Trial of MRSA Polymerase Chain Reaction for Pneumonia

Pneumonia Clinical Trial

Official title:

Rapid Diagnostic Testing to Guide Antibiotic Therapy in Drug Resistant Pneumonia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02660554
• Other study ID #: STU00202148
• Status: Completed
• Phase: N/A
• Start date: January 2016
• Est. completion date: May 3, 2019

Study information

• Verified date: February 2023
• Source: Northwestern University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: May 3, 2019
• Est. primary completion date: February 28, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

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

Related Conditions & MeSH terms

• Methicillin-Resistant Staphylococcus Aureus
• Pneumonia
• Staphylococcal Infections

Intervention

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.

Locations

Country	Name	City	State
United States	Northwestern Memorial Hospital	Chicago	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
Northwestern University

Country where clinical trial is conducted

United States, 

References & Publications (13)

American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005 Feb 15;171(4):388-416. doi: 10.1164/rccm.200405-644ST. No abstract available. — View Citation

Cercenado E, Marin M, Burillo A, Martin-Rabadan P, Rivera M, Bouza E. Rapid detection of Staphylococcus aureus in lower respiratory tract secretions from patients with suspected ventilator-associated pneumonia: evaluation of the Cepheid Xpert MRSA/SA SSTI assay. J Clin Microbiol. 2012 Dec;50(12):4095-7. doi: 10.1128/JCM.02409-12. Epub 2012 Sep 19. — View Citation

Goff DA, Jankowski C, Tenover FC. Using rapid diagnostic tests to optimize antimicrobial selection in antimicrobial stewardship programs. Pharmacotherapy. 2012 Aug;32(8):677-87. doi: 10.1002/j.1875-9114.2012.01137.x. — View Citation

Haley CC, Mittal D, Laviolette A, Jannapureddy S, Parvez N, Haley RW. Methicillin-resistant Staphylococcus aureus infection or colonization present at hospital admission: multivariable risk factor screening to increase efficiency of surveillance culturing. J Clin Microbiol. 2007 Sep;45(9):3031-8. doi: 10.1128/JCM.00315-07. Epub 2007 Jul 11. — View Citation

Kollef MH, Micek ST. Strategies to prevent antimicrobial resistance in the intensive care unit. Crit Care Med. 2005 Aug;33(8):1845-53. doi: 10.1097/01.ccm.0000171849.04952.79. — View Citation

Leone M, Malavieille F, Papazian L, Meyssignac B, Cassir N, Textoris J, Antonini F, La Scola B, Martin C, Allaouchiche B, Hraiech S; AzuRea Network. Routine use of Staphylococcus aureus rapid diagnostic test in patients with suspected ventilator-associated pneumonia. Crit Care. 2013 Aug 6;17(4):R170. doi: 10.1186/cc12849. — View Citation

Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, Torres A, Whitney CG; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007 Mar 1;44 Suppl 2(Suppl 2):S27-72. doi: 10.1086/511159. No abstract available. — View Citation

Oh AC, Lee JK, Lee HN, Hong YJ, Chang YH, Hong SI, Kim DH. Clinical utility of the Xpert MRSA assay for early detection of methicillin-resistant Staphylococcus aureus. Mol Med Rep. 2013 Jan;7(1):11-5. doi: 10.3892/mmr.2012.1121. Epub 2012 Oct 9. — View Citation

Raman K, Nailor MD, Nicolau DP, Aslanzadeh J, Nadeau M, Kuti JL. Early antibiotic discontinuation in patients with clinically suspected ventilator-associated pneumonia and negative quantitative bronchoscopy cultures. Crit Care Med. 2013 Jul;41(7):1656-63. doi: 10.1097/CCM.0b013e318287f713. — View Citation

Rimawi RH, Mazer MA, Siraj DS, Gooch M, Cook PP. Impact of regular collaboration between infectious diseases and critical care practitioners on antimicrobial utilization and patient outcome. Crit Care Med. 2013 Sep;41(9):2099-107. doi: 10.1097/CCM.0b013e31828e9863. — View Citation

Salgado CD, Farr BM, Calfee DP. Community-acquired methicillin-resistant Staphylococcus aureus: a meta-analysis of prevalence and risk factors. Clin Infect Dis. 2003 Jan 15;36(2):131-9. doi: 10.1086/345436. Epub 2003 Jan 3. — View Citation

Shindo Y, Ito R, Kobayashi D, Ando M, Ichikawa M, Shiraki A, Goto Y, Fukui Y, Iwaki M, Okumura J, Yamaguchi I, Yagi T, Tanikawa Y, Sugino Y, Shindoh J, Ogasawara T, Nomura F, Saka H, Yamamoto M, Taniguchi H, Suzuki R, Saito H, Kawamura T, Hasegawa Y. Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2013 Oct 15;188(8):985-95. doi: 10.1164/rccm.201301-0079OC. — View Citation

Wunderink RG. How important is methicillin-resistant Staphylococcus aureus as a cause of community-acquired pneumonia and what is best antimicrobial therapy? Infect Dis Clin North Am. 2013 Mar;27(1):177-88. doi: 10.1016/j.idc.2012.11.006. Epub 2012 Dec 14. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Days of anti-MRSA antibiotic therapy	days for initially suspected MRSA pneumonia	14 days
Secondary	Mortality	All cause mortality	28 days post randomization
Secondary	Organ dysfunction	Days alive and organ dysfunction free for 28 days (based on daily SOFA score)	28 days post randomization
Secondary	Renal Organ dysfunction	Days alive and renal organ dysfunction free for 28 days (based on daily SOFA renal organ score)	28 days post randomization
Secondary	Days of subsequent anti-MRSA treatment	total days of vancomycin or linezolid treatment	28 days post randomization