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PCR to Guide Antibiotic Therapy for Pneumonia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02660554
Recruitment Status : Active, not recruiting
First Posted : January 21, 2016
Last Update Posted : April 23, 2018
Information provided by (Responsible Party):
Richard Wunderink, Northwestern University

Brief Summary:
The purpose of this study is to conduct a randomized clinical trial to compare an antibiotic strategy based on a novel diagnostic test, polymerase chain reaction (PCR) to usual care, in critically ill adults with pneumonia suspected to be caused by methicillin resistant staphylococcus aureus (MRSA). The investigators hypothesize that when automated PCR is used to guide antibiotic therapy, antibiotic exposure will be reduced in critically ill subjects with pneumonia.

Condition or disease Intervention/treatment Phase
Pneumonia Methicillin-Resistant Staphylococcus Aureus Other: Polymerase Chain Reaction (PCR) Not Applicable

Detailed Description:

Bacterial resistance to antibiotics is a major problem in intensive care units (ICUs). The Centers for Disease Control (CDC) estimate drug resistant infections affect more than 2 million individuals nationwide and cause 23,000 deaths annually. In a recent executive order, the President of the United States called for improved antibiotic stewardship and the development of rapid diagnostic tests to identify antibiotic resistant infections. In ICU patients with pneumonia, guidelines advocate the routine use of broad spectrum antibiotics in most patients. In large part this is because diagnostic testing for pneumonia is too insensitive and too slow to inform decision making about appropriate antibiotics. Overuse of broad spectrum antibiotics promotes drug resistance by selecting for antibiotic resistant bacterial strains. This proposal will apply a new diagnostic test, polymerase chain reaction (PCR), to rapidly identify a drug resistant pathogen, methicillin resistant staphylococcus aureus (MRSA) to reduce inappropriate antibiotics in ICU patients with suspected pneumonia.

MRSA is an important cause of drug resistant pneumonia associated with high mortality. Methicillin resistance in Staphylococcus aureus (SA) results from acquisition of the mecA gene located in the mobile element staphylococcal cassette chromosome mec (SCCmec). MRSA pneumonia requires specific antibiotic therapy, treatment guidelines recommend addition of empiric antibiotics against MRSA in patients admitted to the ICU with risk factors for DRPs. The investigators prior work demonstrates that there is significant overlap of MRSA risk factors with risk factors for other DRPs, which potentially leads to the overuse of anti-MRSA antibiotics. Globally, MRSA pneumonia occurs in an estimated 2-6% of ICU patients. By contrast, empiric anti-MRSA therapy is prescribed in the majority of ICU patients with suspected pneumonia. The investigators have shown that at their own institution, the prevalence of MRSA is 5.5%, but empiric anti-MRSA therapy is prescribed in 89.5% of ICU patients with pneumonia. The large gap between empiric antibiotic therapy for MRSA pneumonia and actual cases of MRSA pneumonia is due to the lack of specificity of DRP risk factors, and the time delay of bacterial cultures. Overuse of antibiotics against MRSA has adverse consequences for patients, including new hospital acquired infections (HAIs), increased hospital length of stay (LOS), and higher cost.

Faster and more accurate diagnostic tests for MRSA, such as PCR, have the potential to reduce antibiotic exposure and improve patient outcomes. The time delay of bacterial cultures and the lack of specificity of DRP risk factors is a major limitation to the treatment of pneumonia, particularly in ICUs where the rapid delivery of appropriate antibiotics could be life saving. PCR has the potential to change the paradigm of empiric antibiotics by increasing diagnostic certainty and reducing the time to diagnosis or exclusion of a resistant pathogen. However, molecular diagnostic tests have not yet been validated for routine clinical practice.

The goal of this trial is to compare conduct a clinical trial to compare a PCR guided approach to MRSA therapy to usual care to determine if 1) an antibiotic strategy that utilizes rapid automated PCR reduces antibiotic-days in ICU subject with suspected pneumonia, 2) To compare the safety of an antibiotic strategy that relies on rapid automated PCR to usual care, and 3) To compare costs of the rapid automated PCR based strategy to routine microbiologic cultures.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 45 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: A Randomized Clinical Trial to Compare Early Pneumonia Diagnosis Using Polymerase Chain Reaction to Usual Care in Critically Ill Adults
Study Start Date : January 2016
Actual Primary Completion Date : February 28, 2017
Estimated Study Completion Date : December 31, 2018

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
No Intervention: Usual care
In the usual care arm, antibiotic therapy against methicillin resistant Staphylococcus aureus (MRSA) will be given at the discretion of the care team. If bacterial cultures are negative for MRSA at 72 hours, the treating physician will be prompted to discontinue MRSA therapy.
Experimental: Polymerase Chain Reaction
In subjects randomized to the polymerase chain reaction (PCR) arm, antibiotic therapy against methicillin resistant Staphylococcus aureus (MRSA) will be determined by the results of the PCR test. In subjects who are clinically stable, results from the PCR must be available prior to the administration of MRSA therapy. Subjects with a positive MRSA PCR will be administered MRSA therapy. In subjects with a negative MRSA PCR, MRSA therapy will be withheld. In subjects randomized to the automated PCR arm who are clinically unstable, empiric MRSA therapy will be allowed until the PCR is completed. In these cases of unstable subjects, empiric MRSA therapy will be discontinued if the PCR is negative.
Other: Polymerase Chain Reaction (PCR)
Respiratory samples called bronchoalveolar lavage (BAL) gathered from subjects in the PCR arm will be tested for the presence of MRSA using the Cepheid Xpert® Assay. Xpert® is a qualitative in vitro test designed for rapid detection and differentiation of Staphylococcus aureus (SA) and methicillin resistant Staphylococcus aureus (MRSA) using PCR amplification. MRSA is identified by the mecA gene and staphylococcal cassette chromosome mec (SCCmec). Xpert® Assay is approved by the Federal Drug Administration to detect MRSA in soft tissue samples. Once the PCR is completed, the results will be relayed to the treating physician, and antibiotic therapy (vancomycin or linezolid) will be started or stopped based on the study protocol. All BAL samples will be sent for routine bacterial cultures.

Primary Outcome Measures :
  1. Days of anti-MRSA antibiotic therapy [ Time Frame: 14 days ]
    days for initially suspected MRSA pneumonia

Secondary Outcome Measures :
  1. Mortality [ Time Frame: 28 days post randomization ]
    All cause mortality

  2. Organ dysfunction [ Time Frame: 28 days post randomization ]
    Days alive and organ dysfunction free for 28 days (based on daily SOFA score)

  3. Renal Organ dysfunction [ Time Frame: 28 days post randomization ]
    Days alive and renal organ dysfunction free for 28 days (based on daily SOFA renal organ score)

  4. Days of subsequent anti-MRSA treatment [ Time Frame: 28 days post randomization ]
    total days of vancomycin or linezolid treatment

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Adults aged 18 years and older with known or suspected pneumonia who are endotracheally intubated and mechanically ventilated
  2. Can receive bronchoalveolar lavage (BAL) while intubated
  3. Have received 24 hours or less of MRSA therapy (the antibiotics vancomycin or linezolid) prior to study enrollment

Exclusion Criteria:

  1. More than 24 hours of MRSA therapy therapy (the antibiotics vancomycin or linezolid),
  2. Subjects with extra pulmonary infection requiring treatment with vancomycin or linezolid
  3. Neutropenic fever
  4. Chronic airway infection
  5. Patient/surrogate refusal
  6. Subjects in whom BAL is deemed unsafe by the treating physician
  7. Treating physician refusal to discontinue antibiotics to treat MRSA if PCR negative
  8. Prisoners
  9. Pregnant women

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02660554

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United States, Illinois
Northwestern Memorial Hospital
Chicago, Illinois, United States, 60611
Sponsors and Collaborators
Northwestern University
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Principal Investigator: Richard G Wunderink, MD Northwestern University


Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Richard Wunderink, Professor, Department of Pulmonary and Critical Care Medicine, Northwestern University Identifier: NCT02660554     History of Changes
Other Study ID Numbers: STU00202148
First Posted: January 21, 2016    Key Record Dates
Last Update Posted: April 23, 2018
Last Verified: April 2018
Keywords provided by Richard Wunderink, Northwestern University:
Methicillin-Resistant Staphylococcus aureus
Polymerase Chain Reaction
Intensive care units
Drug Resistance
Additional relevant MeSH terms:
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Gram-Positive Bacterial Infections
Bacterial Infections
Anti-Bacterial Agents
Anti-Infective Agents
Antitubercular Agents
Staphylococcal Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Antibiotics, Antitubercular