Volatile metabolites of pathogens: a systematic review

Abstract

Ideally, invading bacteria are detected as early as possible in critically ill patients: the strain of morbific pathogens is identified rapidly, and antimicrobial sensitivity is known well before the start of new antimicrobial therapy. Bacteria have a distinct metabolism, part of which results in the production of bacteria-specific volatile organic compounds (VOCs), which might be used for diagnostic purposes. Volatile metabolites can be investigated directly in exhaled air, allowing for noninvasive monitoring. The aim of this review is to provide an overview of VOCs produced by the six most abundant and pathogenic bacteria in sepsis, including Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. Such VOCs could be used as biological markers in the diagnostic approach of critically ill patients. A systematic review of existing literature revealed 31 articles. All six bacteria of interest produce isopentanol, formaldehyde, methyl mercaptan, and trimethylamine. Since humans do not produce these VOCs, they could serve as biological markers for presence of these pathogens. The following volatile biomarkers were found for identification of specific strains: isovaleric acid and 2-methyl-butanal for Staphylococcus aureus; 1-undecene, 2,4-dimethyl-1-heptane, 2-butanone, 4-methyl-quinazoline, hydrogen cyanide, and methyl thiocyanide for Pseudomonas aeruginosa; and methanol, pentanol, ethyl acetate, and indole for Escherichia coli. Notably, several factors that may effect VOC production were not controlled for, including used culture media, bacterial growth phase, and genomic variation within bacterial strains. In conclusion, VOCs produced by bacteria may serve as biological markers for their presence. Goal-targeted studies should be performed to identify potential sets of volatile biological markers and evaluate the diagnostic accuracy of these markers in critically ill patients.

Figure 1. Inclusion flow diagram.

The initial search resulted in 837 hits. Fifty-nine were selected based on title and abstract. Full text was read and references were checked for additional hits. This resulted in ten additional hits. Thirty papers were included based on the full text.

Figure 2. Interaction plot.

The six investigated pathogenic bacteria are plotted on both sides, with gram-positive bacteria on the left and gram-negative on the right. All the metabolites for which convincing evidence on production by at least one of the bacteria was available (as indicated by a green cell in Tables S1 to S9 in Text S1) were included in the figure and connected with a line to all bacteria known to produce a particular metabolite. The stronger the available evidence for the production of a metabolite by one strain of bacteria, the closer the metabolite is situated to the pathogen. Four zones of interest are highlighted. The blue zone in the middle indicates metabolites that are (almost) always produced by all pathogens and are therefore candidate markers with a high sensitivity that might thus qualify for the exclusion of infection (high negative predictive value). The three red zones indicate metabolites that are produced by only or mainly one strain of bacteria; these are possibly volatile biomarkers specific for a pathogen with a very high positive predictive value.