Clinical trial NCT00438269: Pilot Study of the Utility of Empiric Antibiotic Therapy for Suspected ICU-Acquired Infection
Official title: Appropriate Antimicrobial Therapy in Critical Care: A Pilot Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Nosocomial Infection
Pneumonia
Systemic Inflammatory Response Syndrome
Critical Illness
Pyrexia
Keywords: Infection
Empiric
Antibiotics
Nosocomial
Pyrexia
Leukocytosis
Resistance
Lead sponsor: Canadian Critical Care Trials Group
Sponsor class: OTHER
Collaborators: name: The Physicians' Services Incorporated Foundation
First posted: 2007-02-22
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Infection developing in the intensive care unit is a common complication of critical illness, but notoriously difficult to diagnose. A definite diagnosis based on the most reliable tests usually is not possible for at least two days. It is unclear what the optimal management approach should be while awaiting the results of diagnostic tests. In some circumstances, broad spectrum antibiotics are started with a plan to adjust them once the results of cultures are available. Observational studies show that this results in greater antibiotic use, and the risk of superinfection and resistance. In other circumstances, antibiotics may be withheld pending the results of cultures, a strategy that leads to a delay in therapy when cultures are positive, and that may be associated with a worse clinical outcome.

We undertook a randomized pilot study to address the question: "In a critically ill patient for whom clinicians are uncertain whether infection may be present, and in whom potential sites of infection have been managed by removing or changing invasive devices, can a policy of delaying antibiotic treatment until cultures are available reduce the risks of excessive antibiotic use, without increasing the risks associated with delayed therapy?"

Recognizing that the question has not been formally addressed before, and that approaches to clinical management are both widely divergent and passionately held, our pilot study tested the feasibility and acceptability of undertaking a larger trial with sufficient power to determine equivalence.

Detailed description: We randomized critically ill patients who had been in hospital for at least 72 hours, and in the ICU for at least 24 hours, and who manifested either a temperature \>38.5 degrees, or a temperature\>38.0 degrees and a white cell count \>12,000, and in whom clinicians entertained the possibility of infection as a diagnosis, to either site-specific broad spectrum empiric antibiotics or the corresponding placebo. All patients underwent a comprehensive series of investigations to identify an infectious focus, and all patients had full source control, including changes of central lines and urinary catheters, and change of nasogastric to orogastric tubes.

Patients were maintained in assigned study arm for seven days, or until culture data were available, at which time they were switched to culture-guided narrow spectrum therapy

Eligibility criteria: Inclusion Criteria:

* In hospital \> 72 hrs and in ICU \> 24hrs, and
* Core temperature ≥38.5°C, or temperature ≥ 38.0°C with a WBC\>12,000/mm3, or temperature ≤ 36.0°C with a WBC \> 12,000/mm3
* Suspicion of infection

Exclusion Criteria:

* Age \< 18 years
* Imminent death (within 24 hrs) or withdrawal of aggressive therapy
* Prosthetic heart valve or vascular graft
* Neutropenia (Absolute neutrophil count \< 1000/mm3)
* Received \> 16 hours of a broad spectrum antibiotic in the last 24 hours (3rd gen cephalosporin, fluoroquinolone, carbapenem, anti-pseudomonal penicillin) or any combination therapy
* History of allergic reaction to both study medications
* New physical findings consistent with infection:

  * Meningeal signs
  * Peritonitis + free air on Abdo x-ray
  * Soft tissue infection / cellulitis
  * Murmur \& suspicion of endocarditis
* Newly available (within past 24 hours) culture results consistent with infection

Primary outcomes:
measure: Feasibility: = % of eligible patients who were consented and randomized
measure: Acceptability: = % of patients in each study arm who were switched to open label therapy prior to culture results
Secondary outcomes:
measure: Mortality (14, 30, 90 day)
measure: Microbial resistance patterns
measure: ICU-free days
measure: Antibiotic-free days
measure: Change in organ dysfunction (MOD scores)
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
Study officials:
affiliation: University of Toronto
name: Mary-Anne W Aarts, MD MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Toronto
name: John C Marshall, MD
role: PRINCIPAL_INVESTIGATOR
References: