Pulmonary Health Hub

SAN FRANCISCO – Linezolid works better than vancomycin in obese patients with MRSA pneumonia, according to an industry-supported analysis.

Clinical success – ICU or hospital discharge by day 14 in the absence of death, therapy change, or intubation – was more likely among 49 patients with body-mass-indices of 30 or more treated with 600 mg of linezolid IV or orally every 12 hours, the standard dose, than among 740 treated with standard dosing of vancomycin (HR 1.77, 95% CI 1.18-2.64). The findings come from a national retrospective cohort analysis of Veterans Affairs hospital data. The study was funded in part by Pfizer, which markets linezolid as Zyvox.

"Clinical success rates were higher [in obese patients] with linezolid. We don’t know exactly why," lead investigator Aisling Caffrey, Ph.D., assistant professor of pharmacoepidemiology at the University of Rhode Island College of Pharmacy in Kingston, R.I., said at the Interscience Conference on Antimicrobial Agents and Chemotherapy.

Maybe it was because vancomycin dosing is, in part, weight based and perhaps problematic for obese patients. Clinicians may be reluctant to exceed standard dosing even if BMIs suggest it, due to toxicity concerns; it’s unclear if patients in the study received adequate doses.

Linezolid "is a little more straightforward. Maybe obese patients were more likely to get the right dose," Dr. Caffrey said.

She and her coinvestigators hope to look further into the antibiotic treatment of MRSA pneumonia in the overweight population.

The investigation was a subgroup analysis of a larger MRSA pneumonia comparison study that found nonobese patients treated with linezolid were less likely to have 30-day hospital readmissions (HR 0.60, 95% CI 0.37-0.97). There were no other outcome differences between the drugs. Patients in the study were treated for at least 3 days.

The conference was sponsored by the American Society for Microbiology. Pfizer and the Department of Veterans Affairs funded the study. Two of the researchers were Pfizer employees. Dr. Caffrey\'s research is funded in part by Pfizer.

SAN FRANCISCO – Linezolid works better than vancomycin in obese patients with MRSA pneumonia, according to an industry-supported analysis.

Clinical success – ICU or hospital discharge by day 14 in the absence of death, therapy change, or intubation – was more likely among 49 patients with body-mass-indices of 30 or more treated with 600 mg of linezolid IV or orally every 12 hours, the standard dose, than among 740 treated with standard dosing of vancomycin (HR 1.77, 95% CI 1.18-2.64). The findings come from a national retrospective cohort analysis of Veterans Affairs hospital data. The study was funded in part by Pfizer, which markets linezolid as Zyvox.

"Clinical success rates were higher [in obese patients] with linezolid. We don’t know exactly why," lead investigator Aisling Caffrey, Ph.D., assistant professor of pharmacoepidemiology at the University of Rhode Island College of Pharmacy in Kingston, R.I., said at the Interscience Conference on Antimicrobial Agents and Chemotherapy.

Maybe it was because vancomycin dosing is, in part, weight based and perhaps problematic for obese patients. Clinicians may be reluctant to exceed standard dosing even if BMIs suggest it, due to toxicity concerns; it’s unclear if patients in the study received adequate doses.

Linezolid "is a little more straightforward. Maybe obese patients were more likely to get the right dose," Dr. Caffrey said.

She and her coinvestigators hope to look further into the antibiotic treatment of MRSA pneumonia in the overweight population.

The investigation was a subgroup analysis of a larger MRSA pneumonia comparison study that found nonobese patients treated with linezolid were less likely to have 30-day hospital readmissions (HR 0.60, 95% CI 0.37-0.97). There were no other outcome differences between the drugs. Patients in the study were treated for at least 3 days.

The conference was sponsored by the American Society for Microbiology. Pfizer and the Department of Veterans Affairs funded the study. Two of the researchers were Pfizer employees. Dr. Caffrey\'s research is funded in part by Pfizer.

SAN FRANCISCO – Linezolid works better than vancomycin in obese patients with MRSA pneumonia, according to an industry-supported analysis.

Clinical success – ICU or hospital discharge by day 14 in the absence of death, therapy change, or intubation – was more likely among 49 patients with body-mass-indices of 30 or more treated with 600 mg of linezolid IV or orally every 12 hours, the standard dose, than among 740 treated with standard dosing of vancomycin (HR 1.77, 95% CI 1.18-2.64). The findings come from a national retrospective cohort analysis of Veterans Affairs hospital data. The study was funded in part by Pfizer, which markets linezolid as Zyvox.

"Clinical success rates were higher [in obese patients] with linezolid. We don’t know exactly why," lead investigator Aisling Caffrey, Ph.D., assistant professor of pharmacoepidemiology at the University of Rhode Island College of Pharmacy in Kingston, R.I., said at the Interscience Conference on Antimicrobial Agents and Chemotherapy.

Maybe it was because vancomycin dosing is, in part, weight based and perhaps problematic for obese patients. Clinicians may be reluctant to exceed standard dosing even if BMIs suggest it, due to toxicity concerns; it’s unclear if patients in the study received adequate doses.

Linezolid "is a little more straightforward. Maybe obese patients were more likely to get the right dose," Dr. Caffrey said.

She and her coinvestigators hope to look further into the antibiotic treatment of MRSA pneumonia in the overweight population.

The investigation was a subgroup analysis of a larger MRSA pneumonia comparison study that found nonobese patients treated with linezolid were less likely to have 30-day hospital readmissions (HR 0.60, 95% CI 0.37-0.97). There were no other outcome differences between the drugs. Patients in the study were treated for at least 3 days.

The conference was sponsored by the American Society for Microbiology. Pfizer and the Department of Veterans Affairs funded the study. Two of the researchers were Pfizer employees. Dr. Caffrey\'s research is funded in part by Pfizer.

SAN FRANCISCO – In a national cohort of VA patients with MRSA pneumonia, treatment with linezolid was the only modifiable variable in predicting clinical success.

"Pneumonia is the No. 1 cause of infectious disease–related deaths in the United States yet there are limited treatment options for pneumonia caused by MRSA," Aisling R. Caffrey, Ph.D., said at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy. "Identification of independent predictors of clinical success can optimize patient care."

In an effort to identify independent predictors of clinical success in MRSA pneumonia, Dr. Caffrey, assistant professor of pharmacoepidemiology at the University of Rhode Island College of Pharmacy, and her associates conducted a retrospective cohort study of VA hospital admissions between January 2002 and September 2010 with diagnosis codes for MRSA and pneumonia. They used pharmacy records to identify initiation of linezolid or vancomycin during admission, with at least 3 days of therapy as dosed per protocol.

Patients who died or were discharged within 3 days of treatment initiation with either agent were excluded from the study, as were those whose treatment was initiated in a nursing home and those who were exposed to more than 2 consecutive days of antibiotic therapy with MRSA activity within 3 days prior to initiation of linezolid or vancomycin or during treatment with either agent.

Clinical success was defined as discharge from the hospital or intensive care unit by day 14 after treatment initiation, in the absence of death, therapy change, or intubation. Nonsuccess was defined as therapy change, intubation, discharge, and readmission, or death between treatment initiation and day 14. They also investigated numerous potential predictors of clinical success, including treatment with linezolid or vancomycin, demographics and admission characteristics, and comorbidities and medical history.

Dr. Caffrey reported data from 231 patients who received linezolid and 3,501 patients who received vancomycin. Their mean age was 70 years and most (98%) were male. Predictors of clinical success included treatment with linezolid (OR 1.53) and having a previous complication of an implant or graft (OR 1.55). Factors associated with nonsuccess included dialysis (OR 0.54), intravenous line (OR 0.76), having three or more inpatient procedures (OR 0.53), inpatient surgery (OR 0.48), urinary tract infection (0.82), previous coagulopathy (0.74), previous endocarditis (0.24), and previous amputation procedure (OR 0.72).

Dr. Caffrey acknowledged certain limitations of the study, including the reliance on diagnostic codes to ascertain the number of MRSA pneumonia cases. "We’re probably only capturing 20%-40% of MRSA diagnoses by using the diagnosis codes," she said at the meeting, which was sponsored by the American Society for Microbiology.

Low generalizability of the findings to other patient populations is another limitation: "The VA is the largest integrated health care system in the United States but it [consists of] mainly older white males with a lot of comorbidities," she explained.

She concluded that patients with MRSA pneumonia "are often complex, and identifying predictors of success is useful in maximizing clinical decision making."

The study was supported by the Department of Veterans Affairs and Pfizer.

SAN FRANCISCO – In a national cohort of VA patients with MRSA pneumonia, treatment with linezolid was the only modifiable variable in predicting clinical success.

"Pneumonia is the No. 1 cause of infectious disease–related deaths in the United States yet there are limited treatment options for pneumonia caused by MRSA," Aisling R. Caffrey, Ph.D., said at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy. "Identification of independent predictors of clinical success can optimize patient care."

In an effort to identify independent predictors of clinical success in MRSA pneumonia, Dr. Caffrey, assistant professor of pharmacoepidemiology at the University of Rhode Island College of Pharmacy, and her associates conducted a retrospective cohort study of VA hospital admissions between January 2002 and September 2010 with diagnosis codes for MRSA and pneumonia. They used pharmacy records to identify initiation of linezolid or vancomycin during admission, with at least 3 days of therapy as dosed per protocol.

Patients who died or were discharged within 3 days of treatment initiation with either agent were excluded from the study, as were those whose treatment was initiated in a nursing home and those who were exposed to more than 2 consecutive days of antibiotic therapy with MRSA activity within 3 days prior to initiation of linezolid or vancomycin or during treatment with either agent.

Clinical success was defined as discharge from the hospital or intensive care unit by day 14 after treatment initiation, in the absence of death, therapy change, or intubation. Nonsuccess was defined as therapy change, intubation, discharge, and readmission, or death between treatment initiation and day 14. They also investigated numerous potential predictors of clinical success, including treatment with linezolid or vancomycin, demographics and admission characteristics, and comorbidities and medical history.

Dr. Caffrey reported data from 231 patients who received linezolid and 3,501 patients who received vancomycin. Their mean age was 70 years and most (98%) were male. Predictors of clinical success included treatment with linezolid (OR 1.53) and having a previous complication of an implant or graft (OR 1.55). Factors associated with nonsuccess included dialysis (OR 0.54), intravenous line (OR 0.76), having three or more inpatient procedures (OR 0.53), inpatient surgery (OR 0.48), urinary tract infection (0.82), previous coagulopathy (0.74), previous endocarditis (0.24), and previous amputation procedure (OR 0.72).

Dr. Caffrey acknowledged certain limitations of the study, including the reliance on diagnostic codes to ascertain the number of MRSA pneumonia cases. "We’re probably only capturing 20%-40% of MRSA diagnoses by using the diagnosis codes," she said at the meeting, which was sponsored by the American Society for Microbiology.

Low generalizability of the findings to other patient populations is another limitation: "The VA is the largest integrated health care system in the United States but it [consists of] mainly older white males with a lot of comorbidities," she explained.

She concluded that patients with MRSA pneumonia "are often complex, and identifying predictors of success is useful in maximizing clinical decision making."

The study was supported by the Department of Veterans Affairs and Pfizer.

SAN FRANCISCO – In a national cohort of VA patients with MRSA pneumonia, treatment with linezolid was the only modifiable variable in predicting clinical success.

"Pneumonia is the No. 1 cause of infectious disease–related deaths in the United States yet there are limited treatment options for pneumonia caused by MRSA," Aisling R. Caffrey, Ph.D., said at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy. "Identification of independent predictors of clinical success can optimize patient care."

In an effort to identify independent predictors of clinical success in MRSA pneumonia, Dr. Caffrey, assistant professor of pharmacoepidemiology at the University of Rhode Island College of Pharmacy, and her associates conducted a retrospective cohort study of VA hospital admissions between January 2002 and September 2010 with diagnosis codes for MRSA and pneumonia. They used pharmacy records to identify initiation of linezolid or vancomycin during admission, with at least 3 days of therapy as dosed per protocol.

Patients who died or were discharged within 3 days of treatment initiation with either agent were excluded from the study, as were those whose treatment was initiated in a nursing home and those who were exposed to more than 2 consecutive days of antibiotic therapy with MRSA activity within 3 days prior to initiation of linezolid or vancomycin or during treatment with either agent.

Clinical success was defined as discharge from the hospital or intensive care unit by day 14 after treatment initiation, in the absence of death, therapy change, or intubation. Nonsuccess was defined as therapy change, intubation, discharge, and readmission, or death between treatment initiation and day 14. They also investigated numerous potential predictors of clinical success, including treatment with linezolid or vancomycin, demographics and admission characteristics, and comorbidities and medical history.

Dr. Caffrey reported data from 231 patients who received linezolid and 3,501 patients who received vancomycin. Their mean age was 70 years and most (98%) were male. Predictors of clinical success included treatment with linezolid (OR 1.53) and having a previous complication of an implant or graft (OR 1.55). Factors associated with nonsuccess included dialysis (OR 0.54), intravenous line (OR 0.76), having three or more inpatient procedures (OR 0.53), inpatient surgery (OR 0.48), urinary tract infection (0.82), previous coagulopathy (0.74), previous endocarditis (0.24), and previous amputation procedure (OR 0.72).

Dr. Caffrey acknowledged certain limitations of the study, including the reliance on diagnostic codes to ascertain the number of MRSA pneumonia cases. "We’re probably only capturing 20%-40% of MRSA diagnoses by using the diagnosis codes," she said at the meeting, which was sponsored by the American Society for Microbiology.

Low generalizability of the findings to other patient populations is another limitation: "The VA is the largest integrated health care system in the United States but it [consists of] mainly older white males with a lot of comorbidities," she explained.

She concluded that patients with MRSA pneumonia "are often complex, and identifying predictors of success is useful in maximizing clinical decision making."

The study was supported by the Department of Veterans Affairs and Pfizer.

Pramipexole, the dopamine agonist approved for treating Parkinson’s disease and restless legs syndrome, may be associated with an increased risk for heart failure, according to a statement issued by the Food and Drug Administration.

"Results of recent studies suggest a potential risk of heart failure that needs further review of available data," but the FDA has not concluded that the drug increases the risk of heart failure, the FDA said in the Sept. 19 statement.

The FDA is currently working with Boehringer Ingelheim, which markets pramipexole as Mirapex, to investigate this association further and will provide an update when more information is available.

The studies include a pooled analysis of randomized clinical trials, which found more cases of heart failure (12 of 4,157 patients) among patients treated with pramipexole than among those on placebo (4 of 2,820). The difference between groups, however, was not statistically significant.

In two epidemiologic studies using European data, though, the increased risk of heart failure associated with pramipexole was statistically significant. In one of the studies, a case control study using a database of patients aged 40-89 years treated with anti-parkinsonian drugs, the risk of heart failure associated with any use of a dopamine agonist compared with no use was increased by almost 60% (relative risk, 1.58). The heart failure risk associated with use of pramipexole (RR, 1.86) and with another dopamine agonist, cabergoline (RR, 2.07), were each higher compared with no use of these drugs.

In the other epidemiologic study, current use of pramipexole was associated with an increased risk of heart failure, compared with levodopa. The risk was increased in the first 3 months of treatment and among patients aged 80 years and older, but was no higher among people who had been treated with pramipexole for more than 3 months.

This last finding is "difficult to explain," since heart failure is a chronic condition, and the studies had limitations, which "make it difficult to determine whether excess heart failure was related to Mirapex use or other influencing factors," the FDA statement said.

The agency advises that health care professionals continue following recommendations in the pramipexole label and that patients continue to take the medication as directed.

Pramipexole was approved in July 1997.

The full FDA notice is available here. Serious adverse events associated with pramipexole should be reported to the FDA’s MedWatch program by clicking here or by calling 800-332-1088.

Pramipexole, the dopamine agonist approved for treating Parkinson’s disease and restless legs syndrome, may be associated with an increased risk for heart failure, according to a statement issued by the Food and Drug Administration.

"Results of recent studies suggest a potential risk of heart failure that needs further review of available data," but the FDA has not concluded that the drug increases the risk of heart failure, the FDA said in the Sept. 19 statement.

The FDA is currently working with Boehringer Ingelheim, which markets pramipexole as Mirapex, to investigate this association further and will provide an update when more information is available.

The studies include a pooled analysis of randomized clinical trials, which found more cases of heart failure (12 of 4,157 patients) among patients treated with pramipexole than among those on placebo (4 of 2,820). The difference between groups, however, was not statistically significant.

In two epidemiologic studies using European data, though, the increased risk of heart failure associated with pramipexole was statistically significant. In one of the studies, a case control study using a database of patients aged 40-89 years treated with anti-parkinsonian drugs, the risk of heart failure associated with any use of a dopamine agonist compared with no use was increased by almost 60% (relative risk, 1.58). The heart failure risk associated with use of pramipexole (RR, 1.86) and with another dopamine agonist, cabergoline (RR, 2.07), were each higher compared with no use of these drugs.

In the other epidemiologic study, current use of pramipexole was associated with an increased risk of heart failure, compared with levodopa. The risk was increased in the first 3 months of treatment and among patients aged 80 years and older, but was no higher among people who had been treated with pramipexole for more than 3 months.

This last finding is "difficult to explain," since heart failure is a chronic condition, and the studies had limitations, which "make it difficult to determine whether excess heart failure was related to Mirapex use or other influencing factors," the FDA statement said.

The agency advises that health care professionals continue following recommendations in the pramipexole label and that patients continue to take the medication as directed.

Pramipexole was approved in July 1997.

The full FDA notice is available here. Serious adverse events associated with pramipexole should be reported to the FDA’s MedWatch program by clicking here or by calling 800-332-1088.

Pramipexole, the dopamine agonist approved for treating Parkinson’s disease and restless legs syndrome, may be associated with an increased risk for heart failure, according to a statement issued by the Food and Drug Administration.

"Results of recent studies suggest a potential risk of heart failure that needs further review of available data," but the FDA has not concluded that the drug increases the risk of heart failure, the FDA said in the Sept. 19 statement.

The FDA is currently working with Boehringer Ingelheim, which markets pramipexole as Mirapex, to investigate this association further and will provide an update when more information is available.

The studies include a pooled analysis of randomized clinical trials, which found more cases of heart failure (12 of 4,157 patients) among patients treated with pramipexole than among those on placebo (4 of 2,820). The difference between groups, however, was not statistically significant.

In two epidemiologic studies using European data, though, the increased risk of heart failure associated with pramipexole was statistically significant. In one of the studies, a case control study using a database of patients aged 40-89 years treated with anti-parkinsonian drugs, the risk of heart failure associated with any use of a dopamine agonist compared with no use was increased by almost 60% (relative risk, 1.58). The heart failure risk associated with use of pramipexole (RR, 1.86) and with another dopamine agonist, cabergoline (RR, 2.07), were each higher compared with no use of these drugs.

In the other epidemiologic study, current use of pramipexole was associated with an increased risk of heart failure, compared with levodopa. The risk was increased in the first 3 months of treatment and among patients aged 80 years and older, but was no higher among people who had been treated with pramipexole for more than 3 months.

This last finding is "difficult to explain," since heart failure is a chronic condition, and the studies had limitations, which "make it difficult to determine whether excess heart failure was related to Mirapex use or other influencing factors," the FDA statement said.

The agency advises that health care professionals continue following recommendations in the pramipexole label and that patients continue to take the medication as directed.

Pramipexole was approved in July 1997.

The full FDA notice is available here. Serious adverse events associated with pramipexole should be reported to the FDA’s MedWatch program by clicking here or by calling 800-332-1088.

VAIL, COLO. – A major theme running through the latest guidelines for management of community-acquired pneumonia in children is that Streptococcus pneumoniae is the most common bacterial pathogen – and the best target for empiric therapy.

"It’s really all about pneumococcus," declared Dr. Mark J. Abzug, professor of pediatrics at the University of Colorado, Denver.

The guidelines put forth jointly by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America endorse high-dose amoxicillin as first-line therapy for previously healthy, appropriately immunized infants, preschoolers, school-aged children, and adolescents with mild to moderate community-acquired pneumonia (CAP) of suspected bacterial origin (Clin. Infect. Dis. 2011; 53: e25-76).

High-dose oral amoxicillin at 90 mg/kg per day covers 87%-95% of S. pneumoniae isolates nationally, whereas most second- and third-generation oral cephalosporins cover only 60%-70%. Azithromycin isn’t recommended for suspected pneumococcal CAP because of an associated resistance rate of up to 40%. Amoxicillin/clavulanic acid offers no incremental benefit over amoxicillin alone for pneumococcus, Dr. Abzug observed at the conference, which was sponsored by Children’s Hospital Colorado.

The guidelines recommend b.i.d. dosing of amoxicillin based largely on extrapolation from experience in acute otitis media. But Dr. Abzug takes issue with that guidance.

"I’m going to beg to differ with that recommendation and suggest that for pneumonia, which is a bit different from otitis, dividing t.i.d. is going to be better," the pediatrician asserted.

Modeling studies indicate b.i.d. dosing of amoxicillin at 90 mg/kg per day is effective for 99% of highly susceptible (minimal inhibitory concentration of 0.5 mcg/mL) S. pneumococcus isolates, but only for 65% of strains with a minimum inhibitory concentration (MIC) of 2 mcg/mL, whereas t.i.d. dosing is sufficient for 90% of such strains. And at Children’s Hospital Colorado, nearly 20% of S. pneumoniae isolates in 2011 were intermediately susceptible (MIC = 4 mcg/mL) or resistant (MIC = 8 mcg/mL) to penicillin.

"For the 20% or so that are intermediate or resistant, b.i.d. dosing is not going to be the answer," Dr. Abzug stressed.

For patients with nonserious amoxicillin allergies, the guidelines recommend cefuroxime, cefprozil, or cefpodoxime as oral alternatives; nationally, 67%-80% of S. pneumoniae strains are susceptible to these agents. Clindamycin is an alternative option. Levofloxacin and linezolid are effective for close to 100% of isolates, but are best reserved for second- or third-line therapy.

It may come as a surprise to many physicians that the guidelines deem routine chest x-rays "not necessary" for suspected CAP in the outpatient setting.

"Will this encourage antibiotic overuse? The guidelines don’t address this," the pediatrician noted.

The guidelines also recommend against routine complete blood counts, blood cultures, and urinary antigen detection tests in outpatients.

In fully immunized children with suspected bacterial CAP sufficiently serious for hospitalization, the recommendation is for parenteral ampicillin or penicillin G so long as local epidemiologic data indicate a lack of substantial resistance for invasive pneumococci as defined by an MIC greater than 8 mcg/mL and the patient doesn’t have empyema or other potentially life-threatening complications. When those conditions aren’t met, however, the guidelines endorse the third-generation cephalosporins ceftriaxone or cefotaxime.

Dr. Abzug applauded a recent study by pediatricians at Children’s Mercy Hospitals and Clinics in Kansas City, Mo., that provided support in everyday clinical practice for the ampicillin-first management strategy recommended in the national guidelines. The retrospective study included 1,033 patients admitted with CAP to the tertiary referral hospital during the 12 months before and after the 2008 introduction of a clinical practice guideline encouraging the use of ampicillin as the first-line empiric antibiotic in previously healthy children with uncomplicated CAP.

The Kansas City pediatricians noted that the use of ampicillin as first-line therapy has historically been uncommon at tertiary children’s hospitals, as evidenced by a mere 5.5% rate in a study using the Pediatric Hospital Information Systems database (Pediatrics 2011;127:e255-63). The goal was to turn that situation around at Children’s Mercy Hospitals and Clinics, since ampicillin is a narrower-spectrum antibiotic than the third-generation cephalosporins, and hence less likely to promote antibiotic resistance.

Prior to introduction of the hospital guideline, ceftriaxone was prescribed as empiric therapy for CAP in 72% of cases, with ampicillin being the second most commonly prescribed antibiotic at 13%. In the year after the guideline was introduced, ampicillin was the most common antibiotic, prescribed in 63% of cases, with ceftriaxone prescribed in 21%. And even though the prevalence of S. pneumoniae isolates with intermediate susceptibility or resistance to penicillin was 24% at the hospital during that time period, the change in therapy didn’t result in an increase in adverse outcomes: The preguideline treatment failure rate was 1.5% and the postguideline rate was similar at 1% (Pediatrics 2012;129:e597-604).

"Here’s some real-world data that suggest ampicillin for the most part is probably sufficient as the parenteral empiric drug of choice for uncomplicated CAP," Dr. Abzug commented.

Dr. Abzug reported having no financial conflicts.

VAIL, COLO. – A major theme running through the latest guidelines for management of community-acquired pneumonia in children is that Streptococcus pneumoniae is the most common bacterial pathogen – and the best target for empiric therapy.

"It’s really all about pneumococcus," declared Dr. Mark J. Abzug, professor of pediatrics at the University of Colorado, Denver.

The guidelines put forth jointly by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America endorse high-dose amoxicillin as first-line therapy for previously healthy, appropriately immunized infants, preschoolers, school-aged children, and adolescents with mild to moderate community-acquired pneumonia (CAP) of suspected bacterial origin (Clin. Infect. Dis. 2011; 53: e25-76).

High-dose oral amoxicillin at 90 mg/kg per day covers 87%-95% of S. pneumoniae isolates nationally, whereas most second- and third-generation oral cephalosporins cover only 60%-70%. Azithromycin isn’t recommended for suspected pneumococcal CAP because of an associated resistance rate of up to 40%. Amoxicillin/clavulanic acid offers no incremental benefit over amoxicillin alone for pneumococcus, Dr. Abzug observed at the conference, which was sponsored by Children’s Hospital Colorado.

The guidelines recommend b.i.d. dosing of amoxicillin based largely on extrapolation from experience in acute otitis media. But Dr. Abzug takes issue with that guidance.

"I’m going to beg to differ with that recommendation and suggest that for pneumonia, which is a bit different from otitis, dividing t.i.d. is going to be better," the pediatrician asserted.

Modeling studies indicate b.i.d. dosing of amoxicillin at 90 mg/kg per day is effective for 99% of highly susceptible (minimal inhibitory concentration of 0.5 mcg/mL) S. pneumococcus isolates, but only for 65% of strains with a minimum inhibitory concentration (MIC) of 2 mcg/mL, whereas t.i.d. dosing is sufficient for 90% of such strains. And at Children’s Hospital Colorado, nearly 20% of S. pneumoniae isolates in 2011 were intermediately susceptible (MIC = 4 mcg/mL) or resistant (MIC = 8 mcg/mL) to penicillin.

"For the 20% or so that are intermediate or resistant, b.i.d. dosing is not going to be the answer," Dr. Abzug stressed.

For patients with nonserious amoxicillin allergies, the guidelines recommend cefuroxime, cefprozil, or cefpodoxime as oral alternatives; nationally, 67%-80% of S. pneumoniae strains are susceptible to these agents. Clindamycin is an alternative option. Levofloxacin and linezolid are effective for close to 100% of isolates, but are best reserved for second- or third-line therapy.

It may come as a surprise to many physicians that the guidelines deem routine chest x-rays "not necessary" for suspected CAP in the outpatient setting.

"Will this encourage antibiotic overuse? The guidelines don’t address this," the pediatrician noted.

The guidelines also recommend against routine complete blood counts, blood cultures, and urinary antigen detection tests in outpatients.

In fully immunized children with suspected bacterial CAP sufficiently serious for hospitalization, the recommendation is for parenteral ampicillin or penicillin G so long as local epidemiologic data indicate a lack of substantial resistance for invasive pneumococci as defined by an MIC greater than 8 mcg/mL and the patient doesn’t have empyema or other potentially life-threatening complications. When those conditions aren’t met, however, the guidelines endorse the third-generation cephalosporins ceftriaxone or cefotaxime.

Dr. Abzug applauded a recent study by pediatricians at Children’s Mercy Hospitals and Clinics in Kansas City, Mo., that provided support in everyday clinical practice for the ampicillin-first management strategy recommended in the national guidelines. The retrospective study included 1,033 patients admitted with CAP to the tertiary referral hospital during the 12 months before and after the 2008 introduction of a clinical practice guideline encouraging the use of ampicillin as the first-line empiric antibiotic in previously healthy children with uncomplicated CAP.

The Kansas City pediatricians noted that the use of ampicillin as first-line therapy has historically been uncommon at tertiary children’s hospitals, as evidenced by a mere 5.5% rate in a study using the Pediatric Hospital Information Systems database (Pediatrics 2011;127:e255-63). The goal was to turn that situation around at Children’s Mercy Hospitals and Clinics, since ampicillin is a narrower-spectrum antibiotic than the third-generation cephalosporins, and hence less likely to promote antibiotic resistance.

Prior to introduction of the hospital guideline, ceftriaxone was prescribed as empiric therapy for CAP in 72% of cases, with ampicillin being the second most commonly prescribed antibiotic at 13%. In the year after the guideline was introduced, ampicillin was the most common antibiotic, prescribed in 63% of cases, with ceftriaxone prescribed in 21%. And even though the prevalence of S. pneumoniae isolates with intermediate susceptibility or resistance to penicillin was 24% at the hospital during that time period, the change in therapy didn’t result in an increase in adverse outcomes: The preguideline treatment failure rate was 1.5% and the postguideline rate was similar at 1% (Pediatrics 2012;129:e597-604).

"Here’s some real-world data that suggest ampicillin for the most part is probably sufficient as the parenteral empiric drug of choice for uncomplicated CAP," Dr. Abzug commented.

Dr. Abzug reported having no financial conflicts.

VAIL, COLO. – A major theme running through the latest guidelines for management of community-acquired pneumonia in children is that Streptococcus pneumoniae is the most common bacterial pathogen – and the best target for empiric therapy.

"It’s really all about pneumococcus," declared Dr. Mark J. Abzug, professor of pediatrics at the University of Colorado, Denver.

The guidelines put forth jointly by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America endorse high-dose amoxicillin as first-line therapy for previously healthy, appropriately immunized infants, preschoolers, school-aged children, and adolescents with mild to moderate community-acquired pneumonia (CAP) of suspected bacterial origin (Clin. Infect. Dis. 2011; 53: e25-76).

High-dose oral amoxicillin at 90 mg/kg per day covers 87%-95% of S. pneumoniae isolates nationally, whereas most second- and third-generation oral cephalosporins cover only 60%-70%. Azithromycin isn’t recommended for suspected pneumococcal CAP because of an associated resistance rate of up to 40%. Amoxicillin/clavulanic acid offers no incremental benefit over amoxicillin alone for pneumococcus, Dr. Abzug observed at the conference, which was sponsored by Children’s Hospital Colorado.

The guidelines recommend b.i.d. dosing of amoxicillin based largely on extrapolation from experience in acute otitis media. But Dr. Abzug takes issue with that guidance.

"I’m going to beg to differ with that recommendation and suggest that for pneumonia, which is a bit different from otitis, dividing t.i.d. is going to be better," the pediatrician asserted.

Modeling studies indicate b.i.d. dosing of amoxicillin at 90 mg/kg per day is effective for 99% of highly susceptible (minimal inhibitory concentration of 0.5 mcg/mL) S. pneumococcus isolates, but only for 65% of strains with a minimum inhibitory concentration (MIC) of 2 mcg/mL, whereas t.i.d. dosing is sufficient for 90% of such strains. And at Children’s Hospital Colorado, nearly 20% of S. pneumoniae isolates in 2011 were intermediately susceptible (MIC = 4 mcg/mL) or resistant (MIC = 8 mcg/mL) to penicillin.

"For the 20% or so that are intermediate or resistant, b.i.d. dosing is not going to be the answer," Dr. Abzug stressed.

For patients with nonserious amoxicillin allergies, the guidelines recommend cefuroxime, cefprozil, or cefpodoxime as oral alternatives; nationally, 67%-80% of S. pneumoniae strains are susceptible to these agents. Clindamycin is an alternative option. Levofloxacin and linezolid are effective for close to 100% of isolates, but are best reserved for second- or third-line therapy.

It may come as a surprise to many physicians that the guidelines deem routine chest x-rays "not necessary" for suspected CAP in the outpatient setting.

"Will this encourage antibiotic overuse? The guidelines don’t address this," the pediatrician noted.

The guidelines also recommend against routine complete blood counts, blood cultures, and urinary antigen detection tests in outpatients.

In fully immunized children with suspected bacterial CAP sufficiently serious for hospitalization, the recommendation is for parenteral ampicillin or penicillin G so long as local epidemiologic data indicate a lack of substantial resistance for invasive pneumococci as defined by an MIC greater than 8 mcg/mL and the patient doesn’t have empyema or other potentially life-threatening complications. When those conditions aren’t met, however, the guidelines endorse the third-generation cephalosporins ceftriaxone or cefotaxime.

Dr. Abzug applauded a recent study by pediatricians at Children’s Mercy Hospitals and Clinics in Kansas City, Mo., that provided support in everyday clinical practice for the ampicillin-first management strategy recommended in the national guidelines. The retrospective study included 1,033 patients admitted with CAP to the tertiary referral hospital during the 12 months before and after the 2008 introduction of a clinical practice guideline encouraging the use of ampicillin as the first-line empiric antibiotic in previously healthy children with uncomplicated CAP.

The Kansas City pediatricians noted that the use of ampicillin as first-line therapy has historically been uncommon at tertiary children’s hospitals, as evidenced by a mere 5.5% rate in a study using the Pediatric Hospital Information Systems database (Pediatrics 2011;127:e255-63). The goal was to turn that situation around at Children’s Mercy Hospitals and Clinics, since ampicillin is a narrower-spectrum antibiotic than the third-generation cephalosporins, and hence less likely to promote antibiotic resistance.

Prior to introduction of the hospital guideline, ceftriaxone was prescribed as empiric therapy for CAP in 72% of cases, with ampicillin being the second most commonly prescribed antibiotic at 13%. In the year after the guideline was introduced, ampicillin was the most common antibiotic, prescribed in 63% of cases, with ceftriaxone prescribed in 21%. And even though the prevalence of S. pneumoniae isolates with intermediate susceptibility or resistance to penicillin was 24% at the hospital during that time period, the change in therapy didn’t result in an increase in adverse outcomes: The preguideline treatment failure rate was 1.5% and the postguideline rate was similar at 1% (Pediatrics 2012;129:e597-604).

"Here’s some real-world data that suggest ampicillin for the most part is probably sufficient as the parenteral empiric drug of choice for uncomplicated CAP," Dr. Abzug commented.

Dr. Abzug reported having no financial conflicts.

Adding tiotropium to standard combination therapy may help reduce exacerbations in some adults whose asthma is poorly controlled despite the use of inhaled glucocorticoids and long-acting beta-agonists, according to a report of two randomized, controlled trials published online Sept. 3 in the New England Journal of Medicine.

However, tiotropium use did not increase the number of symptom-free days or boost patients’ asthma-related quality of life scores.

Compared with placebo, tiotropium administered once daily via a soft-mist inhaler significantly lengthened the time to a severe exacerbation of asthma, reduced the number of exacerbations, and provided "modest" bronchodilation when added to inhaled glucocorticoids and LABAs, said Dr. Huib A. M. Kerstjens of the University of Groningen (the Netherlands) and the Groningen Research Institute for Asthma and COPD, and his associates (N. Engl. J. Med. 2012 Sept. 3 [doi:10.1056/NEJMoa1208606]).

However, the improvements in forced expiratory volume in 1 second (FEV₁) were "relatively small (less than 10%)," and the number of symptom-free days did not differ between patients who received tiotropium and those who received placebo.

Moreover, the use of rescue medications was the same between the two groups, and patient ratings of asthma-related quality of life also were the same on two measures, the researchers noted.

Tiotropium is the most widely used long-acting anticholinergic inhaled bronchodilator in the world for the treatment of chronic obstructive pulmonary disease, but it has only recently been investigated as a potential adjunctive therapy for asthma.

Dr. Kerstjens and his colleagues assessed the drug’s effects in two 48-week randomized, controlled trials conducted in 15 countries, both of which were funded by Boehringer Ingelheim and Pfizer. They presented their findings at the annual meeting of the European Respiratory Society simultaneously with online publication.

The studies included 912 adults aged 18-75 years who had a 5-year or longer history of asthma and persistent airflow limitation despite self-reported daily use of inhaled glucocorticoids and LABAs. They were randomly assigned to self administer puffs of either tiotropium (237 patients in study 1 and 219 patients in study 2) or placebo (222 patients in study 1 and 234 patients in study 2) every morning as add-on therapy.

Patients were allowed to continue the use of stable doses of sustained-release theophylline, leukotriene modifiers, anti-immunoglobulin E antibody, or oral glucocorticoids, and were given open-label inhalers of salbutamol or albuterol for use as rescue medication.

The first two lung-function end points of both studies were the peak FEV₁ response and the trough FEV₁ response at week 24, expressed as the change from baseline FEV₁. Tiotropium topped placebo in peak FEV₁ response by an average of 86 mL in trial 1 and 154 mL in trial 2, differences that were significant.

The average difference in trough FEV₁ response between tiotropium and placebo groups was 88 mL in trial 1 and 111 mL in trial 2. Those differences were "relatively small" but also statistically significant.

"It should be noted that [these differences occurred] in patients who were already receiving a long-acting bronchodilator and had fixed airflow limitation," the investigators noted. The results also should be considered "in the context of the need for additional treatments for this patient population and the limitations of current alternatives," they added.

A third lung-function end point was the time until at least 25% of patients had their first severe exacerbation of asthma. That interval was 56 days longer with tiotropium (282 days), compared with placebo (226 days).

The number of severe exacerbations was a secondary end point of both trials. That number was 0.53 exacerbations per patient-year with tiotropium, significantly fewer than the 0.66 per patient-year with placebo. In addition, 27% of patients in both tiotropium groups had at least one severe exacerbation, which was significantly less than the 33% rate in both placebo groups.

However, asthma-related quality of life did not differ significantly between tiotropium and placebo groups in either trial. The minimal clinically important difference between the two groups was not achieved when measured by both the Asthma Control Questionnaire 7 and the 32-item Asthma Quality of Life Questionnaire.

Similarly, daily symptom diaries showed "small or nonsignificant" differences between the active drug and the placebo groups in symptom-free days. And the use of rescue medications also was similar.

Adverse events occurred in 73.5% of the tiotropium group and 80.3% of the placebo group, and allergic rhinitis was the only one that occurred more often in the tiotropium group. Adverse events were judged to be treatment related in 5.7% of the tiotropium group and 4.6% of the placebo group.

Serious adverse events occurred in 8.1% of the tiotropium group and 8.8% of the placebo group. Three of those events – two asthma exacerbations and one cerebral infarction – occurred in the tiotropium group and were considered life threatening.

Cardiac events occurred in less than 2% of both study groups; they were considered drug related in 0.4% of patients in the tiotropium group and 0.2% of those in the placebo group. Adverse changes in blood pressure, pulse rate, laboratory measures, and electrocardiograms were balanced between the two study groups.

Less than 2% of all patients experienced dry mouth – a typical adverse event with anticholinergic agents – but it was reported more frequently in the tiotropium group (eight patients vs. three patients), Dr. Kerstjens and his associates said.

Dr. Kerstjens reported additional associations with Almirall, Chiesi, Novartis, and Nycomed, and his associates reported ties to numerous industry sources.

Adding tiotropium to standard combination therapy may help reduce exacerbations in some adults whose asthma is poorly controlled despite the use of inhaled glucocorticoids and long-acting beta-agonists, according to a report of two randomized, controlled trials published online Sept. 3 in the New England Journal of Medicine.

However, tiotropium use did not increase the number of symptom-free days or boost patients’ asthma-related quality of life scores.

Compared with placebo, tiotropium administered once daily via a soft-mist inhaler significantly lengthened the time to a severe exacerbation of asthma, reduced the number of exacerbations, and provided "modest" bronchodilation when added to inhaled glucocorticoids and LABAs, said Dr. Huib A. M. Kerstjens of the University of Groningen (the Netherlands) and the Groningen Research Institute for Asthma and COPD, and his associates (N. Engl. J. Med. 2012 Sept. 3 [doi:10.1056/NEJMoa1208606]).

However, the improvements in forced expiratory volume in 1 second (FEV₁) were "relatively small (less than 10%)," and the number of symptom-free days did not differ between patients who received tiotropium and those who received placebo.

Moreover, the use of rescue medications was the same between the two groups, and patient ratings of asthma-related quality of life also were the same on two measures, the researchers noted.

Tiotropium is the most widely used long-acting anticholinergic inhaled bronchodilator in the world for the treatment of chronic obstructive pulmonary disease, but it has only recently been investigated as a potential adjunctive therapy for asthma.

Dr. Kerstjens and his colleagues assessed the drug’s effects in two 48-week randomized, controlled trials conducted in 15 countries, both of which were funded by Boehringer Ingelheim and Pfizer. They presented their findings at the annual meeting of the European Respiratory Society simultaneously with online publication.

The studies included 912 adults aged 18-75 years who had a 5-year or longer history of asthma and persistent airflow limitation despite self-reported daily use of inhaled glucocorticoids and LABAs. They were randomly assigned to self administer puffs of either tiotropium (237 patients in study 1 and 219 patients in study 2) or placebo (222 patients in study 1 and 234 patients in study 2) every morning as add-on therapy.

Patients were allowed to continue the use of stable doses of sustained-release theophylline, leukotriene modifiers, anti-immunoglobulin E antibody, or oral glucocorticoids, and were given open-label inhalers of salbutamol or albuterol for use as rescue medication.

The first two lung-function end points of both studies were the peak FEV₁ response and the trough FEV₁ response at week 24, expressed as the change from baseline FEV₁. Tiotropium topped placebo in peak FEV₁ response by an average of 86 mL in trial 1 and 154 mL in trial 2, differences that were significant.

The average difference in trough FEV₁ response between tiotropium and placebo groups was 88 mL in trial 1 and 111 mL in trial 2. Those differences were "relatively small" but also statistically significant.

"It should be noted that [these differences occurred] in patients who were already receiving a long-acting bronchodilator and had fixed airflow limitation," the investigators noted. The results also should be considered "in the context of the need for additional treatments for this patient population and the limitations of current alternatives," they added.

A third lung-function end point was the time until at least 25% of patients had their first severe exacerbation of asthma. That interval was 56 days longer with tiotropium (282 days), compared with placebo (226 days).

The number of severe exacerbations was a secondary end point of both trials. That number was 0.53 exacerbations per patient-year with tiotropium, significantly fewer than the 0.66 per patient-year with placebo. In addition, 27% of patients in both tiotropium groups had at least one severe exacerbation, which was significantly less than the 33% rate in both placebo groups.

However, asthma-related quality of life did not differ significantly between tiotropium and placebo groups in either trial. The minimal clinically important difference between the two groups was not achieved when measured by both the Asthma Control Questionnaire 7 and the 32-item Asthma Quality of Life Questionnaire.

Similarly, daily symptom diaries showed "small or nonsignificant" differences between the active drug and the placebo groups in symptom-free days. And the use of rescue medications also was similar.

Adverse events occurred in 73.5% of the tiotropium group and 80.3% of the placebo group, and allergic rhinitis was the only one that occurred more often in the tiotropium group. Adverse events were judged to be treatment related in 5.7% of the tiotropium group and 4.6% of the placebo group.

Serious adverse events occurred in 8.1% of the tiotropium group and 8.8% of the placebo group. Three of those events – two asthma exacerbations and one cerebral infarction – occurred in the tiotropium group and were considered life threatening.

Cardiac events occurred in less than 2% of both study groups; they were considered drug related in 0.4% of patients in the tiotropium group and 0.2% of those in the placebo group. Adverse changes in blood pressure, pulse rate, laboratory measures, and electrocardiograms were balanced between the two study groups.

Less than 2% of all patients experienced dry mouth – a typical adverse event with anticholinergic agents – but it was reported more frequently in the tiotropium group (eight patients vs. three patients), Dr. Kerstjens and his associates said.

Dr. Kerstjens reported additional associations with Almirall, Chiesi, Novartis, and Nycomed, and his associates reported ties to numerous industry sources.

Adding tiotropium to standard combination therapy may help reduce exacerbations in some adults whose asthma is poorly controlled despite the use of inhaled glucocorticoids and long-acting beta-agonists, according to a report of two randomized, controlled trials published online Sept. 3 in the New England Journal of Medicine.

However, tiotropium use did not increase the number of symptom-free days or boost patients’ asthma-related quality of life scores.

Compared with placebo, tiotropium administered once daily via a soft-mist inhaler significantly lengthened the time to a severe exacerbation of asthma, reduced the number of exacerbations, and provided "modest" bronchodilation when added to inhaled glucocorticoids and LABAs, said Dr. Huib A. M. Kerstjens of the University of Groningen (the Netherlands) and the Groningen Research Institute for Asthma and COPD, and his associates (N. Engl. J. Med. 2012 Sept. 3 [doi:10.1056/NEJMoa1208606]).

However, the improvements in forced expiratory volume in 1 second (FEV₁) were "relatively small (less than 10%)," and the number of symptom-free days did not differ between patients who received tiotropium and those who received placebo.

Moreover, the use of rescue medications was the same between the two groups, and patient ratings of asthma-related quality of life also were the same on two measures, the researchers noted.

Tiotropium is the most widely used long-acting anticholinergic inhaled bronchodilator in the world for the treatment of chronic obstructive pulmonary disease, but it has only recently been investigated as a potential adjunctive therapy for asthma.

Dr. Kerstjens and his colleagues assessed the drug’s effects in two 48-week randomized, controlled trials conducted in 15 countries, both of which were funded by Boehringer Ingelheim and Pfizer. They presented their findings at the annual meeting of the European Respiratory Society simultaneously with online publication.

The studies included 912 adults aged 18-75 years who had a 5-year or longer history of asthma and persistent airflow limitation despite self-reported daily use of inhaled glucocorticoids and LABAs. They were randomly assigned to self administer puffs of either tiotropium (237 patients in study 1 and 219 patients in study 2) or placebo (222 patients in study 1 and 234 patients in study 2) every morning as add-on therapy.

Patients were allowed to continue the use of stable doses of sustained-release theophylline, leukotriene modifiers, anti-immunoglobulin E antibody, or oral glucocorticoids, and were given open-label inhalers of salbutamol or albuterol for use as rescue medication.

The first two lung-function end points of both studies were the peak FEV₁ response and the trough FEV₁ response at week 24, expressed as the change from baseline FEV₁. Tiotropium topped placebo in peak FEV₁ response by an average of 86 mL in trial 1 and 154 mL in trial 2, differences that were significant.

The average difference in trough FEV₁ response between tiotropium and placebo groups was 88 mL in trial 1 and 111 mL in trial 2. Those differences were "relatively small" but also statistically significant.

"It should be noted that [these differences occurred] in patients who were already receiving a long-acting bronchodilator and had fixed airflow limitation," the investigators noted. The results also should be considered "in the context of the need for additional treatments for this patient population and the limitations of current alternatives," they added.

A third lung-function end point was the time until at least 25% of patients had their first severe exacerbation of asthma. That interval was 56 days longer with tiotropium (282 days), compared with placebo (226 days).

The number of severe exacerbations was a secondary end point of both trials. That number was 0.53 exacerbations per patient-year with tiotropium, significantly fewer than the 0.66 per patient-year with placebo. In addition, 27% of patients in both tiotropium groups had at least one severe exacerbation, which was significantly less than the 33% rate in both placebo groups.

However, asthma-related quality of life did not differ significantly between tiotropium and placebo groups in either trial. The minimal clinically important difference between the two groups was not achieved when measured by both the Asthma Control Questionnaire 7 and the 32-item Asthma Quality of Life Questionnaire.

Similarly, daily symptom diaries showed "small or nonsignificant" differences between the active drug and the placebo groups in symptom-free days. And the use of rescue medications also was similar.

Adverse events occurred in 73.5% of the tiotropium group and 80.3% of the placebo group, and allergic rhinitis was the only one that occurred more often in the tiotropium group. Adverse events were judged to be treatment related in 5.7% of the tiotropium group and 4.6% of the placebo group.

Serious adverse events occurred in 8.1% of the tiotropium group and 8.8% of the placebo group. Three of those events – two asthma exacerbations and one cerebral infarction – occurred in the tiotropium group and were considered life threatening.

Cardiac events occurred in less than 2% of both study groups; they were considered drug related in 0.4% of patients in the tiotropium group and 0.2% of those in the placebo group. Adverse changes in blood pressure, pulse rate, laboratory measures, and electrocardiograms were balanced between the two study groups.

Less than 2% of all patients experienced dry mouth – a typical adverse event with anticholinergic agents – but it was reported more frequently in the tiotropium group (eight patients vs. three patients), Dr. Kerstjens and his associates said.

Dr. Kerstjens reported additional associations with Almirall, Chiesi, Novartis, and Nycomed, and his associates reported ties to numerous industry sources.

Long-term use of inhaled budesonide is associated not only with slowed growth in prepubertal children, but with reduced final adult height as well.

An 8-year observational study found that children who had used budesonide during an asthma treatment trial were more than 1 cm shorter than those who used nedocromil or placebo. The findings suggest that glucocorticoid-related growth impairment has a lasting effect on potential adult height, H. William Kelly, Pharm.D., and his colleagues wrote in the Sept. 3 issue of the New England Journal of Medicine (2012;367:904-12 [doi: 10.1056/NEJMoa1203229]).

The prospective study followed 943 children who had participated in the Childhood Asthma Management Program (CAMP) trial. CAMP randomized children with asthma aged 5-13 years to placebo, 400 mcg/day budesonide, or 16 mg/day nedocromil.

Comstock/thinkstockphotos.com

Initial follow-up averaged 4.3 years, with height measured once or twice a year for the subsequent 8 years. Final height was measured at a mean age of 25 years.

The mean adult height in the budesonide group was 171.1 cm – significantly shorter than the 172.3 cm in the placebo group. Mean adult height in the nedocromil group was almost the same as in the placebo group (172.1 cm).

Women in the budesonide group were particularly affected; they were a mean of 1.8 cm shorter than women in the placebo group. Men who took budesonide were a mean of 0.8 cm shorter than men who took placebo as children.

During the first 2 years of the CAMP trial, growth had already slowed, showing a 1.3-cm difference between the budesonide and placebo groups. At the end of that trial, the difference was 1.2 cm, a deficit that did not change as the patients entered young adulthood.

Final height was related to daily dosage during the randomized trial, with a decrement of 0.1 cm for each microgram per kilogram of budesonide. Several baseline characteristics were also significantly related to lower adult height, including Hispanic ethnicity and being female, or having a higher Tanner stage, greater body mass index, longer duration of asthma, and low vitamin D levels.

Since the CAMP trial concluded, research has shown that 200 mcg/day budesonide in a dry-powder inhaler is sufficient to control mild to moderate asthma and prevent exacerbations in children. "Even at this lower dose, there was a reported mean reduction of 1.0 cm in height during the first 2 years of therapy," the investigators noted. "Although the systemic effects of inhaled glucocorticoids are dose dependent, they are also dependent on the therapeutic index of the specific inhaled glucocorticoid and the delivery device used. Thus, it seems prudent to select inhaled glucocorticoids and devices with higher therapeutic indexes, and to use them in the lowest effective doses in children with persistent asthma."

Ultimately, they concluded, parents and physicians must work together to decide the risk-benefit ratio that is most appropriate and acceptable for each individual patient.

"In the information about inhaled glucocorticoids and their side effects that is provided to parents, the potential effect on adult height must be balanced against the large and well-established benefits of these drugs in controlling persistent asthma," concluded Dr. Kelly of the University of New Mexico, Albuquerque, and his coauthors.

The CAMP trial and its observational study were funded by the National Heart, Lung, and Blood Institute and the National Center for Research Resources. Dr. Kelly serves on steering committees for and has received consulting fees from AstraZeneca, GlaxoSmithKline, and other companies. His coauthors also reported multiple financial relationships with pharmaceutical companies.

Long-term use of inhaled budesonide is associated not only with slowed growth in prepubertal children, but with reduced final adult height as well.

An 8-year observational study found that children who had used budesonide during an asthma treatment trial were more than 1 cm shorter than those who used nedocromil or placebo. The findings suggest that glucocorticoid-related growth impairment has a lasting effect on potential adult height, H. William Kelly, Pharm.D., and his colleagues wrote in the Sept. 3 issue of the New England Journal of Medicine (2012;367:904-12 [doi: 10.1056/NEJMoa1203229]).

The prospective study followed 943 children who had participated in the Childhood Asthma Management Program (CAMP) trial. CAMP randomized children with asthma aged 5-13 years to placebo, 400 mcg/day budesonide, or 16 mg/day nedocromil.

Comstock/thinkstockphotos.com

Initial follow-up averaged 4.3 years, with height measured once or twice a year for the subsequent 8 years. Final height was measured at a mean age of 25 years.

The mean adult height in the budesonide group was 171.1 cm – significantly shorter than the 172.3 cm in the placebo group. Mean adult height in the nedocromil group was almost the same as in the placebo group (172.1 cm).

Women in the budesonide group were particularly affected; they were a mean of 1.8 cm shorter than women in the placebo group. Men who took budesonide were a mean of 0.8 cm shorter than men who took placebo as children.

During the first 2 years of the CAMP trial, growth had already slowed, showing a 1.3-cm difference between the budesonide and placebo groups. At the end of that trial, the difference was 1.2 cm, a deficit that did not change as the patients entered young adulthood.

Final height was related to daily dosage during the randomized trial, with a decrement of 0.1 cm for each microgram per kilogram of budesonide. Several baseline characteristics were also significantly related to lower adult height, including Hispanic ethnicity and being female, or having a higher Tanner stage, greater body mass index, longer duration of asthma, and low vitamin D levels.

Since the CAMP trial concluded, research has shown that 200 mcg/day budesonide in a dry-powder inhaler is sufficient to control mild to moderate asthma and prevent exacerbations in children. "Even at this lower dose, there was a reported mean reduction of 1.0 cm in height during the first 2 years of therapy," the investigators noted. "Although the systemic effects of inhaled glucocorticoids are dose dependent, they are also dependent on the therapeutic index of the specific inhaled glucocorticoid and the delivery device used. Thus, it seems prudent to select inhaled glucocorticoids and devices with higher therapeutic indexes, and to use them in the lowest effective doses in children with persistent asthma."

Ultimately, they concluded, parents and physicians must work together to decide the risk-benefit ratio that is most appropriate and acceptable for each individual patient.

"In the information about inhaled glucocorticoids and their side effects that is provided to parents, the potential effect on adult height must be balanced against the large and well-established benefits of these drugs in controlling persistent asthma," concluded Dr. Kelly of the University of New Mexico, Albuquerque, and his coauthors.

The CAMP trial and its observational study were funded by the National Heart, Lung, and Blood Institute and the National Center for Research Resources. Dr. Kelly serves on steering committees for and has received consulting fees from AstraZeneca, GlaxoSmithKline, and other companies. His coauthors also reported multiple financial relationships with pharmaceutical companies.

Long-term use of inhaled budesonide is associated not only with slowed growth in prepubertal children, but with reduced final adult height as well.

An 8-year observational study found that children who had used budesonide during an asthma treatment trial were more than 1 cm shorter than those who used nedocromil or placebo. The findings suggest that glucocorticoid-related growth impairment has a lasting effect on potential adult height, H. William Kelly, Pharm.D., and his colleagues wrote in the Sept. 3 issue of the New England Journal of Medicine (2012;367:904-12 [doi: 10.1056/NEJMoa1203229]).

The prospective study followed 943 children who had participated in the Childhood Asthma Management Program (CAMP) trial. CAMP randomized children with asthma aged 5-13 years to placebo, 400 mcg/day budesonide, or 16 mg/day nedocromil.

Comstock/thinkstockphotos.com

Initial follow-up averaged 4.3 years, with height measured once or twice a year for the subsequent 8 years. Final height was measured at a mean age of 25 years.

The mean adult height in the budesonide group was 171.1 cm – significantly shorter than the 172.3 cm in the placebo group. Mean adult height in the nedocromil group was almost the same as in the placebo group (172.1 cm).

Women in the budesonide group were particularly affected; they were a mean of 1.8 cm shorter than women in the placebo group. Men who took budesonide were a mean of 0.8 cm shorter than men who took placebo as children.

During the first 2 years of the CAMP trial, growth had already slowed, showing a 1.3-cm difference between the budesonide and placebo groups. At the end of that trial, the difference was 1.2 cm, a deficit that did not change as the patients entered young adulthood.

Final height was related to daily dosage during the randomized trial, with a decrement of 0.1 cm for each microgram per kilogram of budesonide. Several baseline characteristics were also significantly related to lower adult height, including Hispanic ethnicity and being female, or having a higher Tanner stage, greater body mass index, longer duration of asthma, and low vitamin D levels.

Since the CAMP trial concluded, research has shown that 200 mcg/day budesonide in a dry-powder inhaler is sufficient to control mild to moderate asthma and prevent exacerbations in children. "Even at this lower dose, there was a reported mean reduction of 1.0 cm in height during the first 2 years of therapy," the investigators noted. "Although the systemic effects of inhaled glucocorticoids are dose dependent, they are also dependent on the therapeutic index of the specific inhaled glucocorticoid and the delivery device used. Thus, it seems prudent to select inhaled glucocorticoids and devices with higher therapeutic indexes, and to use them in the lowest effective doses in children with persistent asthma."

Ultimately, they concluded, parents and physicians must work together to decide the risk-benefit ratio that is most appropriate and acceptable for each individual patient.

"In the information about inhaled glucocorticoids and their side effects that is provided to parents, the potential effect on adult height must be balanced against the large and well-established benefits of these drugs in controlling persistent asthma," concluded Dr. Kelly of the University of New Mexico, Albuquerque, and his coauthors.

The CAMP trial and its observational study were funded by the National Heart, Lung, and Blood Institute and the National Center for Research Resources. Dr. Kelly serves on steering committees for and has received consulting fees from AstraZeneca, GlaxoSmithKline, and other companies. His coauthors also reported multiple financial relationships with pharmaceutical companies.

In the PURL, “Consider adding this drug to fight COPD that’s severe”(J Fam Pract. 2012;61:414-416), Drs. Hobbs and Brown state that “there was an increase in the prevalence of macrolide-resistant respiratory pathogens in patients on daily azithromycin.” This statement is technically correct but terribly misleading. It implies that azithromycin caused increased resistance, which it did not.

Prevalence is a proportion, and in this case refers to the proportion of all isolates that were macrolide resistant. An increased proportion may be due to either an increased numerator (resistance) or a decreased denominator (isolates).

In the study in question¹ there were actually fewer macrolide-resistant pathogens isolated during treatment with azithromycin compared with placebo. All else being equal, this would have resulted in a decreased prevalence. However, there were also far fewer total isolates in the azithromycin group. This relatively larger decrease in the denominator prevailed, resulting in “increased” prevalence, due to fewer pathogens, not more resistance. This finding (of fewer pathogens isolated) has a clinical correlate. The 2 largest trials comparing azithromycin with placebo both found decreased acute respiratory illnesses in the azithromycin groups compared with the placebo groups.^2,3

The correct way to assess resistance would have been to calculate the incidence of newly detected resistant pathogens over a defined period of time in both the azithromycin and placebo groups. In fact, the incidence of macrolide resistance was 24% lower in the azithromycin group (11.1 per 100 patients per year vs 14.9 per 100 per year in the placebo group).⁴ Thus, the increased “prevalence” referred to by Hobbs and Brown does not indicate increased resistance, but rather decreased pathogens.

David L. Hahn, MD, MS
Madison, Wis

Drs. Hobbs and Mounsey respond

We thank Dr. Hahn for his comments and agree that further clarification of the impact of azithromycin on macrolide resistance is appropriate. As Dr. Hahn notes, the number of colonized patients in the azithromycin group (66/479) was lower than in the placebo group (172/476), as would be expected because they had been on azithromycin for one year.¹ Dr. Hahn calculates the incidence of macrolide resistance using as the denominator all the patients in both the azithromycin and placebo groups and shows that the rate is higher in the azithromycin group.

We chose to determine macrolide resistance by comparing resistance rates only in the colonized patients (66 on azithromycin and 172 on placebo), not the whole group—the majority of whom were not colonized at all. Albert et al used similar methodology, reporting that “the incidence of resistance to macrolides was 81% [in the azithromycin group] and 41% [in the placebo group].”¹

So as Dr. Hahn states, patients on azithromycin were less likely to become colonized with bacteria, but when they did, the organisms were more likely to be macrolide resistant.

Whichever way the data are presented, the finding of macrolide-resistant organisms in 81% of the isolates after only a year must raise concern about the long-term use of prophylactic azithromycin. In a recent commentary on the use of prophylactic azithromycin, Wenzel et al called this a “major concern” and stated that the Albert trial was not long enough to elucidate the extent or clinical implications of the problem.²

Keia Hobbs, MD
Anne Mounsey, MD
Chapel Hill, NC

In the PURL, “Consider adding this drug to fight COPD that’s severe”(J Fam Pract. 2012;61:414-416), Drs. Hobbs and Brown state that “there was an increase in the prevalence of macrolide-resistant respiratory pathogens in patients on daily azithromycin.” This statement is technically correct but terribly misleading. It implies that azithromycin caused increased resistance, which it did not.

Prevalence is a proportion, and in this case refers to the proportion of all isolates that were macrolide resistant. An increased proportion may be due to either an increased numerator (resistance) or a decreased denominator (isolates).

In the study in question¹ there were actually fewer macrolide-resistant pathogens isolated during treatment with azithromycin compared with placebo. All else being equal, this would have resulted in a decreased prevalence. However, there were also far fewer total isolates in the azithromycin group. This relatively larger decrease in the denominator prevailed, resulting in “increased” prevalence, due to fewer pathogens, not more resistance. This finding (of fewer pathogens isolated) has a clinical correlate. The 2 largest trials comparing azithromycin with placebo both found decreased acute respiratory illnesses in the azithromycin groups compared with the placebo groups.^2,3

The correct way to assess resistance would have been to calculate the incidence of newly detected resistant pathogens over a defined period of time in both the azithromycin and placebo groups. In fact, the incidence of macrolide resistance was 24% lower in the azithromycin group (11.1 per 100 patients per year vs 14.9 per 100 per year in the placebo group).⁴ Thus, the increased “prevalence” referred to by Hobbs and Brown does not indicate increased resistance, but rather decreased pathogens.

David L. Hahn, MD, MS
Madison, Wis

Drs. Hobbs and Mounsey respond

We thank Dr. Hahn for his comments and agree that further clarification of the impact of azithromycin on macrolide resistance is appropriate. As Dr. Hahn notes, the number of colonized patients in the azithromycin group (66/479) was lower than in the placebo group (172/476), as would be expected because they had been on azithromycin for one year.¹ Dr. Hahn calculates the incidence of macrolide resistance using as the denominator all the patients in both the azithromycin and placebo groups and shows that the rate is higher in the azithromycin group.

We chose to determine macrolide resistance by comparing resistance rates only in the colonized patients (66 on azithromycin and 172 on placebo), not the whole group—the majority of whom were not colonized at all. Albert et al used similar methodology, reporting that “the incidence of resistance to macrolides was 81% [in the azithromycin group] and 41% [in the placebo group].”¹

So as Dr. Hahn states, patients on azithromycin were less likely to become colonized with bacteria, but when they did, the organisms were more likely to be macrolide resistant.

Whichever way the data are presented, the finding of macrolide-resistant organisms in 81% of the isolates after only a year must raise concern about the long-term use of prophylactic azithromycin. In a recent commentary on the use of prophylactic azithromycin, Wenzel et al called this a “major concern” and stated that the Albert trial was not long enough to elucidate the extent or clinical implications of the problem.²

Keia Hobbs, MD
Anne Mounsey, MD
Chapel Hill, NC

In the PURL, “Consider adding this drug to fight COPD that’s severe”(J Fam Pract. 2012;61:414-416), Drs. Hobbs and Brown state that “there was an increase in the prevalence of macrolide-resistant respiratory pathogens in patients on daily azithromycin.” This statement is technically correct but terribly misleading. It implies that azithromycin caused increased resistance, which it did not.

Prevalence is a proportion, and in this case refers to the proportion of all isolates that were macrolide resistant. An increased proportion may be due to either an increased numerator (resistance) or a decreased denominator (isolates).

In the study in question¹ there were actually fewer macrolide-resistant pathogens isolated during treatment with azithromycin compared with placebo. All else being equal, this would have resulted in a decreased prevalence. However, there were also far fewer total isolates in the azithromycin group. This relatively larger decrease in the denominator prevailed, resulting in “increased” prevalence, due to fewer pathogens, not more resistance. This finding (of fewer pathogens isolated) has a clinical correlate. The 2 largest trials comparing azithromycin with placebo both found decreased acute respiratory illnesses in the azithromycin groups compared with the placebo groups.^2,3

The correct way to assess resistance would have been to calculate the incidence of newly detected resistant pathogens over a defined period of time in both the azithromycin and placebo groups. In fact, the incidence of macrolide resistance was 24% lower in the azithromycin group (11.1 per 100 patients per year vs 14.9 per 100 per year in the placebo group).⁴ Thus, the increased “prevalence” referred to by Hobbs and Brown does not indicate increased resistance, but rather decreased pathogens.

David L. Hahn, MD, MS
Madison, Wis

Drs. Hobbs and Mounsey respond

We thank Dr. Hahn for his comments and agree that further clarification of the impact of azithromycin on macrolide resistance is appropriate. As Dr. Hahn notes, the number of colonized patients in the azithromycin group (66/479) was lower than in the placebo group (172/476), as would be expected because they had been on azithromycin for one year.¹ Dr. Hahn calculates the incidence of macrolide resistance using as the denominator all the patients in both the azithromycin and placebo groups and shows that the rate is higher in the azithromycin group.

We chose to determine macrolide resistance by comparing resistance rates only in the colonized patients (66 on azithromycin and 172 on placebo), not the whole group—the majority of whom were not colonized at all. Albert et al used similar methodology, reporting that “the incidence of resistance to macrolides was 81% [in the azithromycin group] and 41% [in the placebo group].”¹

So as Dr. Hahn states, patients on azithromycin were less likely to become colonized with bacteria, but when they did, the organisms were more likely to be macrolide resistant.

Whichever way the data are presented, the finding of macrolide-resistant organisms in 81% of the isolates after only a year must raise concern about the long-term use of prophylactic azithromycin. In a recent commentary on the use of prophylactic azithromycin, Wenzel et al called this a “major concern” and stated that the Albert trial was not long enough to elucidate the extent or clinical implications of the problem.²

Keia Hobbs, MD
Anne Mounsey, MD
Chapel Hill, NC

Evidence summary

A systematic review of 4 RCTs with a total of 356 patients found that antibiotic therapy reduced mortality more than placebo in moderately to severely ill hospitalized patients with COPD. Short-term mortality (7 days after treatment to 18 months after hospital discharge) decreased by 77% with antibiotic use in acute exacerbations of COPD (number needed to treat [NNT]=8; 95% confidence interval [CI], 6-17).

This same Cochrane review and a meta-analysis of 4 hospital-based trials with 321 patients evaluated failure to improve, deterioration, or death during the study period.^1,2 The results favored treatment with antibiotics over placebo (NNT=3; 95% CI, 3-5).

Don’t wait to give antibiotics
A large retrospective cohort study of 84,621 hospitalized patients compared outcomes in patients given antibiotics for acute exacerbations of COPD during their first 2 days in the hospital with patients treated later or not at all.³ Outcomes assessed included need for later ventilation and readmission within 30 days for acute exacerbations of COPD.

The study included patients 40 years or older with a principal diagnosis, based on ICD 9 codes, of acute exacerbation of COPD, emphysema, or respiratory failure paired with a secondary diagnosis of COPD with acute exacerbation or emphysema. Patients who had been admitted directly to the intensive care unit were excluded, as were patients with other bacterial infections, such as pneumonia or cellulitis, for which they might receive antibiotics.

Early administration of antibiotics delayed the need for subsequent ventilation when compared with no antibiotics or antibiotics given later (1.07% vs 1.80%; P<.001; NNT=137). Giving antibiotics early also lowered readmission rates for acute exacerbations of COPD (7.91% vs 8.79%; P<.001; NNT=114), improved mortality rates (1.04% vs 1.59%; P<.001; NNT=182), and decreased treatment failure (9.77% vs 11.75%; P<.001; NNT=51).

Recommendations

The recommendations of the Global Initiative for Chronic Obstructive Lung Disease (GOLD), updated in 2008, call for antibiotics to be given to patients with 2 or more of the cardinal symptoms of acute exacerbations of COPD (shortness of breath, increased sputum production, and sputum purulence). Patients with severe exacerbations who require a ventilator should also receive antibiotics.⁴

The Primary Care Consensus Guidelines from 2004, consistent with the GOLD recommendations, state that a newer macrolide, extended-spectrum cephalosporin, or doxycycline is appropriate for moderately severe exacerbations. High-dose amoxicillin/clavulanate or a respiratory fluoroquinolone should be given for severe exacerbations.⁵

Evidence summary

A systematic review of 4 RCTs with a total of 356 patients found that antibiotic therapy reduced mortality more than placebo in moderately to severely ill hospitalized patients with COPD. Short-term mortality (7 days after treatment to 18 months after hospital discharge) decreased by 77% with antibiotic use in acute exacerbations of COPD (number needed to treat [NNT]=8; 95% confidence interval [CI], 6-17).

This same Cochrane review and a meta-analysis of 4 hospital-based trials with 321 patients evaluated failure to improve, deterioration, or death during the study period.^1,2 The results favored treatment with antibiotics over placebo (NNT=3; 95% CI, 3-5).

Don’t wait to give antibiotics
A large retrospective cohort study of 84,621 hospitalized patients compared outcomes in patients given antibiotics for acute exacerbations of COPD during their first 2 days in the hospital with patients treated later or not at all.³ Outcomes assessed included need for later ventilation and readmission within 30 days for acute exacerbations of COPD.

The study included patients 40 years or older with a principal diagnosis, based on ICD 9 codes, of acute exacerbation of COPD, emphysema, or respiratory failure paired with a secondary diagnosis of COPD with acute exacerbation or emphysema. Patients who had been admitted directly to the intensive care unit were excluded, as were patients with other bacterial infections, such as pneumonia or cellulitis, for which they might receive antibiotics.

Early administration of antibiotics delayed the need for subsequent ventilation when compared with no antibiotics or antibiotics given later (1.07% vs 1.80%; P<.001; NNT=137). Giving antibiotics early also lowered readmission rates for acute exacerbations of COPD (7.91% vs 8.79%; P<.001; NNT=114), improved mortality rates (1.04% vs 1.59%; P<.001; NNT=182), and decreased treatment failure (9.77% vs 11.75%; P<.001; NNT=51).

Recommendations

The recommendations of the Global Initiative for Chronic Obstructive Lung Disease (GOLD), updated in 2008, call for antibiotics to be given to patients with 2 or more of the cardinal symptoms of acute exacerbations of COPD (shortness of breath, increased sputum production, and sputum purulence). Patients with severe exacerbations who require a ventilator should also receive antibiotics.⁴

The Primary Care Consensus Guidelines from 2004, consistent with the GOLD recommendations, state that a newer macrolide, extended-spectrum cephalosporin, or doxycycline is appropriate for moderately severe exacerbations. High-dose amoxicillin/clavulanate or a respiratory fluoroquinolone should be given for severe exacerbations.⁵

Evidence summary

A systematic review of 4 RCTs with a total of 356 patients found that antibiotic therapy reduced mortality more than placebo in moderately to severely ill hospitalized patients with COPD. Short-term mortality (7 days after treatment to 18 months after hospital discharge) decreased by 77% with antibiotic use in acute exacerbations of COPD (number needed to treat [NNT]=8; 95% confidence interval [CI], 6-17).

This same Cochrane review and a meta-analysis of 4 hospital-based trials with 321 patients evaluated failure to improve, deterioration, or death during the study period.^1,2 The results favored treatment with antibiotics over placebo (NNT=3; 95% CI, 3-5).

Don’t wait to give antibiotics
A large retrospective cohort study of 84,621 hospitalized patients compared outcomes in patients given antibiotics for acute exacerbations of COPD during their first 2 days in the hospital with patients treated later or not at all.³ Outcomes assessed included need for later ventilation and readmission within 30 days for acute exacerbations of COPD.

The study included patients 40 years or older with a principal diagnosis, based on ICD 9 codes, of acute exacerbation of COPD, emphysema, or respiratory failure paired with a secondary diagnosis of COPD with acute exacerbation or emphysema. Patients who had been admitted directly to the intensive care unit were excluded, as were patients with other bacterial infections, such as pneumonia or cellulitis, for which they might receive antibiotics.

Early administration of antibiotics delayed the need for subsequent ventilation when compared with no antibiotics or antibiotics given later (1.07% vs 1.80%; P<.001; NNT=137). Giving antibiotics early also lowered readmission rates for acute exacerbations of COPD (7.91% vs 8.79%; P<.001; NNT=114), improved mortality rates (1.04% vs 1.59%; P<.001; NNT=182), and decreased treatment failure (9.77% vs 11.75%; P<.001; NNT=51).

Recommendations

The recommendations of the Global Initiative for Chronic Obstructive Lung Disease (GOLD), updated in 2008, call for antibiotics to be given to patients with 2 or more of the cardinal symptoms of acute exacerbations of COPD (shortness of breath, increased sputum production, and sputum purulence). Patients with severe exacerbations who require a ventilator should also receive antibiotics.⁴

The Primary Care Consensus Guidelines from 2004, consistent with the GOLD recommendations, state that a newer macrolide, extended-spectrum cephalosporin, or doxycycline is appropriate for moderately severe exacerbations. High-dose amoxicillin/clavulanate or a respiratory fluoroquinolone should be given for severe exacerbations.⁵

The Food and Drug Administration is warning physicians not to use off-label Revatio (sildenafil) to treat pulmonary arterial hypertension in children younger than 18 years.

The FDA made the announcement after a pediatric trial revealed high doses of Revatio increased mortality, and low doses failed to improve exercise ability among young PAH patients.

Revatio is a phosphodiesterase-5 inhibitor approved by the FDA to improve exercise ability and delay the progression of PAH in adults. However, the drug is not approved for treatment in children.

Results from a recent randomized, controlled study of Revatio use in 234 children aged 1-17 years with mild to moderate PAH demonstrated that low doses of the drug didn’t improve patients’ exercise ability. In addition, the mortality rate among children taking high doses of Revatio was 3.5 times greater than that of children taking low doses, a statistically significant difference.

The FDA has added a warning to Revatio’s labeling stating that the drug is not recommended for pediatric patients. The agency also has required the drug’s manufacturer, Pfizer, to evaluate Revatio’s mortality risk in adults.

Physicians can report adverse side effects involving Revatio to the FDA MedWatch program.

The Food and Drug Administration is warning physicians not to use off-label Revatio (sildenafil) to treat pulmonary arterial hypertension in children younger than 18 years.

The FDA made the announcement after a pediatric trial revealed high doses of Revatio increased mortality, and low doses failed to improve exercise ability among young PAH patients.

Revatio is a phosphodiesterase-5 inhibitor approved by the FDA to improve exercise ability and delay the progression of PAH in adults. However, the drug is not approved for treatment in children.

Results from a recent randomized, controlled study of Revatio use in 234 children aged 1-17 years with mild to moderate PAH demonstrated that low doses of the drug didn’t improve patients’ exercise ability. In addition, the mortality rate among children taking high doses of Revatio was 3.5 times greater than that of children taking low doses, a statistically significant difference.

The FDA has added a warning to Revatio’s labeling stating that the drug is not recommended for pediatric patients. The agency also has required the drug’s manufacturer, Pfizer, to evaluate Revatio’s mortality risk in adults.

Physicians can report adverse side effects involving Revatio to the FDA MedWatch program.

The Food and Drug Administration is warning physicians not to use off-label Revatio (sildenafil) to treat pulmonary arterial hypertension in children younger than 18 years.

The FDA made the announcement after a pediatric trial revealed high doses of Revatio increased mortality, and low doses failed to improve exercise ability among young PAH patients.

Revatio is a phosphodiesterase-5 inhibitor approved by the FDA to improve exercise ability and delay the progression of PAH in adults. However, the drug is not approved for treatment in children.

Results from a recent randomized, controlled study of Revatio use in 234 children aged 1-17 years with mild to moderate PAH demonstrated that low doses of the drug didn’t improve patients’ exercise ability. In addition, the mortality rate among children taking high doses of Revatio was 3.5 times greater than that of children taking low doses, a statistically significant difference.

The FDA has added a warning to Revatio’s labeling stating that the drug is not recommended for pediatric patients. The agency also has required the drug’s manufacturer, Pfizer, to evaluate Revatio’s mortality risk in adults.

Physicians can report adverse side effects involving Revatio to the FDA MedWatch program.

An updated clinical practice guideline from the American Academy of Pediatrics spells out which children with obstructive sleep apnea syndrome who undergo adenotonsillectomy should be admitted as inpatients.

"That’s really important because the vast majority of children have adenotonsillectomy on an outpatient basis," said Dr. Carole L. Marcus, who chaired a subcommittee that assembled the guideline, which was updated from a 2002 version and published online Aug. 27 in Pediatrics.

Courtesy Dr. Carole L. Marcus

Another new component of the 10-page guideline, titled "Diagnosis and Management of Childhood Obstructive Sleep Apnea Syndrome," includes an option for clinicians to prescribe intranasal steroids for a subset of children with obstructive sleep apnea syndrome (OSAS).

"For children with mild obstructive sleep apnea – especially for those in whom surgery might be contraindicated, or in those who have already had surgery and have some residual obstructive apnea – intranasal steroids could be helpful," Dr. Marcus, who directs the Sleep Center at the Children’s Hospital of Philadelphia, said in an interview. "There are still a lot of unanswered questions [about this practice], one of the biggest being that all of the studies have been relatively short term, meaning weeks to months, not years. Does a child need just one course, or do they need to be on it for the rest of their lives? Those are studies that need to be done."

To update the 2002 guideline, Dr. Marcus and 11 other members of the interdisciplinary AAP Subcommittee on Obstructive Sleep Apnea Syndrome reviewed 3,166 articles from the medical literature related to the diagnosis and management of OSAS in children and adolescents that were published during 1999-2008. Then subcommittee members "selectively updated this literature search for articles published from 2008 to 2011 specific to guideline categories." Of the 3,166 studies, 350 were used to formulate eight recommendations, termed "key action statements" (Pediatrics 2012;130:576-84).

Since publication of the previous guideline, "there has been a huge amount of research done in this field," noted Dr. Marcus, who is also a professor of pediatrics at the University of Pennsylvania, Philadelphia. "Many of the initial studies we looked at for the first guideline were case series. Now people are doing well-structured studies and looking at some of the detailed outcomes such as neurocognitive findings."

The first recommendation in the updated guideline advises clinicians to screen for OSAS during routine health maintenance visits, "because OSA in children is underdiagnosed," Dr. Marcus explained. "Parents don’t necessarily think of snoring as a sign of a serious disease. They might think it’s funny, but it’s actually a sign of illness.

"Knowing how busy pediatricians are, there are two questions that are crucial," she continued. "One is, ‘How does your child sleep?’ The other is, ‘Does your child snore?’ If you get a positive [response] to the snoring [question] you do need to go into more detail. The next question would be, ‘Is there labored breathing with the snoring?’ Your history will tell you which children need further objective evaluation, such as a sleep study."

The guideline also recommends that the following subset of children be admitted as inpatients after tonsillectomy: those younger than age 3; those with severe OSAS on polysomnography; those with cardiac complications of OSAS; those with failure to thrive; those who are obese; and those with craniofacial anomalies, neuromuscular disorders, or a current respiratory infection.

Another component to the guideline is the recommendation that clinicians refer patients for continuous positive airway pressure (CPAP) management if OSAS signs and symptoms persist after adenotonsillectomy or if adenotonsillectomy is not performed. Dr. Marcus described CPAP as "the best way to go as a second-line option. Since the previous guidelines came out, the prevalence of obesity in children has gone up even more dramatically. Therefore, there is a lot more OSA out there, and pediatricians will be seeing a lot more in children of all ages."

One component of the guideline related to polysomnography proved difficult for the committee members and the consulting medical societies to reach consensus on. This recommendation states that clinicians should obtain a polysomnogram or refer the patient to a sleep specialist or otolaryngologist if the child or adolescent snores regularly or meets the symptoms and signs of OSAS.

"If one agrees that sleep studies are the only objective way to tell what’s going on, we just don’t have the resources in this country to study every child," Dr. Marcus said. "The literature is very strong showing that a history and physical exam could give you an idea of which children you should have an index of suspicion about, but do not tell you which children have sleep apnea. The vast number of children who have adenotonsillectomy for suspected OSA are having it done without any sort of objective finding. The studies that have been done show that about 50% of the time, even with a history that seems indicative of OSA, the children will have normal sleep studies."

Because of this quandary, the committee included a related recommendation, which reads that if polysomnography is not available, "then clinicians may order alternative diagnostic tests, such as nocturnal video recording, nocturnal oximetry, daytime nap polysomnography, or ambulatory polysomnography."

Dr. Marcus said that further changes to the new guideline may be warranted pending the results of the Childhood Adenotonsillectomy Study for Children With OSAS (CHAT). Sponsored by the National Heart, Lung, and Blood Institute, the goal of this multicenter, randomized trial is to determine the effect of adenotonsillectomy surgery on OSAS in children. "That study has just been completed, but nothing has been published yet," said Dr. Marcus, who is one of CHAT’s investigators. "That might change things even more."

There is a 44-page technical report that details the procedures the subcommittee members followed and the data they considered (Pediatrics 2012;130:e714-55).

Dr. Marcus disclosed that she has received research support from Philips Respironics. Another subcommittee member, Dr. David Gozal, disclosed having research support from AstraZeneca and being a speaker for Merck.; Dr. Ann C. Halbower disclosed receiving research funding from Resmed; and Dr. Michael S. Schechter disclosed that he is a consultant to Genentech and Gilead, and that he has received research support from Mpex Pharmaceuticals, Vertex Pharmaceuticals, and other companies.

An updated clinical practice guideline from the American Academy of Pediatrics spells out which children with obstructive sleep apnea syndrome who undergo adenotonsillectomy should be admitted as inpatients.

"That’s really important because the vast majority of children have adenotonsillectomy on an outpatient basis," said Dr. Carole L. Marcus, who chaired a subcommittee that assembled the guideline, which was updated from a 2002 version and published online Aug. 27 in Pediatrics.

Courtesy Dr. Carole L. Marcus

Another new component of the 10-page guideline, titled "Diagnosis and Management of Childhood Obstructive Sleep Apnea Syndrome," includes an option for clinicians to prescribe intranasal steroids for a subset of children with obstructive sleep apnea syndrome (OSAS).

"For children with mild obstructive sleep apnea – especially for those in whom surgery might be contraindicated, or in those who have already had surgery and have some residual obstructive apnea – intranasal steroids could be helpful," Dr. Marcus, who directs the Sleep Center at the Children’s Hospital of Philadelphia, said in an interview. "There are still a lot of unanswered questions [about this practice], one of the biggest being that all of the studies have been relatively short term, meaning weeks to months, not years. Does a child need just one course, or do they need to be on it for the rest of their lives? Those are studies that need to be done."

To update the 2002 guideline, Dr. Marcus and 11 other members of the interdisciplinary AAP Subcommittee on Obstructive Sleep Apnea Syndrome reviewed 3,166 articles from the medical literature related to the diagnosis and management of OSAS in children and adolescents that were published during 1999-2008. Then subcommittee members "selectively updated this literature search for articles published from 2008 to 2011 specific to guideline categories." Of the 3,166 studies, 350 were used to formulate eight recommendations, termed "key action statements" (Pediatrics 2012;130:576-84).

Since publication of the previous guideline, "there has been a huge amount of research done in this field," noted Dr. Marcus, who is also a professor of pediatrics at the University of Pennsylvania, Philadelphia. "Many of the initial studies we looked at for the first guideline were case series. Now people are doing well-structured studies and looking at some of the detailed outcomes such as neurocognitive findings."

The first recommendation in the updated guideline advises clinicians to screen for OSAS during routine health maintenance visits, "because OSA in children is underdiagnosed," Dr. Marcus explained. "Parents don’t necessarily think of snoring as a sign of a serious disease. They might think it’s funny, but it’s actually a sign of illness.

"Knowing how busy pediatricians are, there are two questions that are crucial," she continued. "One is, ‘How does your child sleep?’ The other is, ‘Does your child snore?’ If you get a positive [response] to the snoring [question] you do need to go into more detail. The next question would be, ‘Is there labored breathing with the snoring?’ Your history will tell you which children need further objective evaluation, such as a sleep study."

The guideline also recommends that the following subset of children be admitted as inpatients after tonsillectomy: those younger than age 3; those with severe OSAS on polysomnography; those with cardiac complications of OSAS; those with failure to thrive; those who are obese; and those with craniofacial anomalies, neuromuscular disorders, or a current respiratory infection.

Another component to the guideline is the recommendation that clinicians refer patients for continuous positive airway pressure (CPAP) management if OSAS signs and symptoms persist after adenotonsillectomy or if adenotonsillectomy is not performed. Dr. Marcus described CPAP as "the best way to go as a second-line option. Since the previous guidelines came out, the prevalence of obesity in children has gone up even more dramatically. Therefore, there is a lot more OSA out there, and pediatricians will be seeing a lot more in children of all ages."

One component of the guideline related to polysomnography proved difficult for the committee members and the consulting medical societies to reach consensus on. This recommendation states that clinicians should obtain a polysomnogram or refer the patient to a sleep specialist or otolaryngologist if the child or adolescent snores regularly or meets the symptoms and signs of OSAS.

"If one agrees that sleep studies are the only objective way to tell what’s going on, we just don’t have the resources in this country to study every child," Dr. Marcus said. "The literature is very strong showing that a history and physical exam could give you an idea of which children you should have an index of suspicion about, but do not tell you which children have sleep apnea. The vast number of children who have adenotonsillectomy for suspected OSA are having it done without any sort of objective finding. The studies that have been done show that about 50% of the time, even with a history that seems indicative of OSA, the children will have normal sleep studies."

Because of this quandary, the committee included a related recommendation, which reads that if polysomnography is not available, "then clinicians may order alternative diagnostic tests, such as nocturnal video recording, nocturnal oximetry, daytime nap polysomnography, or ambulatory polysomnography."

Dr. Marcus said that further changes to the new guideline may be warranted pending the results of the Childhood Adenotonsillectomy Study for Children With OSAS (CHAT). Sponsored by the National Heart, Lung, and Blood Institute, the goal of this multicenter, randomized trial is to determine the effect of adenotonsillectomy surgery on OSAS in children. "That study has just been completed, but nothing has been published yet," said Dr. Marcus, who is one of CHAT’s investigators. "That might change things even more."

There is a 44-page technical report that details the procedures the subcommittee members followed and the data they considered (Pediatrics 2012;130:e714-55).

Dr. Marcus disclosed that she has received research support from Philips Respironics. Another subcommittee member, Dr. David Gozal, disclosed having research support from AstraZeneca and being a speaker for Merck.; Dr. Ann C. Halbower disclosed receiving research funding from Resmed; and Dr. Michael S. Schechter disclosed that he is a consultant to Genentech and Gilead, and that he has received research support from Mpex Pharmaceuticals, Vertex Pharmaceuticals, and other companies.

An updated clinical practice guideline from the American Academy of Pediatrics spells out which children with obstructive sleep apnea syndrome who undergo adenotonsillectomy should be admitted as inpatients.

"That’s really important because the vast majority of children have adenotonsillectomy on an outpatient basis," said Dr. Carole L. Marcus, who chaired a subcommittee that assembled the guideline, which was updated from a 2002 version and published online Aug. 27 in Pediatrics.

Courtesy Dr. Carole L. Marcus

Another new component of the 10-page guideline, titled "Diagnosis and Management of Childhood Obstructive Sleep Apnea Syndrome," includes an option for clinicians to prescribe intranasal steroids for a subset of children with obstructive sleep apnea syndrome (OSAS).

"For children with mild obstructive sleep apnea – especially for those in whom surgery might be contraindicated, or in those who have already had surgery and have some residual obstructive apnea – intranasal steroids could be helpful," Dr. Marcus, who directs the Sleep Center at the Children’s Hospital of Philadelphia, said in an interview. "There are still a lot of unanswered questions [about this practice], one of the biggest being that all of the studies have been relatively short term, meaning weeks to months, not years. Does a child need just one course, or do they need to be on it for the rest of their lives? Those are studies that need to be done."

To update the 2002 guideline, Dr. Marcus and 11 other members of the interdisciplinary AAP Subcommittee on Obstructive Sleep Apnea Syndrome reviewed 3,166 articles from the medical literature related to the diagnosis and management of OSAS in children and adolescents that were published during 1999-2008. Then subcommittee members "selectively updated this literature search for articles published from 2008 to 2011 specific to guideline categories." Of the 3,166 studies, 350 were used to formulate eight recommendations, termed "key action statements" (Pediatrics 2012;130:576-84).

Since publication of the previous guideline, "there has been a huge amount of research done in this field," noted Dr. Marcus, who is also a professor of pediatrics at the University of Pennsylvania, Philadelphia. "Many of the initial studies we looked at for the first guideline were case series. Now people are doing well-structured studies and looking at some of the detailed outcomes such as neurocognitive findings."

The first recommendation in the updated guideline advises clinicians to screen for OSAS during routine health maintenance visits, "because OSA in children is underdiagnosed," Dr. Marcus explained. "Parents don’t necessarily think of snoring as a sign of a serious disease. They might think it’s funny, but it’s actually a sign of illness.

"Knowing how busy pediatricians are, there are two questions that are crucial," she continued. "One is, ‘How does your child sleep?’ The other is, ‘Does your child snore?’ If you get a positive [response] to the snoring [question] you do need to go into more detail. The next question would be, ‘Is there labored breathing with the snoring?’ Your history will tell you which children need further objective evaluation, such as a sleep study."

The guideline also recommends that the following subset of children be admitted as inpatients after tonsillectomy: those younger than age 3; those with severe OSAS on polysomnography; those with cardiac complications of OSAS; those with failure to thrive; those who are obese; and those with craniofacial anomalies, neuromuscular disorders, or a current respiratory infection.

Another component to the guideline is the recommendation that clinicians refer patients for continuous positive airway pressure (CPAP) management if OSAS signs and symptoms persist after adenotonsillectomy or if adenotonsillectomy is not performed. Dr. Marcus described CPAP as "the best way to go as a second-line option. Since the previous guidelines came out, the prevalence of obesity in children has gone up even more dramatically. Therefore, there is a lot more OSA out there, and pediatricians will be seeing a lot more in children of all ages."

One component of the guideline related to polysomnography proved difficult for the committee members and the consulting medical societies to reach consensus on. This recommendation states that clinicians should obtain a polysomnogram or refer the patient to a sleep specialist or otolaryngologist if the child or adolescent snores regularly or meets the symptoms and signs of OSAS.

"If one agrees that sleep studies are the only objective way to tell what’s going on, we just don’t have the resources in this country to study every child," Dr. Marcus said. "The literature is very strong showing that a history and physical exam could give you an idea of which children you should have an index of suspicion about, but do not tell you which children have sleep apnea. The vast number of children who have adenotonsillectomy for suspected OSA are having it done without any sort of objective finding. The studies that have been done show that about 50% of the time, even with a history that seems indicative of OSA, the children will have normal sleep studies."

Because of this quandary, the committee included a related recommendation, which reads that if polysomnography is not available, "then clinicians may order alternative diagnostic tests, such as nocturnal video recording, nocturnal oximetry, daytime nap polysomnography, or ambulatory polysomnography."

Dr. Marcus said that further changes to the new guideline may be warranted pending the results of the Childhood Adenotonsillectomy Study for Children With OSAS (CHAT). Sponsored by the National Heart, Lung, and Blood Institute, the goal of this multicenter, randomized trial is to determine the effect of adenotonsillectomy surgery on OSAS in children. "That study has just been completed, but nothing has been published yet," said Dr. Marcus, who is one of CHAT’s investigators. "That might change things even more."

There is a 44-page technical report that details the procedures the subcommittee members followed and the data they considered (Pediatrics 2012;130:e714-55).

Dr. Marcus disclosed that she has received research support from Philips Respironics. Another subcommittee member, Dr. David Gozal, disclosed having research support from AstraZeneca and being a speaker for Merck.; Dr. Ann C. Halbower disclosed receiving research funding from Resmed; and Dr. Michael S. Schechter disclosed that he is a consultant to Genentech and Gilead, and that he has received research support from Mpex Pharmaceuticals, Vertex Pharmaceuticals, and other companies.