Azithromycin administered at either low or high dose demonstrated safety in a randomized, placebo-controlled phase II trial of 48 young children hospitalized for treatment of respiratory syncytial virus (RSV)-induced respiratory failure, a team of researchers from the University of Alabama at Birmingham report in JAMA Network Open.
Moreover, Michele Kong, MD, of the UAB Department of Pediatrics, and colleagues, wrote that patients “who received high-dose AZM had fewer median (interquartile range) hospital days compared with those receiving the placebo (8 [6-14] days versus 11 [8-20] days; mean ratio estimate, 0.57; 95% CI, 0.38-0.87; P = .01),” which was a secondary outcome measure.
The authors noted that endotracheal elevation of matrix metalloproteinase-9 (MMP-9) levels was previously shown to be a potential marker of RSV disease severity; thus, MMP-9 nasal and endotracheal levels were the main outcome measures.
In this study, there was no difference in MMP-9 levels between the two AZM dosing groups (10 mg/kg/d or 20 mg/kg/d), but among a subset of patients who “required mechanical ventilation and received high-dose AZM, endotracheal active and total MMP-9 levels were lower on day 3. Compared with baseline, active and total MMP-9 levels in endotracheal aspirates were 1.0 log lower in the high-dose AZM group (active MMP-9: 99.8% CI, −1.28 to −0.64; P < .001; total MMP-9: 99.8% CI, −1.37 to −0.57; P < .001).”
Additionally, “RSV titer in the nasal and lung compartment decreased among all patients, and although those treated with high doses of AZM had the lowest viral burden at the end of the third dose, this finding was not significant,” they noted.
“Given the uncertainty regarding optimal dosing to achieve anti-inflammatory activity, we included a high-dose AZM group to maximize the likelihood of achieving adequate and sustained AZM levels,” the study authors wrote. “Others have suggested increased effectiveness of high-dose AZM in Ureaplasma urealyticum clearance in preterm infants. In this study, we demonstrated that high doses of AZM were safe.
Based on these results, Kong and colleagues wrote that the “positive secondary clinical outcome, while exploratory, provides insight for end points in a multicenter randomized trial.”
The researchers screened 147 patients and randomized 48. “The median (range) age of patients at randomization was 12 (1-125) months, with 36 (75.0%) younger than 2 years. Overall, 26 participants (54.2%) were boys, and 29 (60.4%) had a comorbidity… At the time of randomization, 34 patients (70.8%) required mechanical ventilation, 2 (4.2%) received BiPAP (bilevel positive airway pressure) support, and the remaining 12 patients (25.0%) received HFNC (high-flow nasal canula). Once extubated, 4 (11.8%) received BiPAP, and 22 (64.8%) were transitioned to HFNC,” they wrote.
They noted that RSV carries a high disease burden and yet there is no effective treatment. This study, they wrote, is “the first randomized placebo-controlled trial of AZM at multiple doses in children with severe RSV infection and lung disease who required PICU management and positive pressure ventilation. We demonstrated preliminary efficacy of AZM, specifically at a higher dose, in the reduction of biomarkers modulated by RSV infection and in reducing duration of hospitalization in a critically ill cohort of hospitalized children.”
Kong and colleagues cautioned that there were several limitations to the study, including its single-tertiary center design and small sample size.
“Although we observed decreased numbers of ventilator support and oxygen days as well as shorter duration of PICU stay in the high-dose AZM group, future studies will need to be powered to detect changes in these clinical outcome measures based on the findings of this trial,” they wrote. “Also, it is possible that practice variation might have contributed to the clinical differences seen between the placebo versus treatment group. However, the masking of the study ensured no biases toward any particular group, and practice variation was also limited given that our unit in general follows the same respiratory weaning protocol.”
Additionally, although sensorineural hearing loss is a known side-effect of AZM, the authors did not test for it.
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Be aware that this report describes a phase II study designed to assess safety of azithromycin in children with RSV. It was not designed to assess efficacy.
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In this phase II study, high doses of AZM were safe, reduced endotracheal MMP-9 levels in patients receiving mechanical ventilation, and potentially improved outcomes in critically ill children with respiratory syncytial virus infections; however, a multicenter, randomized trial is needed to confirm the findings.
Peggy Peck, Editor-in-Chief, BreakingMED™
The study was funded by the University of Alabama at Birmingham.
Kong had no disclosures.
Cat ID: 138
Topic ID: 85,138,730,125,138,192,195,925
