Uncomplicated Community Acquired Pneumonia Clinical Care Guideline Posted: 11-5-2012 Table of Contents Target Population 1 Definitions Prevention Clinical Assessment Monitoring Diagnostic Tests and Studies Therapeutics Parent/Caregiver Education Material Admission/Discharge Criteria Guideline Measures References Appendix A Appendix B-Algorithm Intended for previously healthy patients : days through 21 years of age • With signs, symptoms, or other findings suggesting a diagnosis of uncomplicated pneumonia acquired by exposure to organisms in the community. • For patients under 90 days of age, reference appropriate clinical care guideline for: o Infant Fever: Age less than 28 days o Infant Fever: Age 28 to 90 days • 90 Not intended for: • Patients with complicated pneumonia (i.e. empyema, large effusion) • Immune-compromised host • Medically complicated child • Patients in need of immediate critical care • Systemic illness concerning for sepsis, hospital acquired pneumonia, or illness necessitating ICU admission Key Recommendations Indicated: • Clinical Care Guideline use starting in the office or emergency department (ED), • Blood cultures for hospitalized patients for presumed bacterial pneumonia that is moderate to severe • Ampicillin or amoxicillin as first line antimicrobial Not routinely indicated: • Complete blood count (CBC)/White blood cell count (WBC) • C-Reactive Protein (CRP) • Erythrocyte sedimentation rate (ESR) • Chest physiotherapy (CPT) • Albuterol in the absence of asthma Please Note: Clinical care guidelines are designed to assist clinicians and patients make decisions about appropriate health care for specific clinical circumstances. These guidelines should not be considered inclusive of all proper methods of care or exclusive of other methods of care reasonably directed at obtaining the same results. The ultimate judgment regarding care of a particular patient must be made by the clinician in light of the individual circumstances presented by the patient and the needs and resources particular to the locality or institution. Definitions: Community Acquired Pneumonia: Infection of airways and lung tissue caused by a multitude of organisms, including a viral and 1 bacterial etiology, which has been acquired outside of the hospital . Uncomplicated Pneumonia: Pneumonia in the absence of significant effusion, empyema, severe or impending respiratory failure, and/or signs and symptoms of sepsis or shock. Occult pneumonia: the presence of radiographic pneumonia in children who do not show signs of respiratory distress or lower 2 respiratory tract findings on physical examination . Clinical Management Prevention • Hand hygiene • Isolation procedures • Influenza and pneumococcal vaccine protocols Clinical Assessment • History o General symptoms of pneumonia include fever, cough, tachypnea, increased work of breathing, and chest pain o Abdominal pain and or vomiting may be a symptom of pneumonia even in the absence of other respiratory symptoms o Assessment elements should include: Immunization history TB exposure including exposure to anyone with a chronic cough History of foreign body aspiration risk Animal exposure Travel history Other ill contacts including family members or day care/school exposures Literature review of predictors of Pneumonia/Diagnosis 3 • The best individual examination measures for predicting pneumonia in children less than 5 years are : 4 o Nasal flaring (age less than 12 months) 4 o Decreased oxygen saturation ** 4,5 o Tachypnea (see Table 1 for criteria) 5 o Retractions 6 Occult pneumonia has been identified in 6.8% of children who underwent chest radiograph for suspicion of pneumonia . 3 6 In children with fever 39.0°C or greater and WBC 20,000/mm or greater, 9% had evidence of occult pneumonia . Uncomplicated Community Acquired Pneumonia Strength of Recommendation: (I) Strong (II) Weak PAGE 1 of 11 Quality of Evidence: (A) High quality (B) Moderate Quality (C) Low quality (D) Very low quality (E) Expert opinion 7 Best negative predictive indicator is absence of tachypnea : negative predictive value (NPV) 88% 4 • The best combined group of predictors for radiographic pneumonia are : o Fever o Tachypnea o Hypoxemia **This citation is based on patients at elevation lower than Denver, CO. Decreased oxygen saturation at this elevation is typically less than 90% on room air. Table 1: World Health Organization Age-Specific Criteria for Tachypnea Age 2 to 12 months 1 to 5 years 5 years or over Approximate normal respiratory rates (breaths/min) 25 to 40 20 to 30 15 to 25 7 Tachypnea threshold (breaths/min) 50 40 30 • Examination o Physical findings commonly present with pneumonia Crackles (see Table 2) Decreased breath sound intensity Bronchial breath sounds—abnormally loud breath sounds audible throughout the respiratory cycle, resembling sounds normally heard only over large airways Absence of these findings doesn’t exclude pneumonia Wheezing is usually seen with airway inflammation and less commonly seen with pneumonia but may be present with pneumonia o Physical findings commonly present with pneumonia that may be easier to elicit in older children Egophony Whispered pectroliloquy Increased fremitus Bronchophony 8 Table 2: Recommended Nomenclature of Adventitious Breath Sounds Accepted Nomenclature Acoustic Characteristic Associated Pathology Typical Phase of respiration Other commonly associated terminology Course Crackle Discontinuous “popping” sound Inspiration Course rale* Fine Crackle Higher pitched discontinuous “popping” sound Inspiration Fine rale* Crepitation Wheeze Continuous high pitched “whistling” sound Rhonchus Continuous low pitched “snoring” sound Larger airways popping open associated with edema or inflammation (suggestive of pneumonia) Smaller airways popping open associated with edema or inflammation (suggestive of pneumonia) Small airway constriction (suggestive of asthma, bronchiolitis, or viral pneumonitis) More central airway sound often associated with secretions Expiration Inspiration “course breath sound” and/or expiration *discouraging use of the term “rale” per Pulmonary terms and symbols. A report of the ACCP-STS Joint Committee on Pulmonary 9 Nomenclature Monitoring 1 • Check pulse oximetry with vital signs or with a change in clinical condition. • Continuous cardiac/pulse oximetry monitoring is only recommended for unstable patients and/or for patients under 3 months of age. • Patients under 3 months of age; patients who are unstable; and patients who have a history of apnea should have their oxygen titrated to keep SaO2 at or above 90% while on continuous monitoring. Clinical Titration of Oxygen for Stable Infants over 3 Months of Age 1. If respiratory rate is less than 50 bpm, minimal retractions, and child is active and feeding well: wean oxygen flow in increments of 0.125 to 0.5 Lpm. Assess for titration of oxygen at least every 4 hours. 2. If respiratory rate is rapid for age, infant has significant retractions or nasal flaring, or infant is feeding poorly: increase oxygen incrementally. Consider continuous pulse oximetry if oxygen flow is greater than 1 Lpm for infants 3 to 6 months of age or greater than 2 Lpm for children older than 6 months. PAGE 2 of 11 Community Acquired Pneumonia Strength of Recommendation: (I) Strong (II) Weak Quality of Evidence: (A) High quality (B) Moderate Quality (C) Low quality (D) Very low quality (E) Expert opinion Diagnostic Tests/Studies: Diagnostic tests are only indicated if they will change outcome. • Radiologic studies o Chest x-ray (CXR) is not routinely indicated in patients well enough to be treated as outpatients 10-12 o Traditionally, diagnosis of pneumonia relies on positive radiographic findings 1 o CXR should be performed in hospitalized patients with suspected pneumonia. 2-view CXR is encouraged to: Establish diagnosis of pneumonia Evaluate for foreign body Promote judicious use of antibiotics Direct appropriate therapy 1 o Repeat CXR is only indicated for clinical deterioration or lack of clinical improvement . 1 o If child has recurrent pneumonia (defined as 3 times in lifetime or 2 times within 6 months), consider repeat CXR in 4 to 6 weeks after clinical resolution to confirm radiographic resolution. • Laboratory studies o CBC* It is recommended that a CBC and differential not be obtained unless adjunctive information is necessary to help decide 13-15 whether to use antibiotics 16,17 • Note: CBC has a limited role, and is often not useful, in differentiating between viral and bacterial pneumonia ° In young children (less than age 5), presenting with fever without source (temperature 39 C or greater), significant 3 leukocytosis (WBC 20,000/mm or greater) may be predictive of radiographic pneumonia (9% have radiographic evidence 6 of pneumonia) o Viral Studies Viral testing is indicated if results would change management o Testing for atypical bacteria Mycoplasma pneumonia serology testing and PCR are not recommended in the diagnostic workup of routine community acquired pneumonia o CRP/ESR* It is recommended that C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and other measures of acute phase 13,14,16,18,19 reactants not be performed, as these tests are not specific enough to be useful ESR and procalcitonin have a limited role in differentiating viral from bacterial pneumonia, and the sensitivity of CRP is too 1,16,17 poor to be clinically useful. o Sputum It is recommended that sputum Gram stain and culture on high quality specimens be considered when managing children 1,20 capable of producing an adequate sample (typically school age) . • Note: A high quality sputum is usually defined by the presence of less than 10 squamous epithelial cells and greater 20 than 25 WBCs per low power field o Tuberculin Skin Testing (TST) It is recommended that TST be conducted in children with a history of exposure to tuberculosis, chronic cough, personal or 21 family travel in areas where tuberculosis is prevalent. TB isolation precautions and notification of epidemiology is required if TB is strongly suspected or confirmed. See http://prdplanetcf02.thechildrenshospital.org/policiesfitz/general/pdf/487.pdf o Blood Cultures 1,22,23 It is recommended that blood cultures not be routinely obtained in outpatients • Note 1: When pneumonia is diagnosed in an outpatient setting, the likelihood of a positive blood culture is less than 23 2.7% It is suggested that blood cultures be obtained in hospitalized patients for presumed bacterial pneumonia that is moderate to 1,24 severe If child is well appearing and reliable follow up can be assured, discharge to home should not be delayed for final results of blood culture o Urinary Antigen Detection Tests 1 Urinary antigen detection tests are not recommended for the diagnosis of pneumococcal pneumonia in children o Other It is recommended that when historical, physical, radiologic, or laboratory findings are inconsistent, additional studies be considered to evaluate for alternative or coincident conditions, such as foreign body aspiration or immunodeficiency (Local Expert Consensus [E]). Consider pertussis PCR for patients when predominant clinical component is cough (as opposed to pneumonia), particularly if paroxysmal, or prolonged, or diagnosis supported epidemiologically *CBC/ESR/CRP may be used to help monitor response in patients who aren’t typically improving with initial therapy or those who present with systemic illness concerning for sepsis (this population is excluded in this CCG). Therapeutics • Route of treatment: 1 o According to PIDSA Guidelines , PAGE 3 of 11 Community Acquired Pneumonia Strength of Recommendation: (I) Strong (II) Weak Quality of Evidence: (A) High quality (B) Moderate Quality (C) Low quality (D) Very low quality (E) Expert opinion “Children with suspected bacterial CAP that is serious enough to warrant hospitalization should routinely be treated with parenteral antibiotics to provide reliable blood and tissue concentrations.” Therefore, IV antibiotics for initial therapy should be considered in patients admitted to the hospital with moderate to severe illness, or those with vomiting, suspected decreased GI absorption, or systemic illness concerning for sepsis. o For patients with mild illness, initial therapy with oral antibiotics may be appropriate. • Duration of treatment: o Duration of antimicrobial therapy is typically 7 to 10 days (Local Expert Consensus [E]). 1 o If child fails to improve within 48 to 72 hours of initiation of treatment, consultation and further investigation should be considered • Modification of treatment: o Should specific pathogen identification become available tailor antibiotic therapy based on microbiology results Table 3: Common infectious causes of pneumonia in childhood and recommended antibiotic therapies Recommended Antibiotic for Most Common Etiology (See Appendix A for drug comparison table) Viral Bacterial Viral causes similar in both age groups. In children less than 5 years of age, etiology much more likely to be viral and routine use of antibiotics is not recommended. Viral causes: Influenza A and B, Respiratory syncytial virus Parainfluenza viruses human metapneumovirus, adenovirus rhinovirus ORAL • Streptococcus pneumoniae • Staphylococcus aureus including MRSA • Haemophilus influenzae (if under-immunized) • Group A streptococcus • Bordetella pertussis • Mycoplasma pneumoniae (school age children) • Chlamydophila pneumoniae (school age children) INTRAVENOUS Preferred: Amoxicillin 90 mg/kg/day in 2 to 3 doses or 45 mg/kg/day in 3 doses; 90 mg/kg/day divided in 3 doses preferred if suspicion of S. pneumoniae high in order to achieve adequate time above the MIC for non-susceptible strains; only 75% of S. pneumonia isolates at Children’s Colorado are fully susceptible. Preferred: Ampicillin Alternative: Amoxicillin/clavulanic acid, dosing amoxicillin component as above. High dose formulation cannot be used for low dose TID regimen (see Appendix A). If CA-MRSA suspected, substitute clindamycin or vancomycin Alternative: Ampicillin/sulbactam, ceftriaxone, or cefotaxime Alternatives for PCN allergic patients include certain oral cephalosporins (see Appendix A). Oral cephalosporin formulations are considered pharmacologically inferior to amoxicillin, particularly for non-susceptible S. pneumoniae. If used, it should be used in highest dose and shortest interval allowable. If patient is under-immunized, include coverage for Haemophilus influenzae (amoxicillin/beta lactamase inhibitor or certain cephalosporins in Appendix A) If atypical pathogen suspected (Chlamydophila pneumoniae, Bordetella pertussis, or Mycoplasma pneumoniae) include azithromycin. Alternatives are clarithromycin, erythromycin, or if pt is older than 7 years: doxycyline (See Bugs and Drugs Handbook for dosing) Antiviral: per recommendation for suspected or confirmed influenza (Refer to CDC website for current recommendations) Additional considerations for the treatment of Mycoplasma pneumoniae Azithromycin cannot be used to treat Streptococcus pneumoniae pneumonia, so should only be used “if atypical suspected” AND Streptococcus pneumoniae not suspected. No clear definition of atypical pneumonia exists, however it is often interpreted as those in the school-aged group with more diffuse lung sounds and “walking” type pneumonia, or those who have failed initial treatment for Streptococcus pneumoniae. On occasion, mycoplasma can cause a lobar pneumonia, but this is not a usual finding. The literature is not clear that there is benefit to treating mycoplasma pneumonia. Pneumonia in the setting of influenza: Pneumonia is a common complication in children hospitalized with influenza. In one study, 27% of children hospitalized with laboratory confirmed influenza had radiologically confirmed pneumonia. Children aged 6 months to 4 years and those with underlying asthma were more likely to have pneumonia. Staphylococcus aureus was the most commonly identified bacterial co25 infection in children with influenza-associated pneumonia . 26 Children hospitalized with influenza co-infected with S. aureus have higher rates of severe outcomes (ICU admission, death) . It may be difficult to differentiate primary viral (influenza) pneumonia from secondary bacterial pneumonia. Indicators of bacterial superinfection may include: secondary fever after a period of defervescence, lobar consolidation, increased WBC, and later onset 27 (4 to 7 days) of respiratory compromise after initial symptoms . Empiric coverage for S. aureus infection in children hospitalized with influenza-associated pneumonia should be considered. • Other Therapies o It is recommended that therapies directed towards airway clearance (CPT, VEST, cough assist) not be used for patients with 28,29 30 ; there are some studies that suggest it can be harmful to some patient . Chest physiotherapy uncomplicated pneumonia 31 does not decrease length of stay in children hospitalized with pneumonia . PAGE 4 of 11 Community Acquired Pneumonia Strength of Recommendation: (I) Strong (II) Weak Quality of Evidence: (A) High quality (B) Moderate Quality (C) Low quality (D) Very low quality (E) Expert opinion o Gentle activity should be encouraged as the best way to mobilize secretions. In infants repositioning is considered a form of 32 gentle activity . o Bronchodilators should not be routinely used unless there is known component of asthma. Wheezing that is typically heard in a 32 patient with pneumonia is most likely related to airway inflammation . o There is no evidence-based literature to support the use of positive pressure therapy (EzPAP) in pediatrics with pneumonia; however, there has been some noted clinical response within our institution where patients were able to wean on oxygen requirements. Parent/Caregiver Education • Pneumonia (English version) • Pneumonia (Spanish version) • Home Oxygen Therapy (English version) • Home Oxygen Therapy (Spanish version) Admission/Discharge Criteria • Admission 1 o Critical care Respiratory failure or impending respiratory failure [hypercapnea, acidosis, supplemental O2 need greater than 50% FiO2, severe dehydration, altered mental status, ventilation (invasive or noninvasive)] with need for increased support, underlying neuromuscular issues, or compromised ability to handle secretions or maintain airway Sustained tachycardia, serious hypotension, or need for pharmacologic support of blood pressure or perfusion o Inpatient setting Cannot take oral antibiotics Dehydration requiring IV fluids O2 requirement Concern or risk for progressive or complicated pneumonia Underlying co-morbidity Baseline NIV o Discharge home Oxygen requirements: See Table 4 Table 4: Maximum oxygen liter flow for discharge Maximum liter flow for Age of Patient: discharge: Less than 24 months and ½ liter per minute or less stable Older than 24 months and 1 liter per minute or less stable o Stable and improving O2 requirement and improving clinical status, patients may be discharged home on O2 after 24 hours or more of observation and treatment. These clinical care guidelines are designed to assist clinicians and patients make decisions about appropriate care of the patient with uncomplicated community acquired pneumonia and are not meant as a substitute for sound clinical judgment. Reliable follow up and social situation Clinical status Respiratory rate approaching normal as expected for age Normal work of breathing Able to maintain adequate oral intake Baseline mental status Medications • Able to take oral medications • Able to obtain prescription to complete course o Follow up Establish PCP follow up within 2 to 3 days Clinical Care Guideline Measures Measures Length of stay Antibiotic choice (Amox or Amp 1st choice) Route of antibiotic (oral preferred) Location TCH Target IP TBD IP ED/UC IP ED/UC TBD TBD TBD TBD PAGE 5 of 11 Community Acquired Pneumonia Strength of Recommendation: (I) Strong (II) Weak Quality of Evidence: (A) High quality (B) Moderate Quality (C) Low quality (D) Very low quality (E) Expert opinion 2012 Uncomplicated Community Acquired Pneumonia Task Force Members Jennifer Reese Paul Stillwell Ann-Chris Nyquist Jason Child Denise Pickard Gwendolyn Kerby Barry Seltz Sarah Parker Emily Wei REFERENCES: 1. 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. Clin Infect Dis 2011;53:e25-76. 2. Shah S, Mathews B, Neuman MI, Bachur R. Detection of occult pneumonia in a pediatric emergency department. Pediatr Emerg Care 2010;26:615-21. 3. Ebell M. Clinical diagnosis of pneumonia in children. Am Fam Physician 2010;82:192-3. 4. Mahabee-Gittens EM, Grupp-Phelan J, Brody AS, et al. Identifying children with pneumonia in the emergency department. Clin Pediatr (Phila) 2005;44:427-35. 5. Harari M, Shann F, Spooner V, Meisner S, Carney M, de Campo J. Clinical signs of pneumonia in children. Lancet 1991;338:928-30. 6. Rutman MS, Bachur R, Harper MB. Radiographic pneumonia in young, highly febrile children with leukocytosis before and after universal conjugate pneumococcal vaccination. Pediatr Emerg Care 2009;25:1-7. 7. Shah S, Bachur R, Kim D, Neuman MI. Lack of predictive value of tachypnea in the diagnosis of pneumonia in children. Pediatr Infect Dis J 2010;29:406-9. 8. Murphy RL. In defense of the stethoscope. Respir Care 2008;53:355-69. 9. n.a. Pulmonary terms and symbols. A report of the ACCP-STS Joint Committee on Pulmonary Nomenclature. Chest 1975;67:583-93. 10. Redd SC, Patrick E, Vreuls R, Metsing M, Moteetee M. Comparison of the clinical and radiographic diagnosis of paediatric pneumonia. Trans R Soc Trop Med Hyg 1994;88:307-10. 11. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44 Suppl 2:S27-72. 12. McIntosh K. Community-acquired pneumonia in children. N Engl J Med 2002;346:429-37. 13. Korppi M. Non-specific host response markers in the differentiation between pneumococcal and viral pneumonia: what is the most accurate combination? Pediatr Int 2004;46:545-50. 14. Toikka P, Irjala K, Juven T, et al. Serum procalcitonin, C-reactive protein and interleukin-6 for distinguishing bacterial and viral pneumonia in children. Pediatr Infect Dis J 2000;19:598-602. 15. Bachur R, Perry H, Harper MB. Occult pneumonias: empiric chest radiographs in febrile children with leukocytosis. Ann Emerg Med 1999;33:166-73. 16. Virkki R, Juven T, Rikalainen H, Svedstrom E, Mertsola J, Ruuskanen O. Differentiation of bacterial and viral pneumonia in children. Thorax 2002;57:438-41. 17. Don M, Valent F, Korppi M, Canciani M. Differentiation of bacterial and viral community-acquired pneumonia in children. Pediatr Int 2009;51:91-6. 18. Heiskanen-Kosma T, Korppi M. Serum C-reactive protein cannot differentiate bacterial and viral aetiology of community-acquired pneumonia in children in primary healthcare settings. Scand J Infect Dis 2000;32:399-402. 19. Ruuskanen O, Mertsola J. Childhood community-acquired pneumonia. Semin Respir Infect 1999;14:163-72. 20. Skerrett SJ. Diagnostic testing for community-acquired pneumonia. Clin Chest Med 1999;20:531-48. 21. Alves dos Santos JW, Torres A, Michel GT, et al. Non-infectious and unusual infectious mimics of community-acquired pneumonia. Respir Med 2004;98:488-94. 22. Claesson BA, Trollfors B, Brolin I, et al. Etiology of community-acquired pneumonia in children based on antibody responses to bacterial and viral antigens. Pediatr Infect Dis J 1989;8:856-62. 23. Hickey RW, Bowman MJ, Smith GA. Utility of blood cultures in pediatric patients found to have pneumonia in the emergency department. Ann Emerg Med 1996;27:721-5. 24. Shah SS, Dugan MH, Bell LM, et al. Blood cultures in the emergency department evaluation of childhood pneumonia. Pediatr Infect Dis J 2011;30:475-9. Community Acquired Pneumonia Strength of Recommendation: (I) Strong (II) Weak PAGE 6 of 11 Quality of Evidence: (A) High quality (B) Moderate Quality (C) Low quality (D) Very low quality (E) Expert opinion 25. Dawood FS, Fiore A, Kamimoto L, et al. Influenza-associated pneumonia in children hospitalized with laboratory-confirmed influenza, 2003-2008. Pediatr Infect Dis J 2010;29:585-90. 26. Reed C, Kallen AJ, Patton M, et al. Infection with community-onset Staphylococcus aureus and influenza virus in hospitalized children. Pediatr Infect Dis J 2009;28:572-6. 27. Wright PF, Kirkland KB, Modlin JF. When to consider the use of antibiotics in the treatment of 2009 H1N1 influenza-associated pneumonia. N Engl J Med 2009;361:e112. 28. Hardy KA. A review of airway clearance: new techniques indications and recommendations. Respiratory Care 1994;39:440. 29. De Boeck K, Vermeulen F, Vreys M, Moens M, Proesmans M. Airway clearance techniques to treat acute respiratory disorders in previously healthy children: where is the evidence? Eur J Pediatr 2008;167:607-12. 30. Selsby DS. Chest physiotherapy. BMJ 1989;298:541-2. 31. Paludo C, Zhang L, Lincho CS, Lemos DV, Real GG, Bergamin JA. Chest physical therapy for children hospitalised with acute pneumonia: a randomised controlled trial. Thorax 2008;63:791-4. 32. Pediatric pneumonia treatment & management. n.d. (Accessed March 17, 2010, at http://emedicine.medscape.com/article/967822-treatment#aw2aab6b6b4.) Approved by Children’s Hospital Colorado Guideline Review Committee Scheduled for review for invalidating evidence on November 5, 2013 Scheduled for full review on November 5, 2015 Community Acquired Pneumonia Strength of Recommendation: (I) Strong (II) Weak PAGE 7 of 11 Quality of Evidence: (A) High quality (B) Moderate Quality (C) Low quality (D) Very low quality (E) Expert opinion APPENDIX A CAP Antibiotics—Evaluating Oral Choices Children’s Hospital Colorado Antimicrobial Stewardship Committee, 2012 Sarah K. Parker, MD and Jason Child, PharmD Goal for % time over the mean inhibitory concentration (MIC) for beta lactam antibiotics is 40%. % times in this table are based on adult data (peak serum mcg/mL and drug half life), using shortest dosing interval allowable, and do not take into account protein binding. Protein binding reduces the amount of active drug. Antibiotic Oral Dose and Frequency Maximum Dose per day MICs (S, I, R#) non-meningeal S. pneumo S. aureus MSSA % time over MIC Cost ## Taste Other H. influenzae S and I # (S. pneumoniae) Amoxicillin is the drug of choice for bacterial CAP because of its favorable pharmacokinetics against S. pneumonia susceptible and intermediate strains for non-meningeal infection. Our non-susceptible rates are 25%, thus we recommend use of 90/kg/day divided TID as optimal therapy. Amoxicillin* 90mg/kg/ day divided TID 90mg/kg/day divided BID 45mg/kg/day divided TID 45mg/kg/day divided BID:NEVER USE FOR CAP 2 to 4 grams per day S: Less than or equal to 2 Don’t use, Normally +beta lactamase; if not: I: 4 R: Greater than or equal to Greater than or equal to 8 S: Less than or equal to 0.25 Often +beta lactamase; if not: S: Less than or equal to 1 I: 2 R: Greater than or equal to 0.5 S: 42 to 50% I: 35 to 40% S: 33 to 44% I: 30% S: 33 to 37% I: 15 to 25% S: 20% $13 to $36, liquid more expensive Good but depends on formulation and brand 90/kg/day divided TID is the best choice for susceptible and intermediate S. pneumoniae. Other regimens acceptable for susceptible, but not intermediate, S. pneumoniae. R: Greater than or equal to 4 Amoxicillin/ clavulanate adds some gram negative coverage and some MSSA coverage. It should be reserved for particular situations in which this expanded coverage is desirable, for example an unimmunized child in whom Haemophilus influenza is on the differential. However, care must be taken with the clavulanate component when dosing. Maximum daily dose is 4 grams amoxicillin component per day, but balance with clavulanate appropriately. Amoxicillin/ clavulanate XR (1000 mg-62.5 mg tab) [ratio 16:1] Amoxicillin/ clavulanate ES* (600 mg/5 mL- 42.9 mg/5 mL suspension) [ratio 14:1] Amox/clav (200 mg/28.5 mg*, 400 mg/57 mg*, 875 mg/125 mg tab*) [ratio 7:1] Amox/clav (125m g/31.25 mg*, 250 mg/62.5 mg*, 500 mg/125 mg*) [ratio 4:1] 1000 mg (amox component) per dose BID (1 tab BID) 90 mg/kg/day (amox component) divided BID or TID Cannot use at 45 mg/kg (not enough clav) 45mg/kg/day (amox component) divided BID or TID. Cannot use at 90/kg (too much clav) 45mg/kg/day (amox component) divided TID Cannot use at 90/kg (too much clav) 2 to 4 grams amox per day S: Less than or equal to 2/1 S: Less than or equal to 4/2 S: Less than or equal to 4/2 I: 4/2 R: Greater than or equal to 8/4 R: Greater than or equal to 8/4 R: Greater than or equal to 8/4 As above for amoxicillin dosing Generic $80 to $172, liquid more expensive Good to fair (brand name tastier) Dosing of the amoxicillin component is as above. Formulations vary in ratio of amoxicillin to clavulanate, so not all formulations can be used for high/low dosing. Addition of the clavulanate provides a beta lactamase inhibitor, and thus expanded coverage, for example to Haemophilus influenzae. Oral cephalosporins have inferior pharmacokinetics as compared to amoxicillin for treatment of S. pneumoniae. This is because they are relatively poorly absorbed and are highly protein bound (35-70%, thus less free active drug), such that it is difficult to get levels above the S. pneumoniae MIC for greater than 40% of the day. Oral cephalosporins should be reserved for PCN allergic patients only, and if used, should be dosed at highest allowed dose and most number of intervals per day. Notice that oral cefuroxime, cefpodoxime and cefprozil are the only oral cephalosporins included in the National CAP guidelines as a choice for treatment of susceptible S. pneumonaie CAP. Others are listed for treatment of H. influenza CAP. Cefuroxime axetil* Cefpodoxime Cefprozil Cefdinir * Notice high dose needed (see right) 30 mg/kg/day divided BID 10 mg/kg/day divided BID 30 mg/kg/day divided BID 30mg/kg/day divided BID 1 gm per day 800 mg per day 1 gram per day 600 mg per day S: Less than or equal to 1 S: Less than or equal to 4 S: Less than or equal to 4 S: 50% I: 30 to 40% $351 brand Fair I: 2 I: 8-16 I: 8 R:Greater than or equal to 4 S: Less than or equal to 0.5 R: Greater than or equal to 32 S: Less than or equal to 2 I: 1 I: 4 R: Greater than or equal to 2 S: Less than or equal to 2 R: Greater than or equal to 16 S: Less than or equal to 2 S: 58% I: 40% $143 brand Bad R: Greater than or equal to 8 S: Less than or equal to 8 S: Less than or equal to 8 S: 40% I: 30% $174 Fair I: 4 I: 16 I: 16 R: Greater than or equal to 8 S: Less than or equal to 0.5 R: Greater than or equal to 32 S: Less than or equal to 1 R: Greater than or equal to 32 S: Less than or equal to 1 S: 40% $102 Good I: 1 I: 2 Cefdinir dose high to achieve levels over susceptible MIC for 40% of the day. See bullets in note section below. R: Greater than or equal to 2 R: Greater than or equal to 4 I: 20% Notice that, even when at high dose and most intervals per day, it is difficult to achieve the goal of 40% of dosing interval over the MIC for susceptible S. pneumoniae, and for non-susceptible essentially cannot achieve. These numbers do not take into account protein binding, which will further reduce active drug. Oral drugs with different pharmacokinetic parameters used for CAP, for comparison Azithromycin* See comment to right Clindamycin* 10 mg/kg/day 1st day, then 5 mg/kg/day 30 to 40 mg/kg/day divided TID 500mg per day 1.8 grams per day S: Less than or equal to 0.5 S: Less than or equal to 2 I: 1 I: 4 R: Greater than or equal to 2 S: Less than or equal to 0.25 R: Greater than or equal to 8 S: Less than or equal to 0.5 I: 0.5 I: 1 to 2 R: Greater than or equal to 1 R: Greater than or equal to 4 S: Less than or equal to 4 NA; serum peak is 0.4 $88 Good ONLY indicated for coverage of atypical pneumonias. 40% of S. pneumoniae predicted to be resistant. NA NA; serum peak 2.5 to 10 mcg/mL $372 Bad 27% of our S. pneumoniae is resistant Has post antibiotic effect for prolonged killing * ON CHILDREN’S HOSPITAL FORMULARY. # S= susceptible, I = intermediate, R = resistant. ## Cost based on 20kg child x 10days, purchased from Walgreen’s pharmacy in Colorado for cash-paying customers during first quarter of 2012. ND = no data (for lack of susceptible MIC data), NA = non-applicable (different PK and % time above MIC not necessarily applicable). Comments and Useful Information for Interpretation of this While all of these options are on the national CAP guidelines (Bradley et al, CID, 53(7):617-630, 1011), pharmacokinetic models strongly support use of amoxicillin over cephalosporins. Though no clear clinical studies, some cephalosporins likely achieve greater time over the S. pneumoniae MIC than others, as depicted in the above table. The half life of many drugs in the middle ear is longer than in serum, thus making fewer dosing intervals still achieve greater than 40% time above the MIC; rationale for BID dosing in otitis media thus cannot be directly extrapolated to CAP. Intravenous options on national CAP guideline all achieve greater than 40% time (most are >90%) above the MIC for Streptococcus pneumoniae strains (non-meningeal). Our PCN non-susceptible rate amongst S. pneumoniae strains is clinically significant. For meningeal strains, only 46% are PCN susceptible, and 77% cefotaxime susceptible; the non-susceptible strains were all fully resistant (MIC greater thanor equal to 8). For non-meningeal, 76% are fully susceptible to both PCN and cefotaxime; the non-susceptible strains were mostly intermediately resistant (MIC 4). See Children’s Hospital Colorado Bugs and Drugs handbook for full details. MIC based on “Performance Standards for Antimicrobial Susceptibility Testing; 21st Informational Supplement”, vol. 30, No.1, 2011. For S. pneumoniae, the non-meningeal MIC is reported in the above table. % time over MIC per day based on peak and half life reported in “The Sanford Guide to Antimicrobial Therapy”, 37th edition, 2007. This is based on adult dosing. We used maximum dosing ranges, if available, and assumed maximum number of doses per day allowable. It does not take into account protein binding, which can significantly decrease available active drug, and is based on serum levels. Levels at the site of infection will vary. The high cefdinir dosing is based on Mercy Children’s Hospital guideline, published in: Newman et al, Pediatrics 2012;129;e597. Taste based on “Formulations of Antibiotics for Children in Primary Care”, Ramgoolam and Steele, Pediatric Drugs 2002:4(5):323-333. My personal ranking (Sarah Parker) is: cefixime > cefdinir > cefuroxime > cefodoxime. Cefpodoxime is the only cephalosporin that is unpalatable. Amoxicillin is better tasting than augmentin. For clindamycin (unpalatable), Sarah Parker’s personal ranking is: liquid + chocolate syrup = coat mouth with cheez whiz, take capsule broken in chocolate syrup, do chaser of cheez whiz > liquid in any syrup > liquid alone > capsule opened in chocolate frosting = capsule opened in chocolate in syrup. Liquid has nasty smell, but less aftertaste, capsule mild smell, but very strong and lingering aftertaste. If you would like to set up a taste test, discuss these antibiotics, or set up a presentation, please email [email protected]. Mechanism of action: Beta-lactam antibiotics act by inhibiting penicillin binding proteins. These PBPs normally catalyze cross-linking of peptidoglycan in the cell wall. When this is inhibited, it is detrimental in itself, but also the build-up of peptidoglycan precursors stimulates breakdown of the peptidoglycan and thus the cell wall, potentiating the effects of beta lactam antibiotics. They are generally cidal, have no post-antibioitic effect (though perhaps some with S. aureus). The number of PBPs varies amongst species, and the affinity of PBPs for the various beta lactams also varies. Though in general PCN susceptible S. pneumoniae strains are cephalosporin susceptible, this is not uniform. The pharmacokinetic goal is to be over the MIC of the target organism for greater than 40% of the day. Mechanisms of resistance: organisms can have resistance to beta lactams by a few mechanisms, the most common of which are: Beta lactamases hydrolyze the beta lactam ring. There are many different kinds of beta lactamases, some of which are plasmid based and some of which are chromosomal, and all have different affinities for the different beta lactam rings. Example of this is the general resistance of MSSA to ampicillin. An organism can alter its PBPs so that a beta lactam drug cannot bind. Examples of this are MRSA and PCN resistant streptococcus pneumoniae. APPENDIX B: ALGORITHM Assess clinical signs and symptoms: • Tachypnea • Fever 39° C or greater • Decreased O2 saturation • Nasal flaring (age less than 12 months) • Abnormal breath sounds • Retractions PPD if history of exposure Uncomplicated CAP Suspected Pneumonia not suspected Ambiguous clinical findings or Age less than 5 yrs with high fever of uncertain source Manage as appropriate to findings. Management • Antibiotic therapy 7 to10 days: o Amoxicillin/Ampicillin preferred, consider a macrolide if atypical organism suspected or see Table 3 or Appendix A for alternate choices • CXR not routinely indicated Complication suspected or Prolonged course unresponsive to antibiotics Consider: • WBC w/ diff (WBC of greater than 20,000/mm3 indicates increased risk for a bacterial cause) • Chest X-ray NO YES Suspect uncomplicated bacterial CAP or influenza*? YES Suspect CAP with complications? NO Observe without antibiotic treatment. Off guideline If findings are inconsistent, reexamine patient, consider alternative diagnosis, and reevaluate as appropriate. Follow up as appropriate to clinical course. Adjust antibiotic if necessary. * For suspected or confirmed influenza refer to CDC website for current antiviral recommendations Off guideline
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