Early Azithromycin Reduces Severe Respiratory Tract Infections

Tara Haelle

November 18, 2015

Children with recurrent wheeze had a lower risk for severe lower respiratory tract illness (LRTI) when they received azithromycin at the earliest signs of an infection compared with children who received a placebo, according to a randomized controlled study published in the November 17 issue of JAMA.

"Positive effects were detectable irrespective of modified [asthma predictive index] status, identifying a treatment option for children at both high and low risk for subsequent persistent asthma," write Leonard B. Bacharier, MD, from the Department of Pediatrics in the Washington University St Louis School of Medicine in St. Louis, Missouri, and colleagues. "Furthermore, azithromycin therapy was well tolerated, with low rates of treatment-related adverse effects."

In an online interview released with the study, Dr Bacharier said translating this strategy into actual clinical practice will take time, however.

"This requires a proactive discussion with the child's healthcare provider in advance, so that if this strategy is to be undertaken, it is available at home, with the parent well instructed as to the earliest signs of illness and knows when to start this," Dr Bacharier said.

The researchers conducted a randomized controlled, double-blind trial with 607 children from across nine US academic medical centers between April 2011 and December 2014. The children, ranging from 12 to 71 months old, all had "recurrent severe wheezing in the context of clinically significant LRTI that required systemic corticosteroids, an unscheduled physician office visit, an urgent or emergency department visit, or hospitalization," the authors write. Among the children, 39.1% had allergic sensitization to at least one allergen, and 46.8% were at high risk for asthma based on their Asthma Predictive Index score.

One group of 307 children received 12 mg/kg per day of azithromycin for 5 days, whereas the other group of 300 children received a placebo. Children in both groups started their treatment at the first sign of a LRTI. The researchers compared how many RTIs did not progress to an infection severe enough to warrant oral corticosteroids.

In the intervention group, 223 children experienced 473 RTIs compared with 464 infections among 220 children in the placebo group. Severe RTIs occurred 35 times among children receiving azithromycin and 57 times among children receiving the placebo. Administering azithromycin reduced the risk for progression to severe RTI by 36% (hazard ratio, 0.64; 95% confidence interval [CI], 0.41 - 0.98; P = .04). The absolute risk for a severe RTI was 5% in children receiving azithromycin and 8% in children receiving placebo, for an absolute risk difference of 3% (95% CI, 0.00 - 0.06).

"Azithromycin therapy decreased the overall severity of symptoms during severe LRTIs compared with placebo, as reflected by lower mean total symptom scores over the duration of RTI, but not during episodes not progressing to severe LRTI," the authors report. Total albuterol use did not significantly differ between the groups, and 3.6% of children receiving azithromycin had urgent care or emergency department visits compared with 5.4% of those receiving placebo.

The researchers isolated azithromycin-resistant organisms from 12.2% of children in the azithromycin group and 8.9% of children in the placebo group at the time of randomization. At study completion, 20.0% of children receiving azithromycin and 17.0% of children receiving placebo had azithromycin-resistant organisms. "Over the duration of the study, 6 of 36 participants treated with azithromycin (16.7%) and 4 of 37 participants not treated with azithromycin (10.8%) acquired azithromycin-resistant organisms," the authors write. "[Staphylococcus] aureus was the most common azithromycin-resistant organism isolated."

The mechanism by which azithromycin reduces severe LRTI risk is unclear, the researchers note, and they acknowledge the controversy surrounding antibiotic use in children with wheezing illnesses. "Although not recommended by national asthma guidelines, antibiotics (frequently macrolides) are widely used in clinical practice during RTIs and asthma episodes," they write. "A major, justified concern in general pediatrics is the overuse of antibiotics for viral illnesses leading to the potential development of antibiotic-resistant pathogens."

In an accompanying editorial, Robyn T. Cohen, MD, MPH, and Stephen I. Pelton, MD, from Boston Medical Center at Boston University School of Medicine in Massachusetts, suggest several possible mechanisms.

"The finding that macrolides may be helpful in this challenging population potentially reflects both their antimicrobial effects (atypical bacteria do play a significant role in some LRTIs in young children) and, more likely, their anti-inflammatory effects," Dr Cohen and Dr Pelton write. "Alternative hypotheses regarding direct antiviral effects and modulation of steroid sensitivity by azithromycin either directly or indirectly through its antibacterial effect are also being evaluated."

Yet they issued several caveats regarding the clinical significance of the findings, including the study's limited generalizability, given the strict inclusion criteria for participants; the lack of reductions in urgent or emergency care or hospitalizations; the inability to identify subgroups showing greater benefits from the azithromycin; potential adverse effects on the children's gut microbiome from azithromycin use; and "the reality that more widespread azithromycin use for a condition as common as early, intermittent childhood wheezing would increase the prevalence of macrolide resistance."

Dr Cohen and Dr Pelton recommend further research to identify the specific subgroups of children most likely to benefit from early azithromycin use. "Until a higher-risk population can be prospectively identified (rather than all children with intermittent wheezing associated with viral RTI) for progression to severe LRTI, the consequences of widespread use of azithromycin, both known and hypothesized, outweigh the benefit for most children," they conclude.

The research was funded by the National Heart, Lung and Blood Institute as a part of AsthmaNet; products for National Heart, Lung and Blood Institute AsthmaNet studies have been provided by GlaxoSmithKline, Merck, Teva, Boehringer Ingelheim, and Sunovion. Various coauthors reported receiving grant funding and/or personal fees from a wide range of pharmaceutical companies and/or other industry organizations. Full conflict-of-interest information is available in the article. Dr Pelton has received research funds from Merck, Pfizer, and Cempra and personal fees from Policy Analysis Incorporated, Sanofi and Pfizer. Dr Cohen has disclosed no relevant financial relationships.

JAMA. 2015;314:2027-2029, 2034-2044. Article full text, Editorial extract

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