More Than the Sniffles - nodakpharmacy.netnodakpharmacy.net/docs/Convention2014/1pedsid.pdf · glomerulonephritis, tonsillar abscess, mastoiditis Shulman ST, et al. Practice Guidelines

More Than the Sniffles: Update on the Treatment of

Pediatric Respiratory Infections

Amy Crawford, Pharm.D. R.Ph

NDPhA 2014 Annual Convention

April 5th, 2014

Conflict of Interest

�  No relevant financial or commercial conflicts of interest to disclose

Objectives

�  Describe treatment strategies for pediatric respiratory infections

�  Recommend an antibiotic regimen for a pediatric patient: including appropriate drug/formulation and dose

�  Determine patients eligible for shorter courses of antibiotic therapy

�  Analyze current literature evaluating the PK/PD parameters and therapeutic goals of vancomycin in children

Pharyngitis

Patient Case #1

GS is a 7 yom, 25kg, presenting to the clinic with a sore throat and rash on his abdomen and back. He started feeling “icky” and having problems swallowing within the last 48 hrs. Per mom, he had a fever up to 101.7 last night. Mom doesn’t think he has any allergies. RADT returned positive.

Pharyngitis

�  Sudden onset of fever and tonsillopharyngeal inflammation �  Patchy tonsillar exudates, “beefy” uvula, palatal petechiae, and

cervical adenitis +/- scarlatiniform rash

�  Most prevalent in school-aged children (5-15 yrs), Nov-May

�  Diagnosis: clinical characteristics + rapid antigen detection test (RADT) for Group A Streptococcus (GAS) �  Not indicated for children <3

�  Sequelae: acute rheumatic fever, poststreptococcal glomerulonephritis, tonsillar abscess, mastoiditis

Shulman ST, et al. Practice Guidelines for GAS Pharyngitis. CID. 2012. online

Pharyngitis

Bacterial Etiology

�  GAS (20-30% cause in children)

�  Group C/G Strep

�  Arcanobacterium

�  Neisseria gonorrhoeae

�  Corynebacterium diphtheriae

Viral Etiology

�  Influenza A/B

�  Respiratory Syncytial Virus

�  Adenovirus

�  Epstein-Barr virus

�  Herpes Simplex Virus 1 or 2

�  Coxsackievirus, Rhinovirus, Coronavirus, Parainfluenza

�  S/Sx: rhinorrhea, cough, oral ulcers, hoarseness, conjunctivitis, diarrhea


Treatment Strategy

�  Antibiotics only proven to be effective against GAS, Corynebacterium, or Neisseria

�  Treatment of choice: PCN or amoxicillin �  PCN allergic: 1G cephalosporin,

clindamycin, clarithromycin or azithromycin

�  Not recommended: tetracyclines, TMP/SMX, ciprofloxacin, levofloxacin/moxifloxacin

�  Treatment course usually 10 days



Regimens for Chronic Carriers of GAS

�  Chronic carriers of GAS will have a positive RADT but have no active immunologic response �  Do not need prophylaxis �  Require treatment during outbreaks (family, community) of

rheumatic fever or GAS nephritis, or if tonsillectomy is being considered because of carriage

�  Regimens �  Clindamycin �  Penicillin + Rifampin �  Amoxicillin/Clavulanate �  Benzathine penicillin G + Rifampin


Regimens for Chronic Carriers of GAS


Short Course Antibiotics

�  Guidelines do not endorse short-course regimens

�  FDA approved 5-day short courses �  Cefdinir, cefpodoxime, azithromycin

�  Studies not well designed, performed in 1994-1998

�  Short vs Long-Course Therapy: Meta-Analysis �  Microbiological eradication (p<0.001) and clinical success

(p=0.04) significantly less in 5-7 day course vs 10 day course �  Not significant findings in 2/3G cephalosporins (p=0.07)

�  No difference in bacteriological relapse

Shulman ST, et al. Practice Guidelines for GAS Pharyngitis. CID. 2012. Falagas ME, et al. Mayo Clin Proc. 2008; 83(8): 880-889.

Patient Case #1

GS is a 7 yom, 25kg, presenting to the clinic with a sore throat and rash on his abdomen and back. He started feeling “icky” and having problems swallowing within the last 48 hrs. Per mom, he had a fever up to 101.7 last night. Mom doesn’t think he has any allergies. RADT returned positive.

What is the best antibiotic regimen for this patient?

1.  No antibiotics, likely viral etiology

2.  Penicillin 250 mg tab PO TID x 10 days

3.  Amoxicillin 1000 mg susp. PO daily x 10 days

4.  Cephalexin 500 mg susp. PO TID x 5 days

Acute Otitis Media

Patient Case #2

AM is a 14 month old, 11kg, presents to the clinic with dad. From report, she has been tugging her ears, crying excessively, and has had difficulty sleeping and poor appetite x36 hours. Dad states she also “feels warm”. Upon exam, she has bileratal, bulging, erythematous tympanic membranes (TM). Tmax = 102.5F.

Acute Otitis Media �  Rapid onset of signs of inflammation in the middle ear

�  Severe: moderate to severe otalgia, otalgia >48h, temp >39C �  Mild: mild otalgia, otalgia <48h, temp <39C

�  Diagnosis: no gold standard �  Mod-sev bulging of TM or new onset of otorrhea �  Mild TM bulging + recent onset of ear pain or intense TM

erythema �  AOM should NOT be diagnosed without presence of middle ear

effusion

Lieberthal AS, et al. Pediatrics. 2013; 131: e964-e999.

Acute Otitis Media

�  Usually starts as a viral URI, then leads to eustachian tube inflammation and movement of secretions to middle ear

�  Pathogens

�  S.pneumoniae – strains not included in PCV7 �  Resistance: 58% and 82% susceptible to standard and high dose

(HD)-amoxicillin, respectively

� H.influenzae �  Resistance: 83% and 87% susceptible to standard and HD-

amoxicillin

�  M.catarrhalis �  S.pyogenes


Treatment Strategy

�  Antibiotics indicated for: �  >6 mo (uni/bilateral) with severe AOM �  6-23 mo (bilateral) with mild AOM

� Antibiotics OR observation indicated for: �  6-23 mo (unilateral) with mild AOM �  >24 mo (uni/bilateral) with mild AOM

� Observation option �  Only mild improvement should be expected within first

24 hours à reassess after 48-72 hours for treatment failure

�  “Safety Net” antibiotics

Routine PCV13 and seasonal influenza vaccines!!


Antibiotics VS Observation

�  Rationale for initial antibiotics �  Benefit is seen in cases with bilateral AOM, S.pneumoniae, and

AOM with otorrhea �  Decreased duration of pain, analgesic use, or school/work

absences �  70-96% of middle ear fluid collections contain bacterial +/-

viruses

�  Rationale for initial observation �  AOM is usually self-limiting

�  In watchful waiting studies, 66% of children completed study without need for antibiotics

�  May decrease antibiotic resistance


Treatment Strategy – Antibiotic Choice

�  HD Amoxicillin is 1st line

�  Amoxicillin/clavulanate recommended if patient has: �  Received amoxicillin in last 30 days �  Purulent conjunctivitis or history of recurrent AOM

�  If PCN-allergic: cephalosporins 1st line

�  Resistance problems �  Macrolides have limited efficacy against H.influenzae and

S.pneumoniae �  Clindamycin not active against H.influenzae, but can be used for

PCN-R S.pneumoniae


Antibiotic Regimens – Initial


Antibiotic Regimens – Failures


Antibiotic Taste

�  Amoxicillin: 4/5, BEST ONE!

�  Amoxicillin/clavulanate: 2/5, chalky flavor, lemon-lime

�  Cefdinir: 3/5, smells like berries, tastes like feet

�  Cephalexin: 4/5, fruit punch, almost as good as amoxicillin

�  Azithromycin: 2-4/5, very sweet, gritty, bitter aftertaste

�  Clindamycin: 0/5, WORST ONE! Smells like garbage

�  Linezolid: 1/5, bitter, foul taste

“Several of these choices of antibiotic suspensions are barely palatable or frankly offensive and may lead to avoidance

behaviors or active rejection by spitting out the suspension”

Short Course Antibiotics �  10 day recommendations derived from strep pharyngitis guidelines

�  AAP guidelines endorse �  10 day course for children <2yrs

�  7 days for children 2-5 yrs

�  5-7 days for children >6 yrs

�  Prospective observation of 5, 7, 10 day courses for AOM �  Efficacy < 2yrs: 75% for 5 day, 73% 7 day, 76% 10 day (p<0.001)

�  Efficacy > 2yrs: 87% for 5 day, 90% 7 day, 88% 10 day (p<0.001)

�  Many studies document poorer outcomes in children <2 yrs; but for children > 6 yrs … where’s the data?

Lieberthal AS, et al. Pediatrics. 2013; 131: e964-e999. Pichichero ME, et al. Otolaryngol Head neck Surg. 2001; 124: 381-7. Cohen R, et al. Pediatr Infect Dis J. 2000; 19: 458-63. Cohen R, et al. J Pediatr. 1998; 133: 634-9.

Patient Case #2

AM is a 14 month old, 11kg, presents to the clinic with dad. From report, she has been tugging her ears, crying excessively, and has had difficulty sleeping and poor appetite x36 hours. Dad states she also “feels warm”. Upon exam, she has bileratal, bulging, erythematous tympanic membranes (TM). Tmax = 102.5F.

What is the best antibiotic regimen for this patient?

1.  Amoxicillin 250 mg susp. PO BID x 10 days

2.  Amoxicillin 500 mg susp. PO BID x 10 days

3.  Amoxicillin/clavulanate 500 mg susp. (14:1 ratio) PO BID x 7 days

4.  Antibiotics not indicated, can observe x48h then follow-up

Community Acquired Pneumonia

Patient Case #3

CP is a previously healthy 4 yof, 16kg, admitted to the hospital for respiratory distress. Mom reports that she has had a productive cough x72 hrs.

�  Vitals on admission: RR 44 breaths/min, Tmax=103F, O2 Sats 88% on RA, now requiring O2. CBC/CRP, CXR, Viral panel, cultures pending.

Community Acquired Pneumonia

�  Sign/symptoms of pneumonia in a previously healthy child caused by an infection acquired outside of the hospital �  Simple: single lobe involvement

�  Complicated: effusions, abscesses, empyema, pneumothorax, SIRS

�  Diagnosis �  WHO criteria: cough or difficulty breathing with tachypnea

�  Evaluate vital signs, CBC +/- CRP, viral panel

�  CXR + blood cultures

�  No CURB65 in children …

Bradley JS, et al. Clinical Infectious Diseases. 2011; 53(7): e25-e76.

Bacterial Pathogens �  Typical

�  S.pneumoniae, H.influenzae decreased with vaccination

�  H.influenzae pathogenic in chronic lung disease

�  GAS

�  S.aureus

�  Atypical – 23% of PNA �  M.pneumoniae

�  C.pneumoniae

�  S/sx: slow onset – cough develops over 3-5 days, malaise, sore throat, low-grade fever

Viral Pathogens

�  Most likely etiology in children <2 yrs �  Respiratory syncytial virus �  Influenza A/B �  Adenovirus �  Parainfluenza �  Coronavirus, rhinovirus

�  Presentation vs bacterial �  Fever, chills, nonproductive cough, rhinitis, myalgias,

headache, fatigue, sore throat, rhinorrhea �  Bacterial has higher fevers, productive cough, rapid RR, can

have chest pain


Treatment Strategy - Outpatient

�  Antibiotics �  Preschool-aged: no antibiotics as viral etiology most likely

�  Mild-mod CAP in immunized children: amoxicillin 1st line

�  Atypical CAP: macrolides

�  Duration: 10 days most studied, but shorter courses may be effective

�  Routine PCV13 and seasonal influenza vaccines!!


Antibiotic Regimens - Outpatient

�  S.pneumoniae > nontypeable H.influenzae �  Pneumococcal

�  PCN-S: HD amoxicillin div q12h

�  PCN-R (MIC>4): levofloxacin preferred, HD amoxicillin div q8h, can use linezolid

�  H.influenzae �  B-lactamase negative: HD amoxicillin div q8h

�  B-lactamase positive: HD amoxicillin/clavulanate div q12h or 45 mg/kg/day div q8h, oral 2/3G cephalosporin

�  Quinolones not needed unless allergy to above agents


Antibiotic Regimens

Treatment Strategy - Inpatient

�  Antibiotics �  Ampicillin/PCN in immunized children

�  3rdG IV cephalosporin for un-immunized children, high PCN-R, or empyema

�  Add macrolide if atypical pathogen suspected

�  Add vancomycin or clindamycin if S.aureus is suspected

�  Effusions will likely require drainage + antibiotics up to 4-6 weeks

�  Improvement should be seen 48-72h after initiation of therapy


Antibiotic Regimens - Inpatient

�  Suspect S.pneumoniae and H.influenzae, think about other pathogens �  S.pneumoniae

�  PCN-S: amp 150-200 mg/kg/day, PCN 200-250K U/kg/day �  PCN-R (MIC>4): amp 300-400 mg/kg/day, ceftriaxone 100 mg/kg/

day �  H.influenzae

�  B-lactamase negative: amp 150-200 mg/kg/day �  B-lactamase positive: ceftriaxone 50-100 mg/kg/day

�  Group A Streptococcus �  PCN 100-250K U/kg/day or amp 200 mg/kg/day, 3rdG cephs option

�  S.aureus �  MSSA: nafcillin/cefazolin sufficient �  MRSA: Vancomycin or clindamycin, linezolid may be another option



Vancomycin PK/PD

IDSA Guidelines

�  Adults: �  15-20 mg/kg IV q8-12h (nml renal function) �  Goal serum trough = 15-20 mcg/mL for complicated MRSA

infections (bacteremia, endocarditis, osteomyelitis, HAP) �  Target AUC/MIC > 400, if MIC ≤1

�  Pediatrics: �  15 mg/kg IV q6h for invasive MRSA infections �  CAP guidelines: 40-60 mg/kg/day q6-8h

�  Trough <10 mcg/mL can produce strains with VISA-like characteristics [trough 1.5-10 mcg/mL and AUC/MIC 32-264]

�  Criteria for monitoring: aggressive dosing, risk of nephrotoxicity, courses > 3-5 days, unstable renal function

Rybak M, et al. Am J Health-Syst Pharm. 2009; 66: 82-98. Liu C, et al. Clin Infect Dis. 2011; 52(3): 285-292.

Vancomycin in Pediatrics

�  Is goal trough of 15-20 mcg/mL correct for pediatric patients? �  Troughs do not directly reflect AUC/MIC

�  Data correlating AUC/MIC > 400 with trough 15-20 mcg/mL is ADULT data only

�  Used a q12h interval – would be different in pediatrics requiring q6h or q8h frequencies

�  Lots of literature showing that 15-20 mcg/mL troughs are difficult to achieve in pediatric patients and require many dose adjustments

Moffett BS, Edwards MS. Pediatr Infect Dis J. 2013; 32: 32-35. Eiland LS. Ann Pharmacother. 2011; 45: 582-589.

Desired Vancomycin Trough Serum Concentrations for Treating Invasive MRSA Infections Frymoyer A, Gugliemo BJ, Hersh AL, et al. Desired vancomycin trough serum concentration for treating invasive methicillin-resistant staphylococcal infections. Pediatr Infect Dis J. 2013.

Methods

�  3 separate PK modeling/simulation analyses performed (Chang, Lamarre, Wrisko)

�  “Base patient” was 25kg, receiving vanco 15 mg/kg IV q6h infused over 1h, MIC=1

�  Other regimens evaluated: �  15 mg/kg IV q8h and 20 mg/kg IV q8h

�  MIC of 0.5 and 2 mcg/mL

Frymoyer A, et al. Pediatr Infect Dis J. 2013; Pub ahead of print.

Results – Dosing Regimen

�  15 mg/kg IV q6h �  When MIC = 1, >90% of children meet goal AUC/MIC with

troughs of 7-10 mcg/mL

�  20 mg/kg IV q8h �  Goal AUC/MIC with troughs at 6-8 mcg/mL

�  15 mg/kg IV q8h �  Goal AUC/MIC with troughs 8-10 mcg/mL

�  Only 35% of patients are predicted to achieve troughs >10 mcg/mL with this regimen


Study Conclusions

�  Based on results from simulation data, vanco troughs of 7-10 mcg/mL are predictive of AUC/MIC > 400 at 15 mg/kg IV q6h dosing (MIC=1) in children

�  Goal troughs of 15-20 mcg/mL are likely unnecessary to achieve AUC/MIC > 400 �  Consider alternatives when MIC=2 if patient is not clinically

improving �  Data should not be extrapolated to peds pts with altered PK:

<2 yrs, abnormal renal function, obesity

�  For alternative dosing strategies (q8h v q6h), the impact of dose/interval on trough needs to be considered


Patient Case #3

What is the most appropriate empiric antibiotic regimen for this patient?

1.  Ampicillin 800mg IV q6h

2.  Ceftriaxone 1200mg IV q24h

3.  Ceftriaxone 1600mg IV q24h + Azithromycin 160mg IV q24h

4.  Vancomycin 240mg IV q6h

CP is a previously healthy 4 yof, 16kg, admitted for respiratory distress. Mom reports that she has had a productive cough x72 hrs.

�  Up-to-date on immunizations

�  CBC/CRP suggestive of infection process

�  CXR shows RUL consolidation

�  Influenza/RSV negative, blood cultures NGTD

Conclusions

�  Treatment of pediatric respiratory infections should take into consideration likely pathogen, local resistance rates, and severity of disease

�  Antibiotic regimens vary between disease states and should take into consideration patient tolerability

�  Not all patients are eligible for shorter courses of antibiotics

�  Appears that goal vancomycin trough 15-20 mcg/mL does not reflect target AUC/MIC >400 in children

References

�  Shulman ST, Bisno AL, Clegg HW, et al. Clinical Practice Guideline for the Diagnosis and Management of Group A Streptococcal Pharyngitis: 2012 Update by the Infectious Diseases Society of America. Clinical Infectious Diseases. 2012; online.

�  Lieberthal AS, Carroll AE, Chonmaitree T, et al. The Diagnosis and Management of Acute Otitis Media. Pediatrics. 2013; 131: e964-e999.

�  Bradley JS, Byington CL, Shah SS, et al. The Management of Community-Acquired Pneumonia 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. Clinical Infectious Diseases. 2011; 53(7): e25-e76.

�  Falagas ME, Vouloumanou EK, Matthaiou DK, et al. Effectiveness and Safety of Short-Course vs Long-Course Therapy for GAS Tonsillopharyngitis: A Meta-Analysis of Randomized Trials. Mayo Clin Proc. 2008; 83(8): 880-889.

�  Pichichero ME, Marsocci SM, Murphy ML, et al. A prospective observational study of 5-, 7-, and 10-day antibiotic treatment for acute otitis media. Otolaryngol Head neck Surg. 2001; 124: 381-7.

�  Cohen R, Levy C, boucherat M, et al. Five vs. ten days of antibiotic therapy for acute otitis media in young children. Pediatr Infect Dis J. 2000; 19: 458-63.

�  Cohen R, Levy C, Boucherat M, et al. A multicenter, randomized, double-blind trial of 5 versus 10 dyas of antibiotic therapy for acute otitis media in young children. J Pediatr. 1998; 133: 634-9.

References

�  Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients. Am J Health-Syst Pharm. 2009; 66: 82-98.

�  Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the IDSA for the treatment of MRSA infections in adults and children: executive summary. Clin Infect Dis. 2011; 52(3): 285-292.

�  Moffett BS, Edwards MS. Analysis of Vancomycin therapeutic drug monitoring trends at pediatric hospitals. Pediatr Infect Dis J. 2013; 32: 32-35.

�  Eiland LS, English TM, Eland EH. Assessment of vancomycin dosing and subsequent serum concenrations in pediatric patients. Ann Pharmacother. 2011; 45: 582-589.

�  Le J, Bradley JS, Murray W, et al. Improved vancomycin dosing in children using area under the curve exposure. Pediatr Infect Dis J. 2013; 32: e155-e163.

�  Frymoyer A, Gugliemo BJ, Hersh AL, et al. Desired vancomycin trough serum concentration for treating invasive methicillin-resistant staphylococcal infections. Pediatr Infect Dis J. 2013; Pub ahead of print.

More Than the Sniffles: Update on the Treatment of

Pediatric Respiratory Infections

Thank You!! Questions?

Documents

More Than the Sniffles - nodakpharmacy.netnodakpharmacy.net/docs/Convention2014/1pedsid.pdf · glomerulonephritis, tonsillar abscess, mastoiditis Shulman ST, et al. Practice Guidelines