Trial on the Ideal Duration of Oral Antibiotics in Children With Pneumonia

Pneumonia in Children: Aetiology, Ideal Antibiotic Duration, Quality of Life

To determine, in children hospitalized with pneumonia, if an extended duration of oral antibiotics (10 days) will be superior to a shorter duration (3 days) of antibiotics in improving clinical outcomes.

Secondary Aims:

1. Describe the prevalence of respiratory viruses and bacteria at presentation.
2. Investigate the depression, anxiety and stress scores (DASS21) and quality of life scored (QOL) by parents of the children during admission, pre-discharge and post discharge and at follow-ups.

Study Overview

• Status: Completed
• Conditions: Pneumonia
• Intervention / Treatment: Drug: Amoxicillin-Potassium Clavulanate Combination; Drug: Placebo

Detailed Description

Introduction:

Pneumonia is the single largest cause of death in children less than 5 years old and these are preventable deaths.[1,2] It is also an important cause of morbidity , especially when it is recurrent or severe as it may be linked with future adult lung disease.[3] Determining the aetiology of pneumonia is difficult in children who cannot produce satisfactory sputum for culture. Hence the reliance on molecular methods like polymerase chain reaction (PCR) and Enzyme immunoassays(EIA) looking at serological rise to determine the true aetiology of pneumonia is important especially in the era where mixed infections are common and may be associated with severe infections.

There is currently no information on the suitable duration of antibiotics for uncomplicated severe community acquired pneumonia (CAP). There is also rampant overuse of antibiotics that results in poor compliance and significant side effects.

There is little information on the QOL of the child with severe pneumonia and his parent. It is important to have a holistic approach to medicine hence the importance of analyzing the burden and social issues associated with children admitted with pneumonia.

As opposed to adults, children cannot produce sputum (lower respiratory sample) appropriate for culture which is the traditional method of identifying the causative bacteria. Identification of bacteria in nasopharyngeal secretions (upper respiratory sample) does not equate to that organism causing the infection as the upper airway of a child is often colonized by bacteria. Detecting the organism in blood identifies it as the causative organism. However, blood culture has a very low yield in children with pneumonia and polymerase chain reaction (PCR) is much more sensitive at detecting bacteria in blood and hence it will markedly improve the ability to determine infecting organism.

Development of our own in-house bacterial PCR kit which will detect several different bacteria in blood is planned in this study. We already have an in-house viral PCR kit and the ability to detect atypical bacteria via EIA. Currently there is an international study (Pneumonia Etiology Research for Child Health [PERCH]) looking at aetiology of pneumonia, but this study only involves 2 Asian countries (Thailand and Bangladesh)[5]. In Malaysia, in 2011 there was a study that looked at pneumococcal isolates and antibiotic sensitivity patterns on invasive pneumococcal disease only[6]. There are also studies that look at viral aetiology of pneumonia[7]. Hence information on aetiology of pneumonia is skewed to those involving vaccine associated organisms and use of nasopharyngeal secretions(NPS) to detect viruses..

The evidence for appropriate duration of antibiotics that should be used in hospitalized children with pneumonia is scarce. A randomized controlled trial comparing traditional duration of antibiotics (≥ 7 days) versus shorter duration of antibiotics < 7 days) is what we think is necessary. There are no studies looking at duration of antibiotics in children with severe uncomplicated pneumonia. We hypothesize that there is no need for a longer duration of antibiotics which are only associated with poor compliance and unnecessary side-effects.

Finally, there is little data on quality of life in children and parents during and after a pneumonic episode. It is important to measure the impact of such a common disease on both parent and patient as well as to assess the impact of medical management on QOL so as to have a more holistic approach to medicine. Two previous studies have looked at QOL. One was a study comparing all acute diseases to chronic diseases[8]. The other looked at CAP but without the use of structured questionnaires[9]

Methodology

Randomized, Double Blind, Placebo Controlled Trial Children aged 3 months till <5 years old Admitted to University Malaya Medical Centre (UMMC) hospital with a severe community acquired pneumonia Eligibility Ages Eligible for Study: 3 Months to 59 Months Genders Eligible for Study: Both

Inclusion Criteria:

Children admitted with severe pneumonia as defined by the presence of all the following as defined as below:

• 3 months to 59 months old
• History of cough and/or shortness of breath Unwell for <= 7 days
• Increased respiratory rate ( ≥ 50/min if ≤12 months old, ≥ 40/min)
• Any of the following signs/symptoms are present at examination that would necessitate admission: chest retractions, cyanosis, saturation< 92% on air, poor feeding or lethargy
• Documented fever (axillary /central temp ≥ 38/38.5°C) within 24 hrs of admission
• Abnormal chest radio graph(CXR) with presence of alveolar infiltrates
• Responds to IV antibiotics by the first 72 hrs and able to go home with oral antibiotics i.e. no more hypoxia and afebrile and reduced respiratory symptoms

Exclusion Criteria:

Children who (a) are transferred from another hospital (b) refuse blood taking (c) have a doctor diagnosis of asthma or recurrent wheezing illness (d) have a diagnosis of bronchiolitis i.e. wheezing in a child with a CXR with no consolidation (e) do not have an acute illness ( ie >7 days) (f) are unable to come for follow-up (g) do not have community acquired pneumonia e.g. aspiration pneumonia (h)have a complicated pneumonia with effusion, pneumothorax, clinical suspicion of necrotizing pneumonia (i)require paediatric intensive care unit (PICU) admission or use of non-invasive ventilation (j)significant comorbidities that can increase the risk of having a complicated pneumonia- (k) need other antibiotics like anti-staph or macrolides (l)have an extra-pulmonary infection e.g. meningitis (m)are allergic to penicillin (n) are unable to tolerate oral antibiotics and (o)have underlying illness that can predispose to recurrent pneumonia

Randomized, Double Blind, Placebo Controlled Trial Children aged 3 months till <5 years old Admitted to UMMC hospital with a severe community acquired pneumonia Informed signed consent will be obtained from parents first. All children will have full blood count and CXR taken

Additional blood and urine as detailed below will also be taken:

a. Blood for PCR -streptococcus pneumoniae, staphylococcus aureus, Haemophilus influenzae, Mycoplasma pnuemoniae, Chlamydia pneumoniae will be taken.

NPS for respiratory bacteria and viruses (by culture and PCT-similar as above) All these samples will be tested in our hospital laboratory. If samples cannot be processed immediately, they will be stored in a -80 deg C freezer except for the NPS for bacterial culture.

All data will be collected at enrollment and at each follow-up visit on a standardized data sheet. Baseline demographic data( age, gender, address, ethnicity, household size, income, parent education, caregivers, household appliances) and medical information( birth history, breastfeeding and weaning, growth, immunization, smoke exposure, co-morbidity, daily hospitalization information) will be obtained from parents and medical charts. CXRs and routine blood test results will also be recorded.

Quality of life, stress level, severity of illness , of parents and children with pneumonia, will be assessed at these time points too: during their admission (average of 3-5 days) and during follow-ups( average at, 4 weeks, 3 months(phone call only with no questionnaire administered), 6 months, 1 year post their pneumonic episode) using the following questionnaires-Paediatric proxy cough quality of life-8 (PCQOL-8), Canadian Acute Respiratory Illness and Flu Scale (CARIFS) (in hospital only), cough diary( at home, daily for 1 month),Depression Anxiety Stress Scale 21( DASS21).

The PCQOL-8 and DASS21 have been translated and validated in Bahasa Melayu. The CARIFS and the cough diary was recently translated in Bahasa Melayu and piloted for the purpose of this study.

Treatments will be administered only after at least 48-72 hrs of intravenous(IV) antibiotics ( penicillin/ampicillin/ amoxicillin-clavulanate acid/cefuroxime) and the patients are ready for discharge : afebrile, improved respiratory symptoms and signs, saturation > 92% in air and ready to be converted to oral antibiotics.

Arm 1: Twice a day oral amoxicillin-clavulanate (22.5mg/kg/dose) for 10 days Arm 2: Twice a day oral amoxicillin-clavulanate (22.5mg/kg/dose) for 3 days followed by oral placebo for 7 days The random treatments will be allocated via computer generated number sequence and will be supervised by a statistician.

All medications will be prepared and dispensed by the pharmacy department in suspension form. The appearance of the placebo will be similar to the active medication. Investigators and subjects will be blinded.

At discharge, parents will be asked to fill up a daily cough diary at home. Treatment failure/exit criteria will be fulfilled if any of the following occur: death, recrudescence of fever ≥38 °C (axilla) with respiratory signs of pneumonia, hypoxaemia < 92% on air), need for antibiotic treatment, new CXR changes.

On discharge, children will be followed up at regular intervals of 4 weeks, 3 moths(phone call), 6 months and 1 year, to ensure they are well and also to detect residual or recurring respiratory symptoms i.e. presence of cough/breathlessness/fever, recrudescence of pneumonia and other respiratory illness, fever and upper respiratory tract infection(URTI), growth, need for unscheduled healthcare visits for respiratory symptoms, need for antibiotic treatments for respiratory/upper airway symptoms, abnormal physical findings, over a period of 1 year post-discharge from hospital. Adverse effects of antibiotics e.g. vomiting, diarrhoea, rash and adherence (returned empty bottles) to medication will be recorded.

CXR will be repeated at 4 weeks and at 1 year(if clinically indicated). These will be scored by a radiologist who will be masked to allotted treatment.

At 12 months, if the age allows it, children will be asked to perform lung function tests.

During these follow-ups they will be given questionnaires: PCQOL-8, DASS21. At the 4 week discharge, CXR as well as blood and NPS will be collected for testing for bacterial and viral organisms. At 4 weeks, daily cough diaries will be collected back and reviewed.

Sample size calculation is based on the primary aim. We expect a 20% superiority difference in the extended antibiotic regime and assuming a 20% drop-out, sample size should be 204 children (102 in each arm).

Data will be presented in accordance with the CONSORT guidelines on reporting on RCTs. Analysis will be done by Dr. Rafdzah, a statistician. An intention to treat approach will be used for all analyses. For the primary aim i.e. the clinical outcome of the different antibiotic durations, the main outcomes being looked at are (a) clinical cure-complete resolution of symptoms and signs at 4 weeks ,(b) proportion of children without chronic respiratory symptoms or signs at the 12 month follow-up , using odds ratio(95%CI) with logistic regression and linear regression. For continuous variables, t-tests and Mann-Whitney tests will be used depending on the normality of the data. A Kaplan-Meier curve will be constructed for each group for the time to next respiratory illness and hospitalization and proportions will be compared by regression models. For prevalence of respiratory pathogens, point prevalence will be reported on and multivariable logistic regression adjusting for baseline carriage and antibiotic resistance will examine the effects of treatment duration on the different organisms particularly Streptococcus pneumoniae and Haemophilus influenzae and Staph aureus.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 4

Contacts and Locations

Study Locations

• Malaysia
  • Lembah Pantai
    • Kuala Lumpur, Lembah Pantai, Malaysia, 59100
      • University Malaya Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 4 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Children admitted with severe pneumonia as defined by the presence of all the following as defined as below:

• 3 months to 59 months old
• History of cough and/or shortness of breath
• Unwell for <= 7 days -Increased respiratory rate ( ≥ 50/min if ≤12 months old, ≥ 40/min) or retractions,-
• Any of the following signs/symptoms are present at examination that would necessitate admission: chest retractions, cyanosis, saturation< 92% on air, poor feeding or lethargy
• Documented fever (axillary /central temp ≥ 38/38.5°C) within 24 hrs of admission
• Abnormal CXR with presence of alveolar infiltrates
• Responds to IV antibiotics by the first 72 hrs and able to go home with oral antibiotics i.e. no more hypoxia and afebrile and reduced respiratory symptoms

Exclusion Criteria:

Children who (a) are transferred from another hospital (b) refuse blood taking (c) have a doctor diagnosis of asthma or recurrent wheezing illness (d) have a diagnosis of bronchiolitis i.e. wheezing in a child with a CXR with no consolidation (e) not acute illness ( ie >7 days) (f) unable to come for follow-up (g) not community acquired pneumonia e.g. aspiration pneumonia (h)complicated pneumonia with effusion, pneumothorax, clinical suspicion of necrotizing pneumonia (i)PICU admission or use of Non-invasive ventilation (j)significant comorbidities that can increase the risk of having a complicated pneumonia- (k) need for use of other antibiotics like anti-staph or macrolides (l)extra-pulmonary infection e.g. meningitis (m)allergy to penicillin (n) unable to tolerate oral antibiotics (o) underlying illness that can predispose to recurrent pneumonia

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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Amoxicillin-Potassium Clavulanate; Patient will be on amoxicillin-clavulanate 22.5mg/kg/dose bd for 10 days	Drug: Amoxicillin-Potassium Clavulanate Combination; Oral antibiotic for 10 days; Other Names: Augmentin; Co-amoxiclav; Clomovid
Active Comparator: Placebo; Patient will be on amoxicillin-clavulanate 22.5mg/kg/bd for 3 days followed by another 7 days of placebo medication given at the same dose and frequency	Drug: Amoxicillin-Potassium Clavulanate Combination; Oral antibiotic for 10 days; Other Names: Augmentin; Co-amoxiclav; Clomovid; Drug: Placebo; Placebo made to look like the study drug-main ingredient sugar syrup made by the pharmacy department in the hospital In the placebo arm, patient will be given 3 days of antibiotic followed by 7 days of placebo; Other Names: Placebo arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical cure	Complete resolution of symptoms. No treatment failure or exit failure i.e. need for antibiotics or readmission into hospital for a respiratory condition	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life of child and parent	Severity of cough by using the translated and validated PCQOL-8 to assess impact of cough on the child and parent.	on admission, at discharge, at follow-ups( 4 weeks, 6 months and 1 year)
Impact of pneumonia on the parent	Using the translated and validated DASS21 on parents	on admission, at discharge, at follow-ups(average 1 week, 4 weeks, 6 months and 1 year)
Severity of pneumonia	Using the translated and validated the Canadian Acute Respiratory Influenza Scale(CARIFS)	during the admission which expected duration will be 5 days, daily twice a day to do the questionnaires
Adverse effects	Treatment related adverse effects of antibiotics e.g. diarrhoea, vomiting	at 4 weeks follow-up
Time to next hospitalisation or visit to healthcare unit	Time to the next hospitalization or visit to the doctor for respiratory symptoms	during the one year post pneumonic episode; patient will be seen on an avearge of 1 week, 4 weeks, 6 months and 1 year
Number hospitalised for pneumonia or unscheduled healthcare visits	proportion of children hospitalised for respiratory illness or need for unscheduled healthcare visits	during the one year post pneumonic episode; patient will be seen on an avearge of 1 week, 4 weeks, 6 months and 1 year
Bacterial isolates	Bacterial isolates: resistance pattern, resolution or persistence. Viral isolates: positive or negative These will be assessed at admission and 4 weeks post-discharge	at the 4 weeks appointment
Radiological resolution	Radiological resolution and correlation with respiratory symptoms	at the 4 weeks appointment
Prevalence of chronic respiratory symptoms and signs post pneumonia	Presence of respiratory symptoms and signs e.g. cough, failure to thrive, reduced effort tolerance, clubbing, persistent respiratory signs	during the one year post pneumonic episode; patient will be seen on an avearge of 1 week, 4 weeks, 6 months and 1 yea
Severity of cough during 4 weeks post-discharge	Using the visual scale cough diary	at the 4 weeks appointment, cough diary which will be done by parents daily from discharge

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cost effective analysis of long vs short course of antibiotics for pneumonia	To see if the extended antibiotic course is cost effective	at the 4 weeks appointment

Collaborators and Investigators

• Sponsor: University of Malaya
• Collaborators: Menzies School of Health Research

Publications and helpful links

General Publications

• Walker CLF, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, O'Brien KL, Campbell H, Black RE. Global burden of childhood pneumonia and diarrhoea. Lancet. 2013 Apr 20;381(9875):1405-1416. doi: 10.1016/S0140-6736(13)60222-6. Epub 2013 Apr 12.
• Rudan I, Boschi-Pinto C, Biloglav Z, Mulholland K, Campbell H. Epidemiology and etiology of childhood pneumonia. Bull World Health Organ. 2008 May;86(5):408-16. doi: 10.2471/blt.07.048769.
• Chang AB, Byrnes CA, Everard ML. Diagnosing and preventing chronic suppurative lung disease (CSLD) and bronchiectasis. Paediatr Respir Rev. 2011 Jun;12(2):97-103. doi: 10.1016/j.prrv.2010.10.008. Epub 2010 Dec 4.
• Trenholme AA, Byrnes CA, McBride C, Lennon DR, Chan-Mow F, Vogel AM, Stewart JM, Percival T. Respiratory health outcomes 1 year after admission with severe lower respiratory tract infection. Pediatr Pulmonol. 2013 Aug;48(8):772-9. doi: 10.1002/ppul.22661. Epub 2012 Sep 19.
• Gilani Z, Kwong YD, Levine OS, Deloria-Knoll M, Scott JA, O'Brien KL, Feikin DR. A literature review and survey of childhood pneumonia etiology studies: 2000-2010. Clin Infect Dis. 2012 Apr;54 Suppl 2(Suppl 2):S102-8. doi: 10.1093/cid/cir1053.
• Yasin RM, Zin NM, Hussin A, Nawi SH, Hanapiah SM, Wahab ZA, Raj G, Shafie N, Peng NP, Chu KK, Aziz MN, Maning N, Mohamad JS, Benjamin A, Salleh MA, Zahari SS, Francis A, Ahmad N, Karunakaran R. Current trend of pneumococcal serotypes distribution and antibiotic susceptibility pattern in Malaysian hospitals. Vaccine. 2011 Aug 5;29(34):5688-93. doi: 10.1016/j.vaccine.2011.06.004. Epub 2011 Jun 30.
• Chan PW, Goh AY, Chua KB, Kharullah NS, Hooi PS. Viral aetiology of lower respiratory tract infection in young Malaysian children. J Paediatr Child Health. 1999 Jun;35(3):287-90. doi: 10.1046/j.1440-1754.1999.00359.x.
• Kulpeng W, Sornsrivichai V, Chongsuvivatwong V, Rattanavipapong W, Leelahavarong P, Cairns J, Lubell Y, Teerawattananon Y. Variation of health-related quality of life assessed by caregivers and patients affected by severe childhood infections. BMC Pediatr. 2013 Aug 13;13:122. doi: 10.1186/1471-2431-13-122.
• Shoham Y, Dagan R, Givon-Lavi N, Liss Z, Shagan T, Zamir O, Greenberg D. Community-acquired pneumonia in children: quantifying the burden on patients and their families including decrease in quality of life. Pediatrics. 2005 May;115(5):1213-9. doi: 10.1542/peds.2004-1285.
• Edmond K, Scott S, Korczak V, Ward C, Sanderson C, Theodoratou E, Clark A, Griffiths U, Rudan I, Campbell H. Long term sequelae from childhood pneumonia; systematic review and meta-analysis. PLoS One. 2012;7(2):e31239. doi: 10.1371/journal.pone.0031239. Epub 2012 Feb 22.
• Jimenez Ortega AI, Lopez-Neyra A, Sanz Santiago V, Alvarez-Coca J, Villa Asensi JR. [Pulmonary function in children following community-acquired pneumonia contracted at pre-school age]. An Pediatr (Barc). 2011 Nov;75(5):314-9. doi: 10.1016/j.anpedi.2011.05.002. Epub 2011 Jul 31. Spanish.

Study record dates

Study Major Dates

• Study Start: November 1, 2014
• Primary Completion (Actual): November 1, 2017
• Study Completion (Actual): October 1, 2018

Study Registration Dates

• First Submitted: September 23, 2014
• First Submitted That Met QC Criteria: October 6, 2014
• First Posted (Estimate): October 7, 2014

Study Record Updates

• Last Update Posted (Actual): April 23, 2019
• Last Update Submitted That Met QC Criteria: April 22, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Child; Pneumonia; Antibiotics; Outcome; Etiology
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Pneumonia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Amoxicillin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination
• Other Study ID Numbers: RP026-14HTM