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Antibiotic Prescription in Young Children With Respiratory Syncytial Virus–Associated Respiratory Failure and Associated Outcomes

Shein, Steven L., MD1; Kong, Michele, MD2; McKee, Bryan, MD1; O’Riordan, MaryAnn, PhD1; Toltzis, Philip, MD1; Randolph, Adrienne G., MD, MSc3,4

Pediatric Critical Care Medicine: February 2019 - Volume 20 - Issue 2 - p 101–109
doi: 10.1097/PCC.0000000000001839
Late Breaker Articles

Objectives: To describe antibiotic prescribing practices during the first 2 days of mechanical ventilation among previously healthy young children with respiratory syncytial virus–associated lower respiratory tract infection and evaluate associations between the prescription of antibiotics at onset of mechanical ventilation with clinical outcomes.

Design: Retrospective cohort study.

Setting: Forty-six children’s hospitals in the United States.

Patients: Children less than 2 years old discharged between 2012 and 2016 with an International Classification of Diseases diagnosis of respiratory syncytial virus–associated lower respiratory tract infection, no identified comorbid conditions, and receipt of mechanical ventilation.

Interventions: Antibiotic prescription during the first 2 days of mechanical ventilation.

Measurements and Main Results: We compared duration of mechanical ventilation and hospital length of stay between children prescribed antibiotics on both of the first 2 days of mechanical ventilation and children not prescribed antibiotics during the first 2 days of mechanical ventilation. We included 2,107 PICU children with respiratory syncytial virus–associated lower respiratory tract infection (60% male, median age of 1 mo [interquartile range, 1–4 mo]). The overall proportion of antibiotic prescription on both of the first 2 days of mechanical ventilation was 82%, decreasing over the study period (p = 0.004) and varying from 36% to 100% across centers. In the bivariate analysis, antibiotic prescription was associated with a shorter duration of mechanical ventilation (6 d [4–9 d] vs 8 d [6–11 d]; p < 0.001) and a shorter hospital length of stay (11 d [8–16 d] vs 13 d [10–18 d]; p < 0.001). After adjustment for center, demographics, and vasoactive medication prescription, antibiotic prescription was associated with a 1.21-day shorter duration of mechanical ventilation and a 2.07-day shorter length of stay. Ultimately, 95% of children were prescribed antibiotics sometime during hospitalization, but timing, duration, and antibiotic choice varied markedly.

Conclusions: Although highly variable across centers and decreasing over time, the practice of instituting antibiotics after intubation in young children with respiratory syncytial virus–associated lower respiratory tract infection was associated with a shortened clinical course after adjustment for the limited available covariates. A prudent approach to identify and optimally treat bacterial coinfection is needed.

1Department of Pediatrics, Rainbow Babies and Children’s Hospital, Cleveland, OH.

2Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL.

3Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA.

4Departments of Anaesthesia and Pediatrics, Harvard Medical School, Boston, MA.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/pccmjournal).

Dr. Shein received funding from Accelerate Diagnostics. Dr. Randolph’s institution received funding from Genentech, and she received funding from Bristol Myers Squibb, La Jolla Pharma, and UpToDate (Section Editor, Pediatric Critical Care Medicine). The remaining authors have disclosed that they do not have any potential conflicts of interest.

Address requests for reprints to: Steven L. Shein, MD, Department of Pediatrics, Rainbow Babies and Children’s Hospital, 11100 Euclid Ave, RB&C 3rd floor (PCCM), Cleveland, OH 44106. E-mail: steven.shein@uhhospitals.org

Bronchiolitis is the most common cause of hospitalization in young children, leading to hospitalization of 2% of infants worldwide (1 , 2). Over 80% of these illnesses are associated with respiratory syncytial virus (RSV), which infects almost all young children (3 , 4). Children with RSV-associated lower respiratory tract infections (RSV-LRTI) commonly require PICU admission and many receive invasive mechanical ventilation (MV). Although use of MV varies by center and region (5 , 6), it is especially common in children with risk factors for severe disease such as younger age, chronic comorbidities, and higher viral load (7–9). Therapy for RSV-LRTI is limited to supportive treatment for sequelae, including dehydration and hypoxia (8). Viral lower respiratory tract infection also predispose children to develop secondary bacterial pneumonia (10). Diagnosing bacterial pneumonia in a child with RSV-LRTI is not standardized, possibly underlying the wide-ranging prevalences of 17–56% across studies (11–14). Consequently, it is difficult for clinicians to decide if antibiotics are indicated in a critically ill child with RSV-LRTI. Therapeutic strategies include presumptively initiating antibiotics in all children with RSV-LRTI receiving MV (colloquially a “48-hour rule out”) or withholding antibiotics pending additional evidence supportive of bacterial pneumonia, such as a positive culture from an endotracheal tube (ETT) aspirate (15).

Current antibiotic prescribing practices in children with severe RSV-LRTI are important to assess in an era where antibiotic stewardship is emphasized to preserve antibiotic efficacy, reduce costs, and limit toxicity (16). In addition, exposure to antibiotics early in life may alter a child’s microbiome, which has been associated with future asthma (17 , 18). Therefore, the purposes of this study are to describe antibiotic prescribing practices over time across major pediatric referral centers at the onset of MV in young children with RSV-associated acute respiratory failure and assess whether earlier antibiotic prescription was associated with their clinical course.

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MATERIALS AND METHODS

Data Source

Data for this study were obtained from the Pediatric Health Information System (PHIS), an administrative database that contains encounter-level data from not-for-profit, tertiary care pediatric hospitals in the United States affiliated with the Children’s Hospital Association (Overland Park, KS). Data quality and reliability are assured through a joint effort between the Children’s Hospital Association and participating hospitals. Portions of the data submission and data quality processes for the PHIS database are managed by Truven Health Analytics (Ann Arbor, MI). The PHIS database contains several “flags” that use Clinical Transaction Classification and International Classification of Diseases (ICD) codes to identify patients meeting criteria of interest. Please see the Online-Only Supplementary Text (Supplemental Digital Content 1, http://links.lww.com/PCC/A853) for additional details. For this study, data from 46 hospitals were included. This study was approved by the University Hospitals of Cleveland Institutional Review Board and the Children’s Hospital Association.

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Construction of the Study Dataset

We queried the PHIS database for children discharged between January 2012 and December 2016. Inclusion criteria were 1) age less than 2 years at hospital admission, 2) an ICD diagnosis code for RSV bronchiolitis (466.11 or J21.0) or RSV pneumonia (480.1 or J12.1), 3) a billing charge for ICU care (excluding neonatal ICU care), and 4) use of MV (defined by the presence of both the PHIS MV flag and a billing code for a neuromuscular antagonist) (19). Exclusion criteria were 1) preexisting medical conditions identified by the PHIS Complex Chronic Condition flag (20 , 21); 2) hospital length of stay (LOS) greater than or equal to 90 days; 3) incomplete billing data; 4) ICD diagnosis codes for bacteremia (790.7, 771.93 or R78.81), meningitis (320.x, 322.9, G00.x or G03.9) or urinary tract infection (590.x, 595.x, 599.0, 771.82, N39.0 or P39.3); and 5) onset of MV greater than or equal to 1 day prior to admission to the PHIS hospital PICU. Data extracted included demographics, primary payment method, antibiotics and parenteral vasoactive medications prescribed (using inpatient pharmacy billing data) (19), and ICD diagnosis and procedure codes. For each subject, only the first admission during the study period was analyzed.

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Definitions

Days on which antibiotics were prescribed were referenced to the first day of MV. Only systemic (enteral or parenteral) antibiotics during the 28 days following onset of MV were evaluated. “Early antibiotic” usage was defined as antibiotics prescribed on both of the first 2 days of MV. The “no early antibiotic” group consisted of subjects not prescribed antibiotics on either of the first 2 days of MV. Children prescribed antibiotics on just one of the first 2 days of MV were not classified in either group and were excluded from all analyses. Patients in the no early antibiotic group were further divided into patients who were prescribed antibiotics on greater than or equal to 2 consecutive days later in their hospitalization (“late antibiotic group”) and those who were not (“never antibiotic group”). Bacterial pneumonia was defined by an ICD diagnosis code for pneumonia due to a specific species of bacteria (e.g., 481 [Streptococcus pneumoniae pneumonia]) or pneumonia due to a specific class of bacteria (e.g., 482.83 [Gram-negative pneumonia not elsewhere classified]), but not by a code for pneumonia without any specifics related to the causative bacteria (e.g., 482.9 [bacterial pneumonia not otherwise specified]).

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Analyses

Variables were compared between treatment groups with chi-square analysis, Wilcoxon rank-sum tests, or Kruskal-Wallis analysis of variance (ANOVA). The percentage of subjects prescribed early antibiotics was calculated (early antibiotics/[early antibiotics + no early antibiotics]) for each year in the study period and compared with chi-square for trend. Prescription of specific antibiotics (e.g., ceftriaxone, ampicillin, etc.) during the first 2 consecutive days of antibiotic prescription was compared between the early antibiotic group and the late antibiotic group using Fisher exact test. Antibiotics were classified based on chemical structure (e.g., penicillins, macrolides, etc.) and functional classes (antipseudomonal, community acquired [CA] pathogens, etc.), and prescription was again compared between groups with Fisher exact test (for additional classification details, see Online-Only Supplementary Text, Supplemental Digital Content 1, http://links.lww.com/PCC/A853) (22–25). For these early versus late antibiotic analyses, alpha was set conservatively at 0.001 in order to account for multiple comparisons.

Clinical outcomes (duration of MV and hospital LOS) were compared between the early antibiotic group and the no early antibiotics group with Wilcoxon rank-sum tests. Associations between outcomes and other patient-level variables were evaluated with Wilcoxon rank-sum tests (gender, ethnicity, insurance type, vasoactive medication use on the first day of MV, apnea), Kruskal-Wallis ANOVA (race) or Spearman correlation (age). Patient-level variables that were associated (p ≤ 0.10) with outcome in the bivariate analyses were included as fixed effects in mixed-effect multivariate regression models for duration of MV and hospital LOS. In order to adjust for institutional variation, each center’s difference from the overall average proportion of early antibiotic administration (i.e., center usage rate minus overall usage rate) was included in the mixed-effect models as a random effect. Subjects were then divided into two groups based on the presence or absence of a discharge diagnosis of bacterial pneumonia, and similar models were created for each subgroup. We also repeated our analyses after dividing the groups based on age (< 2 and ≥ 2 mo). Finally, in a sensitivity analysis, we assessed whether including children with non-RSV bronchiolitis (ICD diagnosis code of 466.19, J21.1, J21.8 or J21.9) influenced the results. Outcomes related to early antibiotic use in this cohort were analyzed as described above.

Nominal variables are described using frequencies and percentages, continuous variables are described with medians and interquartile ranges, and results of the multivariate models are shown as parameter estimate (β). All analyses were performed using SAS, v9.4 (The SAS Institute, Cary NC). Unless otherwise stated, the level of significance was set at p value of less than 0.05.

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RESULTS

We identified 2,973 PICU patients with RSV-LRTI who underwent MV and 2,107 children were included in the analysis (Fig. 1). Antibiotics were prescribed on greater than or equal to 2 consecutive days during the study period to 1,989 (94.4%) children, 1,727 of whom (82.0%) were in the early antibiotics group. The duration of early antibiotics was 2–3 days long in 425 (24.6%) children, 4–6 days in 378 (21.9%), and greater than or equal to7 days in 924 (53.5%). Antibiotic prescription was reinitiated at a later date in 185 children (23.0%) who initially received a less than 7-day course. Overall, these 1,727 children were prescribed antibiotics for a median of 10 days (7–14 d) during the study. Of the 380 children in the no early antibiotics group, 262 (68.9%) received late antibiotics for a median duration of 8 days (7–10 d). The median initial day of antibiotic prescription in these children was the fourth day of MV (3–5). Children in the early antibiotic group were younger and more frequently prescribed vasoactive medications on the first day of MV than children in the no early antibiotic group (Table 1).

TABLE 1

TABLE 1

Figure 1

Figure 1

There was a trend for decreased early antibiotic use over the study period (2012: 85.9%, 2013: 83.0%, 2014: 83.9%, 2015: 77.1%, 2016: 80.4; p for trend = 0.004). Use of early antibiotics varied from 36.4% to 100% across centers (Fig. 2). In both the early and late antibiotic groups, the most common antibiotics prescribed during the first 2 days of antibiotic therapy were cefotaxime (49.0% of early antibiotic subjects; 27.1% of late antibiotic subjects), ceftriaxone (45.6%; 43.1%), and vancomycin (37.2%; 27.5%) (Supplemental Fig. 1a, Supplemental Digital Content 1, http://links.lww.com/PCC/A853). No single antibiotic was prescribed to greater than 50% of children, five different drugs were prescribed to greater than 10% of children, and nine drugs were prescribed to greater than 5% of children. Cefotaxime, ampicillin, and azithromycin were more likely to be prescribed in the early antibiotic group, and piperacillin/tazobactam, ceftazadime, ampicillin/sulbactam, cefuroxime, and amoxicillin/clavulanic acid were more likely to be prescribed in the late antibiotic group. When classified by chemical structure, late-generation cephalosporins (93.1% vs 76.0%) and macrolides (8.6% vs 0.4%) were more likely to be prescribed in the early antibiotic group, and early-generation cephalosporins (0.9% vs 3.4%) were more likely to be prescribed in the late antibiotic group (all p < 0.001) (Supplemental Fig. 1b, Supplemental Digital Content 1, http://links.lww.com/PCC/A853). When classified functionally, antibiotics indicated for common CA and atypical pathogens were more likely to be prescribed in the early antibiotic group, and antibiotics effective against Pseudomonas aeruginosa (13.1% vs 24.8%) were more likely to be prescribed in the late antibiotic group (all p < 0.001) (Supplemental Fig. 1c, Supplemental Digital Content 1, http://links.lww.com/PCC/A853).

Figure 2

Figure 2

Compared with the no early antibiotics group, the early antibiotic group had a shorter duration of MV (6 d [4–9 d] vs 8 d [6–11 d]; p < 0.001) and a shorter hospital LOS (11 d [8–16 d] vs 13 d [10–18 d];p < 0.001). Younger age, race, gender, vasoactive medication use on the first day of MV, and insurance type all met the a priori criteria to be included in the multivariate models as fixed effects based on results of the bivariate analyses (Table 2), along with treatment center as a random effect. Early antibiotic use was associated with a 1.21-day shorter duration of MV and a 2.07-day shorter hospital LOS after adjusting for these factors (Table 3). Results were similar when the cohort was divided based on the presence (n = 579) or absence (n = 1,528) of a diagnosis code for bacterial pneumonia, with early antibiotic usage associated with approximately 1.5-day improvement in duration of MV and approximately 2-day improvement in hospital LOS in both subgroups (Tables 4 and 5). Results were also similar in the 1,058 subjects less than 2 months at hospital admission, 84.8% of whom received early antibiotics, and the 1,049 subjects greater than or equal to 2 months at hospital admission, 79.1% of whom received early antibiotics (Supplemental Tables 1 and 2 and Supplemental Figs. 2 and 3, Supplemental Digital Content 1, http://links.lww.com/PCC/A853).

TABLE 2

TABLE 2

TABLE 3

TABLE 3

TABLE 4

TABLE 4

TABLE 5

TABLE 5

In the secondary analysis of 2,904 children that also included subjects with non-RSV-LRTI, antibiotic usage for the first 2 days of MV (82.5% of cases) was again associated with both shorter duration of MV (6 d [4–8 d] vs 7 d [5–11 d]; p < 0.001) and shorter hospital LOS (11 d [8–15 d] vs 12 d [9–18 d]; p < 0.001) compared with children not prescribed antibiotics during the first 2 days of MV. In the multivariate models adjusted for treatment center, age, race, gender, vasoactive medication use, and insurance type (Supplemental Table 3, Supplemental Digital Content 1, http://links.lww.com/PCC/A853), antibiotic use was associated with a 1.34-day shorter duration of MV and a 1.55-day shorter hospital LOS (both p < 0.001).

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DISCUSSION

In this multicenter dataset of over 2,000 previously healthy infants and toddlers with RSV-LRTI undergoing invasive MV in the PICU of one of 46 U.S. children’s hospitals, prescription of antibiotics during MV was common and typically for at least 7 days duration, even though only one quarter of these children had a discharge diagnosis of bacterial pneumonia. Furthermore, practices varied widely in regards to timing, duration, and type of antibiotics. Prescription at onset of MV varied from greater than 95% in the eight highest-usage centers to less than 65% in the seven lowest-usage centers. Most children who had antibiotics withheld initially had them prescribed by the fifth day of MV, and restarting antibiotics was common among early antibiotic children initially treated for less than 7 days. Regardless of the timing of initiation, there was not one antibiotic prescribed to the majority of children; instead, nine different drugs were prescribed to 5–49% of children. These haphazard variations in care may be particularly important given that children who were prescribed antibiotics at onset of MV had better outcomes than children not prescribed antibiotics during the first 2 days of MV and that the prescription of early antibiotics became less common over the study period.

Nearly universal prescription of antibiotics to mechanically ventilated children with bronchiolitis has also been reported by centers outside of the United States (11 , 13 , 14 , 26), and antibiotic prescription that varies widely between centers and has decreased in recent years was recently reported among the general PICU populations at PHIS hospitals (16 , 25), suggesting that the practice patterns that we observed are not limited by practice region nor disease process. The variations in antibiotic selection observed between the early and late antibiotic groups were also not unexpected, with shifts from drugs recommended for CA infections toward those effective against nosocomial pathogens, specifically P. aeruginosa. Although the antibiotics prescribed were often those recommended for CA pneumonia or neonatal sepsis, the recommendation to discontinue antibiotics after 48 hours if cultures are negative and the risk of infection is low appears to have been followed inconsistently (27 , 28). More than 75% of early antibiotic subjects continued antibiotics for greater than 3 days (i.e., beyond the “48-hour rule out”), which is higher than the reported rates of positive ETT cultures (~40%) in children with bronchiolitis (13) and likely reflects the previously reported practice of continuing antibiotics for suspected pneumonia during MV despite negative ETT cultures (29). Interestingly, among children who initially were not treated with antibiotics, antibiotics were initiated in ~50% of patients on the third or fourth day of MV, which may represent reaction to growth of a pathogen in ETT culture and may mitigate potential benefits of withholding antibiotics on financial costs, antimicrobial resistance, and clinical outcomes (17 , 18).

This varied prescription of antibiotics may represent an important opportunity for quality improvement. Although the nearly universal prescription of antibiotics suggests the need for improved antimicrobial stewardship to limit unnecessary antibiotic usage, this must be balanced with our finding that the practice of prescribing antibiotics on the first 2 days of MV was associated with shorter clinical courses, which may then lessen the risks of ventilator-related lung injury or infection, the exposure to potentially toxic sedative medications, and financial costs (19 , 30 , 31). The direction of this association is somewhat surprising given that retrospective studies of clinical practices are inherently at risk for confounding by indication, in which treatments—even beneficial ones—are associated with unfavorable outcomes because they are more likely provided to “sicker” patients (32). The children prescribed antibiotics in our study may have been less ill, but that is doubtful given their younger age and more common prescription of vasoactive medications. Macrolides and tetracyclines may reduce inflammation, but those agents were rarely prescribed in our cohort (33 , 34). It is quite possible that the antibiotics were simply treating bacterial pneumonia, even among some of the 73% of patients who did not have a discharge diagnosis of bacterial pneumonia, suggesting the need for better methods to diagnose bacterial pneumonia than current practice, in which ETT aspirate cultures often guide therapy despite limited specificity (35 , 36).

Although we excluded a substantial number of children from analysis, we believe these exclusions strengthen our study. Children diagnosed with other invasive bacterial infections who benefit from antibiotic therapies were excluded to avoid biasing our results toward antibiotic therapy. Children with significant comorbidities were excluded using a well-established identification system (37 , 38) to make the cohort as homogenous as possible and minimize confounding variables. Children prescribed only 1 day of antibiotic prescription during the first 2 days of MV may have actually received 2 days of antibiotics (e.g., given the first dose in the prehospital setting) or 0 days (e.g., the medication may have been prescribed inadvertently and not administered), so they were excluded from all analyses.

Use of an administrative database has associated limitations (39). The PHIS database has been used previously in RSV-LRTI studies and uses multiple measures to optimize data quality, but the inherent risk of misclassification is nontrivial (26 , 40–44). To minimize this, our criteria for MV required both the PHIS MV flag and prescription of a neuromuscular antagonist (19). This increased accuracy but reduced the size of our cohort. We also used specific criteria for bacterial pneumonia, including documentation of a relevant pathogen, although the specificity of endotracheal aspirate cultures for ventilator-associated pneumonia is suboptimal and highly dependent on the timing and methods of collection (35). Medication usage was based on pharmacy billing data, and some medications could have not been administered, but this is less likely when prescribed on multiple days. Therefore, prescription for 2 consecutive days was used for early antibiotics and late antibiotics definitions. We were unable to evaluate antibiotic prescription prior to PICU admission, which may be important given the improved outcomes from early antibiotic treatment in PICU patients with severe infections (45). We did not evaluate for associations between outcomes and duration of antibiotics but focused instead on timing of antibiotic initiation. We used vasoactive medication prescription as a proxy of disease severity since data were not available to calculate an illness severity score (46 , 47), but this may not have adequately controlled for illness severity. Prescription of early antibiotics may have been a marker of increased severity of illness at onset of MV, but prescription of late antibiotics may have been prompted by a child’s inability to wean from MV; both of these possible treatment biases may have influenced our outcomes, although in opposite directions. We did not evaluate subsequent infections by resistant pathogens or postdischarge outcomes, including influence on the microbiome and chronic respiratory conditions such as asthma (17 , 18). There were relatively few subjects in the “no early antibiotics” group, although our analyses were adequately powered to identify statistically significant differences between groups. Finally, all data come from U.S. children’s hospitals and our findings may not be generalizable to other settings.

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CONCLUSIONS

Antibiotic prescription is common in previously healthy children with RSV-LRTI receiving invasive MV in the PICU of U.S. children’s hospitals but varies among centers and in regards to timing, duration, and type of antibiotic. Delaying antibiotic use in this population may lead to worse short-term clinical outcomes, as the practice of prescribing antibiotics for the first 2 days of MV was associated with faster clinical recovery. Only a randomized trial can establish if this practice is truly efficacious, but that may not be feasible given our findings of its widespread use and potential clinical benefits. Instead, the best way forward may be prospective epidemiologic studies to measure the contemporary prevalence of bacterial pneumonia in children with RSV-LRTI, evaluate rapid diagnostic technologies (48), and identify accurate biomarkers of bacterial coinfection (49). The potential effects of widespread antibiotic exposure during very early life on the child’s microbiome and long-term health must also be considered.

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Keywords:

bronchiolitis; pneumonia; database; pediatric; mechanical ventilation

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