Trial of Antimicrobial Restraint in Presumed Pneumonia

Study Overview
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Brief Summary
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The objective of this cluster-randomized crossover study is to determine the effect of delaying antimicrobial initiation until objective microbiologic data is obtained in patients with presumed ICU-acquired pneumonia without septic shock.

Detailed Description
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This study will involve 8 centers is to determine the effect of delaying antimicrobial initiation until objective microbiologic data is obtained in patients with presumed ICU-acquired pneumonia without septic shock. The study team will compare two sequential 4-month periods in each unit, one 'aggressive' antimicrobial initiation period and one 'conservative' antimicrobial initiation period. This study will serve the following specific aims: Specific Aim 1: To determine feasibility of a larger multicenter study of the same design as well as assess protocol adherence across multiple centers. Specific Aim 2: Prospectively determine the all-cause, in-hospital mortality for all patients with suspected pneumonia who were treated under either an aggressive or conservative antimicrobial initiation protocol. Specific Aim 3: Prospectively determine antimicrobial initiation rates, total days of antimicrobial administration, hospital and ICU length of stay, and ventilator-free alive days for patients treated under each protocol. Specific Aim 4: To survey physicians that participated in the study to assess their feelings about the study including level of comfort starting antimicrobials aggressively, level of comfort withholding antimicrobials until definitive evidence of infection, perceived protocol adherence, perceived importance of the study, and willingness to participate in other studies of its kind (to be performed after closure of the clinical portion of the study).

Official Title
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Trial of Antimicrobial Restraint in Presumed Pneumonia

Conditions
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Healthcare-Associated Pneumonia, Sepsis

Intervention / Treatment
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* Other: antimicrobial initiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Intubated patients admitted to a surgical or trauma intensive care unit that have had an appropriate quantitative or semi-quantitative endobronchial sputum culture sent ≥48 hours into their ICU admission Primary pathology managed by surgical specialty Age ≥18 years. Exclusion Criteria: Non-intubated patients. Intubated patients with concern for active infection that is not suspected to be pneumonia (i.e. intra-abdominal infection, skin and soft tissue infection, urinary tract infection, etc.) Primary disease not surgical or traumatic in nature Primary diagnosis of burns Incarcerated status Pregnant status or delivery during this hospitalization. On active immunosuppressive medications (or taking as a home medication prior to arrival)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This will be a pragmatic, before-and-after, cluster-randomized, protocol crossover study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Aggressive Arm<br>If an intubated patient is suspected of having an ICU-acquired HAP/VAP during the aggressive period, antimicrobials should be initiated immediately after quantitative or semi-quantitative endobronchial cultures are sent regardless of clinical status. This will include patients who, as determined by the attending intensivist, are in sepsis or septic shock. If, after 72 hours, cultures and other clinical data do not point to a pneumonia, the antimicrobials should be stopped in the absence of another source of infection. | Other: antimicrobial initiation<br>* antimicrobial initiation based on protocol assignment.<br>|
| Other: Conservative Arm<br>If a patient is suspected of having an ICU-acquired HAP/VAP during the conservative period, quantitative or semi-quantitative endobronchial cultures should be sent. If the patient is in septic shock persistent hypotension requiring vasoactive medications to maintain mean arterial pressure (MAP) ≥65 mm HG or persistent lactic acidosis (>2 mmol/L) despite adequate resuscitation) antimicrobials will be initiated immediately. If the patient has new onset organ dysfunction that is presumed to be due to infection (sepsis) then antimicrobials will be initiated at the discretion of the attending intensivist. In the absence of septic shock or sepsis (intensivist discretion), antimicrobials will not be initiated unless objective evidence of pneumonia is present or another documented source of infection is identified mandating treatment with antimicrobials. | Other: antimicrobial initiation<br>* antimicrobial initiation based on protocol assignment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| protocol adherence | as a pilot study the primary outcome will be protocol adherence as defined by using the criteria below: Aggressive Protocol: Failure to send appropriate culture before initiation of antimicrobials in the absence of septic shock Failure to stop antimicrobials in the absence of pneumonia or other documented infection after 72 hours. Conservative Protocol: Failure to send appropriate culture Initiation of antimicrobials (in the absence of septic shock, new onset or worsening organ dysfunction, or other indicated source of infection) without any objective evidence of pneumonia. Failure to initiate antimicrobials in the setting of objective evidence of pneumonia. Failure to stop antimicrobials in the absence of other documented infection if final cultures return as negative. | by time of culture finalization or 1 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In-hospital mortality | All-cause, by treatment protocol assignment (intent-to-treat), ICU mortality, pneumonia-related | until hospital discharge or 1 year | 
| Days of antimicrobials administered | includes empiric, therapeutic, prophylactic, and perioperative antimicrobials | until hospital discharge or 1 year | 
| Ventilator-free alive days |  | until hospital discharge or 1 year | 
| ICU length of stay |  | Until discharge from ICU or 1 year | 
| Hospital length of stay |  | until hospital discharge or 1 year |