Pediatric Respiratory Infections

Pediatric Respiratory Infections Brenda Kelly PharmD BCPS Residency Program Director Virginia Mason Memorial, Yakima, Washington brendakelly@yvmh.org Disclosure The presenter has no actual or potential conflict of interest in relation to this presentation. The presenter will not discuss off label use and/or investigational use in this presentation. Objectives Given a patient case, identify opportunities for improved antimicrobial stewardship in the treatment of pediatric pneumonia. Explain how pharmacokinetic differences affect antibiotic dosing in pneumonia versus otitis media. Differentiate clinical presentations of pneumonia, bronchiolitis and croup in pediatric patients. Describe appropriate and inappropriate treatment strategies for bronchiolitis. Determine the optimal steroid dose formulation for the treatment of croup based on a patient case. 1

Outline Pneumonia Acute otitis media Bronchiolitis Croup Pneumonia Pneumonia guidelines The Management of Community-Acquired Pneumonia (CAP) in Infants and Children Older Than 3 Months of Age: Clinical Practice Guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Bradley JS, et al. Clin Infect Dis. 2011 Oct;53(7):e25-76. 2

Case 1: Alex 2 year old female, 12 kg Presents to emergency dept. in respiratory distress Pulse ox 85% on room air, respiratory rate 52 Vaccines up to date. NKDA Diagnosis: Pneumonia Plan: admit to pediatric unit Pneumonia treatment What is the most appropriate antimicrobial for Alex on admission? A. Ceftriaxone B. Ampicillin C. Azithromycin D. Levofloxacin E. Oseltamivir http://respond.cc Code: 134955 Pathogens in hospitalized children with CAP Community-Acquired Pneumonia Requiring Hospitalization among U.S. Children 2358 with radiographic evidence of pneumonia Pathogen detected in 81% 1 or more viral pathogens detected in 73% Bacteria detected in 15% Multiple pathogens detected in 26% Jain MD et al. N Engl J Med. 2015 Feb 26; 372(9): 835 845. 3

Pathogens in hospitalized children with CAP Jain MD et al. N Engl J Med. 2015 Feb 26; 372(9): 835 845. Pathogens in hospitalized children with CAP AdV = adenovirus CoV = coronavirus Flu = influenza A or B virus HMPV = human metapneumovirus HRV = human rhinovirus PIV = parainfluenza virus RSV = respiratory syncytial virus Jain MD et al. N Engl J Med. 2015 Feb 26; 372(9): 835 845. Pathogens in hospitalized children with CAP Conclusions Study demonstrates the substantial reduction of pneumococcal and [Haemophilus influenzae type b] Hib disease owing to conjugate vaccines. The incidence of bacterial pneumonia is lower than previously reported. Challenges with detection of bacteria Invasive procedures to obtain samples not performed Despite state of the art technology, the sensitivity of current tests for bacterial pneumonia is not optimal. Jain MD et al. N Engl J Med. 2015 Feb 26; 372(9): 835 845. 4

Vaccine history Pneumococcal conjugate vaccine PCV7 was added to the recommended childhood vaccination schedule in 2000 PCV13 (Prevnar 13) replaced it on the schedule in 2010 Since the initial recommendation, invasive pneumococcal disease in children has dropped by nearly 80% in the United States Hib vaccine first produced 1985, more effective formulation in 1990s Rates of severe Hib infections have decreased more than 90% Centers for Disease Control and Prevention. Pneumococcal Disease. Atkinson, W., et al. 13th ed. Washington DC: Public Health Foundation, 2015. Accessed 5/1/2017. Haemophilus influenzae type b (Hib) Vaccination Position Paper July 2013." (PDF). Wkly Epidemiol Rec. 88 (39): 413 26. Sep 27, 2013. PMID 24143842. Pathogens - viral Guideline recommendation: Antimicrobial therapy is not routinely required for preschool-aged children with CAP, because viral pathogens are responsible for the great majority of clinical disease. (strong recommendation; high-quality evidence) Test for influenza, respiratory syncytial virus (RSV) Antibiotics recommended for CAP suspected to be of bacterial origin Bradley JS, et al. Clin Infect Dis. 2011 Oct;53(7):e25-76. Pathogens: influenza Recommendation: Presumed influenza infection: Oseltamivir (option zanamivir if >7 yrs old) Bradley JS, et al. Clin Infect Dis. 2011 Oct;53(7):e25-76. 5

Oseltamivir controversy Financial conflicts of interest and conclusions about neuraminidase inhibitors for influenza: an analysis of systematic reviews. Annals of Internal Medicine 2014 7 of 8 (88%) of favorable reviews had financial conflicts of interest vs. 5 of 29 (17%) of unfavorable reviews Dunn AG, et al. Ann Intern Med. 2014 Oct 7;161(7):513-8. Oseltamivir controversy Reviewers with financial conflicts are more likely to author systematic reviews that are favorable to the use of neuraminidase inhibitors, suggesting that industry influence may have contributed to inconsistent conclusions of their clinical benefit. In 2009, governments around the world spent $6.9 billion building stockpiles of oseltamivir, an investment that remains poorly supported by available clinical evidence. Dunn AG, et al. Ann Intern Med. 2014 Oct 7;161(7):513-8. Pathogens - bacterial Streptococcus pneumoniae Haemophilus influenza, typeable (A-F) or nontypeable Vaccine over past 25 years has virtually eliminated this pathogen in children Group A streptococcus S aureus + in school age kids (>5yrs old) Mycoplasma pneumoniae Chlamydia trachomatis or Chlamydophila pneumoniae Bradley JS, et al. Clin Infect Dis. 2011 Oct;53(7):e25-76. 6

Empiric therapy Inpatient (all ages) Fully immunized: Presumed bacterial: Ampicillin Alternative ceftriaxone or cefotaxime + clindamycin or vancomycin if suspected MRSA Bradley JS, et al. Clin Infect Dis. 2011 Oct;53(7):e25-76. Empiric therapy Inpatient (all ages) NOT fully immunized or local penicillin resistance in invasive strains of pneumococcus is significant: Ceftriaxone or cefotaxime + vancomycin or clindamycin for suspected MRSA Bradley JS, et al. Clin Infect Dis. 2011 Oct;53(7):e25-76. Empiric therapy Presumed atypical: azithromycin, most often in addition to β-lactam (for both immunized and not) Presentation Age Bradley JS, et al. Clin Infect Dis. 2011 Oct;53(7):e25-76. 7

Case 1: Alex 2 year old female, 12 kg, Vaccines up to date, NKDA Plan: admission to pediatric unit What is the most appropriate antimicrobial for Alex? A. Ceftriaxone B. Ampicillin C. Azithromycin D. Levofloxacin E. Oseltamivir Case 1: Alex 2 year old female, 12 kg, Vaccines up to date, NKDA Plan: admission to pediatric unit What is the most appropriate antimicrobial for Alex? A. Ceftriaxone B. Ampicillin C. Azithromycin D. Levofloxacin E. Oseltamivir Outpatient management During her time in the emergency room, Alex improves immensely. The provider decides she will discharge Alex home. What antibiotic do you recommend? (http://respond.cc code: 247996) A. Cefprozil B. Amoxicillin C. Azithromycin D. Levofloxacin E. Combination of the above 8

Empiric therapy - outpatient Presumed bacterial: amoxicillin Alternative amoxicillin/clavulanate Cephalosporins NOT included as an option Presumed atypical: azithromycin <5 yrs old (preschool): atypical pathogens rare >5 yrs old: atypicals common Bradley JS, et al. Clin Infect Dis. 2011 Oct;53(7):e25-76. No oral cephalosporin at doses studied in children provides activity at the site of infection that equals high-dose amoxicillin. Most second- or third-generation oral cephalosporins provide adequate activity against only 60% 70% of currently isolated strains of pneumococcus. Bradley JS, et al. Clin Infect Dis. 2011 Oct;53(7):e25-76. Outpatient management What antibiotic do you recommend for Alex? A. Cefprozil B. Amoxicillin C. Azithromycin D. Levofloxacin E. Combination of the above 9

Outpatient management What antibiotic do you recommend for Alex? A. Cefprozil B. Amoxicillin C. Azithromycin D. Levofloxacin E. Combination of the above What if allergies? Only inferior options Consider trial of amoxicillin under medical supervision Cephalosporins (cefpodoxime, cefprozil, cefuroxime) Levofloxacin Macrolide: Up to 40% of community isolates of S pneumoniae resistant Clindamycin: ~30% resistance rate for S pneumoniae Bradley JS, et al. Clin Infect Dis. 2011 Oct;53(7):e25-76. Fluoroquinolones in pediatrics Can you use fluoroquinolones in kids? Yes! Should you use fluoroquinolones in kids? No! Jackson MA, et al. Pediatrics. 2016 Nov;138(5) 10

Amoxicillin dosing What dose of amoxicillin do you recommend for Alex s pneumonia? A. 90 mg/kg/day B. 75 mg/kg/day C. 45 mg/kg/day D. 20 mg/kg/day http://respond.cc Code: 836520 Step-up therapy Using amoxicillin/clavulanate will improve coverage for resistant S pneumoniae? A. True B. False http://respond.cc Code: 557970 Acute Otitis Media 11

Acute otitis media (AOM) Same bugs (sort of), same drugs S pneumoniae H influenzae M catarrhalis 1 st line: amoxicillin 2 nd line: amoxicillin/clavulanate Lieberthal AS, et al. The diagnosis and management of acute otitis media. Pediatrics. 2013 Mar;131(3):e964-99 AOM: not everyone gets antibiotics Lieberthal AS. Pediatrics. 2013 Mar;131(3):e964-99 AOM treatment Lieberthal AS, et al. Pediatrics. 2013 Mar;131(3):e964-99 12

S pneumoniae resistance Resistance mechanism: alterations in penicillin binding proteins In early 1970s, S pneumoniae highly susceptible to standard dosing (40-45mg/kg/day) amoxicillin Widespread pneumococcal resistance emerged in 1990s Recommendations changed to high dose amoxicillin 90 mg/kg/day, studied first in AOM Lieberthal AS, et al. Pediatrics. 2013 Mar;131(3):e964-99. S pneumoniae resistance Introduction of PCV7 (2000) decreased resistance Possible to return to low dose amoxicillin? Resistance of serotype 19A then emerged included in PCV13 The antibiotic susceptibility pattern for S pneumoniae is expected to continue to evolve with the use of PCV13 Lieberthal AS, et al. Pediatrics. 2013 Mar;131(3):e964-99. H influenzae & M catarrhalis resistance Resistance mechanism: β-lactamase production a significant decrease in β-lactamase producing H influenzae, compared with data reported in the 2004 AOM guideline. 100% of M catarrhalis derived from the upper respiratory tract are β-lactamase positive but remain susceptible to amoxicillinclavulanate. However, the high rate of spontaneous clinical resolution occurring in children with AOM attributable to M catarrhalis treated with amoxicillin reduces the concern for the first-line coverage for this microorganism. Lieberthal AS, et al. Pediatrics. 2013 Mar;131(3):e964-99 13

Resistance High dose amoxicillin overcomes S pneumoniae resistance Adding clavulanate broadens coverage for resistant H influenzae and M catarrhalis Amoxicillin/clavulanate dosing Lieberthal AS, et al. Pediatrics. 2013 Mar;131(3):e964-99 Amoxicillin-clavulanate products 125: Amoxicillin 125 mg / clavulanate 31.25 mg per 5 ml = 4:1 200: Amoxicillin 200 mg / clavulanate 28.5 mg per 5 ml = 7:1 250: Amoxicillin 250 mg / clavulanate 62.5 mg per 5 ml = 4:1 400: Amoxicillin 400 mg / clavulanate 57 mg per 5 ml = 7:1 ES 600: Amoxicillin 600 mg / clavulanate 42.9 mg per 5 ml = 14:1 14

Amoxicillin-clavulanate product selection With high dose amoxicillin-clavulanate, only need high dose of amoxicillin, not clavulanate side effects Amoxicillin-clavulanate 90 mg/kg/day of amoxicillin, with 6.4 mg/kg per day of clavulanate = 14:1 amox:clav Only 600mg/5mL (ES formulation) has 14:1 amox:clav ratio Use 600mg/5ml product if dosing at 90mg/kg/day amoxicillin ( highdose ) Alex s amoxicillin (CAP) What dose of amoxicillin do you recommend for Alex s pneumonia? A. 90 mg/kg/day B. 75 mg/kg/day C. 45 mg/kg/day D. 20 mg/kg/day Alex s amoxicillin (CAP) What dose of amoxicillin do you recommend for Alex s pneumonia? A. 90 mg/kg/day B. 75 mg/kg/day C. 45 mg/kg/day D. 20 mg/kg/day 15

Step-up therapy Using amoxicillin/clavulanate will improve coverage for resistant S pneumoniae? A. True B. False Step-up therapy Using amoxicillin/clavulanate will improve coverage for resistant S pneumoniae? A. True B. False Alex s amoxicillin (CAP) How should Alex s amoxicillin be divided? A. Twice daily B. Three times daily http://respond.cc Code: 819084 16

AOM treatment Lieberthal AS, et al. Pediatrics. 2013 Mar;131(3):e964-99 Pneumonia treatment Bradley JS, et al. Clin Infect Dis. 2011 Oct;53(7):e25-76. BID vs TID in pneumonia AOM: amoxicillin 90mg/kg/day divided BID x 10 days BID dosing studied and found successful in AOM Half-life of amoxicillin in middle ear fluid is 4-6 hours Serum half-life only 1 hour Bradley JS, et al. Clin Infect Dis. 2011 Oct;53(7):e25-76. 17

BID vs TID in pneumonia To achieve the appropriate amoxicillin exposure in lung infected by relatively resistant pneumococci (MICs of 2.0 lg/ml), a high total daily dose (90 mg/kg/day) in 3 equally divided portions is predicted to achieve a clinical and microbiologic cure in about 90% of children treated, compared with only 65% of children treated with the same total daily dose divided into 2 equal doses. However, for fully susceptible strains, a dosage of 90 mg/kg/day in 2 divided portions, as indicated for otitis media, is likely to be successful. Bradley JS, et al. Clin Infect Dis. 2011 Oct;53(7):e25-76. How should Alex s amoxicillin dose be divided? TID is optimal BID is acceptable Patient specific Moving on 18

Case 2: Raul 5 month old male presents to the emergency dept. in respiratory distress with poor oral intake RR 60, O2 sat 84% on RA, with retractions, nasal flaring Wheezing and crackles on auscultation Previously healthy infant, born at term, vaccines up to date Influenza swab negative Chest x-ray shows perihilar infiltrates bilaterally Case 2: Raul What is the best treatment for Raul? A. Amoxicillin B. Amoxicillin/clavulanate C. Albuterol D. Prednisone E. Combination of the above F. None of the above http://respond.cc Code: 553541 19

Bronchiolitis Bronchiolitis Viral lower respiratory track infection in infants Characterized by acute inflammation, edema, necrosis of epithelial cells of small airways, increased mucus production Tachypnea, wheezing, rales, use of accessory muscles, nasal flaring Most commonly caused by RSV 90% of kids have RSV before age 2 Most common cause of hospitalization in first year of life Ralston SL, et al. Pediatrics. 2014 Nov;134(5):e1474-502 Bronchiolitis guideline Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics. 2014 Patients 1-23 months old Ralston SL, et al. Pediatrics. 2014 Nov;134(5):e1474-502 20

Bronchiolitis - treatment IV hydration as needed Supplementation oxygen to keep O2 sats >90% Continuous pulse ox not recommended Routine chest radiography not recommended Ralston SL, et al. Pediatrics. 2014 Nov;134(5):e1474-502 Treatment NON-options Antibiotics Correct diagnosis? Ralston SL, et al. Pediatrics. 2014 Nov;134(5):e1474-502 Treatment NON-options Corticosteroids Large trials provide clear evidence there is no benefit Ralston SL, et al. Pediatrics. 2014 Nov;134(5):e1474-502 21

Treatment NON-options Bronchodilators Do not affect disease resolutions, need for hospitalization or length of stay (LOS) The potential adverse effects (tachycardia and tremors) and cost of these agents outweigh any potential benefits Epinephrine, albuterol Ralston SL, et al. Pediatrics. 2014 Nov;134(5):e1474-502 Treatment potential option 3% saline nebulized Very inconsistent findings in trials Currently recommended for consideration in hospitalized infants only Ralston SL, et al. Pediatrics. 2014 Nov;134(5):e1474-502 Palivizumab (Synagis ) Monoclonal antibody for infants at high risk of morbidity/mortality from RSV Not a vaccine Not intended to prevent RSV 15mg/kg IM monthly during RSV season (Nov-March) Expensive! AAP Committee on infectious diseases and bronchiolitis guidelines committee. Pediatrics. 2014;134(2):415. 22

Palivizumab who gets it AAP guidelines 1st RSV season only Infants born at <29 weeks gestational age Born at 29-32 weeks AND with chronic lung disease (CLD) defined at requiring O2 past 28 days of life Hemodynamically significant congenital heart disease Pulmonary abnormality or neuromuscular disease that impairs the ability to clear secretions AAP Committee on infectious diseases and bronchiolitis guidelines committee. Pediatrics. 2014;134(2):415. Palivizumab who gets it May get a 2 nd season if: CLD still requiring medical therapy (e.g. O2, steroids, diuretics) Profoundly immunocompromised May consider if having cardiac transplant during RSV season Discontinue monthly prophylaxis if hospitalized with RSV AAP Committee on infectious diseases and bronchiolitis guidelines committee. Pediatrics. 2014;134(2):415. Raul, 5 month old with bronchiolitis What is the best treatment for Raul? A. Amoxicillin B. Augmentin C. Albuterol D. Prednisone E. Combination of the above F. None of the above 23

Raul, 5 month old with bronchiolitis What is the best treatment for Raul? A. Amoxicillin B. Augmentin C. Albuterol D. Prednisone E. Combination of the above F. None of the above Croup Case 3: Brayden 23 month old male presenting to emergency dept. in respiratory distress, with stridor, barking cough. He s had a low grade fever and rhinorrhea for 2 days Diagnosed with mild croup 24

Croup What is the best treatment option for Brayden? A. Amoxicillin B. Albuterol C. Prednisone D. Dexamethasone E. Nebulized epinephrine http://respond.cc Code: 695639 Croup Most commonly laryngotracheitis aka viral croup Upper airway edema can significantly compromise airway Stridor, barking cough Usually occurs between 6 months and 3 years of age Most common pathogen: parainfluenza virus More common in males (3:2) Seasonal (winter) Cherry JD. Croup. N Engl J Med 2008;358:384-91. Treatment: nebulized epinephrine First studied early 1970s Vasoconstriction decreases swelling and airway narrowing. Also causes bronchodilation Indicated for moderate to severe croup Racemic epinephrine 2.25% 0.5ml (diluted to 3mL with NS) nebulized every 2 hours as needed Cherry JD. N Engl J Med 2008;358:384-91. Bjornson C, et al. Cochrane Database Syst Rev. 2013 Oct 10;(10):CD006619. 25

Treatment: dexamethasone Revolutionized management of croup, starting ~1990 Mild to severe croup Single dose 0.6 mg/kg oral/im/iv Oral route preferred Maximum dose debated. Usually 16 mg, some say 10 mg Some studies show 0.15 mg/kg or 0.3 mg/kg may be equally effective Most clinicians use 0.6 mg/kg: more data, assured efficacy, well tolerated Russell KF et al. Cochrane Database Syst Rev 2011; :CD001955. Croup What is the best treatment option for Brayden? A. Amoxicillin B. Albuterol C. Prednisone D. Dexamethasone E. Nebulized epinephrine Croup What is the best treatment option for Brayden? A. Amoxicillin B. Albuterol C. Prednisone D. Dexamethasone E. Nebulized epinephrine 26

Dexamethasone Brayden is 23 months old and weighs 14.5 kg. What dose do you recommend for dexamethasone? What route and product? Dexamethasone dose forms Dexamethasone Brayden is 23 months old and weights 14.5 kg. What dose do you recommend for dexamethasone? What route and product? 14.5 kg x 0.6mg/kg = 8.7 mg 9 mg = 0.9 ml of 10mg/ml IV product given orally 27

Objectives Given a patient case, identify opportunities for improved antimicrobial stewardship in the treatment of pediatric pneumonia. Explain how pharmacokinetic differences affect antibiotic dosing in pneumonia versus otitis media. Differentiate clinical presentations of pneumonia, bronchiolitis and croup in pediatric patients. Describe appropriate and inappropriate treatment strategies for bronchiolitis. Determine the optimal steroid dose formulation for the treatment of croup based on a patient case. Conclusion Peds is awesome! Thank you! Brenda Kelly brendakelly@yvmh.org 28