Kloman Metre: An EMD-Based Tool for Triaging Diseases Leading to Lung Infections Including COVID-19

AbstractMetabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. However, it is not known if this evolutionarily conserved mechanism has been coopted by the host immune defense to eradicate bacterial pathogens and influence post-sepsis immunosuppression. Parkin, AMPK levels, and the effects of AMPK activators were investigated in human leukocytes from sepsis survivors as well as wild type and Park2−/− murine macrophages. In vivo, the impact of AMPK and Parkin was determined in mice subjected to polymicrobial intra-abdominal sepsis and secondary lung bacterial infections. Mice were treated with metformin during established immunosuppression. We showed that bacteria and mitochondria share mechanisms of autophagic killing/clearance triggered by sentinel events that involve depolarization of mitochondria and recruitment of Parkin in macrophages. Parkin-deficient mice/macrophages fail to form phagolysosomes and kill bacteria. This impairment of host defense is seen in the context of sepsis-induced immunosuppression with decreased levels of Parkin. AMPK activators, including metformin, stimulate Parkin-independent autophagy and bacterial killing in leukocytes from post-shock patients and in lungs of sepsis-immunosuppressed mice. Our results support a dual role of Parkin and AMPK in the clearance of dysfunctional mitochondria and killing of pathogenic bacteria, and explain the immunosuppressive phenotype associated Parkin and AMPK deficiency. AMPK activation appeared to be a crucial therapeutic target for the macrophage immunosuppressive phenotype and to reduce severity of secondary bacterial lung infections and respiratory failure.

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The Impact of an Efflux Pump Inhibitor on the Activity of Free and Liposomal Antibiotics against Pseudomonas aeruginosa

Pharmaceutics ◽

10.3390/pharmaceutics13040577 ◽

2021 ◽

Vol 13 (4) ◽

pp. 577

Author(s):

Douweh Leyla Gbian ◽

Abdelwahab Omri

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Efflux Pump ◽

Antimicrobial Activities ◽

Dilution Method ◽

Efflux Pump Inhibitor ◽

Signal Production ◽

Lung Infections ◽

The Impact ◽

Microbroth Dilution

The eradication of Pseudomonas aeruginosa in cystic fibrosis patients has become continuously difficult due to its increased resistance to treatments. This study assessed the efficacy of free and liposomal gentamicin and erythromycin, combined with Phenylalanine arginine beta-naphthylamide (PABN), a broad-spectrum efflux pump inhibitor, against P. aeruginosa isolates. Liposomes were prepared and characterized for their sizes and encapsulation efficiencies. The antimicrobial activities of formulations were determined by the microbroth dilution method. Their activity on P. aeruginosa biofilms was assessed, and the effect of sub-inhibitory concentrations on bacterial virulence factors, quorum sensing (QS) signals and bacterial motility was also evaluated. The average diameters of liposomes were 562.67 ± 33.74 nm for gentamicin and 3086.35 ± 553.95 nm for erythromycin, with encapsulation efficiencies of 13.89 ± 1.54% and 51.58 ± 2.84%, respectively. Liposomes and PABN combinations potentiated antibiotics by reducing minimum inhibitory and bactericidal concentrations by 4–32 fold overall. The formulations significantly inhibited biofilm formation and differentially attenuated virulence factor production as well as motility. Unexpectedly, QS signal production was not affected by treatments. Taken together, the results indicate that PABN shows potential as an adjuvant of liposomal macrolides and aminoglycosides in the management of lung infections in cystic fibrosis patients.

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Aerosol-based antimicrobial photoinactivation in the lungs: an action spectrum study

Photochemical & Photobiological Sciences ◽

10.1007/s43630-021-00066-2 ◽

2021 ◽

Author(s):

Chiara Treghini ◽

Alfonso Dell’Accio ◽

Franco Fusi ◽

Giovanni Romano

Keyword(s):

Light Source ◽

A Priori ◽

Action Spectrum ◽

Multidrug Resistant ◽

Theoretical Modelling ◽

Resistant Bacteria ◽

Lung Infections ◽

Killing Action ◽

Definition Of

AbstractChronic lung infections are among the most diffused human infections, being often associated with multidrug-resistant bacteria. In this framework, the European project “Light4Lungs” aims at synthesizing and testing an inhalable light source to control lung infections by antimicrobial photoinactivation (aPDI), addressing endogenous photosensitizers only (porphyrins) in the representative case of S. aureus and P. aeruginosa. In the search for the best emission characteristics for the aerosolized light source, this work defines and calculates the photo-killing action spectrum for lung aPDI in the exemplary case of cystic fibrosis. This was obtained by applying a semi-theoretical modelling with Monte Carlo simulations, according to previously published methodology related to stomach infections and applied to the infected trachea, bronchi, bronchioles and alveoli. In each of these regions, the two low and high oxygen concentration cases were considered to account for the variability of in vivo conditions, together with the presence of endogenous porphyrins and other relevant absorbers/diffusers inside the illuminated biofilm/mucous layer. Furthermore, an a priori method to obtain the “best illumination wavelengths” was defined, starting from maximizing porphyrin and light absorption at any depth. The obtained action spectrum is peaked at 394 nm and mostly follows porphyrin extinction coefficient behavior. This is confirmed by the results from the best illumination wavelengths, which reinforces the robustness of our approach. These results can offer important indications for the synthesis of the aerosolized light source and definition of its most effective emission spectrum, suggesting a flexible platform to be considered in further applications.

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Bacterial superinfections among persons with coronavirus disease 2019:A comprehensive review of data from postmortem studies

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab065 ◽

2021 ◽

Author(s):

Cornelius J Clancy ◽

Ilan S Schwartz ◽

Brittany Kula ◽

M Hong Nguyen

Keyword(s):

Rank Order ◽

Diffuse Alveolar Damage ◽

Antimicrobial Treatment ◽

Beta Lactam ◽

Quality Of Data ◽

Major Objective ◽

Postmortem Studies ◽

Lung Infections ◽

Histopathologic Findings

Abstract Background Limited clinical data suggest ~16% prevalence of bacterial superinfections among critically ill patients with coronavirus disease 2019 (COVID-19). Methods We reviewed postmortem studies of patients with COVID-19 published in English through 26 September 2020 for histopathologic findings consistent with bacterial lung infections. Results Worldwide, 621 patients from 75 studies were included. The quality of data was uneven, likely because identifying superinfections was not a major objective in 96% (72/75) of studies. Histopathology consistent with potential lung superinfection was reported in 32% (200/621) of patients (22-96 years old; 66% men). Types of infections were pneumonia (95%), abscesses or empyema (3.5%), and septic emboli (1.5%). Seventy-three percent of pneumonias were focal rather than diffuse. Predominant histopathologic findings were intra-alveolar neutrophilic infiltrations that were distinct from those typical of COVID-19-associated diffuse alveolar damage. In studies with available data, 79% of patients received antimicrobial treatment; most common agents were beta-lactam/beta-lactamase inhibitors (48%), macrolides (16%), cephalosoprins (12%), and carbapenems (6%). Superinfections were proven by direct visualization or recovery of bacteria in 25.5% (51/200) of potential cases, and 8% of all patients in postmortem studies. In rank order, pathogens included Acinetobacter baumannii, Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae. Lung superinfections were causes of death in 16% of potential cases, and 3% of all patients with COVID-19. Conclusions Potential bacterial lung superinfections were evident at postmortem examination in 32% of persons who died with COVID-19 (proven, 8%; possible, 24%), but they were uncommonly the cause of death.

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