Rapid Diagnosis of Infection in the Critically Ill, a Multicenter Study of Molecular Detection in Bloodstream Infections, Pneumonia, and Sterile Site Infections

Jean-Louis Vincent, MD, PhD, FCCM; David Brealey, MD; Nicolas Libert, MD; Nour Elhouda Abidi, MD; Michael O'Dwyer, MD; Kai Zacharowski, MD; Malgorzata Mikaszewska-Sokolewicz, MD; Jacques Schrenzel, MD; François Simon, MD; Mark Wilks, PhD; Marcus Picard-Maureau, PhD; Donald B. Chalfin, MD, MPH; David J. Ecker, PhD; Rangarajan Sampath, PhD; Mervyn Singer, MD; the Rapid Diagnosis of Infections in the Critically Ill Team

Disclosures

Crit Care Med. 2015;43(11):2283-2291. 

In This Article

Abstract and Introduction

Abstract

Objective: Early identification of causative microorganism(s) in patients with severe infection is crucial to optimize antimicrobial use and patient survival. However, current culture-based pathogen identification is slow and unreliable such that broad-spectrum antibiotics are often used to insure coverage of all potential organisms, carrying risks of overtreatment, toxicity, and selection of multidrug-resistant bacteria. We compared the results obtained using a novel, culture-independent polymerase chain reaction/electrospray ionization-mass spectrometry technology with those obtained by standard microbiological testing and evaluated the potential clinical implications of this technique.

Design: Observational study.

Setting: Nine ICUs in six European countries.

Patients: Patients admitted between October 2013 and June 2014 with suspected or proven bloodstream infection, pneumonia, or sterile fluid and tissue infection were considered for inclusion.

Interventions: None.

Measurements and Main Results: We tested 616 bloodstream infection, 185 pneumonia, and 110 sterile fluid and tissue specimens from 529 patients. From the 616 bloodstream infection samples, polymerase chain reaction/electrospray ionization-mass spectrometry identified a pathogen in 228 cases (37%) and culture in just 68 (11%). Culture was positive and polymerase chain reaction/electrospray ionization-mass spectrometry negative in 13 cases, and both were negative in 384 cases, giving polymerase chain reaction/electrospray ionization-mass spectrometry a sensitivity of 81%, specificity of 69%, and negative predictive value of 97% at 6 hours from sample acquisition. The distribution of organisms was similar with both techniques. Similar observations were made for pneumonia and sterile fluid and tissue specimens. Independent clinical analysis of results suggested that polymerase chain reaction/electrospray ionization-mass spectrometry technology could potentially have resulted in altered treatment in up to 57% of patients.

Conclusions: Polymerase chain reaction/electrospray ionization-mass spectrometry provides rapid pathogen identification in critically ill patients. The ability to rule out infection within 6 hours has potential clinical and economic benefits.

Introduction

The availability of rapid and reliable infectious disease diagnostics that can provide results directly from patient specimens represents a major unmet need in managing critically ill patients. Current sepsis guidelines recommend initiation of IV antibiotic therapy as early as possible, ideally within the first hour,[1] as any delay in effective antimicrobial therapy may result in decreased survival.[2] Effective therapy requires that the identity of causative pathogens and their resistance patterns are known. However, the current standard-of-care, which depends on blood culture-based initial diagnosis, often takes at least 48–72 hours to provide a result. Furthermore, cultures often remain negative even when bacterial or fungal infections are strongly suspected,[3] in part, related to concurrent antibiotic treatment.[4]

Molecular diagnostic techniques that do not depend on growth of organisms in culture may offer a distinct advantage over current methods. Most of the recently described molecular methods, however, rely on culture amplification as a precursor to diagnosis.[5–8] Although these techniques may accelerate diagnosis for positive cultures, they do not address the significant proportion of false-negative cultures observed in patients with sepsis. In addition, many of these methods also use targeted pathogen detection with limited pathogen coverage such that negative results are often not highly predictive.

Polymerase chain reaction followed by electrospray ionization-mass spectrometry (PCR/ESI-MS) can detect more than 800 bloodstream infection (BSI)-relevant pathogens in a single assay and in approximately 6 hours.[9–13] It can also identify three classes of antibiotic resistance markers associated with resistance to methicillin (mecA), vancomycin (vanA/vanB), and carbapenems (KPC). Using this technique, we recently demonstrated 83% sensitivity and 94% specificity compared with culture for direct detection of pathogens in whole-blood specimens from patients with suspected BSIs.[13]

Here, we describe findings from the multicenter observational Rapid Diagnosis of Infections in the Critically Ill (RADICAL) study. The primary objective was to compare results obtained using the novel culture-independent PCR/ESI-MS technology with those obtained from standard microbiological testing as a measure of clinical performance. Secondarily, to broadly address the clinical value of PCR/ESI-MS detections, a panel of independent clinical adjudicators was used to identify changes in patient management that may have occurred had the results from the PCR/ESI-MS technology been available for clinical use and assumed to be correct.

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