A.R. Akram et al., Science Translational Medicine (2018)

Current approaches to identify hospital-acquired gram-negative bacterial respiratory infections in intensive care patients on ventilation have fallen short. Lung biopsies are too risky and X-rays are overly sensitive and may lead to unnecessary use of antibiotics. A study in Science Translational Medicine describes how a fluorescent imaging technology was able to safely detect Gram-negative bacteria deep in the lungs of human subjects in less than 60 seconds, paving the way for more efficient diagnosis and treatment of these infections.

“This is the first time anyone had ever seen bacteria inside human lungs in patients, and it will help us to begin understanding disease,” lead investigator Ahsan Akram, MBChB, PhD, a clinical scientist fellow at the Centre for Inflammation Research, part of Queen’s Medical Research Institute at the University of Edinburgh, told CLN Stat.

Pneumonia is one of the leading causes of death in the world, and the rise in antimicrobial resistance makes it even more threatening. “We have a very poor understanding of pneumonia in patients and especially those that are very ill such as in critical care. Also it takes time to grow bacteria and identify causes of suspected pneumonia. Therefore, a major driver is the need to develop bedside rapid approaches,” the study team stated.

Akram and his colleagues developed a fluorescent imaging probe with the capacity to visualize difficult-to-trace Gram-negative bacteria in real time. The probe contains a targeting ligand based on a modified antibiotic called polymyxin and a reporter fluorophore made of 7-nitrobenz-2-oxa-1,3-diazole, which “lights up” when it specifically binds with a lipid (lipid A) of a lipopolysaccharide on the surface of the bacterial membrane. “The probe is detected using a standard piece of equipment involving optical endomicroscopy consisting of a small fiber imaging bundle that is passed into the distal part of the lung for microscopy imaging,” according to the study team.

The investigators initially tested the probe on lungs retrieved from sheep destined for cull, allowing them to evaluate the probe’s specificity and what concentration should be used. Following up with human test subjects, they populated various Gram-negative bacteria into the lungs of six patients with the chronic pulmonary disease bronchiectasis, repeating the process with seven ventilated patients in intensive care.

“Striking fluorescence was seen in lungs of patients with bronchiectasis who had Gram-negative bacteria in the deep parts of their lungs. Bacteria were also successfully visualized in intensive care patients using the new technology with striking results,” according to a statement issued by the University of Edinburgh.

If successful, such an approach could quickly advise clinicians on the need for antibiotics in critically ill patients, and more efficiently monitor illness and guide treatment.

None of the human test subjects experienced any adverse health effects from the bacterial probe. Akram and his colleagues nevertheless recommended that additional studies evaluate the potential risk of repeated uses. Currently, the team is receiving support from CARB-X, a public-private partnership devoted to antibacterial early development research, to develop the technology for clinical trials supported by the Wellcome Trust. “We will perform an evaluation study in 300 patients to observe the safety and performance of the technology in mechanically ventilated critically ill patients,” they said.