TREAT -a Decision Support SystemTREAT -a Decision Support System for Antibiotic Treatment for Antibiotic Treatment

Supported by an EU 5th Framework grant

Coordinator: Steen Andreassen

On behalf of the Treat group:

Rabin Medical Centre, Israel

Freiburg University Hospital, Germany

Universitá Cattolica S. Cuore, Italy

Judex Datasystems A/S, Denmark

Aalborg University, Denmark

The magnitude of the problemThe magnitude of the problem

The mortality associated with severe bacterial The mortality associated with severe bacterial infections is ~30%.infections is ~30%.

A third of patients are prescribed inappropriate A third of patients are prescribed inappropriate empirical antibiotics, and ~20% superfluous drugs empirical antibiotics, and ~20% superfluous drugs (J Intern Med 1998, 244:379; Chest 2000, 118:146 ; Scand J Infect Dis 1997, 29:601; (J Intern Med 1998, 244:379; Chest 2000, 118:146 ; Scand J Infect Dis 1997, 29:601; Am J Med Sci 1978, 275: 271).Am J Med Sci 1978, 275: 271).

Inappropriate empirical Rx is associated with an Inappropriate empirical Rx is associated with an increase in fatality rate: Multi-variable adjusted increase in fatality rate: Multi-variable adjusted OR: 1.6 to 6.9 OR: 1.6 to 6.9 (J Intern Med 1998; 244:379 ); (Chest 2000; 118:146).(J Intern Med 1998; 244:379 ); (Chest 2000; 118:146).

The magnitude of the problemThe magnitude of the problem

Maximum empirical antibiotic treatment is not a Maximum empirical antibiotic treatment is not a viable solution.viable solution.

Antibiotics account for about 20% of drug Antibiotics account for about 20% of drug expenditures: 7 million NIS for Beilinson per expenditures: 7 million NIS for Beilinson per year.year.

The systemThe system

Causal probabilistic network for the diagnosis and Causal probabilistic network for the diagnosis and treatment of infectionstreatment of infections

Treatment based on cost-benefit modelTreatment based on cost-benefit model Benefit:Benefit:

– Improved survival with appropriate antibiotic treatmentImproved survival with appropriate antibiotic treatment– Reduced beddaysReduced beddays

Costs:Costs:– DirectDirect– Side-effectsSide-effects– Ecological costsEcological costs

Advantages of a causal probabilistic Advantages of a causal probabilistic network (CPN):network (CPN):

Natural multiplication of the needed matricesNatural multiplication of the needed matrices (infection (infection probability X pathogen probability X susceptibilities)probability X pathogen probability X susceptibilities)..

Explicit modelling of universal and local factors.Explicit modelling of universal and local factors. The only way to deal with missing data.The only way to deal with missing data. The only way to combine between knowledge and data The only way to combine between knowledge and data

from different sources in one system.from different sources in one system. Cost effectiveness (or benefit) analysis is a natural feature Cost effectiveness (or benefit) analysis is a natural feature

of the system.of the system.

A model of infectionsA model of infections

A (very) simplified version of the TREAT CPN will be used:

1. to demonstrate the concepts of • infection• sepsis• prognosis (sepsis*)• treatment• coverage and• mortality

Two urinary tract pathogensTwo urinary tract pathogens

Sepsis = Yes, Treatment = No,Sepsis = Yes, Treatment = No,Res. Factor = Present (Hosp. Acq.)Res. Factor = Present (Hosp. Acq.)

Treatment = GentamicinTreatment = Gentamicin

The value of morphology, The value of morphology, Gram stain and motilityGram stain and motility

Databases for local calibrationsDatabases for local calibrations

To adapt the TREAT system to a given hospital,

databases are needed for:

• Antibiotics and their costs

• Resistance of pathogns to antibiotics (hospital vs. community acquired)

• Pathogen prevalences

Database for costs of treatments Database for costs of treatments considered by TREATconsidered by TREAT

1.1. All patients for whom antibiotic treatment (but not prophylaxis) is All patients for whom antibiotic treatment (but not prophylaxis) is started (whether with a community or hospital acquired disorder). started (whether with a community or hospital acquired disorder).

2.2. Patients from whom blood cultures are drawn.Patients from whom blood cultures are drawn.3.3. Patients in whom two or more of the following are present:Patients in whom two or more of the following are present:

a.a. Temperature >38°C or <36°CTemperature >38°C or <36°Cb.b. Heart rate >90 beats/minHeart rate >90 beats/minc.c. Respiratory rate >20 breaths/min or PaCO2 <32 mmHgRespiratory rate >20 breaths/min or PaCO2 <32 mmHgd.d. WBC >12,000 cells/mm3, <4000 cells/mm3, or >10 percent WBC >12,000 cells/mm3, <4000 cells/mm3, or >10 percent

immature (band) formsimmature (band) forms4.4. Patients with a focus of infection, mainly: a new infiltrate on chest x-Patients with a focus of infection, mainly: a new infiltrate on chest x-

ray, urinary complaints and leukocyturia, skin findings compatible ray, urinary complaints and leukocyturia, skin findings compatible with skin or soft tissue infections, etc.with skin or soft tissue infections, etc.

5.5. Patients with shock compatible with septic shock.Patients with shock compatible with septic shock.6.6. Febrile neutropenic patients (single oral temperature ≥38.3 or a Febrile neutropenic patients (single oral temperature ≥38.3 or a

temperature of 38 lasting ≥ 1 hour).temperature of 38 lasting ≥ 1 hour).

Eligible patientsEligible patients

Exclusion criteria:Exclusion criteria:

Organ and bone-marrow transplant patientsOrgan and bone-marrow transplant patients Children<16 yearsChildren<16 years Suspected travel infectionsSuspected travel infections Suspected tuberculosisSuspected tuberculosis PregnancyPregnancy HIV positive patients with a current suspected or HIV positive patients with a current suspected or

identified identified opportunistic diseaseopportunistic disease and/or AIDS and/or AIDS defining illness currently or within the past 6 defining illness currently or within the past 6 months months

Re-entriesRe-entries

HIV+ patients

with sepsis included

TREAT is working!Probability of infectionProbability of specific diagnosesProbability of pathogens causing infectionCoverage of single and combination antibiotic regimensCost benefit of these treatments

Different determinants of the costs vs. benefits

can be displayed

TREAT’s first choice shown

Please document treatment prescribed

to the patient

TREATTREAT

Observational trialObservational trial6-12/20026-12/2002

Methods and objectivesMethods and objectives

All patients fulfilling inclusion criteria were All patients fulfilling inclusion criteria were entered into an observational databaseentered into an observational database

Entry, bacteriological, and 30-day outcome data Entry, bacteriological, and 30-day outcome data collected prospectivelycollected prospectively

Each case presented to TREATEach case presented to TREAT TREAT advice compared to physician TREAT advice compared to physician

performanceperformance Primary outcome: antibiotic treatment matching Primary outcome: antibiotic treatment matching

in-vitro susceptibility of clinically relevant isolates in-vitro susceptibility of clinically relevant isolates (‘appropriate treatment’)(‘appropriate treatment’)

ParticipantsParticipants

FreiburgFreiburg IsraelIsrael RomeRome Overall Overall

DepartmentsDepartments 66 55 33 1414

BedsBeds 120120 200200 6060 380380

PatientsPatients 348348 612612 243243 12031203

Primary outcomePrimary outcome

Appropriate antibiotic treatment was prescribed to Appropriate antibiotic treatment was prescribed to 58% of patients.58% of patients.

TREAT’s advice was appropriate in 70% of cases TREAT’s advice was appropriate in 70% of cases (p=0.0001)(p=0.0001)

Increment in the rate of coverage: relative increase Increment in the rate of coverage: relative increase of 21% and an absolute increase of 12%of 21% and an absolute increase of 12%

The improvement reached statistical significance The improvement reached statistical significance in Rabin, Freiburg, and overall.in Rabin, Freiburg, and overall.

Secondary outcomesSecondary outcomes

TREAT used a lower number of antibiotic TREAT used a lower number of antibiotic regimens than the physicianregimens than the physician

TREAT preferred narrow spectrum TREAT preferred narrow spectrum antibiotics to broad spectrum ones. antibiotics to broad spectrum ones.

Overall cost, the overall cost at each site Overall cost, the overall cost at each site and the costs related by the model to future and the costs related by the model to future resistance were significantly reduced by resistance were significantly reduced by TREATTREAT

0

100

200

300

400

500

600

700

Direct Adverse effects Resistance Overall

Physician

TREAT

Euros

P=0.0001 P=0.03

P=0.0001

P=0.0001

TREAT/Physician = 0.5

Treatment costsTreatment costs

Conclusions – observational trialConclusions – observational trial

TREAT has the potential of improving TREAT has the potential of improving significantly on the percentage of significantly on the percentage of appropriate empirical antibiotic treatment appropriate empirical antibiotic treatment while at the same time reducing all while at the same time reducing all components of costs, but mainly the costs components of costs, but mainly the costs assigned by the model to future resistance. assigned by the model to future resistance.

TREATTREAT

InterventionIntervention

Primary outcome - appropriate antibiotic treatment

Analysis by intention to treat, stratified by location, showed a significant improvement in appropriate antibiotic treatment in intervention vs. control, Mantel-Haenzel OR 1.48 (95% CI 1.03-2.11), p=0.033.

N Controls InterventionIntention to treat

p InterventionPer protocol

p

Israel 409 131/ 206 (63.6%) 140/ 203 (69.0%) 0.25 74/87 (85.1%) <0.001

Italy 74 13/ 24 (54.2%) 38/ 50 (76.0%) 0.06 22/28 (78.6%) 0.06

Germany 77 32/ 43 (74.4%) 38/ 44 (86.4%) 0.16 18/19 (85.1%) 0.06

Total 560 176/273 (64.5%) 216/297 (72.7%) 0.03 114/134 (85.1%) <0.001

N patients Control Intervention P-value *

Direct costs, Euro, mean (sd)

Israel 1678 25.5 (30.9) 25.2 (33.2)

0.47Italy 263 84.9 (83.9) 79.1 (87.7)

Germany 379 73.5 (85.4) 68.9 (75.6)

Side effect costs, Euro, mean (sd)

Israel 1678 88.5 (1046.9) 98.3 (1048.6)

0.96Italy 263 24.4 (159.2) 74.6 (992.2)

Germany 379 189.8 (1765.5) 129.2 (1294.4)

Ecological costs, Euro, mean (sd)

Israel 1678 511.7 (439.9) 445.9 (404.7)

0.002Italy 263 372.2 (248.3) 317.2 (282.2)

Germany 379 503.8 (336.7) 517.8 (374.6)

Total antibiotic costs, Euro, mean (sd)

Israel 1678 612.5 (507.7) 546.0 (476.7)

0.007Italy 263 540.0 (371.5) 487.5 (419.5)

Germany 379 716.1 (522.1) 712.1 (532.6)

Duration of hospital stay, all patients, median/ mean (sd)

Israel 1462 5/ 6.91 (7.7) 4/ 6.31 (8.3)

0.03Italy 219 6/ 9.5 (9.4) 7/ 9.6 (7.5)

Germany 305 14/ 16.3 (12.0) 10/ 13.6 (11.2)

Thank youThank you