Introduction

Protracted bacterial bronchitis (PBB) is a leading cause of chronic wet cough in children. The current European and American guidelines recommend 2 weeks of antibiotics, however, the optimal duration of therapy is unknown.

Aim

• To test the hypothesis that a 4-week course of oral amoxicillin–clavulanate is superior to a 2-week course in achieving clinical cure in children with suspected PBB within 28 days
• To test secondary hypotheses that children who receive longer duration antibiotics would have reduced rates of PBB recurrence; longer time to next exacerbation following clinical cure; and greater improvement in Parent-proxy Cough-Specific Quality-of- Life (PC-QoL) between baseline versus 28 days and 7 months follow-up

Patient Profile

• Children (aged 2 months to 19 years) with chronic (>4 weeks duration) wet cough and suspected PBB

Method

Study Design

• Two-arm, parallel-group, double-blind, placebo-controlled randomised controlled trial
• Children were randomly assigned to amoxicillin– clavulanate (25–35 mg/kg twice daily oral suspension) for 4 weeks or 2 weeks followed by 2 weeks of placebo

Endpoints

• Primary outcome: clinical cure by day 28 (a priori as an absence of cough for at least 3 days or >75% improvement over 3 days in cough scores compared with cough at the start of the trial)
• Secondary outcomes: recurrence of PBB at 6 months, time to next exacerbation, change in PC-QoL score from baseline to day 28 and from day 28 to 7 months, adverse events, nasal swab bacteriology, and antimicrobial resistance patterns
• Post-hoc analyses outcomes: mean number of exacerbations (number of defined wet cough recurrence events during 6-month follow-up period), mean number of days each group received antibiotics, if brief duration of cough at baseline (<8 weeks) caused better response to 4 weeks of antibiotic therapy versus 2 weeks, the effect of prolonged cough at baseline (>21·4 weeks) on achieving clinical cure within 28 days in children in the 4-week group and time to next exacerbation

Results

Efficacy

• The primary endpoint of clinical cure by day 28 was not significantly different between amoxicillin–clavulanate 4-week group versus the 2-week group (62% vs. 70% patients; adjusted relative risk 0·87; p=0·49)
• Amoxicillin–clavulanate for 4 weeks significantly increased the time to next wet cough exacerbation by 4 times versus the 2-week group (median 150 days vs 36 days; adjusted hazard ratio 0·47; p=0·02; Figure 1)
• Amoxicillin–clavulanate therapy for 4 weeks was associated with lower rate of recurrence of PBB at 6 months versus the 2-week group (53% vs. 74% patients, adjusted odds ratio 0·39; p=0·07)
• A similar and significant improvement in PC-QoL was achieved from baseline to day 28 in both groups, with no significant difference between the groups (mean difference in change –0·2; p=0·64)
• From day 28 to 7 months, median PC-QoL did not improve in either group and there remained no significant difference between them (mean difference in change, adjusted RR 0·1; p=0·91)
• No differences were identified between groups in prevalence of any pathogens or antimicrobial resistance
• In the post-hoc analyses, no significant difference observed between the groups in the mean number of exacerbations during 6-month follow-up (adjusted OR 0·90; p=0·66) and in the mean number of days children in each group received antibiotics during the intervention and 6-month follow-up (adjusted OR 0·99; p=0·33)
• Prolonged duration of antibiotic treatment (ie, 4 weeks vs 2 weeks) had no significant effect on clinical cure in children with brief duration of cough at baseline (adjusted RR 0·32; p=0·51)
• Duration of cough was associated with response to four weeks of antibiotics as clinical cure was achieved in 62% in those with short (<21·4 weeks) as well as prolonged (>21·4 weeks) duration of cough at baseline (p=1·0)

Figure 1: Effect of amoxicillin–clavulanate 4-weeks and 2-weeks treatment on the time to next wet cough exacerbation

Safety 

• No significant difference observed in adverse events in both 2-week and the 4-week groups (25% vs. 19% children, p=0·57)
• Higher proportion of children in the 2-week group failed to complete the 4 weeks of trial medication versus in the 4-week group, the difference between the groups was not significant (p=0·06)

Conclusion

• A 4-week amoxicillin–clavulanate treatment in children with chronic wet cough and suspected PBB was clinically similar in achieving clinical cure by 28 days compared with a 2-week course. However, the 4-week course significantly increased the time to next wet cough exacerbation vs a 2-week antibiotic course

• This study addressed an identified unmet research need and somewhat resolved the controversy concerning which guidelines should be used for achieving cough resolution in children presenting with chronic wet cough and suspected to have PBB