Prolonged IV vs. Early Conversion Prolonged IV vs. Early Conversion to Oral Antibiotic Therapy? to Oral Antibiotic Therapy?

Is it Time for a ChangeIs it Time for a Change

Theoklis Zaoutis, MD, MSCETheoklis Zaoutis, MD, MSCEAsst. Prof. of Pediatrics and EpidemiologyAsst. Prof. of Pediatrics and Epidemiology

Assoc. Director, Center for Pediatric Clinical Assoc. Director, Center for Pediatric Clinical Effectiveness ResearchEffectiveness Research

Overview: Overview: Acute Osteomyelitis (AO)Acute Osteomyelitis (AO)

BackgroundBackground

Study Methods and ResultsStudy Methods and Results

Bias -misclassificationBias -misclassification

AO: epidemiology and risk factorsAO: epidemiology and risk factors

1 in 5000 each year in US1 in 5000 each year in US

1% of pediatric hospitalizations1% of pediatric hospitalizations

50% occur before 5 years old50% occur before 5 years old

Twice as common in malesTwice as common in males

1/3 have preceding minor trauma1/3 have preceding minor trauma

AO: epidemiology by siteAO: epidemiology by site

Humerus (13%)

Pelvis (7%)

Femur (25%)

Tibia (24%)

Calcaneus (5%)

Vertebrae (2%)

AO: managementAO: management

Traditional management consists of 4-6 Traditional management consists of 4-6 weeks of parenteral (IV) antibiotic therapyweeks of parenteral (IV) antibiotic therapy

Duration of Therapy: Dich 1975Duration of Therapy: Dich 1975

Immediate needle aspiration of Immediate needle aspiration of subperiosteal space and bone.subperiosteal space and bone.

Drainage through bone window if pus Drainage through bone window if pus found on needle aspiration.found on needle aspiration.

Exclusive IV antibioticsExclusive IV antibiotics

Duration of IV therapyDuration of IV therapy Recurrent or chronic osteoRecurrent or chronic osteo

≤ ≤ 21 days21 days 7/37 (19%)7/37 (19%)

>21 days>21 days 1/47 (2%)1/47 (2%)

Route of Therapy: Tetzlaff 1978Route of Therapy: Tetzlaff 1978

IV until signs of IV until signs of ’d inflammation (mean 7.3 d) ’d inflammation (mean 7.3 d) Followed by PO (mean 19.8 d)Followed by PO (mean 19.8 d)Conditions for conversion to PO:Conditions for conversion to PO: Organism identified (blood, bone, joint)Organism identified (blood, bone, joint) Peak bactericidal titer > 1:8Peak bactericidal titer > 1:8 Hospitalized for duration of treatment (including oral Hospitalized for duration of treatment (including oral

therapy)therapy)

Only 1/22 developed chronic osteoOnly 1/22 developed chronic osteo

Route of Therapy: Cole 1982Route of Therapy: Cole 1982

Minimize surgery: bone aspiration for abscess Minimize surgery: bone aspiration for abscess drainage only (22%)drainage only (22%)

Minimize duration of IV therapy (mean 3 d)Minimize duration of IV therapy (mean 3 d)

Complete oral therapy as outpatientComplete oral therapy as outpatient

No bactericidal levels measuredNo bactericidal levels measured

Cured after 6 weeks of therapy:Cured after 6 weeks of therapy: 44/48 with “early” acute osteo (fever < 48 h)44/48 with “early” acute osteo (fever < 48 h) 2/8 with “late” acute osteo (symptoms >5 days, all 2/8 with “late” acute osteo (symptoms >5 days, all

with abscess)with abscess)

Route of Therapy: Peltola 1997 Route of Therapy: Peltola 1997

50 patients with 50 patients with S. aureusS. aureus AO AOSurgery (needle aspiration or drilling) Surgery (needle aspiration or drilling) Conversion to high-dose 1Conversion to high-dose 1stst generation oral generation oral cephalosporin after 3-4 dayscephalosporin after 3-4 daysSerum bactericidal activity and antibiotic Serum bactericidal activity and antibiotic concentrations not measuredconcentrations not measured3-4 weeks total therapy (mean 23 days)3-4 weeks total therapy (mean 23 days)Intensive f/u with ESR x 8; CRP x 12 in 30 d.Intensive f/u with ESR x 8; CRP x 12 in 30 d.Mean 11 days of hospitalizationMean 11 days of hospitalizationNo complications with 1 year follow-upNo complications with 1 year follow-up

Route of Therapy: Le Saux 2002Route of Therapy: Le Saux 2002

Systematic reviewSystematic reviewClinical cure rate at 6 months:Clinical cure rate at 6 months: IV: short course (< 7 d) vs. long-course (>7d) IV: short course (< 7 d) vs. long-course (>7d) Then switch to PO antibiotics.Then switch to PO antibiotics.

12 case series or small observational studies: 7 12 case series or small observational studies: 7 short-course and 5 long-course therapy.short-course and 5 long-course therapy.Clinical cure rate Clinical cure rate Short-course = 95.2% (95% CI; 90.4, 97.7) Short-course = 95.2% (95% CI; 90.4, 97.7) Long-course = 98.8% (95% CI: 93.6, 99.8)Long-course = 98.8% (95% CI: 93.6, 99.8)

No Difference

Safety of Prolonged IV TherapySafety of Prolonged IV Therapy

AOAO

n=80n=80 IV x IV x

2wks 2wks with with CVCCVC

n=75n=75

IV x IV x 5d, 5d,

then then POPO

n-=5n-=5

No rehospitalizationNo rehospitalization

No return to EDNo return to ED

31/75 (41%) developed complications31/75 (41%) developed complications

• 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 the Best Practice?

What is currently being done in practice?What is currently being done in practice?

Is early conversion to PO effective?Is early conversion to PO effective?

We cannot perform the randomized, We cannot perform the randomized, controlled clinical trial because:controlled clinical trial because: Certain centers have already changed to Certain centers have already changed to

practicepractice Clinical trial to find a failure rate of 5% vs. 2 % Clinical trial to find a failure rate of 5% vs. 2 %

would require 1200 patientswould require 1200 patients

Specific AimsSpecific Aims

1.1. To describe the variability in To describe the variability in management of AO in children management of AO in children

2.2. To compare the clinical effectiveness of To compare the clinical effectiveness of long-term IV vs. IV with early PO long-term IV vs. IV with early PO conversion for the treatment of AOconversion for the treatment of AO

MethodsMethods

Study Design: retrospective cohortStudy Design: retrospective cohort

Data Source: Pediatric Hospital Data Source: Pediatric Hospital Information System (PHIS) databaseInformation System (PHIS) database Clinical and billing data on > 6 million Clinical and billing data on > 6 million

hospitalized childrenhospitalized children 35 free-standing children’s hospitals35 free-standing children’s hospitals January 1, 2000 – June 30, 2005January 1, 2000 – June 30, 2005

MethodsMethods

Definition of AO: Definition of AO: ICD9-codes for AO and osteomyelitis unspecifiedICD9-codes for AO and osteomyelitis unspecified

ExposureExposure IV group – placement of a catheterIV group – placement of a catheter PO group – no procedure code for placement of a PO group – no procedure code for placement of a

cathetercatheter

Exclusion CriteriaExclusion Criteria

Hospitalized for chronic osteo in previous 6 mos.Hospitalized for chronic osteo in previous 6 mos.

Hospitals with data validity issues (35 Hospitals with data validity issues (35 29) 29)

Presence of comorbid conditions on index or prior Presence of comorbid conditions on index or prior admissions.admissions.

Diagnoses suggestive of complicated diseaseDiagnoses suggestive of complicated disease Arthritis, sacroilitis, cellulitis, congenital bone diseases, Arthritis, sacroilitis, cellulitis, congenital bone diseases,

post-operative wounds, placement of prosthetic post-operative wounds, placement of prosthetic devicesdevices

Length of stay > 10 daysLength of stay > 10 days

Validation of ExposureValidation of Exposure

10% sample of osteo patients at each 10% sample of osteo patients at each hospitalhospital

19 of 29 agreed to participate19 of 29 agreed to participate

Chart review to confirm classification as Chart review to confirm classification as PO or IVPO or IV

Primary OutcomePrimary Outcome

Treatment failure within 6 months of Treatment failure within 6 months of diagnosisdiagnosis Chronic osteomyelitisChronic osteomyelitis Musculoskeletal surgeryMusculoskeletal surgery Complication of acute osteo (e.g. arthritis, etc)Complication of acute osteo (e.g. arthritis, etc) AO as sole readmission diagnosisAO as sole readmission diagnosis

Secondary OutcomesSecondary Outcomes

Any readmission in 6 monthsAny readmission in 6 months

Catheter-related complicationCatheter-related complication

Adverse effect of antimicrobial therapyAdverse effect of antimicrobial therapy C. C. difficiledifficile infection infection AgranulocytosisAgranulocytosis

AnalysisAnalysis

Descriptive StatisticsDescriptive Statistics

Multivariate Logistic Regression AnalysisMultivariate Logistic Regression Analysis

Propensity Score to adjust for confoundingPropensity Score to adjust for confounding

Adjustment for clustering (intrahospital and Adjustment for clustering (intrahospital and interhospital variability)interhospital variability)

Assembly of Study CohortAssembly of Study Cohort

Osteomyelitis ICD-9 code

N=6348

N=5292

Hospital data issues

N=1056

N=4156

Inadequatefollow-upN=1136

N=2308

Co-morbid conditionsN=1848

LOS 10 days

N=339

Osteomyelitis cohortN=1969

Demographic and Clinical CharacteristicsDemographic and Clinical Characteristics

Antimicrobial TherapyAntimicrobial Therapy

0

5

10

15

20

25

30

35

40

45

1st Ceph Clinda Ox/Naf Vanco

IV

PO

Variability in utilization of early Variability in utilization of early conversion to oral antimicrobial therapyconversion to oral antimicrobial therapy

0

10

20

30

40

50

60

70

80

90

100

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

Co

nve

rted

to

ora

l th

erap

y (%

)

Treatment Outcomes of AOTreatment Outcomes of AO

Results: Validation StudyResults: Validation Study

19 of 29 hospitals participated in validation19 of 29 hospitals participated in validation

13 of 19 had no missclassification13 of 19 had no missclassification

6 hospitals had patients treated with IV but were 6 hospitals had patients treated with IV but were assigned to oral therapyassigned to oral therapy

Repeated analyses:Repeated analyses: for 13 hospitals with no misclassification for 13 hospitals with no misclassification

OR 0.74 (0.21, 2.6) OR 0.74 (0.21, 2.6) 16 hospitals that did not participate or had 16 hospitals that did not participate or had

misclassificationmisclassification

OR 0.71 (0.37, 1.4)OR 0.71 (0.37, 1.4)

Strengths and LimitationsStrengths and Limitations

StrengthsStrengths Large sample sizeLarge sample size multiple hospitalsmultiple hospitals validation of exposurevalidation of exposure

LimitationsLimitations Not randomizedNot randomized Miscoded or inaccurate informationMiscoded or inaccurate information Misclassification of outcomeMisclassification of outcome Preconditions for oral therapy not evaluatedPreconditions for oral therapy not evaluated

ConclusionsConclusions

Early conversion to oral therapy is safe Early conversion to oral therapy is safe and effective for the treatment of and effective for the treatment of uncomplicated AOuncomplicated AO

Consideration to developing a clinical Consideration to developing a clinical practice guidelinepractice guideline reduce variation in practicereduce variation in practice Determine if good clinical outcomes are Determine if good clinical outcomes are

sustainedsustained

Types of ErrorTypes of Error

Random (chance)Random (chance) Evaluation by statisticsEvaluation by statistics Statistics only deal with problems of chanceStatistics only deal with problems of chance

SystematicSystematic BiasBias

SelectionSelection

InformationInformation

Information BiasInformation Bias

Information (misclassification)Information (misclassification) Misclassify IV as PO or vice versaMisclassify IV as PO or vice versa Misclassify treatment failures as non-failures Misclassify treatment failures as non-failures

or vice versaor vice versa What is the direction of the bias?What is the direction of the bias?

Nondifferential misclassification Nondifferential misclassification

Differential misclassificationDifferential misclassification

Implications of Direction of BiasImplications of Direction of Bias

STUDY STUDY EFFECTEFFECT DIRECTION OF BIASDIRECTION OF BIAS IMPLICATIONIMPLICATION

YesYes Toward NullToward Null Real effect even Real effect even strongerstronger

NoNo Toward NullToward Null Might have Might have missed real effectmissed real effect

YesYes Away from NullAway from Null Spurious Spurious conclusionconclusion

NoNo Away from NullAway from Null Really nothing Really nothing going ongoing on

AcknowledgementsAcknowledgements

Ron Keren, MD, MPHRon Keren, MD, MPH

Russell Localio, PhDRussell Localio, PhD

Kateri Leckerman, MSKateri Leckerman, MS

Stephanie Saddlemire, MPHStephanie Saddlemire, MPH

Priya Prasad, MPHPriya Prasad, MPH

Sarah Smathers, MPHSarah Smathers, MPH