Prolonged IV vs. Early Conversion
to Oral Antibiotic Therapy?
Is it Time for a Change
Theoklis Zaoutis, MD, MSCE
Asst. Prof. of Pediatrics and Epidemiology
Assoc. Director, Center for Pediatric Clinical
Effectiveness Research
Overview:
Acute Osteomyelitis (AO)
Background
Study Methods and Results
Bias -misclassification
AO: epidemiology and risk factors
1 in 5000 each year in US
1% of pediatric hospitalizations
50% occur before 5 years old
Twice as common in males
1/3 have preceding minor trauma
AO: epidemiology by site
Humerus (13%)
Vertebrae (2%)
Pelvis (7%)
Femur (25%)
Tibia (24%)
Calcaneus (5%)
AO: management
Traditional management consists of 4-6
weeks of parenteral (IV) antibiotic therapy
Duration of Therapy: Dich 1975
Immediate needle aspiration of
subperiosteal space and bone.
Drainage through bone window if pus
found on needle aspiration.
Exclusive IV antibiotics
Duration of IV therapy
Recurrent or chronic osteo
≤ 21 days
>21 days
7/37 (19%)
1/47 (2%)
Route of Therapy: Tetzlaff 1978
IV until signs of ’d inflammation (mean 7.3 d)
Followed by PO (mean 19.8 d)
Conditions for conversion to PO:



Organism identified (blood, bone, joint)
Peak bactericidal titer > 1:8
Hospitalized for duration of treatment (including oral
therapy)
Only 1/22 developed chronic osteo
Route of Therapy: Cole 1982
Minimize surgery: bone aspiration for abscess
drainage only (22%)
Minimize duration of IV therapy (mean 3 d)
Complete oral therapy as outpatient
No bactericidal levels measured
Cured after 6 weeks of therapy:


44/48 with “early” acute osteo (fever < 48 h)
2/8 with “late” acute osteo (symptoms >5 days, all
with abscess)
Route of Therapy: Peltola 1997
50 patients with S. aureus AO
Surgery (needle aspiration or drilling)
Conversion to high-dose 1st generation oral
cephalosporin after 3-4 days
Serum bactericidal activity and antibiotic
concentrations not measured
3-4 weeks total therapy (mean 23 days)
Intensive f/u with ESR x 8; CRP x 12 in 30 d.
Mean 11 days of hospitalization
No complications with 1 year follow-up
Route of Therapy: Le Saux 2002
Systematic review
Clinical cure rate at 6 months:


IV: short course (< 7 d) vs. long-course (>7d)
Then switch to PO antibiotics.
12 case series or small observational studies: 7
short-course and 5 long-course therapy.
Clinical cure rate


Short-course = 95.2% (95% CI; 90.4, 97.7) No Difference
Long-course = 98.8% (95% CI: 93.6, 99.8)
Safety of Prolonged IV Therapy
IV x
5d,
then
PO
AO
n=80
No rehospitalization
No return to ED
n-=5
31/75 (41%) developed complications
IV x
2wks
with
CVC
n=75
• 17 (23%) CVC malfunction or displacement
• 8 (11%) catheter-assoc bloodstream infection
• 8 (11%) fever with negative blood cx
• 4 (5%) local skin infection at CVC site
Ruebner 2005 Pediatrics
What is the Best Practice?
What is currently being done in practice?
Is early conversion to PO effective?
We cannot perform the randomized,
controlled clinical trial because:


Certain centers have already changed to
practice
Clinical trial to find a failure rate of 5% vs. 2 %
would require 1200 patients
Specific Aims
1. To describe the variability in
management of AO in children
2. To compare the clinical effectiveness of
long-term IV vs. IV with early PO
conversion for the treatment of AO
Methods
Study Design: retrospective cohort
Data Source: Pediatric Hospital
Information System (PHIS) database



Clinical and billing data on > 6 million
hospitalized children
35 free-standing children’s hospitals
January 1, 2000 – June 30, 2005
Methods
Definition of AO:

ICD9-codes for AO and osteomyelitis unspecified
Exposure


IV group – placement of a catheter
PO group – no procedure code for placement of a
catheter
Exclusion Criteria
Hospitalized for chronic osteo in previous 6 mos.
Hospitals with data validity issues (35  29)
Presence of comorbid conditions on index or prior
admissions.
Diagnoses suggestive of complicated disease

Arthritis, sacroilitis, cellulitis, congenital bone diseases,
post-operative wounds, placement of prosthetic
devices
Length of stay > 10 days
Validation of Exposure
10% sample of osteo patients at each
hospital
19 of 29 agreed to participate
Chart review to confirm classification as
PO or IV
Primary Outcome
Treatment failure within 6 months of
diagnosis




Chronic osteomyelitis
Musculoskeletal surgery
Complication of acute osteo (e.g. arthritis, etc)
AO as sole readmission diagnosis
Secondary Outcomes
Any readmission in 6 months
Catheter-related complication
Adverse effect of antimicrobial therapy


C. difficile infection
Agranulocytosis
Analysis
Descriptive Statistics
Multivariate Logistic Regression Analysis
Propensity Score to adjust for confounding
Adjustment for clustering (intrahospital and
interhospital variability)
Assembly of Study Cohort
Osteomyelitis
ICD-9 code
N=6348
Hospital data
issues
N=1056
N=5292
Inadequate
follow-up
N=1136
N=4156
Co-morbid
conditions
N=1848
N=2308
LOS 10
days
N=339
Osteomyelitis
cohort
N=1969
Demographic and Clinical Characteristics
Antimicrobial Therapy
45
40
35
30
25
IV
PO
20
15
10
5
0
1st Ceph
Clinda
Ox/Naf
Vanco
Variability in utilization of early
conversion to oral antimicrobial therapy
100
90
Converted to oral therapy (%)
80
70
60
50
40
30
20
10
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
Hospital
Treatment Outcomes of AO
Results: Validation Study
19 of 29 hospitals participated in validation
13 of 19 had no missclassification
6 hospitals had patients treated with IV but were
assigned to oral therapy
Repeated analyses:


for 13 hospitals with no misclassification
OR 0.74 (0.21, 2.6)
16 hospitals that did not participate or had
misclassification
OR 0.71 (0.37, 1.4)
Strengths and Limitations
Strengths



Large sample size
multiple hospitals
validation of exposure
Limitations




Not randomized
Miscoded or inaccurate information
Misclassification of outcome
Preconditions for oral therapy not evaluated
Conclusions
Early conversion to oral therapy is safe
and effective for the treatment of
uncomplicated AO
Consideration to developing a clinical
practice guideline


reduce variation in practice
Determine if good clinical outcomes are
sustained
Types of Error
Random (chance)


Evaluation by statistics
Statistics only deal with problems of chance
Systematic

Bias
Selection
Information
Information Bias
Information (misclassification)



Misclassify IV as PO or vice versa
Misclassify treatment failures as non-failures
or vice versa
What is the direction of the bias?
Nondifferential misclassification
Differential misclassification
Implications of Direction of Bias
STUDY
EFFECT
DIRECTION OF BIAS
Yes
Toward Null
No
Toward Null
Yes
Away from Null
No
Away from Null
IMPLICATION
Real effect even
stronger
Might have
missed real effect
Spurious
conclusion
Really nothing
going on
Acknowledgements
Ron Keren, MD, MPH
Russell Localio, PhD
Kateri Leckerman, MS
Stephanie Saddlemire, MPH
Priya Prasad, MPH
Sarah Smathers, MPH