More Than the Sniffles: Update on the Treatment of Pediatric Respiratory Infections

Transcription

1 More Than the Sniffles: Update on the Treatment of Pediatric Respiratory Infections Amy Crawford, Pharm.D. R.Ph NDPhA 2014 Annual Convention April 5 th, 2014

2 Conflict of Interest No relevant financial or commercial conflicts of interest to disclose

3 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

4 Pharyngitis

5 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 last night. Mom doesn t think he has any allergies. RADT returned positive.

6 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 online

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

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

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

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

11 Regimens for Chronic Carriers of GAS Shulman ST, et al. Practice Guidelines for GAS Pharyngitis. CID online

12 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 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 Falagas ME, et al. Mayo Clin Proc. 2008; 83(8):

13 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 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

14 Acute Otitis Media

15 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.

16 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.

17 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 HDamoxicillin M.catarrhalis S.pyogenes Lieberthal AS, et al. Pediatrics. 2013; 131: e964-e999.

18 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 Routine PCV13 and seasonal influenza vaccines!! Observation option Only mild improvement should be expected within first 24 hours à reassess after hours for treatment failure Safety Net antibiotics Lieberthal AS, et al. Pediatrics. 2013; 131: e964-e999.

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

20 Treatment Strategy Antibiotic Choice HD Amoxicillin is 1 st line Amoxicillin/clavulanate recommended if patient has: Received amoxicillin in last 30 days Purulent conjunctivitis or history of recurrent AOM If PCN-allergic: cephalosporins 1 st 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 Lieberthal AS, et al. Pediatrics. 2013; 131: e964-e999.

21 Antibiotic Regimens Initial Lieberthal AS, et al. Pediatrics. 2013; 131: e964-e999.

22 Antibiotic Regimens Failures Lieberthal AS, et al. Pediatrics. 2013; 131: e964-e999.

23 Antibiotic 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 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

24 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: Cohen R, et al. Pediatr Infect Dis J. 2000; 19: Cohen R, et al. J Pediatr. 1998; 133:

25 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

26 Community Acquired Pneumonia

27 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.

28 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.

29 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, lowgrade fever

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

31 Treatment Strategy - Outpatient Antibiotics Preschool-aged: no antibiotics as viral etiology most likely Mild-mod CAP in immunized children: amoxicillin 1 st line Atypical CAP: macrolides Duration: 10 days most studied, but shorter courses may be effective Routine PCV13 and seasonal influenza vaccines!! Bradley JS, et al. Clinical Infectious Diseases. 2011; 53(7): e25-e76.

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

33 Antibiotic Regimens

34 Treatment Strategy - Inpatient Antibiotics Ampicillin/PCN in immunized children 3 rd G 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 Bradley JS, et al. Clinical Infectious Diseases. 2011; 53(7): e25-e76.

35 Antibiotic Regimens - Inpatient Suspect S.pneumoniae and H.influenzae, think about other pathogens S.pneumoniae PCN-S: amp mg/kg/day, PCN K U/kg/day PCN-R (MIC>4): amp mg/kg/day, ceftriaxone 100 mg/kg/ day H.influenzae B-lactamase negative: amp mg/kg/day B-lactamase positive: ceftriaxone mg/kg/day Group A Streptococcus PCN K U/kg/day or amp 200 mg/kg/day, 3 rd G cephs option S.aureus MSSA: nafcillin/cefazolin sufficient MRSA: Vancomycin or clindamycin, linezolid may be another option Bradley JS, et al. Clinical Infectious Diseases. 2011; 53(7): e25-e76.

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

37 Vancomycin PK/PD

38 IDSA Guidelines Adults: mg/kg IV q8-12h (nml renal function) Goal serum trough = 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: mg/kg/day q6-8h Trough <10 mcg/ml can produce strains with VISA-like characteristics [trough mcg/ml and AUC/MIC ] 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: Liu C, et al. Clin Infect Dis. 2011; 52(3):

39 Vancomycin in Pediatrics Is goal trough of mcg/ml correct for pediatric patients? Troughs do not directly reflect AUC/MIC Data correlating AUC/MIC > 400 with trough 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 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: Eiland LS. Ann Pharmacother. 2011; 45:

40 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

41 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.

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

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

44 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 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

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46 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 mcg/ml does not reflect target AUC/MIC >400 in children

47 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): 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: 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: 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:

48 References Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients. Am J Health-Syst Pharm. 2009; 66: 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): Moffett BS, Edwards MS. Analysis of Vancomycin therapeutic drug monitoring trends at pediatric hospitals. Pediatr Infect Dis J. 2013; 32: Eiland LS, English TM, Eland EH. Assessment of vancomycin dosing and subsequent serum concenrations in pediatric patients. Ann Pharmacother. 2011; 45: 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.

49 More Than the Sniffles: Update on the Treatment of Pediatric Respiratory Infections Thank You!! Questions?