If the node develops that rock-hard or adherent feel to palpation, I refer earlier to rule out the rare cancerous node. If the node breaks down to drain, or evolves into the purplish node noted above, prompt referral is warranted because of likely NTM.

Barring those or other new clues, can we more quickly feel confident in earlier surgical referral? The Dutch data suggest that we could postpone serologic evaluation until after a TST and perhaps a CXR. Here's how I would proceed, based on the size of the TST induration:

▸ Less than 5 mm and normal CXR. Proceed with serology and use standard observation before surgical referral.

▸ Less than 5 mm and hilar adenopathy. This can signify histoplasma, evolving NTM, or TB. If suspicion for TB is high because of social factors, obtain TST on family members. If family TSTs are negative and still no symptoms are present, then there are two options. First, one could do the serologies and, if they are negative, wait to reapply a TST in 4 weeks. Alternatively, referral for biopsy at this point could more rapidly identify the pathogen.

▸ 5–10 mm in size. Referral for surgical excision is appropriate if the child is not ill, lives where TB prevalence is low, and has no known TB exposure and no BCG vaccination. Excision not only is usually curative, but also provides tissue for microbiologic or histologic diagnosis, rendering serology unnecessary.

I don't agree with the editorial that accompanied this study, in which the author argued for multidrug antimicrobial treatment (Clin. Infect. Dis. 2006;43:1552–4). In my view, unless the position of the node places the facial nerve in jeopardy from excision, surgery is simpler than trying to keep a patient on 3–6 months of multiple, relatively expensive drugs that have potential adverse effects and that children don't like to take. At least one-third of these children either can't tolerate the regimen or don't respond to it, and end up having surgery anyway. The rate of recurrence after surgery is lower, about 5%–8%.

▸ Greater than 10 mm in size. This is generally presumed to be either latent or—if the CXR is positive—active TB. An appropriate TB regimen can be started. Some NTM infections can cause that degree of induration, but these cases are traditionally treated as TB is ruled out. This is possible with node biopsy. Whether to start TB medications before biopsy depends on risk factors.

For this situation, the second article, from Japan, offers future hope for an additional nonsurgical test to reduce the uncertainty about whether the child with a 10-mm or greater induration actually has NTM or TB. The authors evaluated a whole-blood interferon- and enzyme-linked immunosorbent assay (the Quantiferon TB-2G test, made by Cellestis Ltd.) in 50 healthy volunteers, 50 patients with active TB, and 100 patients with known NTM. They also skin-tested each individual (Clin. Infect. Dis. 2006;43:1540–6).

Among the healthy students, TSTs were negative in 64% and the Quantiferon test was negative in 94%. In confirmed TB cases, 64% had greater than 10-mm TST and only 4% had negative Quantiferon results. With pulmonary M. avium-intracellulare, 60% had greater than 10-mm TST and only 7% had positive Quantiferon results. The Quantiferon's mean sensitivity was 86% and specificity 94%. Although the Quantiferon does cross-react with a few NTM species, it does distinguish between TB and M. avium-intracellulare, which is the most common NTM.

The Quantiferon is currently marketed only for adults, and I don't think we have the data to support its use in children just yet. But ongoing studies should produce pediatric data in the next few years. Hopefully, this targeted test will become the new generation TB skin test substitute.

Two new studies may help identify the pathogen for cervical adenopathy in children, an often frustrating condition with numerous and divergent potential causes.

Most of us are comfortable treating certain presentations, such as tender, erythematous, anterior cervical lymphadenitis, for which the cause should be Staphylococcus aureus or Group A streptococci (GAS). We usually prescribe antibiotics and expect improvement within 10 days. A second presentation with a simple disposition is the nontender, unilateral, submandibular node with a purplish color and thinning of the skin over it. Usually, swelling has been present for weeks but has only recently developed the new color and thinning skin. This latter condition is usually nontuberculous mycobacterium (NTM) and is cause for referral to a surgical colleague.

But we have less certainty when predicting the cause of firm, unilateral, nontender adenopathy persisting after the usual 10-day course of antibiotics for initially tender adenitis, or when the child presents initially with nontender, unilateral, soft, mobile cervical adenopathy. Such nodes will often resolve spontaneously if we simply observe them for another 2–3 weeks. Those that don't are often the result of NTM. During the added observation, we often begin a diagnostic quest for such diverse causes as Epstein-Barr virus, Bartonella species, tuberculosis, NTM, Toxoplasma, or in some areas Histoplasma.

If our diagnostic quest is unrevealing and the node persists beyond 4–6 weeks, we usually refer for surgical excision to obtain histopathologic evaluation, plus cultures for mycobacteria, fungi, and conventional bacteria. Where available, fine-needle aspiration can fulfill the same objective. However, parents may become frustrated with the “tincture of time” approach and the slow pace before deciding on surgical referral. Two recent studies offer hope that we can make more rapid and accurate decisions.

A Dutch group reviewed the sensitivity and specificity of tuberculin skin testing (TST) in identifying NTM in Netherlands-born children (median age 48 months) with cervicofacial lymphadenopathy. Of these, 15 had immigrant parents, but none had traveled to TB-endemic areas (Clin. Infect. Dis. 2006;43:1547–51).

A total of 112 received a diagnosis of an NTM, confirmed by culture, polymerase chain reaction testing, or both. The infections were caused by Mycobacterium avium-intracellulare in 83 patients, by M. haemophilum in 21, and by other NTM species in eight. Nonmycobacterial lymphadenopathies were present in 46 of the children, including Bartonella henselae in 20, streptococcal infections in 14, staphylococcal infections in 11, and tuberculosis in one.

Using a cutoff of 5 mm of induration to define a “positive” NTM result, the TST's overall accuracy in detecting NTM was 0.84 (sensitivity, 70%; specificity, 98%; positive predictive value, 98%; and negative predictive value, 64%). Although 10-mm induration is the usual cutoff for M. tuberculosis, this study's data suggest that a 5–10-mm cutoff can predict NTM in previously healthy children with cervical lymphadenopathy, particularly where endemic TB is not common.

In my practice, I have used 5–10 mm of TST induration to strengthen my sense that NTM was the agent for nontender, unilateral cervical adenopathy of greater than 2 weeks' duration. This study increases my confidence with this approach.

In general, because community-acquired methicillin-resistant S. aureus has become more common, my algorithm is to first use 10 days of clindamycin, for antistaphylococcal and -GAS coverage. If the node persists but is asymptomatic and stable in size, I begin a work-up during a 2–4-week observation period before considering surgical referral. Unlike adults, in whom nonpainful neck masses are cancer until proven otherwise, prepubertal children rarely have this presentation for cancer, and so we can wait to see if slow resolution occurs.

My work-up includes serology, TST, and a chest x-ray (CXR). The CXR might show hilar adenopathy, histoplasmosis, or—rarely—tumor. Serology seems helpful only in the approximately 10% of these cases that turn out to be something other than NTM, such as Toxoplasma, Bartonella, or Histoplasma. Unfortunately, this work-up plus observation usually adds up to 6–8 weeks before surgical referral.

Clinical clues can sometimes hasten this process. If the node develops that rock-hard or adherent feel to palpation, I refer earlier to rule out the rare cancerous node. If the node breaks down to drain, or evolves into the purplish node noted above, prompt referral is warranted because of likely NTM.

Barring those or other new clues, can we more quickly feel confident in earlier surgical referral? The Dutch data suggest that we could postpone serologic evaluation until after a TST and perhaps a CXR. Here's how I would proceed, based on the size of the TST induration:

▸ Less than 5 mm and normal CXR. Proceed with serology and use standard observation before surgical referral.

▸ Less than 5 mm and hilar adenopathy. This can signify histoplasma, evolving NTM, or TB. If suspicion for TB is high because of social factors, obtain TST on family members. If family TSTs are negative and still no symptoms are present, then there are two options. First, one could do the serologies and, if they are negative, wait to reapply a TST in 4 weeks. Alternatively, referral for biopsy at this point could more rapidly identify the pathogen.

▸ 5–10 mm in size. Referral for surgical excision is appropriate if the child is not ill, lives where TB prevalence is low, and has no known TB exposure and no BCG vaccination. Excision not only is usually curative, but also provides tissue for microbiologic or histologic diagnosis, rendering serology unnecessary.

I don't agree with the editorial that accompanied this study, in which the author argued for multidrug antimicrobial treatment (Clin. Infect. Dis. 2006;43:1552–4). In my view, unless the position of the node places the facial nerve in jeopardy from excision, surgery is simpler than trying to keep a patient on 3–6 months of multiple, relatively expensive drugs that have potential adverse effects and that children don't like to take. At least one-third of these children either can't tolerate the regimen or don't respond to it, and end up having surgery anyway. The rate of recurrence after surgery is lower, about 5%–8%.

▸ Greater than 10 mm in size. This is generally presumed to be either latent or—if the CXR is positive—active TB. An appropriate TB regimen can be started. Some NTM infections can cause that degree of induration, but these cases are traditionally treated as TB is ruled out. This is possible with node biopsy. Whether to start TB medications before biopsy depends on risk factors.

For this situation, the second article, from Japan, offers future hope for an additional nonsurgical test to reduce the uncertainty about whether the child with a 10-mm or greater induration actually has NTM or TB. The authors evaluated a whole-blood interferon- and enzyme-linked immunosorbent assay (the Quantiferon TB-2G test, made by Cellestis Ltd.) in 50 healthy volunteers, 50 patients with active TB, and 100 patients with known NTM. They also skin-tested each individual (Clin. Infect. Dis. 2006;43:1540–6).

Among the healthy students, TSTs were negative in 64% and the Quantiferon test was negative in 94%. In confirmed TB cases, 64% had greater than 10-mm TST and only 4% had negative Quantiferon results. With pulmonary M. avium-intracellulare, 60% had greater than 10-mm TST and only 7% had positive Quantiferon results. The Quantiferon's mean sensitivity was 86% and specificity 94%. Although the Quantiferon does cross-react with a few NTM species, it does distinguish between TB and M. avium-intracellulare, which is the most common NTM.

The Quantiferon is currently marketed only for adults, and I don't think we have the data to support its use in children just yet. But ongoing studies should produce pediatric data in the next few years. Hopefully, this targeted test will become the new generation TB skin test substitute.

Two new studies may help identify the pathogen for cervical adenopathy in children, an often frustrating condition with numerous and divergent potential causes.

Most of us are comfortable treating certain presentations, such as tender, erythematous, anterior cervical lymphadenitis, for which the cause should be Staphylococcus aureus or Group A streptococci (GAS). We usually prescribe antibiotics and expect improvement within 10 days. A second presentation with a simple disposition is the nontender, unilateral, submandibular node with a purplish color and thinning of the skin over it. Usually, swelling has been present for weeks but has only recently developed the new color and thinning skin. This latter condition is usually nontuberculous mycobacterium (NTM) and is cause for referral to a surgical colleague.

But we have less certainty when predicting the cause of firm, unilateral, nontender adenopathy persisting after the usual 10-day course of antibiotics for initially tender adenitis, or when the child presents initially with nontender, unilateral, soft, mobile cervical adenopathy. Such nodes will often resolve spontaneously if we simply observe them for another 2–3 weeks. Those that don't are often the result of NTM. During the added observation, we often begin a diagnostic quest for such diverse causes as Epstein-Barr virus, Bartonella species, tuberculosis, NTM, Toxoplasma, or in some areas Histoplasma.

If our diagnostic quest is unrevealing and the node persists beyond 4–6 weeks, we usually refer for surgical excision to obtain histopathologic evaluation, plus cultures for mycobacteria, fungi, and conventional bacteria. Where available, fine-needle aspiration can fulfill the same objective. However, parents may become frustrated with the “tincture of time” approach and the slow pace before deciding on surgical referral. Two recent studies offer hope that we can make more rapid and accurate decisions.

A Dutch group reviewed the sensitivity and specificity of tuberculin skin testing (TST) in identifying NTM in Netherlands-born children (median age 48 months) with cervicofacial lymphadenopathy. Of these, 15 had immigrant parents, but none had traveled to TB-endemic areas (Clin. Infect. Dis. 2006;43:1547–51).

A total of 112 received a diagnosis of an NTM, confirmed by culture, polymerase chain reaction testing, or both. The infections were caused by Mycobacterium avium-intracellulare in 83 patients, by M. haemophilum in 21, and by other NTM species in eight. Nonmycobacterial lymphadenopathies were present in 46 of the children, including Bartonella henselae in 20, streptococcal infections in 14, staphylococcal infections in 11, and tuberculosis in one.

Using a cutoff of 5 mm of induration to define a “positive” NTM result, the TST's overall accuracy in detecting NTM was 0.84 (sensitivity, 70%; specificity, 98%; positive predictive value, 98%; and negative predictive value, 64%). Although 10-mm induration is the usual cutoff for M. tuberculosis, this study's data suggest that a 5–10-mm cutoff can predict NTM in previously healthy children with cervical lymphadenopathy, particularly where endemic TB is not common.

In my practice, I have used 5–10 mm of TST induration to strengthen my sense that NTM was the agent for nontender, unilateral cervical adenopathy of greater than 2 weeks' duration. This study increases my confidence with this approach.

In general, because community-acquired methicillin-resistant S. aureus has become more common, my algorithm is to first use 10 days of clindamycin, for antistaphylococcal and -GAS coverage. If the node persists but is asymptomatic and stable in size, I begin a work-up during a 2–4-week observation period before considering surgical referral. Unlike adults, in whom nonpainful neck masses are cancer until proven otherwise, prepubertal children rarely have this presentation for cancer, and so we can wait to see if slow resolution occurs.

My work-up includes serology, TST, and a chest x-ray (CXR). The CXR might show hilar adenopathy, histoplasmosis, or—rarely—tumor. Serology seems helpful only in the approximately 10% of these cases that turn out to be something other than NTM, such as Toxoplasma, Bartonella, or Histoplasma. Unfortunately, this work-up plus observation usually adds up to 6–8 weeks before surgical referral.

Clinical clues can sometimes hasten this process. If the node develops that rock-hard or adherent feel to palpation, I refer earlier to rule out the rare cancerous node. If the node breaks down to drain, or evolves into the purplish node noted above, prompt referral is warranted because of likely NTM.

Barring those or other new clues, can we more quickly feel confident in earlier surgical referral? The Dutch data suggest that we could postpone serologic evaluation until after a TST and perhaps a CXR. Here's how I would proceed, based on the size of the TST induration:

▸ Less than 5 mm and normal CXR. Proceed with serology and use standard observation before surgical referral.

▸ Less than 5 mm and hilar adenopathy. This can signify histoplasma, evolving NTM, or TB. If suspicion for TB is high because of social factors, obtain TST on family members. If family TSTs are negative and still no symptoms are present, then there are two options. First, one could do the serologies and, if they are negative, wait to reapply a TST in 4 weeks. Alternatively, referral for biopsy at this point could more rapidly identify the pathogen.

▸ 5–10 mm in size. Referral for surgical excision is appropriate if the child is not ill, lives where TB prevalence is low, and has no known TB exposure and no BCG vaccination. Excision not only is usually curative, but also provides tissue for microbiologic or histologic diagnosis, rendering serology unnecessary.

I don't agree with the editorial that accompanied this study, in which the author argued for multidrug antimicrobial treatment (Clin. Infect. Dis. 2006;43:1552–4). In my view, unless the position of the node places the facial nerve in jeopardy from excision, surgery is simpler than trying to keep a patient on 3–6 months of multiple, relatively expensive drugs that have potential adverse effects and that children don't like to take. At least one-third of these children either can't tolerate the regimen or don't respond to it, and end up having surgery anyway. The rate of recurrence after surgery is lower, about 5%–8%.

▸ Greater than 10 mm in size. This is generally presumed to be either latent or—if the CXR is positive—active TB. An appropriate TB regimen can be started. Some NTM infections can cause that degree of induration, but these cases are traditionally treated as TB is ruled out. This is possible with node biopsy. Whether to start TB medications before biopsy depends on risk factors.

For this situation, the second article, from Japan, offers future hope for an additional nonsurgical test to reduce the uncertainty about whether the child with a 10-mm or greater induration actually has NTM or TB. The authors evaluated a whole-blood interferon- and enzyme-linked immunosorbent assay (the Quantiferon TB-2G test, made by Cellestis Ltd.) in 50 healthy volunteers, 50 patients with active TB, and 100 patients with known NTM. They also skin-tested each individual (Clin. Infect. Dis. 2006;43:1540–6).

Among the healthy students, TSTs were negative in 64% and the Quantiferon test was negative in 94%. In confirmed TB cases, 64% had greater than 10-mm TST and only 4% had negative Quantiferon results. With pulmonary M. avium-intracellulare, 60% had greater than 10-mm TST and only 7% had positive Quantiferon results. The Quantiferon's mean sensitivity was 86% and specificity 94%. Although the Quantiferon does cross-react with a few NTM species, it does distinguish between TB and M. avium-intracellulare, which is the most common NTM.

The Quantiferon is currently marketed only for adults, and I don't think we have the data to support its use in children just yet. But ongoing studies should produce pediatric data in the next few years. Hopefully, this targeted test will become the new generation TB skin test substitute.

We should not let the declining rate of tuberculosis in the United States lull us into missing opportunities for identifying and treating children who have latent infection or are at risk for the disease.

Happily, the tuberculosis rate in 2006 was the lowest recorded since national reporting began in 1953. The 13,767 reported cases last year, or 4.6 per 100,000 population, represents a 3.2% decline from the rate in 2005. However, the rate of decline in TB has slowed since 2000. From 1993 through 2000, the average annual percentage decline in TB incidence was 7.3% per year. Since 2000, that rate has been just 3.8% per year, according to the latest data from the Centers for Disease Control and Prevention (MMWR 2007;56:245–50).

Trends among children have been similar. In 2005, the latest year for which age-specific data are available, there were 863 cases among children aged 0–14 years, a rate of 1.4 per 100,000. Among those aged 15–24 years, the 1,542 cases represented a rate of 3.7 per 100,000. Both rates were slightly lower than in 2004 (1.6 and 3.8 per 100,000, respectively), and significantly less than the 2.9 and 5.0 rates seen in 1993. But, as with the entire population, the decline has slowed among children, too.

Although the highest rates of TB in the United States are still among ethnic minorities in large urban areas, the disease is not limited to those populations. The proportion of TB cases among foreign-born individuals has increased each year since 1993; such cases now account for about one-fourth of all TB cases. In 2006, 56% of those were from five countries: Mexico, the Philippines, Vietnam, India, and China. Most of the foreign-born individuals in the United States who progress from latent TB infection to TB disease became infected while abroad. These cases represent immigrants, internationally adopted children from countries with high TB rates, and children exposed during foreign travel.

For physicians in the United States who provide primary care for children, identifying children who are at risk for TB is critical. In 2004, the American Academy of Pediatrics (AAP), the American Thoracic Society (ATS), and the CDC issued a comprehensive set of guidelines we all should follow, entitled “Targeted Tuberculin Skin Testing and Treatment of Latent Tuberculosis Infection in Children and Adolescents” (Pediatrics 2004;114:1175).

The three organizations' Pediatric Tuberculosis Collaborative Group recommended four questions to be asked about every patient:

▸ Was the child born outside the United States? (If yes, ask in which country. If the child was born in Africa, Asia, Latin America, or Eastern Europe, place a tuberculin skin test [TST]).

▸ Has the child traveled outside the United States? (If yes, ask where. If the child stayed with friends or family in any of the above-mentioned areas for a week or longer, place a TST test.)

▸ Has the child been exposed to anyone with TB disease? (If yes, a series of questions should follow to determine if the person had TB or latent disease, when the exposure occurred, and the nature of the contact. If exposure is confirmed, place a TST test. If the child has been in contact with someone who has TB disease, notify local health authorities and consult with an infectious disease specialist.)

▸ Does the child have close contact with a person who has a positive TB skin test? (Ask the same follow-up questions as in the preceding.)

The only TB test now recommended is the intradermal injection of 5 tuberculin units of purified protein derivative from Mycobacterium tuberculosis administered by the Mantoux technique.

The AAP/ATC/CDC guidelines define positive TST results in children and adolescents using three cutoff levels for the transverse diameter of the reaction: less than or equal to 5 mm, 10 mm, and 15 mm.

The 5-mm cutoff is used for children at high risk, including those in close contact with TB cases, those with positive findings on chest radiograph, or those with clinical evidence of TB disease.

The 10-mm cutoff is for those at moderate risk, including children less than 4 years of age, those with concomitant medical conditions, or those who were born in a country with a high TB prevalence.

The highest cutoff, 15 mm, is reserved for children aged 4 and older with no known risk factors.

Most physicians are familiar with the correct technique for TB testing, but fewer have had experience in interpreting the results. Guidelines suggest that the reaction must be read by a trained health care provider at 48–72 hours after placement. Interpretation should not be left to the parents. In fact, your office practice personnel may not be experienced either and, therefore, it may not be appropriate to place and read TST in the practice setting.

Evidence suggests that interpretation of TST even by health care providers may be fraught with error. In one study of 107 health care providers including 52 practicing pediatricians, 33 pediatric house officers, and 10 pediatric academicians, 93% identified a known tuberculin converter as tuberculin negative, based on their interpretation of the degree of induration. When presented with an induration of 15 mm, the group's median reading of its size was only 10 mm (Chest 1998;113:1175–7).

Live virus vaccines—measles, mumps, rubella, and varicella—can suppress the TST response. Also be aware that in patients treated with systemic corticosteroids or inpatients who have been treated with the newer tumor necrosis factor antagonists, a false-negative test result can occur, while prior receipt of the BCG vaccine—given at birth in many TB-endemic countries—can produce a false-positive result. However, most children with a history of the BCG vaccine and a positive skin test result have latent tuberculosis. In these instances, consultation with your local infectious disease specialist will be helpful.

Perhaps most important, the identification of children with latent TB infection (LTBI) or tuberculosis disease (who rarely if ever are at risk to transmit TB when less than 10 years of age) is a sentinel event that should provoke an aggressive investigation targeting adult close contacts.

Here in Kansas City, we recently had a TB outbreak in a day care center, mostly among children born in the United States, which was related to their exposure to a foreign-born adult residing in the day care home. Epidemiologic details are being investigated; a combination of problems caused by language barrier, difficulty tracing contacts, and poor record keeping in an unlicensed facility complicate the process.

The guidelines also address treatment for latent TB infection. Daily isoniazid for 9 months is the standard treatment regimen for children and adolescents without a known source case, or those with a source case known to be infected with a susceptible strain. Intermittent regimens are acceptable if given within a directly observed therapy program. Daily rifampin for 6 months is a suitable alternative for those with isoniazid-resistant/rifampin-susceptible strains, or those who can't tolerate isoniazid.

Treatment of LTBI and tuberculosis disease generally should involve the help of your local TB expert. While the proportion of TB cases resistant to both isoniazid and rifampin remained at 1.2% from 2004 to 2005, and isoniazid remains the standard drug for LTBI treatment, we can't be complacent. In 2005, foreign-born individuals accounted for 81.5% of the 124 multidrug-resistant TB cases, and, according to the CDC, that percentage continues to grow. Treatment in such cases is more complicated, involving several drugs that are not generally used in the treatment of TB, and follow-up is important.

We should not let the declining rate of tuberculosis in the United States lull us into missing opportunities for identifying and treating children who have latent infection or are at risk for the disease.

Happily, the tuberculosis rate in 2006 was the lowest recorded since national reporting began in 1953. The 13,767 reported cases last year, or 4.6 per 100,000 population, represents a 3.2% decline from the rate in 2005. However, the rate of decline in TB has slowed since 2000. From 1993 through 2000, the average annual percentage decline in TB incidence was 7.3% per year. Since 2000, that rate has been just 3.8% per year, according to the latest data from the Centers for Disease Control and Prevention (MMWR 2007;56:245–50).

Trends among children have been similar. In 2005, the latest year for which age-specific data are available, there were 863 cases among children aged 0–14 years, a rate of 1.4 per 100,000. Among those aged 15–24 years, the 1,542 cases represented a rate of 3.7 per 100,000. Both rates were slightly lower than in 2004 (1.6 and 3.8 per 100,000, respectively), and significantly less than the 2.9 and 5.0 rates seen in 1993. But, as with the entire population, the decline has slowed among children, too.

Although the highest rates of TB in the United States are still among ethnic minorities in large urban areas, the disease is not limited to those populations. The proportion of TB cases among foreign-born individuals has increased each year since 1993; such cases now account for about one-fourth of all TB cases. In 2006, 56% of those were from five countries: Mexico, the Philippines, Vietnam, India, and China. Most of the foreign-born individuals in the United States who progress from latent TB infection to TB disease became infected while abroad. These cases represent immigrants, internationally adopted children from countries with high TB rates, and children exposed during foreign travel.

For physicians in the United States who provide primary care for children, identifying children who are at risk for TB is critical. In 2004, the American Academy of Pediatrics (AAP), the American Thoracic Society (ATS), and the CDC issued a comprehensive set of guidelines we all should follow, entitled “Targeted Tuberculin Skin Testing and Treatment of Latent Tuberculosis Infection in Children and Adolescents” (Pediatrics 2004;114:1175).

The three organizations' Pediatric Tuberculosis Collaborative Group recommended four questions to be asked about every patient:

▸ Was the child born outside the United States? (If yes, ask in which country. If the child was born in Africa, Asia, Latin America, or Eastern Europe, place a tuberculin skin test [TST]).

▸ Has the child traveled outside the United States? (If yes, ask where. If the child stayed with friends or family in any of the above-mentioned areas for a week or longer, place a TST test.)

▸ Has the child been exposed to anyone with TB disease? (If yes, a series of questions should follow to determine if the person had TB or latent disease, when the exposure occurred, and the nature of the contact. If exposure is confirmed, place a TST test. If the child has been in contact with someone who has TB disease, notify local health authorities and consult with an infectious disease specialist.)

▸ Does the child have close contact with a person who has a positive TB skin test? (Ask the same follow-up questions as in the preceding.)

The only TB test now recommended is the intradermal injection of 5 tuberculin units of purified protein derivative from Mycobacterium tuberculosis administered by the Mantoux technique.

The AAP/ATC/CDC guidelines define positive TST results in children and adolescents using three cutoff levels for the transverse diameter of the reaction: less than or equal to 5 mm, 10 mm, and 15 mm.

The 5-mm cutoff is used for children at high risk, including those in close contact with TB cases, those with positive findings on chest radiograph, or those with clinical evidence of TB disease.

The 10-mm cutoff is for those at moderate risk, including children less than 4 years of age, those with concomitant medical conditions, or those who were born in a country with a high TB prevalence.

The highest cutoff, 15 mm, is reserved for children aged 4 and older with no known risk factors.

Most physicians are familiar with the correct technique for TB testing, but fewer have had experience in interpreting the results. Guidelines suggest that the reaction must be read by a trained health care provider at 48–72 hours after placement. Interpretation should not be left to the parents. In fact, your office practice personnel may not be experienced either and, therefore, it may not be appropriate to place and read TST in the practice setting.

Evidence suggests that interpretation of TST even by health care providers may be fraught with error. In one study of 107 health care providers including 52 practicing pediatricians, 33 pediatric house officers, and 10 pediatric academicians, 93% identified a known tuberculin converter as tuberculin negative, based on their interpretation of the degree of induration. When presented with an induration of 15 mm, the group's median reading of its size was only 10 mm (Chest 1998;113:1175–7).

Live virus vaccines—measles, mumps, rubella, and varicella—can suppress the TST response. Also be aware that in patients treated with systemic corticosteroids or inpatients who have been treated with the newer tumor necrosis factor antagonists, a false-negative test result can occur, while prior receipt of the BCG vaccine—given at birth in many TB-endemic countries—can produce a false-positive result. However, most children with a history of the BCG vaccine and a positive skin test result have latent tuberculosis. In these instances, consultation with your local infectious disease specialist will be helpful.

Perhaps most important, the identification of children with latent TB infection (LTBI) or tuberculosis disease (who rarely if ever are at risk to transmit TB when less than 10 years of age) is a sentinel event that should provoke an aggressive investigation targeting adult close contacts.

Here in Kansas City, we recently had a TB outbreak in a day care center, mostly among children born in the United States, which was related to their exposure to a foreign-born adult residing in the day care home. Epidemiologic details are being investigated; a combination of problems caused by language barrier, difficulty tracing contacts, and poor record keeping in an unlicensed facility complicate the process.

The guidelines also address treatment for latent TB infection. Daily isoniazid for 9 months is the standard treatment regimen for children and adolescents without a known source case, or those with a source case known to be infected with a susceptible strain. Intermittent regimens are acceptable if given within a directly observed therapy program. Daily rifampin for 6 months is a suitable alternative for those with isoniazid-resistant/rifampin-susceptible strains, or those who can't tolerate isoniazid.

Treatment of LTBI and tuberculosis disease generally should involve the help of your local TB expert. While the proportion of TB cases resistant to both isoniazid and rifampin remained at 1.2% from 2004 to 2005, and isoniazid remains the standard drug for LTBI treatment, we can't be complacent. In 2005, foreign-born individuals accounted for 81.5% of the 124 multidrug-resistant TB cases, and, according to the CDC, that percentage continues to grow. Treatment in such cases is more complicated, involving several drugs that are not generally used in the treatment of TB, and follow-up is important.

We should not let the declining rate of tuberculosis in the United States lull us into missing opportunities for identifying and treating children who have latent infection or are at risk for the disease.

Happily, the tuberculosis rate in 2006 was the lowest recorded since national reporting began in 1953. The 13,767 reported cases last year, or 4.6 per 100,000 population, represents a 3.2% decline from the rate in 2005. However, the rate of decline in TB has slowed since 2000. From 1993 through 2000, the average annual percentage decline in TB incidence was 7.3% per year. Since 2000, that rate has been just 3.8% per year, according to the latest data from the Centers for Disease Control and Prevention (MMWR 2007;56:245–50).

Trends among children have been similar. In 2005, the latest year for which age-specific data are available, there were 863 cases among children aged 0–14 years, a rate of 1.4 per 100,000. Among those aged 15–24 years, the 1,542 cases represented a rate of 3.7 per 100,000. Both rates were slightly lower than in 2004 (1.6 and 3.8 per 100,000, respectively), and significantly less than the 2.9 and 5.0 rates seen in 1993. But, as with the entire population, the decline has slowed among children, too.

Although the highest rates of TB in the United States are still among ethnic minorities in large urban areas, the disease is not limited to those populations. The proportion of TB cases among foreign-born individuals has increased each year since 1993; such cases now account for about one-fourth of all TB cases. In 2006, 56% of those were from five countries: Mexico, the Philippines, Vietnam, India, and China. Most of the foreign-born individuals in the United States who progress from latent TB infection to TB disease became infected while abroad. These cases represent immigrants, internationally adopted children from countries with high TB rates, and children exposed during foreign travel.

For physicians in the United States who provide primary care for children, identifying children who are at risk for TB is critical. In 2004, the American Academy of Pediatrics (AAP), the American Thoracic Society (ATS), and the CDC issued a comprehensive set of guidelines we all should follow, entitled “Targeted Tuberculin Skin Testing and Treatment of Latent Tuberculosis Infection in Children and Adolescents” (Pediatrics 2004;114:1175).

The three organizations' Pediatric Tuberculosis Collaborative Group recommended four questions to be asked about every patient:

▸ Was the child born outside the United States? (If yes, ask in which country. If the child was born in Africa, Asia, Latin America, or Eastern Europe, place a tuberculin skin test [TST]).

▸ Has the child traveled outside the United States? (If yes, ask where. If the child stayed with friends or family in any of the above-mentioned areas for a week or longer, place a TST test.)

▸ Has the child been exposed to anyone with TB disease? (If yes, a series of questions should follow to determine if the person had TB or latent disease, when the exposure occurred, and the nature of the contact. If exposure is confirmed, place a TST test. If the child has been in contact with someone who has TB disease, notify local health authorities and consult with an infectious disease specialist.)

▸ Does the child have close contact with a person who has a positive TB skin test? (Ask the same follow-up questions as in the preceding.)

The only TB test now recommended is the intradermal injection of 5 tuberculin units of purified protein derivative from Mycobacterium tuberculosis administered by the Mantoux technique.

The AAP/ATC/CDC guidelines define positive TST results in children and adolescents using three cutoff levels for the transverse diameter of the reaction: less than or equal to 5 mm, 10 mm, and 15 mm.

The 5-mm cutoff is used for children at high risk, including those in close contact with TB cases, those with positive findings on chest radiograph, or those with clinical evidence of TB disease.

The 10-mm cutoff is for those at moderate risk, including children less than 4 years of age, those with concomitant medical conditions, or those who were born in a country with a high TB prevalence.

The highest cutoff, 15 mm, is reserved for children aged 4 and older with no known risk factors.

Most physicians are familiar with the correct technique for TB testing, but fewer have had experience in interpreting the results. Guidelines suggest that the reaction must be read by a trained health care provider at 48–72 hours after placement. Interpretation should not be left to the parents. In fact, your office practice personnel may not be experienced either and, therefore, it may not be appropriate to place and read TST in the practice setting.

Evidence suggests that interpretation of TST even by health care providers may be fraught with error. In one study of 107 health care providers including 52 practicing pediatricians, 33 pediatric house officers, and 10 pediatric academicians, 93% identified a known tuberculin converter as tuberculin negative, based on their interpretation of the degree of induration. When presented with an induration of 15 mm, the group's median reading of its size was only 10 mm (Chest 1998;113:1175–7).

Live virus vaccines—measles, mumps, rubella, and varicella—can suppress the TST response. Also be aware that in patients treated with systemic corticosteroids or inpatients who have been treated with the newer tumor necrosis factor antagonists, a false-negative test result can occur, while prior receipt of the BCG vaccine—given at birth in many TB-endemic countries—can produce a false-positive result. However, most children with a history of the BCG vaccine and a positive skin test result have latent tuberculosis. In these instances, consultation with your local infectious disease specialist will be helpful.

Perhaps most important, the identification of children with latent TB infection (LTBI) or tuberculosis disease (who rarely if ever are at risk to transmit TB when less than 10 years of age) is a sentinel event that should provoke an aggressive investigation targeting adult close contacts.

Here in Kansas City, we recently had a TB outbreak in a day care center, mostly among children born in the United States, which was related to their exposure to a foreign-born adult residing in the day care home. Epidemiologic details are being investigated; a combination of problems caused by language barrier, difficulty tracing contacts, and poor record keeping in an unlicensed facility complicate the process.

The guidelines also address treatment for latent TB infection. Daily isoniazid for 9 months is the standard treatment regimen for children and adolescents without a known source case, or those with a source case known to be infected with a susceptible strain. Intermittent regimens are acceptable if given within a directly observed therapy program. Daily rifampin for 6 months is a suitable alternative for those with isoniazid-resistant/rifampin-susceptible strains, or those who can't tolerate isoniazid.

Treatment of LTBI and tuberculosis disease generally should involve the help of your local TB expert. While the proportion of TB cases resistant to both isoniazid and rifampin remained at 1.2% from 2004 to 2005, and isoniazid remains the standard drug for LTBI treatment, we can't be complacent. In 2005, foreign-born individuals accounted for 81.5% of the 124 multidrug-resistant TB cases, and, according to the CDC, that percentage continues to grow. Treatment in such cases is more complicated, involving several drugs that are not generally used in the treatment of TB, and follow-up is important.

[email protected]

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

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

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

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