Pediatric Respiratory Infections · •Streptococcus pneumoniae •Haemophilus influenza, typeable...

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Pediatric Respiratory Infections

Brenda Kelly PharmD BCPS

Residency Program Director

Virginia Mason Memorial, Yakima, Washington

[email protected]

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.

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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.

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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.

http://respond.cc/

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AdV = adenovirusCoV = coronavirusFlu = influenza A or B virus HMPV = human metapneumovirusHRV = human rhinovirusPIV = parainfluenza virusRSV = respiratory syncytial virus


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.”


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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”


Pathogens: influenza

Recommendation:

Presumed influenza infection:

• Oseltamivir (option zanamivir if >7 yrs old)


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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


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Empiric therapy

Inpatient (all ages)

Fully immunized:

• Presumed bacterial: Ampicillin• Alternative ceftriaxone or cefotaxime

• + clindamycin or vancomycin if suspected MRSA


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


Empiric therapy

• Presumed atypical: azithromycin, most often in addition to 𝛽-lactam (for both immunized and not)

• Presentation

• Age


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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 managementDuring 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

http://respond.cc/

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Empiric therapy - outpatient

• Presumed bacterial: amoxicillin• Alternative amoxicillin/clavulanate

• Cephalosporins NOT included as an option

• Presumed atypical: azithromycin

• 5 yrs old: atypicals common


• “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.”


Outpatient management

What antibiotic do you recommend for Alex?

A. Cefprozil

B. Amoxicillin

C. Azithromycin

D. Levofloxacin


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Outpatient management

What antibiotic do you recommend for Alex?

A. Cefprozil

B. Amoxicillin

C. Azithromycin

D. Levofloxacin


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


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)

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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 resistantS pneumoniae?

A. True

B. False

http://respond.cc

Code: 557970

Acute Otitis Media

http://respond.cc/http://respond.cc/

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Acute otitis media (AOM)

Same bugs (sort of), same drugs

• S pneumoniae

• H influenzae

• M catarrhalis

• 1st line: amoxicillin

• 2nd 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

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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 amoxicillin-clavulanate. 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.”


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Resistance

• High dose amoxicillin overcomes S pneumoniae resistance

• Adding clavulanate broadens coverage for resistant H influenzae and M catarrhalis

Amoxicillin/clavulanate dosing


Amoxicillin-clavulanate products

• 125: Amoxicillin 125 mg / clavulanate 31.25 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

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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 (“high-dose”)

Alex’s amoxicillin (CAP)


A. 90 mg/kg/day

B. 75 mg/kg/day

C. 45 mg/kg/day

D. 20 mg/kg/day



A. 90 mg/kg/day

B. 75 mg/kg/day

C. 45 mg/kg/day

D. 20 mg/kg/day

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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


How should Alex’s amoxicillin be divided?

A. Twice daily

B. Three times daily

http://respond.cc

Code: 819084

http://respond.cc/

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AOM treatment


Pneumonia treatment


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


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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.”


How should Alex’s amoxicillin dose be divided?

• TID is optimal

• BID is acceptable

• Patient specific

Moving on…

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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. AmoxicillinB. Amoxicillin/clavulanateC. AlbuterolD. PrednisoneE. Combination of the aboveF. None of the above

http://respond.ccCode: 553541

http://respond.cc/

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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


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Bronchiolitis - treatment

• IV hydration as needed

• Supplementation oxygen to keep O2 sats >90%• Continuous pulse ox not recommended

• Routine chest radiography not recommended


Treatment NON-options

Antibiotics

• Correct diagnosis?



Corticosteroids

• Large trials provide clear evidence there is no benefit


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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


Treatment potential option

3% saline nebulized

• Very inconsistent findings in trials

• Currently recommended for consideration in hospitalized infants only


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.

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Palivizumab – who gets it

AAP guidelines

• 1st RSV season only• Infants born at

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Raul, 5 month old with bronchiolitis

What is the best treatment for Raul?

A. Amoxicillin

B. Augmentin

C. Albuterol

D. Prednisone


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

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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.

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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


A. Amoxicillin

B. Albuterol

C. Prednisone

D. Dexamethasone


Croup


A. Amoxicillin

B. Albuterol

C. Prednisone

D. Dexamethasone


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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

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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

[email protected]

Pediatric Respiratory Infections · •Streptococcus pneumoniae •Haemophilus influenza, typeable...

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