In the JournalsPerspective

Early administration of antibiotics helps prevent severe lower respiratory infection in children

According to recent research in JAMA, azithromycin administered at the first sign of a cold in children with a history of respiratory tract illnesses reduced the likelihood of developing severe lower respiratory tract illnesses.

“Among young children with histories of recurrent severe lower respiratory tract illnesses, the use of azithromycin early during an apparent respiratory tract illness compared with placebo reduced the likelihood of severe lower respiratory tract illness,” Leonard B. Bacharier, MD, of the department of pediatrics at Washington University School of Medicine, and colleagues wrote.

The researchers conducted a double blind, randomized clinical trial on the effectiveness of azithromycin vs. placebo at reducing the development of severe respiratory tract illness. Six hundred seven children aged 12 to 71 months with histories of severe respiratory tract illness were classified into two groups: a control group assigned placebo (n = 300) and an intervention group assigned 12 mg/kg azithromycin daily for 5 days (n = 307).

Thirty-five of the 473 treated respiratory tract illnesses in the intervention group developed into severe illness, while 57 cases resulted in severe illness among 464 illnesses in the control group. Azithromycin significantly reduced the risk for developing severe lower respiratory tract illness (HR = 0.64; 95% CI, 0.41-0.98) compared with placebo.

The researchers also briefly noted the complications related to pre-emptive administration of antibiotics in order to reduce asthma-related infections.

“Although not recommended by national asthma guidelines, antibiotics are widely used in clinical practice during respiratory tract illnesses and asthma episodes,” Bacharier and colleagues wrote. “More information is needed on the development of antibiotic-resistant pathogens with this strategy.

In a related editorial, Robyn T. Cohen, MD, MPH, and Stephen I. Pelton, MD, of Boston Medical Center at the Boston University School of Medicine, wrote that while Bacharier and colleagues’ findings are encouraging, questions related to antibiotic resistance must be answered before broadly implementing azithromycin in this manner.

“The implications of the study must also be interpreted in light of the reality that more widespread azithromycin use for a condition as common as early, intermittent childhood wheezing would increase the prevalence of macrolide resistance,” they wrote. “Until a higher risk population can be prospectively identified (rather than all children with intermittent wheezing associated with viral respiratory tract illness) for progression to severe lower respiratory tract illness, the consequences of widespread use of azithromycin, both known and hypothesized, outweigh the benefit for most children.” – by David Costill

Disclosure: Bacharier reports personal fees from Aerocrine, AstraZeneca, Boehringer Ingelheim, Cephalon, DBV Technologies, Genentech/Novartis, GlaxoSmithKline, Merck, Schering, Teva, Sanofi and WebMD. Pelton reports personal fees from Pfizer, Policy Analysis and Sanofi, and grant funding from Cempra, Merck and Pfizer. Please see the full study for a list of all other authors’ relevant financial disclosures.

According to recent research in JAMA, azithromycin administered at the first sign of a cold in children with a history of respiratory tract illnesses reduced the likelihood of developing severe lower respiratory tract illnesses.

“Among young children with histories of recurrent severe lower respiratory tract illnesses, the use of azithromycin early during an apparent respiratory tract illness compared with placebo reduced the likelihood of severe lower respiratory tract illness,” Leonard B. Bacharier, MD, of the department of pediatrics at Washington University School of Medicine, and colleagues wrote.

The researchers conducted a double blind, randomized clinical trial on the effectiveness of azithromycin vs. placebo at reducing the development of severe respiratory tract illness. Six hundred seven children aged 12 to 71 months with histories of severe respiratory tract illness were classified into two groups: a control group assigned placebo (n = 300) and an intervention group assigned 12 mg/kg azithromycin daily for 5 days (n = 307).

Thirty-five of the 473 treated respiratory tract illnesses in the intervention group developed into severe illness, while 57 cases resulted in severe illness among 464 illnesses in the control group. Azithromycin significantly reduced the risk for developing severe lower respiratory tract illness (HR = 0.64; 95% CI, 0.41-0.98) compared with placebo.

The researchers also briefly noted the complications related to pre-emptive administration of antibiotics in order to reduce asthma-related infections.

“Although not recommended by national asthma guidelines, antibiotics are widely used in clinical practice during respiratory tract illnesses and asthma episodes,” Bacharier and colleagues wrote. “More information is needed on the development of antibiotic-resistant pathogens with this strategy.

In a related editorial, Robyn T. Cohen, MD, MPH, and Stephen I. Pelton, MD, of Boston Medical Center at the Boston University School of Medicine, wrote that while Bacharier and colleagues’ findings are encouraging, questions related to antibiotic resistance must be answered before broadly implementing azithromycin in this manner.

“The implications of the study must also be interpreted in light of the reality that more widespread azithromycin use for a condition as common as early, intermittent childhood wheezing would increase the prevalence of macrolide resistance,” they wrote. “Until a higher risk population can be prospectively identified (rather than all children with intermittent wheezing associated with viral respiratory tract illness) for progression to severe lower respiratory tract illness, the consequences of widespread use of azithromycin, both known and hypothesized, outweigh the benefit for most children.” – by David Costill

Disclosure: Bacharier reports personal fees from Aerocrine, AstraZeneca, Boehringer Ingelheim, Cephalon, DBV Technologies, Genentech/Novartis, GlaxoSmithKline, Merck, Schering, Teva, Sanofi and WebMD. Pelton reports personal fees from Pfizer, Policy Analysis and Sanofi, and grant funding from Cempra, Merck and Pfizer. Please see the full study for a list of all other authors’ relevant financial disclosures.

    Perspective
    Pedro A Piedra

    Pedro A Piedra

    Wheezing illnesses in preschool children are associated with significant health care utilization, morbidity, and to a lesser extent mortality. Common respiratory viruses are associated with at least 90% of wheezing illnesses in preschool children, and are considered to be the major trigger for recurrent wheezing and acute asthma exacerbation. During the first 3 years of life, the most common viruses detected are rhinovirus and respiratory syncytial virus followed by other less common respiratory viruses.

    Most of the respiratory viruses are mucosally restricted and associated with neutrophilic inflammation. In general, asthma controller medications are suboptimal for the prevention or treatment of virus-induced, severe lower respiratory tract illness (SLRTI) in preschool children, in part, because neutrophilic inflammation as compared with eosinophilic inflammation is less responsive. The use of macrolides, which are bacteriostatic antibiotics that bind to 50S ribosomal subunits, have been used successfully as an anti-inflammatory drug in children with cystic fibrosis. Macrolides have been shown to contain antiviral activity in vitro and antineutrophilic inflammatory property in vivo. There is a strong research interest to understand the medical impact of macrolides for the prevention and treatment of SLRTI in children with a history of recurrent wheezing illness.

    The well-designed, randomized, placebo-control study by Bacharier and colleagues sought to determine if early treatment with azithromycin (12 mg/kg/d for 5 days) in preschool children with recurrent LRTI can prevent progression to SLRTI. There were 780 children enrolled in the study, but only 223 in the azithromycin arm and 220 in the placebo cohort were evaluable for the primary outcome. The use of azithromycin was associated with a significant reduction in SLRTI from 0.08 in the placebo group to 0.05 in the azithromycin group (HR = 0.64; 95% CI, 0.41-0.98). However, there was no significant difference observed in urgent care and ED visits, hospitalization, PCR-confirmed viral respiratory tract illness, or time to second treated respiratory tract illness. An increase in azithromycin resistance bacteria was detected in azithromycin-treated participants over the course of the study. As stated succinctly in the review by Cohen and Pelton, “until a higher risk population can be prospectively identified for progression to SLRTI, the consequences of widespread use of azithromycin outweigh the benefit for most children.”

    • Pedro A Piedra, MD
    • Infectious Diseases in Children Editorial Board member Professor in the departments of molecular virology and microbiology, and pediatrics Baylor College of Medicine

    Disclosures: reports no finanacial disclosures.