1. Antibiotics In Respiratory Infection To Use or Not to Use - that is the question. Dr. James Paton University of Glasgow

2. Paediatric Captain of the Men of Death Pneumonia: - leading cause of death in children younger than 5yrs - 1.4-1.6M children die each year - 13% of 155M episodes severe enough to lead to hospitalisation

3. Increasing Global Concern about Antibiotic Resistance

4. What is Causing the Antibiotic Resistance Problem? Inappropriate use (Patient issues): Not taking antibiotics as prescribed Stopping doses of antibiotics early Not taking antibiotics at regular intervals Saving some for later Sharing with others Inappropriate prescribing (Prescriber issues): Unnecessary prescription of antibiotics Unsuitable use of broad-spectrum antibiotics Wrong selection of antibiotics Inappropriate dose or duration of antibiotic

5. Antibiotics Used in UK in 2011 in Children <5yrs Hospitalised with Pneumonia (1534 reports) Amoxycillin48017.6% Augmentin94134.5% Azithromycin1947.1% Cefotaxime692.5% Cefuroxime2067.5% Cephaclor331.2% Clarithromycin29210.7% Erythromycin632.3% Flucloxacillin271.0% Other2689.8% Penicillin562.1% No Data / Not Recorded1023.7% BTS National Pneumonia Audit 2011

6. Diagnosing Lower Respiratory Infection in Children WHO Classification of ARI in children presenting with cough and/or difficulty breathing No penumonia (Cough and cold) Respiratory rate per minute: <50 (infants 2-11mo) <40 (children 12-59mo) No lower chest indrawing Non-severe pneumonia Respiratory rate per minute >50 (infants 2-11mo) >40 (children 12-59mo) No lower chest indrawing Severe pneumonia Lower chest indrawing with or without rapid breathing Very severe disease Unable to drink; convulsions; abnormally sleepy or difficulties waking; stridor in calm child or clinically severe malnutrition

7. Common Pathogens that Cause Pneumonia in Healthy Children Aged 2-59mths - I Bacterial (20-50%) Estimated Percentage Streptococcus pneumoniae 17-37% Haemophilus influenzae 0-31% Staphyloccus aureus1-33% Non-typhoidal salmonellae 0-28% Mycoplasma pneumoniae 5% Chlamydia pneumoniae 3-10% Moraxella catarrhalis 0-9% Klebsiella pneumoniae 0-4% Lancet Infect Dis 2009; 9: 185-196

8. Common Pathogens that Cause Pneumonia in Healthy Children Aged 2-59mths - II Viral (9-64%) Estimated Percentage Respiratory Syncytial Virus 1-39% Influenza viruses 0-22% Adenovirus0-54% Parainfluenza viruses 0-46% Human metapneumovirus 2-8% Others (bocavirus, coronaviruses, rhinoviruses) 4-30% Lancet Infect Dis 2009; 9: 185-196

9. Comparison of Previous and Revised Classification and Treatment of Childhood Pneumonia

10. The Problem of the Diagnostic Gold Standard for Childhood Pneumonia Lynch et al (2010) 5(8): e11989. doi:10.1371/journal.pone.0011989 A Systematic Review on the Diagnosis of Pediatric Bacterial Pneumonia: When Gold Is Bronze 11 different gold standards in 25 included studies: - Blood cultures in 6 studies - CXR in 5 studies - Others: hematologic, microbiologic, immunologic, serology, and clinical signs and symptoms “There is a critical need for experts in childhood pneumonia to develop an accepted gold standard.”

11. Studies (N) Subjects (N) SensitivitySpecificity+ve Likelihood ratio Symptoms Cough564210.960.141.12 Difficult Breathing 460700.600.521.26 Rapid Breathing444740.790.311.14 Signs Grunting512510.24.0871.78 RR >40bpm410580.780.511.58 RR >50bpm718340.530.721.90 Wheezing648250.220.751.76 Lower chest indrawing 418700.480.721.76 Clinical Features for Diagnosing Pneumonia in Children <5yrs (CXR as gold standard) Lancet Infect Dis 2015; 15: 439–50

12. CXR in Children (2-59mo) with Non-severe Pneumonia (from 3d vs 5d amoxillicin MASCOT Trial) BMJ, doi:10.1136/bmj.38915.673322.80 (published 21 August 2006)

13. Bacterial or Viral? Virkki et al Thorax 2002:57:438-441 S pneumoniae Rhinovirus Parainfluenza 2 & HHV6 Bacterial infection is highly probable in childhood CAP with alveolar infiltrates “Radiological confirmed pneumonia should be treated wiith antibiotics, because, in clinical practice, it is virtually impossible to distinguish exclusively between viral and bacterial pneumonia”

14. Comparison of Oral Amoxicillin with Placebo for the Treatment of World Health Organization – Defined Non-severe Pneumonia in Children Aged 2–59 Months: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial in Pakistan Methods: double-blind, randomized, equivalence trial in 4 tertiary hospitals in Pakistan. Nine hundred children aged 2–59 months with WHO defined non-severe pneumonia were randomized to receive either 3 days of oral amoxicillin (45mg/kg/day) or placebo; 873 children completed the study. All children were followed up on days 3, 5, and 14. The primary outcome was therapy failure defined a priori at 72 h. Results: In per-protocol analysis at day 3, 31 (7.2%) of the 431 children in the amoxicillin arm and 37 (8.3%) of the 442 in placebo group had therapy failure. Difference was not statistically significant (odds ratio 0.85; 95% CI,.50–1.43). Multivariate analysis identified history of difficult breathing (OR, 2.86; 95% CI, 1.29– 7.23) and temperature 37.5°C at presentation (OR 1.99; 95% CI, 1.37–2.90) as risk factors for treatment failure by day 5. Conclusion: Clinical outcome in children aged 2–59 months with WHO-defined non- severe pneumonia is not different when treated with an antibiotic or placebo.

15. Comparison of Oral Amoxicillin with Placebo for the Treatment of World Health Organization – Defined Non-severe Pneumonia in Children Aged 2–59 Months: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial in Pakistan Baseline Characteristic Therapy Success (n = 737) Therapy Failure (n = 136) ORP History of wheeze 30 (4.1%)7 (5.1%)1.840.43 Signs on examination Wheezing372 (50.5%)84 (61.8%)1.580.01 Wheezing, by age 2-5months112/246 (45.5%)36/48 (75.0%3.590.001 6-11months118/232 (50.9%)31/47 (66.0%)1.870.05 12-59 months1142/259 (54.8%)17/41 (41.5%)0.580.11 Hazir et al Clin Infect Dis. 2011 Feb 1;52(3):293- 300

16. Jain S et al. N Engl J Med 2015;372:835-845.

17. Ways Forward for Childhood Pneumonia

18. Oxygen Saturation Can Predict Pneumonia Pneumonia Conclusion: Oxygen saturation was the best clinical predictor for pediatric pneumonia and should be further studied in a prospective sample of children with respiratory symptoms in a resource limited setting. The Journal of Emergency Medicine, 2013; 45:752–760

19. Better Rapid Diagnostics - Immunofluorescence for RSV Infection

20. Rhedin et al. Thorax 2015;70:847-853 Rapid Diagnostics - PCR Based Molecular Testing

21. Ways Forward for Childhood Pneumonia 1.Standardised guidelines for assessment & management -Pneumonia vs no pneumonia -Severe pneumonia & hospital admission vs non-severe pneumonia 2.Better access to hospital care for severe pneumonia -Hydration, oxygen, ventilatory support 3.Improved diagnostic methods 4.More focused and appropriate use of antibiotics 5.Better prevention -Better vaccines, improved socio-economic conditions, better nutrition, better hygiene, air pollution Lancet 2013: 381:1341-42

22. Antibiotics In Respiratory Infection: To Use or Not to Use - that is the question. No Easy Answer!

24. Ways Forward for Childhood Asthma 1.Standardised guidelines for assessment & management 2.Improved diagnostic methods - Asthma clinical test; no diagnostic test available 3.Access to hospital care for severe asthma - Oxygen, bronchodilators, corticosteroids 4.Better prevention - Air pollution (passive smoking), improved socio-economic conditions, better nutrition, better hygiene,

25. Global & Regional Burden of Pneumonia in Children aged 0-4yrs, by WHO region Lancet 2013; 381

26. Follow-up for Non-severe Pneumonia Lancet Infect Dis 2009;9:185-96