Amoxycillin clavulanate in children with chronic wet cough

Journal Club Kavi Aucharaz 22.1.2014

Aim

To determine the efficacy of a 2 week course of Amoxycillin Clavulanate in the treatment of children with chronic wet cough

Case presentation

• 3 year old seen in AAU with a chronic wet cough for 5 months • GP tried salbutamol and steroid inhalers no effect • No audible wheeze • Is it PBB and require prolonged course of antibiotics?

• Can we achieve cough resolution by treating chronic wet coughs with Amoxycillin clavulanate in children?

PBB-Protracted Bacterial Bronchitis

• Defined as presence of isolated chronic wet cough – Resolution of cough with appropriate abx – Absence of an alternative cause for specific cough • Speculation that PBB maybe a precursor to chronic suppurative lung disease - left untreated

Current guidelines

• Recommend abx for children with PBB • Advice based on a Cochrane review prospective and retrospective observational studies • Cochrane review of abx treatment for moist cough in children showed – Abx were effective – 1 clinical cure for every 3 children treated(95% CI 2 to 4)

Cochrane review

• Based on 2 small studies of children with cough >10 days —not current definition • Current definition of chronic cough > 4 weeks • Neither study used validated outcome measures of cough – Parental reporting of cough in children is subject to bias

Placebo controlled RCT –Unicentre parallel study in Brisbane

• Double-blind RCT • Aimed to assess efficacy of 2 weeks of oral amoxicillin clavulanate • Compared with placebo in achieving cough resolution in children with chronic wet cough

Inclusion criteria Excluding criteria

• Children aged 6mo-18 yrs • Gross neuro-devlopmental • Newly referred to delay respiratory practice • CF, Ex-prem (<37 weeks • Jan.2004- Dec 2006 doctor observed gest.) • Chronic cough (> 3 wks)+ • Chr. Disease , interstitial lung disease or cardiac abn.

moist/wet cough • Suspicion of bronchiectasis • Haemoptysis • Abx therapy received in preceding 2 wks • Penicillin allergy/acutely unwell with fever or pnemonia

Randomisation and allocation

 Computer generated  Stratified by age(<6yrs and >6yrs)  Parents and members of study were blinded to the child’s allocated group

Data collection

 Standardised data collection sheets were used  Parents completed a daily cough diary for 28 days post enrolment --presence and severity of cough --any adverse reactions to medications were documented  Validated cough diary using the verbal category descriptive score (VCD) was used  Cough scoring system -- has best correlation with objective counts as measured by cough meter

Verbal Category Descriptive score (validated cough diary)

• 0=no cough • 1=cough for one or two short periods only • 2=cough for more than two short periods • 3=frequent coughing but does not interfere with school and other activities • 4=frequent coughing which interferes with school and other activities • 5=cannot perform most activities due tp severe coughing

Child presenting to RCH with chronic (>3 weeks)cough Assess for eligibility and study explained to parents Clinical assessment : history, Physical exam ±CXR Enrolled , randomised, diary prescription, diary cards explained Prescription taken to pharmacy Amoxicillin-clavulanate 22.5 mg/kg/dose twice daily(0.281ml/kg) Placebo twice daily(0.281 ml/kg) Day 7 review(phone) Day 14 review(phone) Routine clinical appointment arranged if still coughing Diaries and medication bottled received by post

Bronchoscopy

• Some children had flexible bronchoscopy • Not a requirement of the protocol • Children received the trial medication after the bronchoscopy • BAL was performed –European Respiratory Society guidelines • Microbiological exam.

• Cytology and inflammatory markers • Significant bacterial growth ≥ 10 5 cfu/ml of BAL

OUTCOMES

     Primary outcome ‘cough resolution’ Defined as improvement in baseline cough score (>75% reduction of cough)  At ’end of trial’ or cessation of coughing for minimum 3/7 within trial period Baseline cough score -- average score in the 2 days immediately before trial medication commencement ‘End of trial’ score - the score 2 days following completion of 14 days of medication(D15-16) Secondary outcome measure were absolute change in cough score and change in VCD score over the study

Statistical methods

• Sample size of 55-60 • At 5% significance this provides a study power of 82% • With 20-30% dropout rate to detect a difference of 60% between groups-(75% improvement in abx group,30% in placebo group) • Without dropouts- sample size of 23 per group provided same power for the same effect size • Dropout rate was low –study was ceased when 50 enrolled

Statistical analysis

• Data were analysed with intention to treat • Children lost in F/U –considered failures • SPSS V.12

• Medians and IQR were used for descriptive data • Not normally distributed data were analysed using non parametric analyses • Mann-Whitney U test used for comparisons b/w the 2 groups • Proportions between groups were compared using chi-

squared test

• Two tailed p value <0.05 considered significant

Results

• 55 patients approached, 50 enrolled • 3 children lost to FU-unable to contact • All 50 children were included in final analysis • Similar no. in both arms had bronchoscopy(19,18) • BAL data - consistent with PBB in majority children • BAL microscopy identified   Haemophilus influenza(n=14. 34%) Strep, pneumoniae(n=9, 24%)   Moraxella catarrhalis(n=7, 19%) All these organisms were sensitive to Amoxycillin clavulanate

Assessed for eligibility N=55 Excluded(n=5) Decline to participate(n=3) Not meeting inclusion criteria(n=2) Randomised (n=50) Allocated to Abx(n=25) Received allocated intervention(n=25) Lost to follow up(n=2) [reasons :unable to contact(n=2)] Discontinued intervention(n=1) Analysed for cure(n=25) Secondary outcomes: • Excluded from analyses requiring cough scores(as none available)(n=2) • Bronchoscopy data;(n=19) Allocated to placebo(n=25) Received allocated intervention(n=25) Lost to follow-up(n=1) [reasons: unable to contact(n=1)] Discontinued interventions(n=0) Analysed for cure(n=25) Secondary outcomes: • Excluded from analyses requiring cough scores(as none available)(n=1) • Bronchoscopy data(n=18)

Effect of intervention

• Amoxycillin clavulanate group – more likely to achieve cough resolution (n=12, 48%) v/s Placebo group (n=4, 16%) (p=0.015) • Observed difference between proportions is 0.32

(95%CI 0.08-0.56) • OR=4.85

P- Children (6mo-<18ys) with chronic wet cough I- 2 weeks course of Amoxycillin clavulanate in treatment of chronic wet cough C-Placebo O ‘Cough resolution’-defined as a<75 % reduction in validated VCD cough score • • • • Randomisation was computer generated Concealed allocation was used Allocation list and trial medications were dispensed by pharmacy Parents and members of study were blinded until data were analysed.

• 55 patients approached • 50 were enrolled and all received treatment allocation • 3 lost to follow up—unable to be contacted • All 50 children were included in the final analyses for primary outcome

Is it worth continuing?? …Yes • Parents and members of the study were blinded to allocated group until data were analysed • Medication code were revealed in February 2011 • Similar numbers (n=25) in both study arms

• No significant difference between groups in any of parameters • Similar number in both arms had bronchoscopy prior treatment commencement

• • • Primary outcome was ’cough resolution’ Defined as improvement in baseline cough score (>75% reduction in cough score) at ‘end of trial’ or cessation of coughing for minimum period of 3/7 within the trial period Baseline cough score was children with chronic wet cough with a number need to treat – NNT (for benefit at 2 weeks) of 4

• Observed difference between proportions is 0.32(95% CI 0.08-0.56) • OR=4.85, NNT for benefit at 2 weeks was 4 (95% CI 2 to 27) • At 4 weeks further 2 children were cough free (n=14, 56%)

• • • Population are similar to Brisbane Study period Jan 2004-Dec 2006 Both summer and winter period

• 10/13(77%) in treatment group grew significant bacteria on BAL • Side effects were seen in both groups with no significant difference

• • • Re-attendance at GP Substantial amount of burden-family-Impact on QoL The definition of chronic wet cough is different currently in UK(4-6wks)

Tablets 375 mg

, f/c, co-amoxiclav 250/125 (amoxicillin 250 mg as trihydrate, clavulanic acid 125 mg as potassium salt), net price 21-tab pack = £4.19. Label: 9

Tablets 625 mg

, f/c, co-amoxiclav 500/125 (amoxicillin 500 mg as trihydrate, clavulanic acid 125 mg as potassium salt). Net price 21-tab pack = £8.00. Label: 9

Suspension ‘125/31 SF’

, sugar-free, co-amoxiclav 125/31 (amoxicillin 125 mg as trihydrate, clavulanic acid 31.25 mg as potassium salt)/5 mL when reconstituted with water. Net price 100 mL (raspberry- and orange flavoured) = £2.95. Label: 9

Suspension ‘250/62 SF’

, sugar-free, co-amoxiclav 250/62 (amoxicillin 250 mg as trihydrate, clavulanic acid 62.5 mg as potassium salt)/5 mL when reconstituted with water. Net price 100 mL (raspberry- and orange flavoured) = £3.00. Label: 9

Limitations of study

• Lack of follow up over period of months to assess long term value of 2 week antibiotic therapy • Long delay between completion of study and data analyses • Due to personal reasons of primary author

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Summary and Conclusion

VERY WELL DESIGNED STUDY • Amoxycillin Clavulanate is effective in achieving a reduction in symptoms and cough resolution in significant number of children with isolated chronic wet cough

Following Discussion

• No local guidelines at SCH for treatment of chronic wet cough • It was felt that the long term effect of the 2 weeks course of oral antibiotics were not measured • We do not know whether the chronic wet cough resolution was sustained for longer period • Treating children having 3 weeks of wet cough with 2 weeks antibiotics is not justified.

• There is no concrete evidence to prove that untreated PBP leads to chronic suppurative lung disease