Intravenous Versus Oral Outpatient Antibiotic Therapy for Pediatric Acute Osteomyelitis

Abstract

The optimal route (oral versus intravenous) of antibiotic administration for pediatric acute osteomyelitis is not well established. Seventy-eight children from our university hospital and 17 children at our county hospital were treated for acute osteomyelitis. The rates of intravenous antibiotics upon discharge were 95% versus 65% (P=0.002), respectively. The recurrence rate and line complication rates were 10% and 24% at the university hospital, compared to 0% (P=0.34) and 6% (P=0.29) at the county hospital. Based on this data, a prospective comparison between intravenous and early oral antibiotic therapy for pediatric acute osteomyelitis is recommended.

Introduction

Pediatric osteomyelitis is a common disease treated by the orthopaedic surgeon. Treatment includes antibiotic therapy and immobilization, with or without surgical drainage and decompression. Both the route and duration of antibiotic therapy can have significant impact on a child’s clinical course, as these factors determine whether the child will require a central venous catheter. Despite this, a recent review of the literature found no clear data on the optimal route and duration of antibiotic therapy, and recommended continuation of the gold standard of 4-6 weeks of intravenous antibiotics pending further evidence¹.

Historically, early conversion to oral antibiotic therapy was associated with a high failure rate^2-3. With the advent of high dose oral antibiotic dosing and serum assays for antibiotic titers, multiple studies have suggested that oral antibiotic regimens can treat acute osteomyelitis with similar low failure rates^4-21. However, most of these studies do not address the pediatric population, and many of the comparative studies are retrospective and within the same institution, which can lead to bias.

Intravenous antibiotic therapy is often viewed as a relatively benign treatment. However, in the pediatric population complication rates can be high, ranging from 29-41% in previous studies^22-24. Although the majority of these complications are simple line malfunctions, a line sepsis rate of 11% was reported in one study²². Intravenous antibiotics are also associated with adverse drug events in children undergoing prolonged outpatient treatment for osteomyelitis, with a rate of 32% in one recent study²⁵.

We have noticed a difference in treatment philosophy at two of our hospitals. At our university hospital, pediatric patients are routinely treated with approximately six weeks of intravenous antibiotics for acute osteomyelitis. At our county hospital, one of the infectious diseases staff prefers oral antibiotics, and converts patients to oral antibiotics prior to discharge as a first-line treatment unless there is a concern for noncompliance, reaction to the oral antibiotics or lack of an oral antibiotic option. The purpose of this study was to compare the rates of intravenous antibiotic use, line complications and recurrence of infection at our two institutions.

Methods

Patient Selection

This retrospective study was approved by both the University and the County hospital’s Institutional Review Boards. Inclusion criteria included all pediatric patients, ages 17 years and younger, admitted to our institution between January 2000 and December 2006 with ICD-9 codes 711.00-711.09 (septic arthritis) and 730.00-730.29 (osteomyelitis, acute and chronic). Diagnosis of septic arthritis was used to allow inclusion of patients with both septic arthritis and osteomyelitis. Patients were excluded if they were treated at an outside hospital for their inpatient stay, did not carry a diagnosis of osteomyelitis, or did not have a complete inpatient chart establishing the diagnosis and detailing antibiotic treatment. We defined acute osteomyelitis as the initial presentation²⁶, and thus patients who had already been treated for a previous episode were excluded. Finally, we excluded children with significant medical comorbidities that could potentially lead to higher rates of recurrence. These comorbidities included: cerebral palsy, trisomy 21, myelodysplasia, osteosarcoma, premature birth, and Crohn’s disease. These exclusion criteria were utilized in an attempt to equalize the populations between our university and county hospitals.

The same pediatric orthopaedic group covered both hospitals. Surgical drainage was performed for subperiosteal abscess, extension into the joint and clinical deterioration despite antibiotic therapy.

Chart Review

Charts were reviewed for patient demographics (age, gender, medical comorbidities), presentation (duration of symptoms, preceding illness, fever on presentation, ESR and CRP on admission or within first day), site of infection, culture results, treatment (surgery, duration of inpatient stay, intravenous versus oral antibiotics upon discharge, duration of antibiotics), recurrence, line complications (accidental removal, malfunction, infection) and date of last follow up either with orthopaedics, infectious diseases or their primary care practitioner. Recurrence was defined by the need for a repeat course of antibiotics therapy, with or without a repeat surgical debridement.

Statistical Analysis

Age, duration of symptoms, presenting laboratory values, duration of antibiotic treatment, duration of inpatient stay, and duration of follow up were compared with two-tailed t-tests. Gender, preceding illness, fever on admission, rate of exclusions, patients undergoing surgery, intravenous antibiotics upon discharge, recurrence and line complications were compared with Fisher exact tests.

Results

Our review included 78 patients from the university hospital and 17 patients from the county hospital. Demographic data is provided in Table 1. There were no significant differences between the baseline characteristics of the two populations.

Table 1.

Patient Demographics by Hospital

	University Hospital	County Hospital	P Value
Patients	78	17
Age (years)	7.5 ± 4.9	7.8 ± 4.6	0.82
Female	33 (42%)	3 (18%)	0.10
Male	45 (58%)	14 (82%)
Duration of symptoms (days)	13 ± 23	11 ± 11	0.65
Preceding Illness	12 (15%)	1 (6%)	0.45
Fever on Admission	56%	44%	0.72
ESR	54 ± 30	55 ± 32	0.93
CRP	7.0 ± 7.9	4.6 ± 4.6	0.23
Medically excluded	16 (17%)	3 (15%)	1.00

Table 2 lists the comparative treatment data between the two institutions. There was a significantly higher rate of intravenous antibiotic use at discharge in the university group (95% versus 65%, P=0.002). The duration of intravenous and total antibiotic treatment were comparable between the two hospitals except in the case of total duration of antibiotic treatment in children discharged on oral antibiotics (21 days at the university hospital versus 44 days at the county hospital, P=0.04). There were eight recurrences at the university hospital versus none at the county hospital, and 16 line complications at the university hospital versus one at the county hospital, but these differences were not significant (P=0.34 and 0.29). Two of the line complications at the university hospital were considered major (line sepsis), versus no major complications at the county hospital. At the university hospital, two of 16 patients (13%) with line complications developed recurrence, which was not notably different than the rate of recurrence in children without line complication. There was a significantly longer duration of follow up at the county hospital (32 versus 6 months, P=0.009).

Table 2.

Patient Results by Hospital

	University Hospital	County Hospital	P Value
Patients	78	17
Surgery	36 (46%)	7 (41%)	0.79
IV on discharge	74 (95%)	11 (65%)	0.002
Duration IV (days)	36	42	0.22
Total duration (days)	54	53	0.68
PO on discharge	4 (5%)	6 (35%)
Duration IV (days)	2.5	4.5	0.20
Total duration (days)	21	44	0.04
Inpatient stay (days)	6.0 ± 5.2	6.5 ± 3.3	0.65
Recurrence	8 (10%)	0 (0%)	0.34
Line complications	16 (24%)	1 (6%)	0.29
Follow up (months)	6.0 ± 14.1	32 ± 35	0.009

Tables 3 and 4 show demographic and treatment data when comparing all patients treated with intravenous versus oral antibiotics at discharge. The intravenous group presented with an increased duration of symptoms (13.5 versus 5.2 days, P=0.007), and a trend towards a higher initial CRP (6.9 versus 3.5, P=0.11).

Table 3.

Patient Demographics by Treatment

	Intravenous	Oral	P Value
Patients	85	10
Age (years)	7.9 ± 4.8	5.5 ± 5.3	0.21
Female	34 (40%)	2 (20%)	0.31
Duration of symptoms (days)	13.5 ± 22.3	5.2 ± 4.4	0.007
ESR	54 ± 31	58 ±30 30	0.68
CRP	6.9 ± 7.8	3.5 ± 3.6	0.11

Table 5 lists the sites of infection at the two hospitals. Table 6 lists the culture results from peripheral blood, bone aspiration and direct culture either from a wound or within the operating room. The majority of the infections at both hospitals were either culture positive for Staphylococcus aureus or culture negative.

The charts from the eight patients with recurrences were reviewed in additional detail. Seven of the patients were discharged on intravenous cefazolin, while the eighth was discharged on intravenous nafcillin. Of the surgically treated patients, four of 43 patients had recurrences for an overall rate of 9%. Of the nonsurgically treated patients, four of 52 patients had recurrences for an overall rate of 8%.

Discussion

The optimal route of antibiotic therapy for pediatric acute osteomyelitis remains controversial. Most previous studies reported on a single treatment pathway⁴–⁷,⁹–¹¹,¹⁷–¹⁹,²¹. Some studies have compared intravenous versus oral antibiotics, but were limited by the number of patients studied⁸, or were focused on the adult population.^12-15

Our study attempted to normalize two populations by excluding children with significant medical comorbidities. Interestingly, the baseline characteristics of the two patient cohorts were comparable, including the rates of medical exclusion. This may be explained because our two hospitals have some relative geographic separation, with each hospital drawing from its local population for this diagnosis.

We retrospectively studied patients from two different institutions with different treatment philosophies to obtain a less biased comparison of intravenous versus oral antibiotics. Our analysis showed no significant difference in recurrence, despite the increased rate of intravenous antibiotics at the university hospital. Although one might expect a lower duration of follow up at a county hospital, ours had longer follow up which was attributed to the centralized electronic medical record used at the county hospital. The longer follow up at the county hospital increases our confidence in the lower rate of recurrence despite the higher rate of oral antibiotic usage.

Table 4.

Patient Results by Treatment

	Intravenous	Oral	P Value
Patients	85	10
Surgery	40 (47%)	3 (30%)	0.50
Inpatient stay (days)	6.2 ± 5.1	5.2 ± 4.3	0.20
Recurrence	8 (9%)	0 (0%)	0.59
Line complications	17
Follow up (months)	9 ± 19	24 ± 37	0.25

We also found a relatively high rate of line complications, which fits well with the literature range of 29-41%²²,²⁴ Like previous reports, we did not find an increased rate of recurrence in children who had line complications²³. Nevertheless, these complications represent a significant number of visits to the emergency room or clinic, as well as hospital admissions.

When we analyzed our results based on treatment modality, we did find a shorter duration of symptoms, and a trend towards a lower initial CRP, suggesting baseline differences between the intravenous and oral treatment groups. It is possible that these differences were due to the inclusion of the small percentage of patients who received oral antibiotics upon discharge at the university hospital. The patients at the university hospitals had a significantly shorter total duration of antibiotics, suggesting that they were equivocal cases of infection.

Older studies in the literature reported fairly high rates of recurrence with shorter courses of intravenous antibiotics, with one noting a 19% failure rate with three or less weeks of intravenous treatment versus a 2% failure rate with longer durations²–³. Notably, these studies either did not use oral antibiotics after intravenous treatment or use modern dosages of oral antibiotics. Multiple studies have since reported the importance of high dose oral antibiotics and measurement of serum titers to ensure adequate antibiotics levels in the bloodstream⁴,⁶,⁹–¹¹,¹⁷,¹⁹,²⁷.

One study found that in 8 of 75 children the antibiotic dosage was changed based on titers⁶. Notably, it is routine at our county hospital to check serum titers after converting to oral antibiotics, and prior to discharge.

Recent comparison studies in adults have not found differences in recurrence rates when comparing shorter versus longer durations of intravenous antibiotic thera- py¹²–¹⁵. One randomized prospective study in children found similar rates of recurrence when comparing an average of 6 versus 28 days of intravenous antibiotics, but only enrolled 23 patients in the study⁸. A recent database study of 29 pediatric hospitals compared 1,021 children discharged on intravenous antibiotics and 948 children discharged on oral antibiotics for acute osteomyelitis and found similar recurrence rates of 5% and 4%, respectively²⁰.

By comparing two hospitals with different treatment philosophies, rather than separating the treatment groups within a single hospital, we feel that our study reduces the treatment bias of oral antibiotics for more mild cases and offers a useful comparison between the two routes of antibiotic treatment. While a rate of 65% at our county hospital still seems relatively high, this rate was attributed to the fact the only one of the pediatric infectious diseases staff favored oral antibiotics, while the other staff preferred intravenous. The general practice of that staff member was oral antibiotics for all patients unless there were issues with patient noncompliance, or a lack of any available oral antibiotics due to allergies, reactions and susceptibilities.

Our study has important limitations. It is a retrospective study, and it was not possible to create two equal treatment groups, though we attempted to minimize this bias by excluding patients with significant medical comorbidities. As noted above, the significantly increased length of patient symptoms and trend towards a larger CRP indicates that the intravenous group may have had a more significant disease burden than the oral group. In addition, our total number of patients treated with oral antibiotics is relatively small, and our study is not powered to definitively state that intravenous and oral antibiotic treatments are equivalent in terms of recurrence. With our small patient numbers we also did not separate our results by organism, which may be significant in cases where the oral antibiotics available are not as effective as the parental antibiotics. Finally, we did not review patient compliance, which could have a significant impact on our results.

In conclusion, this study supports the growing body of evidence that early transition to oral antibiotic therapy may offer a similar recurrence rate to intravenous therapy, while avoiding the relative high rate of complications seen with central venous catheters. Like many others, we support the use of serum titers to ensure adequate oral dosing. In the future, prospective comparative studies are necessary to determine the optimal route and duration of antibiotic treatment in pediatric acute osteomyelitis.