Changes in Antibiotic Treatment for Children With Lyme Meningitis 2015–2020

We performed a retrospective cohort study using the Pediatric Health Information System (PHIS), an administrative database containing billing data from 45 tertiary care pediatric hospitals in the United States. Our institutional review board designated the study as exempt.

We included patients ≤21 years of age who presented to the emergency department (ED) between October 1, 2015, and September 30, 2020, with Lyme meningitis using the following International Classification of Diseases, 10th Revision (ICD-10) codes: Lyme meningitis (A6921 or A6922) or Lyme disease (A692) and meningitis not otherwise specified (G03). Patients with any chronic comorbid condition were excluded.¹³  If patients had >1 eligible encounter for Lyme meningitis we took the first eligible encounter. However, if encounters occurred >14 days apart, we considered each as an index ED encounter. For the lead study site, we reviewed the medical record to confirm eligibility.

We reviewed the patient-level demographic and clinical data from the index hospitalization, including antibiotic treatment, sedation medications, and duration of hospital stay. We defined procedural sedation as the administration of sedation-specific medications at any time during hospitalization.¹⁴  We also reviewed all return visit to the same ED within 14 days of the index encounter.

Our primary outcome measure was Lyme meningitis treatment with parenteral antibiotics, defined by either a procedure code for indwelling catheter placement¹⁵  before discharge or >7 days of inpatient parenteral therapy with an antibiotic active against Borrelia species (Supplemental Table 2). We selected >7 days because this indicates the child received more than half of the 14-day treatment course parenterally.^10,16  Otherwise, we classified children as being treated with an oral antibiotic after discharge. Our secondary outcome was any complication within 14 days of the index ED encounter.

We compared demographic and clinical characteristics between children discharged with parenteral versus oral antibiotics using the χ² test for categorical variables and the Mann–Whitney test for continuous variables. To examine trends in antibiotic therapy over time, we used a generalized estimating equation adjusted for age, sex, race, ethnicity, and insurance status after clustering by hospital to examine the relationship between study year and parenteral antibiotic therapy.

We used SPSS version 27.0 (IBM SPSS Statistics, IBM Corporation, Armonk, NY) for all analyses.

Of the 296 ED encounters identified by ICD-10 codes, 17 (5.7%) were excluded as repeat ED encounters and 40 (13.5%) were excluded because the patient had a complex comorbid condition (Supplemental Fig 2). Of the remaining 239 study patients, the median age was 10.8 years (interquartile range 7.4–14.0 years) and 132 (55.2%) were male. Only 5 patients were >18 years of age. Twenty-four PHIS hospitals treated children with Lyme meningitis, with 196 (82.0%) encounters to 7 pediatric centers located in highly endemic areas in the Northeast, mid-Atlantic, and upper Midwest. All 21 children identified from the lead study site met eligibility criteria after medical record review.

Overall, 48 children (20.0%) were treated with parenteral antibiotics and 191 (80.0%) were treated with oral antibiotics. Of those treated with parenteral antibiotics, 43 (89.6%) had an indwelling catheter placed and 5 (10.4%) received >7 days of parenteral antibiotics active against Borrelia infection. Approximately two-thirds of children with Lyme meningitis received procedural sedation during their hospital stay. Those children treated with parenteral antibiotics were more likely to receive procedural sedation during their stay, to be hospitalized and, if admitted, to have a 1-day longer length of stay (Table 1). Twenty-five children with Lyme meningitis treated with oral antibiotics were discharged after the initial ED encounter.

The annual rate of parenteral antibiotic treatment decreased over the study period (from 43.8% to 8.9%) (Fig 1). After adjustment and clustering by hospital center, the odds of treatment with parenteral antibiotics after discharge decreased annually across the study period (adjusted odds ratio 0.57; 95% confidence interval 0.41–0.80). ED return visit rates within 14 days for any reason were similar for both treatment groups (Table 1). Of the 39 children with repeat ED encounters, 9 had a treatment complication: 4 related to diagnostic lumbar puncture, 3 related to the indwelling catheter, and 2 related to antibiotic reactions (1 to parenteral antibiotics and 1 to oral antibiotics). Two patients initially treated with enteral antibiotics were switched to parenteral treatment at the time of ED revisit.

In our multicenter cohort of children with Lyme meningitis, less than one-quarter were treated with a parenteral antibiotic after discharge despite published guidelines suggesting parenteral antibiotics as a first-line therapy. Over the study period, the odds of parenteral antibiotic treatment of Lyme meningitis decreased by nearly half for each year.

Lyme meningitis treatment with parenteral antibiotics frequently requires placement of an indwelling catheter to allow the delivery of parenteral antibiotics at home. However, placement of an indwelling catheter is not a trivial intervention, even for previously healthy children.^17,18  First, procedural sedation is frequently required for the successful line placement.¹⁸  Second, up to half of children who have an indwelling catheter will either have an infectious (eg, phlebitis or bloodstream infections)¹⁹  or mechanical (eg, accidental dislodgment or breakage)²⁰  complication. Last, children can have an adverse drug reaction when treated with several weeks of parenteral antibiotics.²¹  In a study of 157 children with Lyme meningitis who had a PICC placed, one-quarter had an infectious or mechanical PICC complication and 10% had an adverse drug reaction,²  similar to the rates we observed in our multicenter cohort. Because short courses of doxycycline are considered safe for young children,⁴  reexamination of Lyme meningitis first-line treatment is needed.

In a change from the 2006 IDSA guidelines,¹⁶  the recently released 2020 IDSA, ACR, and AAN Lyme disease guideline¹⁰  recommends either doxycycline or ceftriaxone as a first-line treatment for Lyme meningitis, despite lack of definitive evidence that oral doxycycline is as effective as parenteral ceftriaxone in US children with Lyme meningitis. Although 32 children with Lyme meningitis were safely treated with only oral antibiotics at a single center,⁹  the single-center design, small sample size, and lack of prospective follow-up limits generalizability. Despite limited evidence, our study reveals that clinical practice has already begun to change before publication of the most recent guidelines. As Lyme meningitis treatment changes, a carefully designed comparative effectiveness study to better understand clinical outcomes²²  as well as patient and parenteral treatment preferences is needed to ensure optimal treatment decisions for children with Lyme meningitis.

Our study has several limitations. First, the PHIS administrative database only includes selected pediatric centers, and our findings may not be generalizable to all children treated for Lyme meningitis. Second, we relied on discharge diagnosis codes for case ascertainment and may have missed including eligible children who were assigned alternate diagnostic codes (eg, meningitis). However, we limited our study period to after the transition to ICD-10, recognizing the increased specificity of these diagnostic codes, which was confirmed by our limited medical record review. Third, we limited our cohort to those children who had an eligible ED encounter, and although uncommon,²³  we would have missed children with Lyme meningitis directly admitted to the hospital. Fourth, although children treated with parenteral antibiotics were more likely to receive procedural sedation, we could not determine the clinical indication for this sedation (eg, performance of the diagnostic lumbar puncture or placement of the indwelling central line). Fifth, we used a proxy measure to define postdischarge antibiotic therapy because we did not have access to outpatient antibiotic prescription data. Most patients who were treated as outpatients with parenteral antibiotics required placement of an indwelling catheter, making this a good surrogate marker. However, we relied on accurate procedure code assignment for identification of indwelling catheter placement. Sixth, we were not able to capture treatment plan changes after hospital discharge unless the patient returned to the hospital. Finally, we could not assess clinical characteristics or illness severity, which could have impacted the decision to treat with parenteral versus oral antibiotics as well as affected clinical outcomes. Further prospective studies are needed to better evaluate these factors and to measure related outcomes.

Before the publication of the IDSA, ACR, and AAN 2020 Lyme disease clinical practice guideline, treatment of children with Lyme meningitis had begun to shift from parenteral ceftriaxone to oral doxycycline. Carefully designed prospective studies are urgently needed to compare the short- and long-term clinical outcomes for children with Lyme meningitis treated with parenteral ceftriaxone compared with oral doxycycline.