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Antibiotics for Aspiration Pneumonia in Neurologically Impaired Children
Neurologic impairment (NI) encompasses static and progressive diseases of the central and/or peripheral nervous systems that result in functional and intellectual impairments.1 While a variety of neurologic diseases are responsible for NI (eg, hypoxic-ischemic encephalopathy, muscular dystrophy), consequences of these diseases extend beyond neurologic manifestations.1 These children are at an increased risk for aspiration of oral and gastric contents given their common comorbidities of dysphagia, gastroesophageal reflux, impaired cough, and respiratory muscle weakness.2 While aspiration may manifest as a self-resolving pneumonitis, the presence of oral or enteric bacteria in aspirated material may result in the development of bacterial pneumonia. Children with NI hospitalized with aspiration pneumonia have higher complication rates, longer and costlier hospitalizations, and higher readmission rates when compared with children with nonaspiration pneumonia.3
While pediatric aspiration pneumonia is commonly attributed to anaerobic bacteria, this is largely based on extrapolation from epidemiologic studies that were conducted in past decades.4-8 A single randomized controlled trial found that penicillin and clindamycin, antimicrobials with similar antimicrobial activity against anaerobes, to be equally effective.9 However, the recent literature emphasizes the polymicrobial nature of aspiration pneumonia in adults, with the common isolation of Gram-negative enteric bacteria.10 Further, while Pseudomonas aeruginosa is often identified in respiratory cultures from children with NI and chronic respiratory insufficiency,11,12 the significance of P. aeruginosa in lower airways remains unclear.
We designed this study to compare hospital outcomes associated with the most commonly prescribed empiric antimicrobial therapies for aspiration pneumonia in children with NI.
MATERIALS AND METHODS
Study Design and Data Source
This multicenter, retrospective cohort study used the Pediatric Health Information System (PHIS) database. PHIS, an administrative database of 50 not-for-profit tertiary care pediatric hospitals, contains data regarding patient demographics, diagnoses and procedures, and daily billed resource utilization, including laboratory and imaging studies. Data quality and reliability are assured through the Children’s Hospital Association (CHA; Lenexa, Kansas) and participating hospitals. Due to incomplete data through the study period and data quality issues, six hospitals were excluded.
STUDY POPULATION
Inclusion Criteria
Children 1-18 years of age who were discharged between July 1, 2007 and June 30, 2015 were included if they had a NI diagnosis,1 a principal diagnosis indicative of aspiration pneumonia (507.x),3,13,14 and received antibiotics in the first two calendar days of admission. NI was determined using previously defined International Classification of Diseases, Ninth Revision-Clinical Modification (ICD-9-CM) diagnosis codes.1 We only included children who received antibiotics in the first two calendar days of admission to minimize the likelihood of including children admitted for other reasons who acquired aspiration pneumonia after hospitalization. For children with multiple hospitalizations, one admission was randomly selected for inclusion to minimize weighting results toward repeat visits.
Exclusion Criteria
Children transferred from another hospital were excluded as records from their initial presentation, including treatment and outcomes, were not available. We also excluded children with tracheostomy15,16 or chronic ventilator dependence,17 those with a diagnosis of human immunodeficiency virus or tuberculosis, and children who received chemotherapy during hospitalization given expected differences in etiology, treatment, and outcomes.18
Exposure
The primary exposure was antibiotic therapy received in the first two days of admission. Antibiotics were classified by their antimicrobial spectra of activity as defined by The Sanford Guide to Antimicrobial Therapy19 against the most commonly recognized pathogens of aspiration pneumonia: anaerobes, Gram-negatives, and P. aeruginosa (Appendix Table 1).10,20 For example, penicillin G and clindamycin were among the antibiotics classified as providing anaerobic coverage alone, whereas ceftriaxone was classified as providing Gram-negative coverage alone and ampicillin-sulbactam or as combination therapy with clindamycin and ceftriaxone were classified as providing anaerobic and Gram-negative coverage. Piperacillin-tazobactam and meropenem were classified as providing anaerobic, Gram-negative, and P. aeruginosa coverage. We excluded antibiotics that do not provide coverage against anaerobes, Gram-negative, or P. aeruginosa (eg, ampicillin, azithromycin) or that provide coverage against Gram-negative and P. aeruginosa, but not anaerobes (eg, cefepime, tobramycin), as these therapies were prescribed for <5% of the cohort. We chose not to examine the coverage for Streptococcus pneumonia or Staphylococcus aureus as antibiotics included in this analysis covered these bacteria for 99.9% of our cohort.
OUTCOMES
Outcomes included acute respiratory failure during hospitalization, intensive care unit (ICU) transfer, and hospital length of stay (LOS). Acute respiratory failure during hospitalization was defined as the presence of Clinical Transaction Classification (CTC) or ICD-9 procedure code for noninvasive or invasive mechanical ventilation on day two or later of hospitalization, with or without the need for respiratory support on day 0 or day 1 (Appendix Table 2). Given the variability in hospital policies that may drive ICU admission criteria for complex patients, our outcome of ICU transfer was defined as the requirement for ICU level care on day two or later of hospitalization without ICU admission. Acute respiratory failure and ICU care occurring within the first two hospital days were not classified as outcomes because these early events likely reflect illness severity at presentation rather than outcomes attributable to treatment failure; these were included as markers of severity in the models.
Patient Demographics and Clinical Characteristics
Demographic and clinical characteristics that might influence antibiotic choice and/or hospital outcomes were assessed. Clinical characteristics included complex chronic conditions,21-23 medical technology assistance,24 performance of diagnostic testing, and markers of severe illness on presentation. Diagnostic testing included bacterial cultures (blood, respiratory, urine) and chest radiograph performance in the first two days of hospitalization. Results of diagnostic testing are not available in the PHIS. Illness severity on presentation included acute respiratory failure, pleural drainage, receipt of vasoactive agents, and transfusion of blood products in the first two days of hospitalization (Appendix Table 2).17,25,26
STASTICAL ANALYSIS
Continuous data were described with median and interquartile ranges (IQR) due to nonnormal distribution. Categorical data were described with frequencies and percentages. Patient demographics, clinical characteristics, and hospital outcomes were stratified by empiric antimicrobial coverage and compared using chi-square and Kruskal–Wallis tests as appropriate.
Generalized linear mixed-effects models with random hospital intercepts were derived to assess the independent effect of antimicrobial spectra of activity on outcomes of acute respiratory failure, ICU transfer, and LOS while adjusting for important differences in demographic and clinical characteristics. LOS had a nonnormal distribution. Thus, we used an exponential distribution. Covariates were chosen a priori given the clinical and biological relevance to exposure and outcomes—age, presence of complex chronic condition diagnoses, the number of complex chronic conditions, technology dependence, the performance of diagnostic tests on presentation, and illness severity on presentation. ICU admission was included as a covariate in acute respiratory failure and LOS outcome models. The results of the model for acute respiratory failure and ICU transfer are presented as adjusted odds ratios (OR) with a 95% CI. LOS results are presented as adjusted rate ratios (RR) with 95% CI.
All analyses were performed with SAS 9.3 (SAS Institute, Cary, North Carolina). P values <.05 were considered statistically significant. Cincinnati Children’s Hospital Medical Center Institutional Review Board considered this deidentified dataset study as not human subjects research.
RESULTS
Study Cohort
At the 44 hospitals included, 4,812 children with NI hospitalized with the diagnosis of aspiration pneumonia met the eligibility criteria. However, 79 received antibiotics with the spectra of activity not examined, leaving 4,733 children in our final analysis (Appendix Figure). Demographic and clinical characteristics of the study cohort are shown in Table 1. Median age was five years (interquartile range [IQR]: 2-11 years). Most subjects were male (53.9%), non-Hispanic white (47.9%), and publicly insured (63.6%). There was a slight variation in the distribution of admissions across seasons (spring 31.6%, summer 19.2%, fall 21.3%, and winter 27.9%). One-third of children had four or more comorbid CCCs (complex chronic conditions; 34.2%). The three most common nonneurologic CCC diagnosis categories were gastrointestinal (63.1%), congenital and/or genetic defects (36.9%), and respiratory (8.9%). Assistance with medical technologies was also common (82%)—particularly gastrointestinal (63.1%) and neurologic/neuromuscular (9.8%) technologies. The vast majority of children (92.5%) had either a chest radiograph (90.5%), respiratory viral study (33.7%), or respiratory culture (10.0%) obtained on presentation. A minority required noninvasive or invasive respiratory support (25.4%), vasoactive agents (8.9%), blood products (1.2%), or pleural drainage (0.3%) in the first two hospital days.
Spectrum of Antimicrobial Coverage
Most children (57.9%) received anaerobic and Gram-negative coverage; 16.2% received anaerobic, Gram-negative and P. aeruginosa coverage; 15.3% received anaerobic coverage alone; and 10.6% received Gram-negative coverage alone. Empiric antimicrobial coverage varied substantially across hospitals: anaerobic coverage was prescribed for 0%-44% of patients; Gram-negative coverage was prescribed for 3%-26% of patients; anaerobic and Gram-negative coverage was prescribed for 25%-90% of patients; and anaerobic, Gram-negative, and P. aeruginosa coverage was prescribed for 0%-65% of patients (Figure 1).
Outcomes
Acute Respiratory Failure
One-quarter (25.4%) of patients had acute respiratory failure on presentation; 22.5% required respiratory support (continued from presentation or were new) on day two or later of hospitalization (Table 2). In the adjusted analysis, children receiving Gram-negative coverage alone had two-fold greater odds (OR 2.15, 95% CI: 1.41-3.27) and children receiving anaerobic and Gram-negative coverage had 1.6-fold greater odds (OR 1.65, 95% CI: 1.19-2.28), of respiratory failure during hospitalization compared with those receiving anaerobic coverage alone (Figure 2). Odds of respiratory failure during hospitalization did not significantly differ for children receiving anaerobic, Gram-negative, and P. aeruginosa coverage compared with those receiving anaerobic coverage alone.
ICU Transfer
Nearly thirty percent (29.0%) of children required ICU admission, with an additional 3.8% requiring ICU transfer following admission (Table 2). In the multivariable analysis, the odds of an ICU transfer were greater for children receiving Gram-negative coverage alone (OR 1.80, 95% CI: 1.03-3.14) compared with those receiving anaerobic coverage alone. There was no statistical difference in ICU transfer for those receiving anaerobic and Gram-negative coverage (with or without P. aeruginosa coverage) compared with those receiving anaerobic coverage alone (Figure 2).
Length of Stay
Median hospital LOS for the total cohort was five days (IQR: 3-9 days; Table 2). In the multivariable analysis, children receiving Gram-negative coverage alone had a longer LOS (RR 1.28; 95% CI: 1.16-1.41) compared with those receiving anaerobic coverage alone, whereas children receiving anaerobic, Gram-negative, and P. aeruginosa coverage had a shorter LOS (RR 0.83; 95% CI: 0.76-0.90) than those receiving anaerobic coverage alone (Figure 2). There was no statistical difference in the LOS between children receiving anaerobic and Gram-negative coverage and those receiving anaerobic coverage alone.
DISCUSSION
In this multicenter study of children with NI hospitalized with aspiration pneumonia, we found substantial variation in empiric antimicrobial coverage for children with aspiration pneumonia. When comparing outcomes across groups, children who received anaerobic and Gram-negative coverage had outcomes similar to children who received anaerobic therapy alone. However, children who did not receive anaerobic coverage (ie, Gram-negative coverage alone) had worse outcomes, most notably a greater than two-fold increase in the odds of experiencing acute respiratory failure during hospitalization when compared with children receiving anaerobic therapy. These findings support prior literature that has highlighted the importance of anaerobic therapy in the treatment of aspiration pneumonia. The benefit of antibiotics targeting Gram-negative organisms, in addition to anaerobes, remains uncertain.
The variability in empiric antimicrobial coverage likely reflects the paucity of available information on oral and/or enteric bacteria required to identify them as causative organisms in aspiration pneumonia. In part, this problem is due to the difficulty in obtaining adequate sputum for culture from pediatric patients.27 While it may be more feasible to obtain tracheal aspirates for respiratory culture in children with a tracheostomy, interpretation of culture results remains challenging because the lower airways of children with tracheostomy are commonly colonized with bacterial pathogens.28 Thus, physicians are often left to choose empiric antimicrobial coverage with inadequate supporting evidence.29 Although the polymicrobial nature of aspiration pneumonia is well recognized in adult and pediatric literature,10,30 it is less clear which organisms are of pathological significance and require treatment.
The treatment standard for aspiration pneumonia has long included anaerobic therapy.29 The worse outcomes of children not receiving anaerobic therapy (ie, Gram-negative coverage alone) compared with children who received anaerobic therapy support the continued importance of anaerobic therapy in the treatment of aspiration pneumonia for hospitalized children with NI. The role of antibiotics covering Gram-negative organisms is less clear. Recent studies suggest the role of anaerobes is overemphasized in the etiology and treatment of aspiration pneumonia.10,29,31-38 Multiple studies on aspiration pneumonia bacteriology in hospitalized adults have demonstrated a predominance of Gram-negative organisms (ranging from 37%-71% of isolates identified on respiratory culture) and a relative scarcity of anaerobes (ranging from 0%-16% of isolates).31-37 A prospective study of 50 children hospitalized with clinical and radiographic evidence of pneumonia with known aspiration risk (eg, neuromuscular disease or dysphagia) found that ~80% of 163 bacterial isolates were Gram-negative.38 However, this study included repeat cultures from the same children, and thus, may overestimate the prevalence of Gram-negative organisms. In our study, children who received both anaerobic and Gram-negative therapy had no differences in ICU transfer or LOS but did experience higher odds of acute respiratory failure. As these results may be due to unmeasured confounding, future studies should further explore the necessity of Gram-negative coverage in addition to anaerobic coverage in this population.
While these recent studies may seem to suggest that anaerobic coverage is not necessary for aspiration pneumonia, there are important limitations worth noting. First, these studies used a variety of sampling techniques. While organisms grown from samples obtained via bronchoalveolar lavage31-34,36 are likely pathogenic, those grown from tracheal or oral samples obtained via percutaneous transtracheal aspiration,34 a protected specimen brush,34,36,37 or expectorated sputum35,38 may not represent lower airway organisms. Second, anaerobic cultures were not obtained in all studies.31,34,38 Anaerobic organisms are difficult to isolate using traditional clinical specimen collection techniques and aerobic culture media.18 Furthermore, anaerobes are not easily recovered from lung infections after the receipt of antibiotic therapy.39 Details regarding pretreatment, which are largely lacking from these studies, are necessary to interpret the relative scarcity of anaerobes on respiratory culture. Finally, caution should be taken when extrapolating the results of studies focused on the etiology and treatment of aspiration pneumonia in elderly adults to children. Our results, particularly in the context of the limitation of these more recent studies, suggest that the role of anaerobes has been underestimated.
Recent studies examining populations of children with cerebral palsy and/or tracheostomy have emphasized the high rates of carriage and infection rates with Gram-negative and drug-resistant bacteria; in particular, P. aeruginosa accounts for 50%-72% of pathogenic bacteria.11,12,38,40
Our multicenter observational study has several limitations. We used diagnosis codes to identify patients with aspiration pneumonia. As validated clinical criteria for the diagnosis of aspiration pneumonia do not exist, clinicians may assign a diagnosis of and treatment for aspiration pneumonia by subjective suspicion based on a child’s severe NI or illness severity on presentation leading to selection bias. Although administrative data are not able to verify pneumonia type with absolute certainty, we previously demonstrated that the differences in the outcomes of children with aspiration and nonaspiration pneumonia diagnosis codes persist after accounting for the complexity that might influence the diagnosis.3
Frthermore, we were unable to account for laboratory, microbiology, or radiology test results, and other management practices (eg, frequency of airway clearance, previous antimicrobial therapy) that may influence outcomes. Future studies should certainly include an examination of the concordance of the antibiotics prescribed with causative organisms, as this undoubtedly affects patient outcomes. Other outcomes are important to examine (eg, time to return to respiratory baseline), but we were unable to do so, given the lack of clinical detail in our database. We randomly selected a single hospitalization for children with multiple admissions; alternative methods could have different results. Although children with NI predominately use children’s hospitals,1 results may not be generalizable.
CONCLUSION
These findings support prior literature that has highlighted the important role anaerobic therapy plays in the treatment of aspiration pneumonia in children with NI. In light of the limitations of our study design, we believe that rigorous clinical trials comparing anaerobic with anaerobic and Gram-negative therapy are an important and necessary next step to determine the optimal treatment for aspiration pneumonia in this population.
Disclosures
The authors do not have any financial relationships relevant to this article to disclose.
Funding
Dr. Thomson was supported by the Agency for Healthcare Research and Quality (AHRQ) under award number K08HS025138. Dr. Ambroggio was supported by the National Institute for Allergy and Infectious Diseases (NIAID) under award number K01AI125413. The content is solely the responsibility of the authors and does not necessarily represent the official views of the AHRQ or NIAID.
1. Berry JG, Poduri A, Bonkowsky JL, et al. Trends in resource utilization by children with neurological impairment in the United States inpatient health care system: a repeat cross-sectional study. PLoS Med. 2012;9(1):e1001158. https://doi.org/10.1371/journal.pmed.1001158.
2. Seddon PC, Khan Y. Respiratory problems in children with neurological impairment. Arch Dis Child. 2003;88(1):75-78. https://doi.org/10.1136/adc.88.1.75.
3. Thomson J, Hall M, Ambroggio L, et al. Aspiration and non-aspiration pneumonia in hospitalized children with neurologic impairment. Pediatrics. 2016;137(2):e20151612. https://doi.org/10.1542/peds.2015-1612.
4. Brook I. Anaerobic pulmonary infections in children. Pediatr Emerg Care. 2004;20(9):636-640. https://doi.org/10.1097/01.pec.0000139751.63624.0b.
5. Bartlett JG, Gorbach SL. Treatment of aspiration pneumonia and primary lung abscess. Penicillin G vs clindamycin. JAMA. 1975;234(9):935-937. https://doi.org/10.1001/jamadermatol.2017.0297.
6. Bartlett JG, Gorbach SL, Finegold SM. The bacteriology of aspiration pneumonia. Am J Med. 1974;56(2):202-207. https://doi.org/10.1016/0002-9343(74)90598-1.
7. Lode H. Microbiological and clinical aspects of aspiration pneumonia. J Antimicrob Chemother. 1988;21:83-90. https://doi.org/10.1093/jac/21.suppl_c.83.
8. Brook I. Treatment of aspiration or tracheostomy-associated pneumonia in neurologically impaired children: effect of antimicrobials effective against anaerobic bacteria. Int J Pediatr Otorhinolaryngol. 1996;35(2):171-177. https://doi.org/10.1016/0165-5876(96)01332-8.
9. Jacobson SJ, Griffiths K, Diamond S, et al. A randomized controlled trial of penicillin vs clindamycin for the treatment of aspiration pneumonia in children. Arch Pediatr Adolesc Med. 1997;151(7):701-704. https://doi.org/10.1001/archpedi.1997.02170440063011.
10. DiBardino DM, Wunderink RG. Aspiration pneumonia: a review of modern trends. J Crit Care. 2015;30(1):40-48. https://doi.org/10.1016/j.jcrc.2014.07.011.
11. Gerdung CA, Tsang A, Yasseen AS, 3rd, Armstrong K, McMillan HJ, Kovesi T. Association between chronic aspiration and chronic airway infection with Pseudomonas aeruginosa and other Gram-negative bacteria in children with cerebral palsy. Lung. 2016;194(2):307-314. https://doi.org/10.1007/s00408-016-9856-5.
12. Thorburn K, Jardine M, Taylor N, Reilly N, Sarginson RE, van Saene HK. Antibiotic-resistant bacteria and infection in children with cerebral palsy requiring mechanical ventilation. Pedr Crit Care Med. 2009;10(2):222-226. https://doi.org/10.1097/PCC.0b013e31819368ac.
13. Lanspa MJ, Jones BE, Brown SM, Dean NC. Mortality, morbidity, and disease severity of patients with aspiration pneumonia. J Hosp Med. 2013;8(2):83-90. https://doi.org/10.1002/jhm.1996.
14. Lanspa MJ, Peyrani P, Wiemken T, Wilson EL, Ramirez JA, Dean NC. Characteristics associated with clinician diagnosis of aspiration pneumonia: a descriptive study of afflicted patients and their outcomes. J Hosp Med. 2015;10(2):90-96. https://doi.org/10.1002/jhm.2280.
15. Berry JG, Graham RJ, Roberson DW, et al. Patient characteristics associated with in-hospital mortality in children following tracheotomy. Arch Dis Child. 2010;95(9):703-710.
16. Berry JG, Graham DA, Graham RJ, et al. Predictors of clinical outcomes and hospital resource use of children after tracheotomy. Pediatrics. 2009;124(2):563-572. https://doi.org/10.1136/adc.2009.180836.
17. Balamuth F, Weiss SL, Hall M, et al. Identifying pediatric severe sepsis and septic shock: Accuracy of diagnosis codes. J Pediatr. 2015;167(6):1295-1300 e1294. https://doi.org/10.1016/j.jpeds.2015.09.027.
18. American Academy of Pediatrics., Pickering LK, American Academy of Pediatrics. Committee on Infectious Diseases. In: Red book : 2012 report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village: American Academy of Pediatrics; 2012.
19. Gilbert DN. The Sanford Guide to Antimicrobial Therapy 2014. 44th ed. Sperryville: Antimicrobial Therapy, Inc; 2011.
20. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344(9):665-671. https://doi.org/10.1056/NEJM200103013440908.
21. Feudtner C, Feinstein JA, Zhong W, Hall M, Dai D. Pediatric complex chronic conditions classification system version 2: updated for ICD-10 and complex medical technology dependence and transplantation. BMC Pediatrics. 2014;14:199. https://doi.org/10.1186/1471-2431-14-199.
22. Feudtner C, Hays RM, Haynes G, Geyer JR, Neff JM, Koepsell TD. Deaths attributed to pediatric complex chronic conditions: national trends and implications for supportive care services. Pediatrics. 2001;107(6):E99. https://doi.org/10.1542/peds.107.6.e99.
23. Feinstein JA, Russell S, DeWitt PE, Feudtner C, Dai D, Bennett TD. R package for pediatric complex chronic condition classification. JAMA Pediatr. 2018;172(6):596-598. https://doi.org/10.1001/jamapediatrics.2018.0256.
24. Berry JG, Hall DE, Kuo DZ, Cohen E, Agrawal R, Feudtner C, Hall M, Kueser J, Kaplan W, Neff J. Hospital utilization and characteristics of patients experiencing recurrent readmissions within children’s hospitals. JAMA. 2011;305(7):682-690. https://doi.org/10.1001/jama.2011.122.
25. Shah SS, Hall M, Newland JG, et al. Comparative effectiveness of pleural drainage procedures for the treatment of complicated pneumonia in childhood. J Hosp Med. 2011;6(5):256-263. https://doi.org/10.1002/jhm.872.
26. Child Health Corporation of America. CTC™ 2010 Code Structure: Module 5 Clinical Services. 2010 January 4; Available at https://sharepoint.chca.com/CHCAForums/PerformanceImprovement/PHIS/Reference Library/CTC Resources/Forms/AllItems.aspx Version: Modified.
27. 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(7):e25-76. https://doi.org/10.1093/cid/cir531.
28. Brook I. Bacterial colonization, tracheobronchitis, and pneumonia following tracheostomy and long-term intubation in pediatric patients. Chest. 1979;76(4):420-424.
29. Waybright RA, Coolidge W, Johnson TJ. Treatment of clinical aspiration: a reappraisal. Am J Health Syst Pharm. 2013;70(15):1291-1300. https://doi.org/10.2146/ajhp120319.
30. Brook I, Finegold SM. Bacteriology of aspiration pneumonia in children. Pediatrics. 1980;65(6):1115-1120.
31. Wei C, Cheng Z, Zhang L, Yang J. Microbiology and prognostic factors of hospital- and community-acquired aspiration pneumonia in respiratory intensive care unit. Am J Infect Control. 2013;41(10):880-884. https://doi.org/10.1016/j.ajic.2013.01.007.
32. El-Solh AA, Pietrantoni C, Bhat A, et al. Microbiology of severe aspiration pneumonia in institutionalized elderly. Am J Respir Crit Care Med. 2003;167(12):1650-1654. https://doi.org/10.1164/rccm.200212-1543OC.
33. Tokuyasu H, Harada T, Watanabe E, et al. Effectiveness of meropenem for the treatment of aspiration pneumonia in elderly patients. Intern Med. 2009;48(3):129-135. https://doi.org/10.2169/internalmedicine.48.1308.
34. Ott SR, Allewelt M, Lorenz J, Reimnitz P, Lode H, German Lung Abscess Study Group. Moxifloxacin vs ampicillin/sulbactam in aspiration pneumonia and primary lung abscess. Infection. 2008;36(1):23-30. https://doi.org/10.1007/s15010-007-7043-6.
35. Kadowaki M, Demura Y, Mizuno S, et al. Reappraisal of clindamycin IV monotherapy for treatment of mild-to-moderate aspiration pneumonia in elderly patients. Chest. 2005;127(4):1276-1282. https://doi.org/10.1016/j.chest.2017.05.019.
36. Marik PE, Careau P. The role of anaerobes in patients with ventilator-associated pneumonia and aspiration pneumonia: a prospective study. Chest. 1999;115(1):178-183. https://doi.org/10.1378/chest.115.1.178.
37. Mier L, Dreyfuss D, Darchy B, et al. Is penicillin G an adequate initial treatment for aspiration pneumonia? A prospective evaluation using a protected specimen brush and quantitative cultures. Intensive Care Med. 1993;19(5):279-284. https://doi.org/10.1007/bf01690548.
38. Ashkenazi-Hoffnung L, Ari A, Bilavsky E, Scheuerman O, Amir J, Prais D. Pseudomonas aeruginosa identified as a key pathogen in hospitalised children with aspiration pneumonia and a high aspiration risk. Acta Paediatr. 2016;105(12):e588-e592. https://doi.org/10.1111/apa.13523.
39. Bartlett JG, Gorbach SL, Tally FP, Finegold SM. Bacteriology and treatment of primary lung abscess. Am Rev Respir Dis. 1974;109(5):510-518. https://doi.org/10.1164/arrd.1974.109.5.510.
40. Russell CJ, Simon TD, Mamey MR, Newth CJL, Neely MN. Pseudomonas aeruginosa and post-tracheotomy bacterial respiratory tract infection readmissions. Pediatr Pulmonol. 2017;52(9):1212-1218. https://doi.org/10.1002/ppul.23716.
41. Russell CJ, Mamey MR, Koh JY, Schrager SM, Neely MN, Wu S. Length of stay and hospital revisit after bacterial tracheostomy-associated respiratory tract infection hospitalizations. Hosp Pediatr. Hosp Pediatr. 2018;8(2):72-80. https://doi.org/10.1542/hpeds.2017-0106.
42. Russell CJ, Mack WJ, Schrager SM, Wu S. Care variations and outcomes for children hospitalized with bacterial tracheostomy-associated respiratory infections. Hosp Pediatr. 2017;7(1):16-23. https://doi.org/10.1542/hpeds.2016-0104.
Neurologic impairment (NI) encompasses static and progressive diseases of the central and/or peripheral nervous systems that result in functional and intellectual impairments.1 While a variety of neurologic diseases are responsible for NI (eg, hypoxic-ischemic encephalopathy, muscular dystrophy), consequences of these diseases extend beyond neurologic manifestations.1 These children are at an increased risk for aspiration of oral and gastric contents given their common comorbidities of dysphagia, gastroesophageal reflux, impaired cough, and respiratory muscle weakness.2 While aspiration may manifest as a self-resolving pneumonitis, the presence of oral or enteric bacteria in aspirated material may result in the development of bacterial pneumonia. Children with NI hospitalized with aspiration pneumonia have higher complication rates, longer and costlier hospitalizations, and higher readmission rates when compared with children with nonaspiration pneumonia.3
While pediatric aspiration pneumonia is commonly attributed to anaerobic bacteria, this is largely based on extrapolation from epidemiologic studies that were conducted in past decades.4-8 A single randomized controlled trial found that penicillin and clindamycin, antimicrobials with similar antimicrobial activity against anaerobes, to be equally effective.9 However, the recent literature emphasizes the polymicrobial nature of aspiration pneumonia in adults, with the common isolation of Gram-negative enteric bacteria.10 Further, while Pseudomonas aeruginosa is often identified in respiratory cultures from children with NI and chronic respiratory insufficiency,11,12 the significance of P. aeruginosa in lower airways remains unclear.
We designed this study to compare hospital outcomes associated with the most commonly prescribed empiric antimicrobial therapies for aspiration pneumonia in children with NI.
MATERIALS AND METHODS
Study Design and Data Source
This multicenter, retrospective cohort study used the Pediatric Health Information System (PHIS) database. PHIS, an administrative database of 50 not-for-profit tertiary care pediatric hospitals, contains data regarding patient demographics, diagnoses and procedures, and daily billed resource utilization, including laboratory and imaging studies. Data quality and reliability are assured through the Children’s Hospital Association (CHA; Lenexa, Kansas) and participating hospitals. Due to incomplete data through the study period and data quality issues, six hospitals were excluded.
STUDY POPULATION
Inclusion Criteria
Children 1-18 years of age who were discharged between July 1, 2007 and June 30, 2015 were included if they had a NI diagnosis,1 a principal diagnosis indicative of aspiration pneumonia (507.x),3,13,14 and received antibiotics in the first two calendar days of admission. NI was determined using previously defined International Classification of Diseases, Ninth Revision-Clinical Modification (ICD-9-CM) diagnosis codes.1 We only included children who received antibiotics in the first two calendar days of admission to minimize the likelihood of including children admitted for other reasons who acquired aspiration pneumonia after hospitalization. For children with multiple hospitalizations, one admission was randomly selected for inclusion to minimize weighting results toward repeat visits.
Exclusion Criteria
Children transferred from another hospital were excluded as records from their initial presentation, including treatment and outcomes, were not available. We also excluded children with tracheostomy15,16 or chronic ventilator dependence,17 those with a diagnosis of human immunodeficiency virus or tuberculosis, and children who received chemotherapy during hospitalization given expected differences in etiology, treatment, and outcomes.18
Exposure
The primary exposure was antibiotic therapy received in the first two days of admission. Antibiotics were classified by their antimicrobial spectra of activity as defined by The Sanford Guide to Antimicrobial Therapy19 against the most commonly recognized pathogens of aspiration pneumonia: anaerobes, Gram-negatives, and P. aeruginosa (Appendix Table 1).10,20 For example, penicillin G and clindamycin were among the antibiotics classified as providing anaerobic coverage alone, whereas ceftriaxone was classified as providing Gram-negative coverage alone and ampicillin-sulbactam or as combination therapy with clindamycin and ceftriaxone were classified as providing anaerobic and Gram-negative coverage. Piperacillin-tazobactam and meropenem were classified as providing anaerobic, Gram-negative, and P. aeruginosa coverage. We excluded antibiotics that do not provide coverage against anaerobes, Gram-negative, or P. aeruginosa (eg, ampicillin, azithromycin) or that provide coverage against Gram-negative and P. aeruginosa, but not anaerobes (eg, cefepime, tobramycin), as these therapies were prescribed for <5% of the cohort. We chose not to examine the coverage for Streptococcus pneumonia or Staphylococcus aureus as antibiotics included in this analysis covered these bacteria for 99.9% of our cohort.
OUTCOMES
Outcomes included acute respiratory failure during hospitalization, intensive care unit (ICU) transfer, and hospital length of stay (LOS). Acute respiratory failure during hospitalization was defined as the presence of Clinical Transaction Classification (CTC) or ICD-9 procedure code for noninvasive or invasive mechanical ventilation on day two or later of hospitalization, with or without the need for respiratory support on day 0 or day 1 (Appendix Table 2). Given the variability in hospital policies that may drive ICU admission criteria for complex patients, our outcome of ICU transfer was defined as the requirement for ICU level care on day two or later of hospitalization without ICU admission. Acute respiratory failure and ICU care occurring within the first two hospital days were not classified as outcomes because these early events likely reflect illness severity at presentation rather than outcomes attributable to treatment failure; these were included as markers of severity in the models.
Patient Demographics and Clinical Characteristics
Demographic and clinical characteristics that might influence antibiotic choice and/or hospital outcomes were assessed. Clinical characteristics included complex chronic conditions,21-23 medical technology assistance,24 performance of diagnostic testing, and markers of severe illness on presentation. Diagnostic testing included bacterial cultures (blood, respiratory, urine) and chest radiograph performance in the first two days of hospitalization. Results of diagnostic testing are not available in the PHIS. Illness severity on presentation included acute respiratory failure, pleural drainage, receipt of vasoactive agents, and transfusion of blood products in the first two days of hospitalization (Appendix Table 2).17,25,26
STASTICAL ANALYSIS
Continuous data were described with median and interquartile ranges (IQR) due to nonnormal distribution. Categorical data were described with frequencies and percentages. Patient demographics, clinical characteristics, and hospital outcomes were stratified by empiric antimicrobial coverage and compared using chi-square and Kruskal–Wallis tests as appropriate.
Generalized linear mixed-effects models with random hospital intercepts were derived to assess the independent effect of antimicrobial spectra of activity on outcomes of acute respiratory failure, ICU transfer, and LOS while adjusting for important differences in demographic and clinical characteristics. LOS had a nonnormal distribution. Thus, we used an exponential distribution. Covariates were chosen a priori given the clinical and biological relevance to exposure and outcomes—age, presence of complex chronic condition diagnoses, the number of complex chronic conditions, technology dependence, the performance of diagnostic tests on presentation, and illness severity on presentation. ICU admission was included as a covariate in acute respiratory failure and LOS outcome models. The results of the model for acute respiratory failure and ICU transfer are presented as adjusted odds ratios (OR) with a 95% CI. LOS results are presented as adjusted rate ratios (RR) with 95% CI.
All analyses were performed with SAS 9.3 (SAS Institute, Cary, North Carolina). P values <.05 were considered statistically significant. Cincinnati Children’s Hospital Medical Center Institutional Review Board considered this deidentified dataset study as not human subjects research.
RESULTS
Study Cohort
At the 44 hospitals included, 4,812 children with NI hospitalized with the diagnosis of aspiration pneumonia met the eligibility criteria. However, 79 received antibiotics with the spectra of activity not examined, leaving 4,733 children in our final analysis (Appendix Figure). Demographic and clinical characteristics of the study cohort are shown in Table 1. Median age was five years (interquartile range [IQR]: 2-11 years). Most subjects were male (53.9%), non-Hispanic white (47.9%), and publicly insured (63.6%). There was a slight variation in the distribution of admissions across seasons (spring 31.6%, summer 19.2%, fall 21.3%, and winter 27.9%). One-third of children had four or more comorbid CCCs (complex chronic conditions; 34.2%). The three most common nonneurologic CCC diagnosis categories were gastrointestinal (63.1%), congenital and/or genetic defects (36.9%), and respiratory (8.9%). Assistance with medical technologies was also common (82%)—particularly gastrointestinal (63.1%) and neurologic/neuromuscular (9.8%) technologies. The vast majority of children (92.5%) had either a chest radiograph (90.5%), respiratory viral study (33.7%), or respiratory culture (10.0%) obtained on presentation. A minority required noninvasive or invasive respiratory support (25.4%), vasoactive agents (8.9%), blood products (1.2%), or pleural drainage (0.3%) in the first two hospital days.
Spectrum of Antimicrobial Coverage
Most children (57.9%) received anaerobic and Gram-negative coverage; 16.2% received anaerobic, Gram-negative and P. aeruginosa coverage; 15.3% received anaerobic coverage alone; and 10.6% received Gram-negative coverage alone. Empiric antimicrobial coverage varied substantially across hospitals: anaerobic coverage was prescribed for 0%-44% of patients; Gram-negative coverage was prescribed for 3%-26% of patients; anaerobic and Gram-negative coverage was prescribed for 25%-90% of patients; and anaerobic, Gram-negative, and P. aeruginosa coverage was prescribed for 0%-65% of patients (Figure 1).
Outcomes
Acute Respiratory Failure
One-quarter (25.4%) of patients had acute respiratory failure on presentation; 22.5% required respiratory support (continued from presentation or were new) on day two or later of hospitalization (Table 2). In the adjusted analysis, children receiving Gram-negative coverage alone had two-fold greater odds (OR 2.15, 95% CI: 1.41-3.27) and children receiving anaerobic and Gram-negative coverage had 1.6-fold greater odds (OR 1.65, 95% CI: 1.19-2.28), of respiratory failure during hospitalization compared with those receiving anaerobic coverage alone (Figure 2). Odds of respiratory failure during hospitalization did not significantly differ for children receiving anaerobic, Gram-negative, and P. aeruginosa coverage compared with those receiving anaerobic coverage alone.
ICU Transfer
Nearly thirty percent (29.0%) of children required ICU admission, with an additional 3.8% requiring ICU transfer following admission (Table 2). In the multivariable analysis, the odds of an ICU transfer were greater for children receiving Gram-negative coverage alone (OR 1.80, 95% CI: 1.03-3.14) compared with those receiving anaerobic coverage alone. There was no statistical difference in ICU transfer for those receiving anaerobic and Gram-negative coverage (with or without P. aeruginosa coverage) compared with those receiving anaerobic coverage alone (Figure 2).
Length of Stay
Median hospital LOS for the total cohort was five days (IQR: 3-9 days; Table 2). In the multivariable analysis, children receiving Gram-negative coverage alone had a longer LOS (RR 1.28; 95% CI: 1.16-1.41) compared with those receiving anaerobic coverage alone, whereas children receiving anaerobic, Gram-negative, and P. aeruginosa coverage had a shorter LOS (RR 0.83; 95% CI: 0.76-0.90) than those receiving anaerobic coverage alone (Figure 2). There was no statistical difference in the LOS between children receiving anaerobic and Gram-negative coverage and those receiving anaerobic coverage alone.
DISCUSSION
In this multicenter study of children with NI hospitalized with aspiration pneumonia, we found substantial variation in empiric antimicrobial coverage for children with aspiration pneumonia. When comparing outcomes across groups, children who received anaerobic and Gram-negative coverage had outcomes similar to children who received anaerobic therapy alone. However, children who did not receive anaerobic coverage (ie, Gram-negative coverage alone) had worse outcomes, most notably a greater than two-fold increase in the odds of experiencing acute respiratory failure during hospitalization when compared with children receiving anaerobic therapy. These findings support prior literature that has highlighted the importance of anaerobic therapy in the treatment of aspiration pneumonia. The benefit of antibiotics targeting Gram-negative organisms, in addition to anaerobes, remains uncertain.
The variability in empiric antimicrobial coverage likely reflects the paucity of available information on oral and/or enteric bacteria required to identify them as causative organisms in aspiration pneumonia. In part, this problem is due to the difficulty in obtaining adequate sputum for culture from pediatric patients.27 While it may be more feasible to obtain tracheal aspirates for respiratory culture in children with a tracheostomy, interpretation of culture results remains challenging because the lower airways of children with tracheostomy are commonly colonized with bacterial pathogens.28 Thus, physicians are often left to choose empiric antimicrobial coverage with inadequate supporting evidence.29 Although the polymicrobial nature of aspiration pneumonia is well recognized in adult and pediatric literature,10,30 it is less clear which organisms are of pathological significance and require treatment.
The treatment standard for aspiration pneumonia has long included anaerobic therapy.29 The worse outcomes of children not receiving anaerobic therapy (ie, Gram-negative coverage alone) compared with children who received anaerobic therapy support the continued importance of anaerobic therapy in the treatment of aspiration pneumonia for hospitalized children with NI. The role of antibiotics covering Gram-negative organisms is less clear. Recent studies suggest the role of anaerobes is overemphasized in the etiology and treatment of aspiration pneumonia.10,29,31-38 Multiple studies on aspiration pneumonia bacteriology in hospitalized adults have demonstrated a predominance of Gram-negative organisms (ranging from 37%-71% of isolates identified on respiratory culture) and a relative scarcity of anaerobes (ranging from 0%-16% of isolates).31-37 A prospective study of 50 children hospitalized with clinical and radiographic evidence of pneumonia with known aspiration risk (eg, neuromuscular disease or dysphagia) found that ~80% of 163 bacterial isolates were Gram-negative.38 However, this study included repeat cultures from the same children, and thus, may overestimate the prevalence of Gram-negative organisms. In our study, children who received both anaerobic and Gram-negative therapy had no differences in ICU transfer or LOS but did experience higher odds of acute respiratory failure. As these results may be due to unmeasured confounding, future studies should further explore the necessity of Gram-negative coverage in addition to anaerobic coverage in this population.
While these recent studies may seem to suggest that anaerobic coverage is not necessary for aspiration pneumonia, there are important limitations worth noting. First, these studies used a variety of sampling techniques. While organisms grown from samples obtained via bronchoalveolar lavage31-34,36 are likely pathogenic, those grown from tracheal or oral samples obtained via percutaneous transtracheal aspiration,34 a protected specimen brush,34,36,37 or expectorated sputum35,38 may not represent lower airway organisms. Second, anaerobic cultures were not obtained in all studies.31,34,38 Anaerobic organisms are difficult to isolate using traditional clinical specimen collection techniques and aerobic culture media.18 Furthermore, anaerobes are not easily recovered from lung infections after the receipt of antibiotic therapy.39 Details regarding pretreatment, which are largely lacking from these studies, are necessary to interpret the relative scarcity of anaerobes on respiratory culture. Finally, caution should be taken when extrapolating the results of studies focused on the etiology and treatment of aspiration pneumonia in elderly adults to children. Our results, particularly in the context of the limitation of these more recent studies, suggest that the role of anaerobes has been underestimated.
Recent studies examining populations of children with cerebral palsy and/or tracheostomy have emphasized the high rates of carriage and infection rates with Gram-negative and drug-resistant bacteria; in particular, P. aeruginosa accounts for 50%-72% of pathogenic bacteria.11,12,38,40
Our multicenter observational study has several limitations. We used diagnosis codes to identify patients with aspiration pneumonia. As validated clinical criteria for the diagnosis of aspiration pneumonia do not exist, clinicians may assign a diagnosis of and treatment for aspiration pneumonia by subjective suspicion based on a child’s severe NI or illness severity on presentation leading to selection bias. Although administrative data are not able to verify pneumonia type with absolute certainty, we previously demonstrated that the differences in the outcomes of children with aspiration and nonaspiration pneumonia diagnosis codes persist after accounting for the complexity that might influence the diagnosis.3
Frthermore, we were unable to account for laboratory, microbiology, or radiology test results, and other management practices (eg, frequency of airway clearance, previous antimicrobial therapy) that may influence outcomes. Future studies should certainly include an examination of the concordance of the antibiotics prescribed with causative organisms, as this undoubtedly affects patient outcomes. Other outcomes are important to examine (eg, time to return to respiratory baseline), but we were unable to do so, given the lack of clinical detail in our database. We randomly selected a single hospitalization for children with multiple admissions; alternative methods could have different results. Although children with NI predominately use children’s hospitals,1 results may not be generalizable.
CONCLUSION
These findings support prior literature that has highlighted the important role anaerobic therapy plays in the treatment of aspiration pneumonia in children with NI. In light of the limitations of our study design, we believe that rigorous clinical trials comparing anaerobic with anaerobic and Gram-negative therapy are an important and necessary next step to determine the optimal treatment for aspiration pneumonia in this population.
Disclosures
The authors do not have any financial relationships relevant to this article to disclose.
Funding
Dr. Thomson was supported by the Agency for Healthcare Research and Quality (AHRQ) under award number K08HS025138. Dr. Ambroggio was supported by the National Institute for Allergy and Infectious Diseases (NIAID) under award number K01AI125413. The content is solely the responsibility of the authors and does not necessarily represent the official views of the AHRQ or NIAID.
Neurologic impairment (NI) encompasses static and progressive diseases of the central and/or peripheral nervous systems that result in functional and intellectual impairments.1 While a variety of neurologic diseases are responsible for NI (eg, hypoxic-ischemic encephalopathy, muscular dystrophy), consequences of these diseases extend beyond neurologic manifestations.1 These children are at an increased risk for aspiration of oral and gastric contents given their common comorbidities of dysphagia, gastroesophageal reflux, impaired cough, and respiratory muscle weakness.2 While aspiration may manifest as a self-resolving pneumonitis, the presence of oral or enteric bacteria in aspirated material may result in the development of bacterial pneumonia. Children with NI hospitalized with aspiration pneumonia have higher complication rates, longer and costlier hospitalizations, and higher readmission rates when compared with children with nonaspiration pneumonia.3
While pediatric aspiration pneumonia is commonly attributed to anaerobic bacteria, this is largely based on extrapolation from epidemiologic studies that were conducted in past decades.4-8 A single randomized controlled trial found that penicillin and clindamycin, antimicrobials with similar antimicrobial activity against anaerobes, to be equally effective.9 However, the recent literature emphasizes the polymicrobial nature of aspiration pneumonia in adults, with the common isolation of Gram-negative enteric bacteria.10 Further, while Pseudomonas aeruginosa is often identified in respiratory cultures from children with NI and chronic respiratory insufficiency,11,12 the significance of P. aeruginosa in lower airways remains unclear.
We designed this study to compare hospital outcomes associated with the most commonly prescribed empiric antimicrobial therapies for aspiration pneumonia in children with NI.
MATERIALS AND METHODS
Study Design and Data Source
This multicenter, retrospective cohort study used the Pediatric Health Information System (PHIS) database. PHIS, an administrative database of 50 not-for-profit tertiary care pediatric hospitals, contains data regarding patient demographics, diagnoses and procedures, and daily billed resource utilization, including laboratory and imaging studies. Data quality and reliability are assured through the Children’s Hospital Association (CHA; Lenexa, Kansas) and participating hospitals. Due to incomplete data through the study period and data quality issues, six hospitals were excluded.
STUDY POPULATION
Inclusion Criteria
Children 1-18 years of age who were discharged between July 1, 2007 and June 30, 2015 were included if they had a NI diagnosis,1 a principal diagnosis indicative of aspiration pneumonia (507.x),3,13,14 and received antibiotics in the first two calendar days of admission. NI was determined using previously defined International Classification of Diseases, Ninth Revision-Clinical Modification (ICD-9-CM) diagnosis codes.1 We only included children who received antibiotics in the first two calendar days of admission to minimize the likelihood of including children admitted for other reasons who acquired aspiration pneumonia after hospitalization. For children with multiple hospitalizations, one admission was randomly selected for inclusion to minimize weighting results toward repeat visits.
Exclusion Criteria
Children transferred from another hospital were excluded as records from their initial presentation, including treatment and outcomes, were not available. We also excluded children with tracheostomy15,16 or chronic ventilator dependence,17 those with a diagnosis of human immunodeficiency virus or tuberculosis, and children who received chemotherapy during hospitalization given expected differences in etiology, treatment, and outcomes.18
Exposure
The primary exposure was antibiotic therapy received in the first two days of admission. Antibiotics were classified by their antimicrobial spectra of activity as defined by The Sanford Guide to Antimicrobial Therapy19 against the most commonly recognized pathogens of aspiration pneumonia: anaerobes, Gram-negatives, and P. aeruginosa (Appendix Table 1).10,20 For example, penicillin G and clindamycin were among the antibiotics classified as providing anaerobic coverage alone, whereas ceftriaxone was classified as providing Gram-negative coverage alone and ampicillin-sulbactam or as combination therapy with clindamycin and ceftriaxone were classified as providing anaerobic and Gram-negative coverage. Piperacillin-tazobactam and meropenem were classified as providing anaerobic, Gram-negative, and P. aeruginosa coverage. We excluded antibiotics that do not provide coverage against anaerobes, Gram-negative, or P. aeruginosa (eg, ampicillin, azithromycin) or that provide coverage against Gram-negative and P. aeruginosa, but not anaerobes (eg, cefepime, tobramycin), as these therapies were prescribed for <5% of the cohort. We chose not to examine the coverage for Streptococcus pneumonia or Staphylococcus aureus as antibiotics included in this analysis covered these bacteria for 99.9% of our cohort.
OUTCOMES
Outcomes included acute respiratory failure during hospitalization, intensive care unit (ICU) transfer, and hospital length of stay (LOS). Acute respiratory failure during hospitalization was defined as the presence of Clinical Transaction Classification (CTC) or ICD-9 procedure code for noninvasive or invasive mechanical ventilation on day two or later of hospitalization, with or without the need for respiratory support on day 0 or day 1 (Appendix Table 2). Given the variability in hospital policies that may drive ICU admission criteria for complex patients, our outcome of ICU transfer was defined as the requirement for ICU level care on day two or later of hospitalization without ICU admission. Acute respiratory failure and ICU care occurring within the first two hospital days were not classified as outcomes because these early events likely reflect illness severity at presentation rather than outcomes attributable to treatment failure; these were included as markers of severity in the models.
Patient Demographics and Clinical Characteristics
Demographic and clinical characteristics that might influence antibiotic choice and/or hospital outcomes were assessed. Clinical characteristics included complex chronic conditions,21-23 medical technology assistance,24 performance of diagnostic testing, and markers of severe illness on presentation. Diagnostic testing included bacterial cultures (blood, respiratory, urine) and chest radiograph performance in the first two days of hospitalization. Results of diagnostic testing are not available in the PHIS. Illness severity on presentation included acute respiratory failure, pleural drainage, receipt of vasoactive agents, and transfusion of blood products in the first two days of hospitalization (Appendix Table 2).17,25,26
STASTICAL ANALYSIS
Continuous data were described with median and interquartile ranges (IQR) due to nonnormal distribution. Categorical data were described with frequencies and percentages. Patient demographics, clinical characteristics, and hospital outcomes were stratified by empiric antimicrobial coverage and compared using chi-square and Kruskal–Wallis tests as appropriate.
Generalized linear mixed-effects models with random hospital intercepts were derived to assess the independent effect of antimicrobial spectra of activity on outcomes of acute respiratory failure, ICU transfer, and LOS while adjusting for important differences in demographic and clinical characteristics. LOS had a nonnormal distribution. Thus, we used an exponential distribution. Covariates were chosen a priori given the clinical and biological relevance to exposure and outcomes—age, presence of complex chronic condition diagnoses, the number of complex chronic conditions, technology dependence, the performance of diagnostic tests on presentation, and illness severity on presentation. ICU admission was included as a covariate in acute respiratory failure and LOS outcome models. The results of the model for acute respiratory failure and ICU transfer are presented as adjusted odds ratios (OR) with a 95% CI. LOS results are presented as adjusted rate ratios (RR) with 95% CI.
All analyses were performed with SAS 9.3 (SAS Institute, Cary, North Carolina). P values <.05 were considered statistically significant. Cincinnati Children’s Hospital Medical Center Institutional Review Board considered this deidentified dataset study as not human subjects research.
RESULTS
Study Cohort
At the 44 hospitals included, 4,812 children with NI hospitalized with the diagnosis of aspiration pneumonia met the eligibility criteria. However, 79 received antibiotics with the spectra of activity not examined, leaving 4,733 children in our final analysis (Appendix Figure). Demographic and clinical characteristics of the study cohort are shown in Table 1. Median age was five years (interquartile range [IQR]: 2-11 years). Most subjects were male (53.9%), non-Hispanic white (47.9%), and publicly insured (63.6%). There was a slight variation in the distribution of admissions across seasons (spring 31.6%, summer 19.2%, fall 21.3%, and winter 27.9%). One-third of children had four or more comorbid CCCs (complex chronic conditions; 34.2%). The three most common nonneurologic CCC diagnosis categories were gastrointestinal (63.1%), congenital and/or genetic defects (36.9%), and respiratory (8.9%). Assistance with medical technologies was also common (82%)—particularly gastrointestinal (63.1%) and neurologic/neuromuscular (9.8%) technologies. The vast majority of children (92.5%) had either a chest radiograph (90.5%), respiratory viral study (33.7%), or respiratory culture (10.0%) obtained on presentation. A minority required noninvasive or invasive respiratory support (25.4%), vasoactive agents (8.9%), blood products (1.2%), or pleural drainage (0.3%) in the first two hospital days.
Spectrum of Antimicrobial Coverage
Most children (57.9%) received anaerobic and Gram-negative coverage; 16.2% received anaerobic, Gram-negative and P. aeruginosa coverage; 15.3% received anaerobic coverage alone; and 10.6% received Gram-negative coverage alone. Empiric antimicrobial coverage varied substantially across hospitals: anaerobic coverage was prescribed for 0%-44% of patients; Gram-negative coverage was prescribed for 3%-26% of patients; anaerobic and Gram-negative coverage was prescribed for 25%-90% of patients; and anaerobic, Gram-negative, and P. aeruginosa coverage was prescribed for 0%-65% of patients (Figure 1).
Outcomes
Acute Respiratory Failure
One-quarter (25.4%) of patients had acute respiratory failure on presentation; 22.5% required respiratory support (continued from presentation or were new) on day two or later of hospitalization (Table 2). In the adjusted analysis, children receiving Gram-negative coverage alone had two-fold greater odds (OR 2.15, 95% CI: 1.41-3.27) and children receiving anaerobic and Gram-negative coverage had 1.6-fold greater odds (OR 1.65, 95% CI: 1.19-2.28), of respiratory failure during hospitalization compared with those receiving anaerobic coverage alone (Figure 2). Odds of respiratory failure during hospitalization did not significantly differ for children receiving anaerobic, Gram-negative, and P. aeruginosa coverage compared with those receiving anaerobic coverage alone.
ICU Transfer
Nearly thirty percent (29.0%) of children required ICU admission, with an additional 3.8% requiring ICU transfer following admission (Table 2). In the multivariable analysis, the odds of an ICU transfer were greater for children receiving Gram-negative coverage alone (OR 1.80, 95% CI: 1.03-3.14) compared with those receiving anaerobic coverage alone. There was no statistical difference in ICU transfer for those receiving anaerobic and Gram-negative coverage (with or without P. aeruginosa coverage) compared with those receiving anaerobic coverage alone (Figure 2).
Length of Stay
Median hospital LOS for the total cohort was five days (IQR: 3-9 days; Table 2). In the multivariable analysis, children receiving Gram-negative coverage alone had a longer LOS (RR 1.28; 95% CI: 1.16-1.41) compared with those receiving anaerobic coverage alone, whereas children receiving anaerobic, Gram-negative, and P. aeruginosa coverage had a shorter LOS (RR 0.83; 95% CI: 0.76-0.90) than those receiving anaerobic coverage alone (Figure 2). There was no statistical difference in the LOS between children receiving anaerobic and Gram-negative coverage and those receiving anaerobic coverage alone.
DISCUSSION
In this multicenter study of children with NI hospitalized with aspiration pneumonia, we found substantial variation in empiric antimicrobial coverage for children with aspiration pneumonia. When comparing outcomes across groups, children who received anaerobic and Gram-negative coverage had outcomes similar to children who received anaerobic therapy alone. However, children who did not receive anaerobic coverage (ie, Gram-negative coverage alone) had worse outcomes, most notably a greater than two-fold increase in the odds of experiencing acute respiratory failure during hospitalization when compared with children receiving anaerobic therapy. These findings support prior literature that has highlighted the importance of anaerobic therapy in the treatment of aspiration pneumonia. The benefit of antibiotics targeting Gram-negative organisms, in addition to anaerobes, remains uncertain.
The variability in empiric antimicrobial coverage likely reflects the paucity of available information on oral and/or enteric bacteria required to identify them as causative organisms in aspiration pneumonia. In part, this problem is due to the difficulty in obtaining adequate sputum for culture from pediatric patients.27 While it may be more feasible to obtain tracheal aspirates for respiratory culture in children with a tracheostomy, interpretation of culture results remains challenging because the lower airways of children with tracheostomy are commonly colonized with bacterial pathogens.28 Thus, physicians are often left to choose empiric antimicrobial coverage with inadequate supporting evidence.29 Although the polymicrobial nature of aspiration pneumonia is well recognized in adult and pediatric literature,10,30 it is less clear which organisms are of pathological significance and require treatment.
The treatment standard for aspiration pneumonia has long included anaerobic therapy.29 The worse outcomes of children not receiving anaerobic therapy (ie, Gram-negative coverage alone) compared with children who received anaerobic therapy support the continued importance of anaerobic therapy in the treatment of aspiration pneumonia for hospitalized children with NI. The role of antibiotics covering Gram-negative organisms is less clear. Recent studies suggest the role of anaerobes is overemphasized in the etiology and treatment of aspiration pneumonia.10,29,31-38 Multiple studies on aspiration pneumonia bacteriology in hospitalized adults have demonstrated a predominance of Gram-negative organisms (ranging from 37%-71% of isolates identified on respiratory culture) and a relative scarcity of anaerobes (ranging from 0%-16% of isolates).31-37 A prospective study of 50 children hospitalized with clinical and radiographic evidence of pneumonia with known aspiration risk (eg, neuromuscular disease or dysphagia) found that ~80% of 163 bacterial isolates were Gram-negative.38 However, this study included repeat cultures from the same children, and thus, may overestimate the prevalence of Gram-negative organisms. In our study, children who received both anaerobic and Gram-negative therapy had no differences in ICU transfer or LOS but did experience higher odds of acute respiratory failure. As these results may be due to unmeasured confounding, future studies should further explore the necessity of Gram-negative coverage in addition to anaerobic coverage in this population.
While these recent studies may seem to suggest that anaerobic coverage is not necessary for aspiration pneumonia, there are important limitations worth noting. First, these studies used a variety of sampling techniques. While organisms grown from samples obtained via bronchoalveolar lavage31-34,36 are likely pathogenic, those grown from tracheal or oral samples obtained via percutaneous transtracheal aspiration,34 a protected specimen brush,34,36,37 or expectorated sputum35,38 may not represent lower airway organisms. Second, anaerobic cultures were not obtained in all studies.31,34,38 Anaerobic organisms are difficult to isolate using traditional clinical specimen collection techniques and aerobic culture media.18 Furthermore, anaerobes are not easily recovered from lung infections after the receipt of antibiotic therapy.39 Details regarding pretreatment, which are largely lacking from these studies, are necessary to interpret the relative scarcity of anaerobes on respiratory culture. Finally, caution should be taken when extrapolating the results of studies focused on the etiology and treatment of aspiration pneumonia in elderly adults to children. Our results, particularly in the context of the limitation of these more recent studies, suggest that the role of anaerobes has been underestimated.
Recent studies examining populations of children with cerebral palsy and/or tracheostomy have emphasized the high rates of carriage and infection rates with Gram-negative and drug-resistant bacteria; in particular, P. aeruginosa accounts for 50%-72% of pathogenic bacteria.11,12,38,40
Our multicenter observational study has several limitations. We used diagnosis codes to identify patients with aspiration pneumonia. As validated clinical criteria for the diagnosis of aspiration pneumonia do not exist, clinicians may assign a diagnosis of and treatment for aspiration pneumonia by subjective suspicion based on a child’s severe NI or illness severity on presentation leading to selection bias. Although administrative data are not able to verify pneumonia type with absolute certainty, we previously demonstrated that the differences in the outcomes of children with aspiration and nonaspiration pneumonia diagnosis codes persist after accounting for the complexity that might influence the diagnosis.3
Frthermore, we were unable to account for laboratory, microbiology, or radiology test results, and other management practices (eg, frequency of airway clearance, previous antimicrobial therapy) that may influence outcomes. Future studies should certainly include an examination of the concordance of the antibiotics prescribed with causative organisms, as this undoubtedly affects patient outcomes. Other outcomes are important to examine (eg, time to return to respiratory baseline), but we were unable to do so, given the lack of clinical detail in our database. We randomly selected a single hospitalization for children with multiple admissions; alternative methods could have different results. Although children with NI predominately use children’s hospitals,1 results may not be generalizable.
CONCLUSION
These findings support prior literature that has highlighted the important role anaerobic therapy plays in the treatment of aspiration pneumonia in children with NI. In light of the limitations of our study design, we believe that rigorous clinical trials comparing anaerobic with anaerobic and Gram-negative therapy are an important and necessary next step to determine the optimal treatment for aspiration pneumonia in this population.
Disclosures
The authors do not have any financial relationships relevant to this article to disclose.
Funding
Dr. Thomson was supported by the Agency for Healthcare Research and Quality (AHRQ) under award number K08HS025138. Dr. Ambroggio was supported by the National Institute for Allergy and Infectious Diseases (NIAID) under award number K01AI125413. The content is solely the responsibility of the authors and does not necessarily represent the official views of the AHRQ or NIAID.
1. Berry JG, Poduri A, Bonkowsky JL, et al. Trends in resource utilization by children with neurological impairment in the United States inpatient health care system: a repeat cross-sectional study. PLoS Med. 2012;9(1):e1001158. https://doi.org/10.1371/journal.pmed.1001158.
2. Seddon PC, Khan Y. Respiratory problems in children with neurological impairment. Arch Dis Child. 2003;88(1):75-78. https://doi.org/10.1136/adc.88.1.75.
3. Thomson J, Hall M, Ambroggio L, et al. Aspiration and non-aspiration pneumonia in hospitalized children with neurologic impairment. Pediatrics. 2016;137(2):e20151612. https://doi.org/10.1542/peds.2015-1612.
4. Brook I. Anaerobic pulmonary infections in children. Pediatr Emerg Care. 2004;20(9):636-640. https://doi.org/10.1097/01.pec.0000139751.63624.0b.
5. Bartlett JG, Gorbach SL. Treatment of aspiration pneumonia and primary lung abscess. Penicillin G vs clindamycin. JAMA. 1975;234(9):935-937. https://doi.org/10.1001/jamadermatol.2017.0297.
6. Bartlett JG, Gorbach SL, Finegold SM. The bacteriology of aspiration pneumonia. Am J Med. 1974;56(2):202-207. https://doi.org/10.1016/0002-9343(74)90598-1.
7. Lode H. Microbiological and clinical aspects of aspiration pneumonia. J Antimicrob Chemother. 1988;21:83-90. https://doi.org/10.1093/jac/21.suppl_c.83.
8. Brook I. Treatment of aspiration or tracheostomy-associated pneumonia in neurologically impaired children: effect of antimicrobials effective against anaerobic bacteria. Int J Pediatr Otorhinolaryngol. 1996;35(2):171-177. https://doi.org/10.1016/0165-5876(96)01332-8.
9. Jacobson SJ, Griffiths K, Diamond S, et al. A randomized controlled trial of penicillin vs clindamycin for the treatment of aspiration pneumonia in children. Arch Pediatr Adolesc Med. 1997;151(7):701-704. https://doi.org/10.1001/archpedi.1997.02170440063011.
10. DiBardino DM, Wunderink RG. Aspiration pneumonia: a review of modern trends. J Crit Care. 2015;30(1):40-48. https://doi.org/10.1016/j.jcrc.2014.07.011.
11. Gerdung CA, Tsang A, Yasseen AS, 3rd, Armstrong K, McMillan HJ, Kovesi T. Association between chronic aspiration and chronic airway infection with Pseudomonas aeruginosa and other Gram-negative bacteria in children with cerebral palsy. Lung. 2016;194(2):307-314. https://doi.org/10.1007/s00408-016-9856-5.
12. Thorburn K, Jardine M, Taylor N, Reilly N, Sarginson RE, van Saene HK. Antibiotic-resistant bacteria and infection in children with cerebral palsy requiring mechanical ventilation. Pedr Crit Care Med. 2009;10(2):222-226. https://doi.org/10.1097/PCC.0b013e31819368ac.
13. Lanspa MJ, Jones BE, Brown SM, Dean NC. Mortality, morbidity, and disease severity of patients with aspiration pneumonia. J Hosp Med. 2013;8(2):83-90. https://doi.org/10.1002/jhm.1996.
14. Lanspa MJ, Peyrani P, Wiemken T, Wilson EL, Ramirez JA, Dean NC. Characteristics associated with clinician diagnosis of aspiration pneumonia: a descriptive study of afflicted patients and their outcomes. J Hosp Med. 2015;10(2):90-96. https://doi.org/10.1002/jhm.2280.
15. Berry JG, Graham RJ, Roberson DW, et al. Patient characteristics associated with in-hospital mortality in children following tracheotomy. Arch Dis Child. 2010;95(9):703-710.
16. Berry JG, Graham DA, Graham RJ, et al. Predictors of clinical outcomes and hospital resource use of children after tracheotomy. Pediatrics. 2009;124(2):563-572. https://doi.org/10.1136/adc.2009.180836.
17. Balamuth F, Weiss SL, Hall M, et al. Identifying pediatric severe sepsis and septic shock: Accuracy of diagnosis codes. J Pediatr. 2015;167(6):1295-1300 e1294. https://doi.org/10.1016/j.jpeds.2015.09.027.
18. American Academy of Pediatrics., Pickering LK, American Academy of Pediatrics. Committee on Infectious Diseases. In: Red book : 2012 report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village: American Academy of Pediatrics; 2012.
19. Gilbert DN. The Sanford Guide to Antimicrobial Therapy 2014. 44th ed. Sperryville: Antimicrobial Therapy, Inc; 2011.
20. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344(9):665-671. https://doi.org/10.1056/NEJM200103013440908.
21. Feudtner C, Feinstein JA, Zhong W, Hall M, Dai D. Pediatric complex chronic conditions classification system version 2: updated for ICD-10 and complex medical technology dependence and transplantation. BMC Pediatrics. 2014;14:199. https://doi.org/10.1186/1471-2431-14-199.
22. Feudtner C, Hays RM, Haynes G, Geyer JR, Neff JM, Koepsell TD. Deaths attributed to pediatric complex chronic conditions: national trends and implications for supportive care services. Pediatrics. 2001;107(6):E99. https://doi.org/10.1542/peds.107.6.e99.
23. Feinstein JA, Russell S, DeWitt PE, Feudtner C, Dai D, Bennett TD. R package for pediatric complex chronic condition classification. JAMA Pediatr. 2018;172(6):596-598. https://doi.org/10.1001/jamapediatrics.2018.0256.
24. Berry JG, Hall DE, Kuo DZ, Cohen E, Agrawal R, Feudtner C, Hall M, Kueser J, Kaplan W, Neff J. Hospital utilization and characteristics of patients experiencing recurrent readmissions within children’s hospitals. JAMA. 2011;305(7):682-690. https://doi.org/10.1001/jama.2011.122.
25. Shah SS, Hall M, Newland JG, et al. Comparative effectiveness of pleural drainage procedures for the treatment of complicated pneumonia in childhood. J Hosp Med. 2011;6(5):256-263. https://doi.org/10.1002/jhm.872.
26. Child Health Corporation of America. CTC™ 2010 Code Structure: Module 5 Clinical Services. 2010 January 4; Available at https://sharepoint.chca.com/CHCAForums/PerformanceImprovement/PHIS/Reference Library/CTC Resources/Forms/AllItems.aspx Version: Modified.
27. 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(7):e25-76. https://doi.org/10.1093/cid/cir531.
28. Brook I. Bacterial colonization, tracheobronchitis, and pneumonia following tracheostomy and long-term intubation in pediatric patients. Chest. 1979;76(4):420-424.
29. Waybright RA, Coolidge W, Johnson TJ. Treatment of clinical aspiration: a reappraisal. Am J Health Syst Pharm. 2013;70(15):1291-1300. https://doi.org/10.2146/ajhp120319.
30. Brook I, Finegold SM. Bacteriology of aspiration pneumonia in children. Pediatrics. 1980;65(6):1115-1120.
31. Wei C, Cheng Z, Zhang L, Yang J. Microbiology and prognostic factors of hospital- and community-acquired aspiration pneumonia in respiratory intensive care unit. Am J Infect Control. 2013;41(10):880-884. https://doi.org/10.1016/j.ajic.2013.01.007.
32. El-Solh AA, Pietrantoni C, Bhat A, et al. Microbiology of severe aspiration pneumonia in institutionalized elderly. Am J Respir Crit Care Med. 2003;167(12):1650-1654. https://doi.org/10.1164/rccm.200212-1543OC.
33. Tokuyasu H, Harada T, Watanabe E, et al. Effectiveness of meropenem for the treatment of aspiration pneumonia in elderly patients. Intern Med. 2009;48(3):129-135. https://doi.org/10.2169/internalmedicine.48.1308.
34. Ott SR, Allewelt M, Lorenz J, Reimnitz P, Lode H, German Lung Abscess Study Group. Moxifloxacin vs ampicillin/sulbactam in aspiration pneumonia and primary lung abscess. Infection. 2008;36(1):23-30. https://doi.org/10.1007/s15010-007-7043-6.
35. Kadowaki M, Demura Y, Mizuno S, et al. Reappraisal of clindamycin IV monotherapy for treatment of mild-to-moderate aspiration pneumonia in elderly patients. Chest. 2005;127(4):1276-1282. https://doi.org/10.1016/j.chest.2017.05.019.
36. Marik PE, Careau P. The role of anaerobes in patients with ventilator-associated pneumonia and aspiration pneumonia: a prospective study. Chest. 1999;115(1):178-183. https://doi.org/10.1378/chest.115.1.178.
37. Mier L, Dreyfuss D, Darchy B, et al. Is penicillin G an adequate initial treatment for aspiration pneumonia? A prospective evaluation using a protected specimen brush and quantitative cultures. Intensive Care Med. 1993;19(5):279-284. https://doi.org/10.1007/bf01690548.
38. Ashkenazi-Hoffnung L, Ari A, Bilavsky E, Scheuerman O, Amir J, Prais D. Pseudomonas aeruginosa identified as a key pathogen in hospitalised children with aspiration pneumonia and a high aspiration risk. Acta Paediatr. 2016;105(12):e588-e592. https://doi.org/10.1111/apa.13523.
39. Bartlett JG, Gorbach SL, Tally FP, Finegold SM. Bacteriology and treatment of primary lung abscess. Am Rev Respir Dis. 1974;109(5):510-518. https://doi.org/10.1164/arrd.1974.109.5.510.
40. Russell CJ, Simon TD, Mamey MR, Newth CJL, Neely MN. Pseudomonas aeruginosa and post-tracheotomy bacterial respiratory tract infection readmissions. Pediatr Pulmonol. 2017;52(9):1212-1218. https://doi.org/10.1002/ppul.23716.
41. Russell CJ, Mamey MR, Koh JY, Schrager SM, Neely MN, Wu S. Length of stay and hospital revisit after bacterial tracheostomy-associated respiratory tract infection hospitalizations. Hosp Pediatr. Hosp Pediatr. 2018;8(2):72-80. https://doi.org/10.1542/hpeds.2017-0106.
42. Russell CJ, Mack WJ, Schrager SM, Wu S. Care variations and outcomes for children hospitalized with bacterial tracheostomy-associated respiratory infections. Hosp Pediatr. 2017;7(1):16-23. https://doi.org/10.1542/hpeds.2016-0104.
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9. Jacobson SJ, Griffiths K, Diamond S, et al. A randomized controlled trial of penicillin vs clindamycin for the treatment of aspiration pneumonia in children. Arch Pediatr Adolesc Med. 1997;151(7):701-704. https://doi.org/10.1001/archpedi.1997.02170440063011.
10. DiBardino DM, Wunderink RG. Aspiration pneumonia: a review of modern trends. J Crit Care. 2015;30(1):40-48. https://doi.org/10.1016/j.jcrc.2014.07.011.
11. Gerdung CA, Tsang A, Yasseen AS, 3rd, Armstrong K, McMillan HJ, Kovesi T. Association between chronic aspiration and chronic airway infection with Pseudomonas aeruginosa and other Gram-negative bacteria in children with cerebral palsy. Lung. 2016;194(2):307-314. https://doi.org/10.1007/s00408-016-9856-5.
12. Thorburn K, Jardine M, Taylor N, Reilly N, Sarginson RE, van Saene HK. Antibiotic-resistant bacteria and infection in children with cerebral palsy requiring mechanical ventilation. Pedr Crit Care Med. 2009;10(2):222-226. https://doi.org/10.1097/PCC.0b013e31819368ac.
13. Lanspa MJ, Jones BE, Brown SM, Dean NC. Mortality, morbidity, and disease severity of patients with aspiration pneumonia. J Hosp Med. 2013;8(2):83-90. https://doi.org/10.1002/jhm.1996.
14. Lanspa MJ, Peyrani P, Wiemken T, Wilson EL, Ramirez JA, Dean NC. Characteristics associated with clinician diagnosis of aspiration pneumonia: a descriptive study of afflicted patients and their outcomes. J Hosp Med. 2015;10(2):90-96. https://doi.org/10.1002/jhm.2280.
15. Berry JG, Graham RJ, Roberson DW, et al. Patient characteristics associated with in-hospital mortality in children following tracheotomy. Arch Dis Child. 2010;95(9):703-710.
16. Berry JG, Graham DA, Graham RJ, et al. Predictors of clinical outcomes and hospital resource use of children after tracheotomy. Pediatrics. 2009;124(2):563-572. https://doi.org/10.1136/adc.2009.180836.
17. Balamuth F, Weiss SL, Hall M, et al. Identifying pediatric severe sepsis and septic shock: Accuracy of diagnosis codes. J Pediatr. 2015;167(6):1295-1300 e1294. https://doi.org/10.1016/j.jpeds.2015.09.027.
18. American Academy of Pediatrics., Pickering LK, American Academy of Pediatrics. Committee on Infectious Diseases. In: Red book : 2012 report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village: American Academy of Pediatrics; 2012.
19. Gilbert DN. The Sanford Guide to Antimicrobial Therapy 2014. 44th ed. Sperryville: Antimicrobial Therapy, Inc; 2011.
20. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344(9):665-671. https://doi.org/10.1056/NEJM200103013440908.
21. Feudtner C, Feinstein JA, Zhong W, Hall M, Dai D. Pediatric complex chronic conditions classification system version 2: updated for ICD-10 and complex medical technology dependence and transplantation. BMC Pediatrics. 2014;14:199. https://doi.org/10.1186/1471-2431-14-199.
22. Feudtner C, Hays RM, Haynes G, Geyer JR, Neff JM, Koepsell TD. Deaths attributed to pediatric complex chronic conditions: national trends and implications for supportive care services. Pediatrics. 2001;107(6):E99. https://doi.org/10.1542/peds.107.6.e99.
23. Feinstein JA, Russell S, DeWitt PE, Feudtner C, Dai D, Bennett TD. R package for pediatric complex chronic condition classification. JAMA Pediatr. 2018;172(6):596-598. https://doi.org/10.1001/jamapediatrics.2018.0256.
24. Berry JG, Hall DE, Kuo DZ, Cohen E, Agrawal R, Feudtner C, Hall M, Kueser J, Kaplan W, Neff J. Hospital utilization and characteristics of patients experiencing recurrent readmissions within children’s hospitals. JAMA. 2011;305(7):682-690. https://doi.org/10.1001/jama.2011.122.
25. Shah SS, Hall M, Newland JG, et al. Comparative effectiveness of pleural drainage procedures for the treatment of complicated pneumonia in childhood. J Hosp Med. 2011;6(5):256-263. https://doi.org/10.1002/jhm.872.
26. Child Health Corporation of America. CTC™ 2010 Code Structure: Module 5 Clinical Services. 2010 January 4; Available at https://sharepoint.chca.com/CHCAForums/PerformanceImprovement/PHIS/Reference Library/CTC Resources/Forms/AllItems.aspx Version: Modified.
27. 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(7):e25-76. https://doi.org/10.1093/cid/cir531.
28. Brook I. Bacterial colonization, tracheobronchitis, and pneumonia following tracheostomy and long-term intubation in pediatric patients. Chest. 1979;76(4):420-424.
29. Waybright RA, Coolidge W, Johnson TJ. Treatment of clinical aspiration: a reappraisal. Am J Health Syst Pharm. 2013;70(15):1291-1300. https://doi.org/10.2146/ajhp120319.
30. Brook I, Finegold SM. Bacteriology of aspiration pneumonia in children. Pediatrics. 1980;65(6):1115-1120.
31. Wei C, Cheng Z, Zhang L, Yang J. Microbiology and prognostic factors of hospital- and community-acquired aspiration pneumonia in respiratory intensive care unit. Am J Infect Control. 2013;41(10):880-884. https://doi.org/10.1016/j.ajic.2013.01.007.
32. El-Solh AA, Pietrantoni C, Bhat A, et al. Microbiology of severe aspiration pneumonia in institutionalized elderly. Am J Respir Crit Care Med. 2003;167(12):1650-1654. https://doi.org/10.1164/rccm.200212-1543OC.
33. Tokuyasu H, Harada T, Watanabe E, et al. Effectiveness of meropenem for the treatment of aspiration pneumonia in elderly patients. Intern Med. 2009;48(3):129-135. https://doi.org/10.2169/internalmedicine.48.1308.
34. Ott SR, Allewelt M, Lorenz J, Reimnitz P, Lode H, German Lung Abscess Study Group. Moxifloxacin vs ampicillin/sulbactam in aspiration pneumonia and primary lung abscess. Infection. 2008;36(1):23-30. https://doi.org/10.1007/s15010-007-7043-6.
35. Kadowaki M, Demura Y, Mizuno S, et al. Reappraisal of clindamycin IV monotherapy for treatment of mild-to-moderate aspiration pneumonia in elderly patients. Chest. 2005;127(4):1276-1282. https://doi.org/10.1016/j.chest.2017.05.019.
36. Marik PE, Careau P. The role of anaerobes in patients with ventilator-associated pneumonia and aspiration pneumonia: a prospective study. Chest. 1999;115(1):178-183. https://doi.org/10.1378/chest.115.1.178.
37. Mier L, Dreyfuss D, Darchy B, et al. Is penicillin G an adequate initial treatment for aspiration pneumonia? A prospective evaluation using a protected specimen brush and quantitative cultures. Intensive Care Med. 1993;19(5):279-284. https://doi.org/10.1007/bf01690548.
38. Ashkenazi-Hoffnung L, Ari A, Bilavsky E, Scheuerman O, Amir J, Prais D. Pseudomonas aeruginosa identified as a key pathogen in hospitalised children with aspiration pneumonia and a high aspiration risk. Acta Paediatr. 2016;105(12):e588-e592. https://doi.org/10.1111/apa.13523.
39. Bartlett JG, Gorbach SL, Tally FP, Finegold SM. Bacteriology and treatment of primary lung abscess. Am Rev Respir Dis. 1974;109(5):510-518. https://doi.org/10.1164/arrd.1974.109.5.510.
40. Russell CJ, Simon TD, Mamey MR, Newth CJL, Neely MN. Pseudomonas aeruginosa and post-tracheotomy bacterial respiratory tract infection readmissions. Pediatr Pulmonol. 2017;52(9):1212-1218. https://doi.org/10.1002/ppul.23716.
41. Russell CJ, Mamey MR, Koh JY, Schrager SM, Neely MN, Wu S. Length of stay and hospital revisit after bacterial tracheostomy-associated respiratory tract infection hospitalizations. Hosp Pediatr. Hosp Pediatr. 2018;8(2):72-80. https://doi.org/10.1542/hpeds.2017-0106.
42. Russell CJ, Mack WJ, Schrager SM, Wu S. Care variations and outcomes for children hospitalized with bacterial tracheostomy-associated respiratory infections. Hosp Pediatr. 2017;7(1):16-23. https://doi.org/10.1542/hpeds.2016-0104.
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