Lung ultrasound and procalcitonin, improving antibiotic management and avoiding radiation exposure in pediatric critical patients with bacterial pneumonia: a randomized clinical trial.

BACKGROUND: Pneumonia is a major public health problem with an impact on morbidity and mortality. Its management still represents a challenge. The aim was to determine whether a new diagnostic algorithm combining lung ultrasound (LUS) and procalcitonin (PCT) improved pneumonia management regarding antibiotic use, radiation exposure, and associated costs, in critically ill pediatric patients with suspected bacterial pneumonia (BP). METHODS: Randomized, blinded, comparative effectiveness clinical trial. Children < 18y with suspected BP admitted to the PICU from September 2017 to December 2019, were included. PCT was determined at admission. Patients were randomized into the experimental group (EG) and control group (CG) if LUS or chest X-ray (CXR) were done as the first image test, respectively. Patients were classified: 1.LUS/CXR not suggestive of BP and PCT < 1 ng/mL, no antibiotics were recommended; 2.LUS/CXR suggestive of BP, regardless of the PCT value, antibiotics were recommended; 3.LUS/CXR not suggestive of BP and PCT > 1 ng/mL, antibiotics were recommended. RESULTS: 194 children were enrolled, 113 (58.2%) females, median age of 134 (IQR 39-554) days. 96 randomized into EG and 98 into CG. 1. In 75/194 patients the image test was not suggestive of BP with PCT < 1 ng/ml; 29/52 in the EG and 11/23 in the CG did not receive antibiotics. 2. In 101 patients, the image was suggestive of BP; 34/34 in the EG and 57/67 in the CG received antibiotics. Statistically significant differences between groups were observed when PCT resulted < 1 ng/ml (p = 0.01). 3. In 18 patients the image test was not suggestive of BP but PCT resulted > 1 ng/ml, all of them received antibiotics. A total of 0.035 mSv radiation/patient was eluded. A reduction of 77% CXR/patient was observed. LUS did not significantly increase costs. CONCLUSIONS: Combination of LUS and PCT showed no risk of mistreating BP, avoided radiation and did not increase costs. The algorithm could be a reliable tool for improving pneumonia management. CLINICAL TRIAL REGISTRATION: NCT04217980.

Cost-effectiveness analysis of CTZ/TAZ for the treatment of ventilated hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia in Japan.

BACKGROUND: Resistant bacterial infections, particularly those caused by gram-negative pathogens, are associated with high mortality and economic burdens. Ceftolozane/tazobactam demonstrated efficacy comparable to meropenem in patients with ventilated hospital-acquired bacterial pneumonia in the ASPECT-NP study. One cost-effectiveness analysis in the United States revealed that ceftolozane/tazobactam was cost effective, but no Japanese studies have been conducted. Therefore, the objective of this study was to assess the cost-effectiveness of ceftolozane/tazobactam compared to meropenem for patients with ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia from a health care payer perspective. METHODS: A hybrid decision-tree Markov decision-analytic model with a 5-year time horizon were developed to estimate costs and quality-adjusted life-years and to calculate the incremental cost-effectiveness ratio associated with ceftolozane/tazobactam and meropenem in the treatment of patients with ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. Clinical outcomes were based on the ASPECT-NP study, costs were based on the national fee schedule of 2022, and utilities were based on published data. One-way sensitivity analysis and probabilistic sensitivity analysis were also conducted to assess the robustness of our modeled estimates. RESULTS: According to our base-case analysis, compared with meropenem, ceftolozane/tazobactam increased the total costs by 424,731.22 yen (£2,626.96) and increased the quality-adjusted life-years by 0.17, resulting in an incremental cost-effectiveness ratio of 2,548,738 yen (£15,763.94) per quality-adjusted life-year gained for ceftolozane/tazobactam compared with meropenem. One-way sensitivity analysis showed that although the incremental cost-effectiveness ratio remained below 5,000,000 yen (£30,925) for most of the parameters, the incremental net monetary benefit may have been less than 0 depending on the treatment efficacy outcome, especially the cure rate and mortality rate for MEPM and mortality rate for CTZ/TAZ. 53.4% of the PSA simulations demonstrated that CTZ/TAZ was more cost-effective than MEPM was. CONCLUSION: Although incremental cost-effectiveness ratio was below ï¿¥5,000,000 in base-case analysis, whether ceftolozane/tazobactam is a cost-effective alternative to meropenem for ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia in Japan remains uncertain. Future research should examine the unobserved heterogeneity across patient subgroups and decision-making settings, to characterise decision uncertainty and its consequences so as to assess whether additional research is required.

Pseudomonas fluorescens pneumonia.

Pseudomonas fluorescens (P. fluorescens) is not generally considered a bacterial pathogen in humans; however, multiple culture-based and culture-independent studies have identified it in the indigenous microbiota of multiple body sites. We herein report a rare case of pneumonia caused by P. fluorescens. A man in his 80 s with chronic obstructive pulmonary disease and diabetes mellitus was diagnosed with stage II rectal cancer. He underwent laparoscopic surgery, and on the 6th postoperative day, he developed a high fever. Chest computed tomography revealed infiltration in the left lower lung. Gram staining of the sputum showed Gram-negative rods phagocytosed by neutrophils, suggesting postoperative nosocomial pneumonia. The patient was started on tazobactam/piperacillin, and his pneumonia quickly improved. Later, only P. fluorescens was detected in a sputum culture. It was susceptible to common antipseudomonal agents. Gram staining of P. fluorescens appears to show a slightly thicker and larger morphology in comparison to Pseudomonas aeruginosa. Although there have been reports of opportunistic infections caused by P. fluorescens in immunosuppressed patients, including those with advanced cancer, most have been bloodstream infections, with very few reports of pneumonia alone. Clinicians should be aware that patients, who are not necessarily immunosuppressed, may develop pneumonia caused by P. fluorescens.

Achromobacter pneumonia in a patient with advanced COPD, a diagnostic challenge.

Bacterial pneumonia causes significant morbidity and mortality especially in elderly and immunocompromised hosts. Achromobacter xylosoxidans denitrificans pneumonia is very rarely reported. However, the reported cases have been in patients who are either immunocompromised or have bronchiectasis. We hereby present a unique case of Achromobacter xylosoxidans denitrificans pneumonia in an immunocompetent patient with advanced chronic obstructive pulmonary disease (COPD). Our patient is a Caucasian male admitted with shortness of breath, fever and cough. Chest X-ray demonstrated right-sided infiltrates and he was treated with intravenous ceftriaxone and azithromycin. He was discharged home on oral amoxicillin-clavulanate 875-125 mg two times per day for a total of 7 days. Patient returned to emergency room after 5 weeks with persistent symptoms and chest X-ray revealed persistent right-sided infiltrate and sputum culture showed Achromobacter xylosoxidans denitrificans. The patient was started on oral levofloxacin 750 mg one time per day for 2 weeks with resolution of symptoms.

Bacterial pneumonia-induced shedding of epithelial heparan sulfate inhibits the bactericidal activity of cathelicidin in a murine model.

Bacterial pneumonia is a common clinical syndrome leading to significant morbidity and mortality worldwide. In the current study, we investigate a novel, multidirectional relationship between the pulmonary epithelial glycocalyx and antimicrobial peptides in the setting of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Using an in vivo pneumonia model, we demonstrate that highly sulfated heparan sulfate (HS) oligosaccharides are shed into the airspaces in response to MRSA pneumonia. In vitro, these HS oligosaccharides do not directly alter MRSA growth or gene transcription. However, in the presence of an antimicrobial peptide (cathelicidin), increasing concentrations of HS inhibit the bactericidal activity of cathelicidin against MRSA as well as other nosocomial pneumonia pathogens (Klebsiella pneumoniae and Pseudomonas aeruginosa) in a dose-dependent manner. Surface plasmon resonance shows avid binding between HS and cathelicidin with a dissociation constant of 0.13 µM. These findings highlight a complex relationship in which shedding of airspace HS may hamper host defenses against nosocomial infection via neutralization of antimicrobial peptides. These findings may inform future investigation into novel therapeutic targets designed to restore local innate immune function in patients suffering from primary bacterial pneumonia.NEW & NOTEWORTHY Primary Staphylococcus aureus pneumonia causes pulmonary epithelial heparan sulfate (HS) shedding into the airspace. These highly sulfated HS fragments do not alter bacterial growth or transcription, but directly bind with host antimicrobial peptides and inhibit the bactericidal activity of these cationic polypeptides. These findings highlight a complex local interaction between the pulmonary epithelial glycocalyx and antimicrobial peptides in the setting of bacterial pneumonia.

Therapeutic Effect and Safety Evaluation of Naringin on Klebsiella pneumoniae in Mice.

Critically ill patients with Corona Virus Disease 2019 (COVID-19) often develop secondary bacterial infections that pose a significant threat to patient life safety, making the development of drugs to prevent bacterial infections in the lungs critical to clinical care. Naringin (NAR) is one of the significant natural flavonoids rich in Pummelo Peel (Hua Ju Hong), with anti-inflammatory, antimicrobial, and antioxidant activities, and is commonly used in treating respiratory tract infectious diseases. In this study, the in vitro and in vivo findings revealed that, after Klebsiella pneumoniae (Kpn) infection, NAR inhibited overactivation of the nuclear factor kappa-B(NF-κB) signaling pathway in alveolar macrophages of mice, reduced neutrophil (NEs) recruitment, and lowered the induced production of proinflammatory markers, such as Interleukin-6(IL-6) and tumor necrosis factor α(TNF-α). Thus, it suppressed excessive immune responses in the lungs, as well as attenuated the induced pulmonary fibrosis and inflammatory infiltrates. These results suggest that NAR has a preventive effect against Kpn in mice. In addition, the study evaluated NAR's potential toxicity, demonstrating that NAR is safe at effective doses. These results suggested that NAR effectively reduces excessive inflammatory damage in the lungs induced by Kpn and enhances the body's ability to clear bacteria. Therefore, NAR may be an effective and safe healthcare drug for preventing and caring for bacterial pneumonia.

The potential clinical value of pairing procalcitonin and lung ultrasonography to guide antibiotic therapy in patients with community-acquired pneumonia: a narrative review.

INTRODUCTION: Lower respiratory tract infections (LRTIs) are among the most frequent infections and are prone to inappropriate antibiotic treatments. This results from a limited accuracy of diagnostic tools in identifying bacterial pneumonia. Lung ultrasound (LUS) has excellent sensitivity and specificity in diagnosing pneumonia. Additionally, elevated procalcitonin (PCT) levels correlate with an increased likelihood of bacterial infection. LUS and PCT appear to be complementary in identifying patients with bacterial pneumonia who are likely to benefit from antibiotics. AREAS COVERED: This narrative review aims to summarize the current evidence for LUS to diagnose pneumonia, for PCT to guide antibiotic therapy and the clinical value of pairing both tools. EXPERT OPINION: LUS has excellent diagnostic accuracy for pneumonia in different settings, regardless of the examiner's experience. PCT guidance safely reduces antibiotic prescription in LRTIs. The combination of both tools has demonstrated an enhanced accuracy in the diagnosis of pneumonia, including CAP in the ED and VAP in the ICU, but randomized controlled studies need to validate the clinical impact of a combined approach.

Aerosol Delivery of a Novel Recombinant Modified Superoxide Dismutase Protein Reduces Oxidant Injury and Attenuates Escherichia coli Induced Lung Injury in Rats.

Background: Acute respiratory distress syndrome (ARDS) is a life-threatening respiratory failure syndrome with diverse etiologies characterized by increased permeability of alveolar-capillary membranes, pulmonary edema, and acute onset hypoxemia. During the ARDS acute phase, neutrophil infiltration into the alveolar space results in uncontrolled release of reactive oxygen species (ROS) and proteases, overwhelming antioxidant defenses and causing alveolar epithelial and lung endothelial injury. Objectives: To investigate the therapeutic potential of a novel recombinant human Cu-Zn-superoxide dismutase (SOD) fusion protein in protecting against ROS injury and for aerosolized SOD delivery to treat Escherichia coli induced ARDS. Methods: Fusion proteins incorporating human Cu-Zn-SOD (hSOD1), with (pep1-hSOD1-his) and without (hSOD1-his) a fused hyaluronic acid-binding peptide, were expressed in E. coli. Purified proteins were evaluated in in vitro assays with human bronchial epithelial cells and through aerosolized delivery to the lung of an E. coli-induced ARDS rat model. Results: SOD proteins exhibited high SOD activity in vitro and protected bronchial epithelial cells from oxidative damage. hSOD1-his and pep1-hSOD1-his retained SOD activity postnebulization and exhibited no adverse effects in the rat. Pep1-hSOD1-his administered through instillation or nebulization to the lung of an E. coli-induced pneumonia rat improved arterial oxygenation and lactate levels compared to vehicle after 48 hours. Static lung compliance was improved when the pep1-hSOD1-his protein was delivered by instillation. White cell infiltration to the lung was significantly reduced by aerosolized delivery of protein, and reduction of cytokine-induced neutrophil chemoattractant-1, interferon-gamma, and interleukin 6 pro-inflammatory cytokine concentrations in bronchoalveolar lavage was observed. Conclusions: Aerosol delivery of a novel recombinant modified SOD protein reduces oxidant injury and attenuates E. coli induced lung injury in rats. The results provide a strong basis for further investigation of the therapeutic potential of hSOD1 in the treatment of ARDS.

Sulbactam/Durlobactam: First Approval.

Sulbactam/durlobactam (XACDURO®), is a co-packaged antibacterial product that has been developed by Entasis Therapeutics Inc. for the treatment of infections caused by Acinetobacter baumannii-calcoaceticus complex (ABC). Coadministration of durlobactam (a ß-lactamase inhibitor with potent activity against a broad range of serine ß-lactamases) with sulbactam (an established class A ß-lactamase inhibitor with antibacterial activity against A. baumannii) prevents sulbactam degradation by ABC-produced ß-lactamases. In May 2023, sulbactam/durlobactam was approved in the USA for use in patients 18 years of age and older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of ABC. This article summarizes the milestones in the development of sulbactam/durlobactam leading to this first approval for the treatment of infections caused by ABC.

Resveratrol-Loaded Dipalmitoylphosphatidylcholine Liposomal Large Porous Microparticle Inhalations for the Treatment of Bacterial Pneumonia Caused by Acinetobacter baumannii.

Background: Acinetobacter baumannii-mediated bacterial pneumonia is a common disease that is harmful to human health. Dipalmitoylphosphatidylcholine (DPPC) is the major lipid component of the pulmonary surfactant (PS) found in the alveolar space; the PS helps to keep surface tension low, which allows for improved oxygen delivery. Resveratrol (RE) is a phytoalexin found in plants that is released in response to injury or infection. The therapeutic effect of Re is limited due to its low solubility and bioavailability. In this study, we report pulmonary delivery of Re-loaded DPPC liposomal large porous microparticles (RDLPMs) for treatment of A. baumannii-induced pneumonia. Methods: Novel RDLPMs were prepared by rotary evaporation and a freeze-drying method in this study. RDLPMs were evaluated by the particle size, electric potential, in vitro release, and particle size distribution. A rat model of A. baumannii-mediated pneumonia was established and used for pharmacodynamic evaluations. Results: The Re-loaded DPPC liposomes (RDLs) consisted of Re/DPPC (1:3, mol/mol) and DPPC/cholesterol (3:1, w/w), with a hydration time of 15 minutes. The RDLs had a high encapsulation efficiency of 69.8% ± 1.6%, a mean size of 191.5 ± 4.5 nm, and a high zeta potential of 12.4 ± 1.5 mV. The RDLPMs were composed of mannitol/large porous microparticles/RDLs (1:4:2, w/w/w) and had a loading efficiency of 2.20% ± 0.24%. The RDLPMs had an aerodynamic diameter (2.73 ± 0.65 µm), a good fluidity (28.30° ± 6.13°), and demonstrated high lung deposition (fine particle fraction = 43.33%). Surprisingly, while penicillin showed better microbial inhibition than the RDLPMs and Re groups in vitro, the RDLPMs were more effective in vivo. Conclusion: The RDLPMs showed good powder properties for pulmonary delivery. The RDLPMs may inhibit the nuclear factor kappa-B pathway and downregulate the expression of cytokines downstream of tumor necrosis factor-α and interleukin-1ß. As well as, RDLPMs demonstrated some antibacterial properties against A. baumannii bacteria. Re, when delivered in RDLPMs as a dry powder inhaler, is a promising substitute for antibiotics in the treatment of A. baumannii pneumonia.

Effects of procalcitonin on antimicrobial treatment decisions in patients with coronavirus disease 2019 (COVID-19).

OBJECTIVE: To describe the natural course of procalcitonin (PCT) in patients with coronavirus disease 2019 (COVID-19) and the correlation between PCT and antimicrobial prescribing to provide insight into best practices for PCT data utilization in antimicrobial stewardship in this population. DESIGN: Single-center, retrospective, observational study. SETTING: Michigan Medicine. PATIENTS: Inpatients aged ≥18 years hospitalized March 1, 2020, through October 31, 2021, who were positive for severe acute respiratory coronavirus virus 2 (SARS-CoV-2), with ≥1 PCT measurement. Exclusion criteria included antibiotics for nonpulmonary bacterial infection on admission, treatment with azithromycin only for chronic obstructive pulmonary disease (COPD) exacerbation, and pre-existing diagnosis of cystic fibrosis with positive respiratory cultures. METHODS: A structured query was used to extract data. For patients started on antibiotics, bacterial pneumonia (bPNA) was determined through chart review. Multivariable models were used to assess associations of PCT level and bPNA with antimicrobial use. RESULTS: Of 793 patients, 224 (28.2%) were initiated on antibiotics: 33 (14.7%) had proven or probable bPNA, 125 (55.8%) had possible bPNA, and 66 (29.5%) had no bPNA. Patients had a mean of 4.1 (SD, ±5.2) PCT measurements if receiving antibiotics versus a mean of 2.0 (SD, ±2.6) if not. Initial PCT level was highest for those with proven/probable bPNA and was associated with antibiotic initiation (odds ratio 95% confidence interval [CI], 1.17-1.30). Initial PCT (rate ratio [RR] 95% CI, 1.01-1.08), change in PCT over time (RR 95% CI, 1.01-1.05), and bPNA group (RR 95% CI, 1.23-1.84) were associated with antibiotic duration. CONCLUSIONS: PCT trends are associated with the decision to initiate antibiotics and duration of treatment, independent of bPNA status and comorbidities. Prospective studies are needed to determine whether PCT level can be used to safely make decisions regarding antibiotic treatment for COVID-19.

Protocolo clínico de atendimento de pneumonia adquirida na comunidade para Pronto-Socorro Infantil do Hospital do Servidor Público Municipal de São Paulo / Clinical protocol for community-acquired pneumonia care for the Children's Emergency Room of the Hospital do Servidor Público Municipal de São Paulo

A pneumonia adquirida na comunidade (PAC) é a infecção aguda do parênquima pulmonar que ocorre no meio comunitário. A PAC representa a maior causa de morbidade e mortalidade em todo o mundo em crianças abaixo de cinco anos. Nesta faixa etária, a etiologia viral é a mais comum; porém, dentre as causas bacterianas, o Streptoccocus pneumoniae é o mais prevalente. As manifestações clínicas variam de acordo com o patógeno, hospedeiro e da gravidade da doença, sendo geralmente descrita com tosse, febre e desconforto respiratório. A PAC complicada é a pneumonia que, apesar do uso de antibióticos, evolui com complicações locais ou sistêmicas. Nos pacientes hospitalizados, as hemoculturas devem ser consideradas para auxiliar no diagnóstico etiológico e planejamento terapêutico. O tratamento inicial deve ser iniciado empiricamente com antibióticos. Caso haja necessidade de hospitalização, hemoculturas devem ser consideradas para auxiliar na propedêutica. Após implementação das vacinas pneumocócicas, principalmente após introdução da vacina pneumocócica 13 valente (PCV 13), houve redução significativa dos casos de pneumonia bacteriana e também da necessidade hospitalização. Diante de tal realidade, a elaboração do trabalho possui como objetivo a melhora dos procedimentos e a padronização dos atendimentos da população pediátrica com um quadro clínico sugestivo pneumonia adquirida na comunidade, que procura o serviço de Pronto Atendimento Infantil do Hospital do Servidor Público Municipal de São Paulo (HSPM), ao construir um protocolo clínico de atendimento específico para a doença. O presente trabalho objetiva elaborar um protocolo clínico de atendimento de pneumonia adquirida na comunidade no Hospital do Servidor Público Municipal de São Paulo, contribuindo na assistência médica dos pacientes pediátricos. Apesar do grande avanço com a introdução das vacinas pneumocócicas, a PAC ainda representa uma importante causa de mortalidade na população infantil, sendo fundamental a elaboração de protocolos clínicos para abordar corretamente os pacientes que recorrem a um Pronto Socorro Infantil. Protocolos clínicos são diretrizes fundamentadas nas melhores práticas para a abordagem e tratamento de determinadas doenças, baseadas em evidência científica. O presente trabalho objetiva a melhora dos procedimentos e a uniformização dos atendimentos da população pediátrica com pneumonia, que procura o serviço de Pronto Atendimento Infantil do Hospital do Servidor Público Municipal de São Paulo (HSPM), com a construção de um protocolo clínico de atendimento específico para a doença, a partir da revisão de literatura atualizada, cujo período de vigência seguirá os progressos científicos sobre o tema. Palavras-chave: Pneumonia Adquirida da Comunidade. Protocolos clínicos. Pediatria. Serviços Médicos de Emergência. Vacinas Pneumocócicas

Boosting lung accumulation of gallium with inhalable nano-embedded microparticles for the treatment of bacterial pneumonia.

The potential of intra-venous gallium nitrate (GaN) administration against Pseudomonas aeruginosa pneumonia was recently demonstrated in mice and in cystic fibrosis (CF) patients. Likewise, the added value of direct lung delivery of Ga(III) has been shown in rats. Therefore, the design of a drug delivery system specifically engineered for Ga(III) inhalation is imperative to improve its accumulation in lungs. To this purpose, Ga(III) was efficiently encapsulated into hyaluronic acid/chitosan nanoparticles (Ga_HA/CS NPs), whose features were tuned to facilitate access to the target by overcoming mucus and biofilm surrounding bacteria. Then, to improve in vivo lung deposition, Ga_HA/CS NPs were engineered into mannitol-based NEM (Ga_Man NEM). The powders showed optimal in vitro aerosol performance, and sustained release kinetics in lung lining fluids. Moreover, good tolerability and antimicrobial properties were shown in vitro. Intratracheal insufflation of Ga_Man NEM in rats resulted in a significant improvement of Ga(III) persistence in the lungs coupled to a lower Ga(III) concentration in plasma and urine, compared to GaN solution. Noteworthy, the developed formulation significantly modifies the unfavorable Ga(III) kinetic increasing the Ga(III) to the lung and preventing Ga(III) accumulation in the kidney, key responsible for adverse effects, conclusively demonstrating the benefit of Ga_Man NEM to exploit the therapeutic effect of Ga(III) via inhalation route.

Prokineticin 2 promotes macrophages-mediated antibacterial host defense against bacterial pneumonia.

OBJECTIVES: Bacterial pneumonia is a common serious infectious disease with high morbidity and mortality. Prokineticin 2 (PK2) has recently been identified as a novel immunomodulator in a variety of diseases; however, its role in bacterial pneumonia remains unclear. METHODS: The levels of PK2 were measured and analyzed in patients with pneumonia and healthy controls. The effects of PK2 on the host response to pneumonia were evaluated by in vivo animal experiments and in vitro cell experiments. RESULTS: PK2 levels dramatically decreased in patients with pneumonia compared with healthy controls, and PK2 levels were lower in patients with severe pneumonia than in pneumonia. In a mouse model of bacterial pneumonia, transtracheal administration of recombinant PK2 significantly alleviated lung injury and improved the survival, which was associated with increased host's bacterial clearance capacity, as manifested by decreased pulmonary bacterial loads. PK2 enhanced the chemotaxis, phagocytosis, and killing ability of macrophages, whereas the protective efficacy of PK2 was abolished after macrophage depletion. CONCLUSION: Impaired alveolar macrophage function caused by decreased PK2 is a new endogenous cause of the occurrence and development of bacterial pneumonia. The administration of recombinant PK2 may be a potential adjuvant therapy for bacterial pneumonia.

Pamoic acid is an inhibitor of HMGB1·CXCL12 elicited chemotaxis and reduces inflammation in murine models of Pseudomonas aeruginosa pneumonia.

BACKGROUND: High-mobility group box 1 protein (HMGB1) is an ubiquitous nuclear protein that once released in the extracellular space acts as a Damage Associated Molecular Pattern and promotes inflammation. HMGB1 is significantly elevated during Pseudomonas aeruginosa infections and has a clinical relevance in respiratory diseases such as Cystic Fibrosis (CF). Salicylates are HMGB1 inhibitors. To address pharmacological inhibition of HMGB1 with small molecules, we explored the therapeutic potential of pamoic acid (PAM), a salicylate with limited ability to cross epithelial barriers. METHODS: PAM binding to HMGB1 and CXCL12 was tested by Nuclear Magnetic Resonance Spectroscopy using chemical shift perturbation methods, and inhibition of HMGB1·CXCL12-dependent chemotaxis was investigated by cell migration experiments. Aerosol delivery of PAM, with single or repeated administrations, was tested in murine models of acute and chronic P. aeruginosa pulmonary infection in C57Bl/6NCrlBR mice. PAM efficacy was evaluated by read-outs including weight loss, bacterial load and inflammatory response in lung and bronco-alveolar lavage fluid. RESULTS: Our data and three-dimensional models show that PAM is a direct ligand of both HMGB1 and CXCL12. We also showed that PAM is able to interfere with heterocomplex formation and the related chemotaxis in vitro. Importantly, PAM treatment by aerosol was effective in reducing acute and chronic airway murine inflammation and damage induced by P. aeruginosa. The results indicated that PAM reduces leukocyte recruitment in the airways, in particular neutrophils, suggesting an impaired in vivo chemotaxis. This was associated with decreased myeloperoxidase and neutrophil elastase levels. Modestly increased bacterial burdens were recorded with single administration of PAM in acute infection; however, repeated administration in chronic infection did not affect bacterial burdens, indicating that the interference of PAM with the immune system has a limited risk of pulmonary exacerbation. CONCLUSIONS: This work established the efficacy of treating inflammation in chronic respiratory diseases, including bacterial infections, by topical delivery in the lung of PAM, an inhibitor of HMGB1.

Epigallocatechin-3-gallate ameliorates liver injury secondary to Pseudomonas aeruginosa pneumonia.

Pseudomonas aeruginosa is a dangerous pathogen causing nosocomial pneumonia. P. aeruginosa infection-induced liver damage is another fatal threat, and antibiotic treatment is not effective in relieving P. aeruginosa virulence-triggered damage. We here evaluated the protective effect of epigallocatechin gallate (EGCG), a substance that inhibits virulence of P. aeruginosa through quorum quenching, on liver damage secondary to P. aeruginosa infection. Mice were pretreated with EGCG (20, 40, and 80 mg/kg) for 3 days, and then infected with P. aeruginosa through intratracheal instillation to model acute pneumonia. The mice were sacrificed after 24 h of infection, and samples were harvested for subsequent analysis. EGCG significantly decreased the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Histopathological changes of liver were significantly ameliorated by EGCG. It also significantly reduced oxidative stress that induced liver damage in P. aeruginosa infection, which relied not on the activation of the Nrf2-HO-1 pathway but on the upregulation of the activity of antioxidative enzymes. Then, the inflammatory response in the liver was tested. EGCG inhibited the release of pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) by blocking the inflammation regulating signaling of the TLR4-myD88-NF-κB pathway. EGCG upregulated the activation of nuclear receptors to stronger the liver protective activity against P. aeruginosa infection. Conclusively, EGCG exhibited a significant hepatoprotective effective against P. aeruginosa infection.

Olsenella uli-induced pneumonia: a case report.

BACKGROUND: Olsenella uli is anaerobic or microaerophilic bacteria, commonly found in oral cavity or gastrointestinal tract, which has not been reported to be associated with lower respiratory tract infection. Herein, we report the first case of Olsenella uli infection in the lung. CASE PRESENTATION: A 70-year-old male farmer with no history of other respiratory tract diseases developed a cough with bloody sputum three times a day without obvious causes or other concomitant symptoms. After a period of treatment with empirical antibiotic, his condition did not improve. The computed tomography (CT) and lung biopsy results indicated bilateral pneumonia, and Olsenella uli was identified by micromorphology, sequence analysis and mass spectrometry analysis recovered from sputum. Ceftazidime, a third generation cephalosporin was used for the treatment, and the patient recovered after 10 days. CONCLUSIONS: Our report suggests a causative role of gingival bacteria in the pathogenesis of pneumonia, thus early diagnosis and prompt antibiotic therapy may play a role in the treatment of Olsenella uli induced pneumonia.

Hematogenous dissemination of pulmonary mucormycosis manifested as multiple subcutaneous nodules: a case report and review of the literature.

BACKGROUND: Disseminated mucormycosis presenting with multiple subcutaneous nodules is a rare condition with a poor prognosis, and delayed diagnosis and treatment is common. CASE PRESENTATION: We report a case of 64-year-old Thai woman with colorectal cancer who initially presented with Acinetobacter baumannii pneumonia and respiratory failure. Following 10 days after her admission to the intensive care unit, she developed hospital-acquired pneumonia. Five days later, multiple subcutaneous nodules appeared on both arms and both legs. Bronchoalveolar lavage and skin biopsy cultures both grew Mucor spp. She was diagnosed with disseminated mucormycosis and was treated with liposomal amphotericin B at a dose of 5 mg/kg/day. Despite treatment, our patient succumbed to septic shock and multiorgan failure on the third day after definitive diagnosis. CONCLUSIONS: This case demonstrates that the subcutaneous nodules caused by hematogenously disseminated mucormycosis are unusual in a patient with a solid tumor. Clinicians should be aware of this atypical presentation of mucormycosis in patients with solid tumors.

Risk factors of carbapenem-resistant gram-negative bacteria pneumonia and mortality.

This experiment aimed to study the risk factors of carbapenem-resistant Gram-negative bacteria pneumonia and death. For this aim, a total of 181 patients with Gram-negative bacterial pneumonia treated from March 2020 to March 2022 were retrospectively selected and divided into the drug-resistance group (n = 96) and the non-drug resistance group (n = 85) according to the carbapenem resistance. According to the prognosis, the drug resistance group was divided into the survival group (n = 82) and the non-survival group (n = 14), respectively. The risk factors of single and multi-factor carbapenem-resistant Gram-negative bacteria pneumonia and death were studied. Results showed that univariate analysis showed that the rates of recent surgery, respiratory failure, shock, indwelling catheterization and disturbance of consciousness were significantly higher in the drug-resistant group than in the non-drug-resistant group. The univariate analysis also showed that the rates of coronary heart disease, diabetes, shock, renal insufficiency, deep venous catheterization and respiratory failure were significantly higher in the non-survival group than in the survival group. Multivariate analysis showed an increased risk of carbapenem-resistant gram-negative pneumonia in patients who had used carbapenem-resistant antibiotics, hypertension, coronary heart disease, and malignancy in the previous 90 days. Patients with carbapenem-resistant gram-negative pneumonia who had coronary heart disease, diabetes mellitus, shock, renal insufficiency, deep venous catheterization, and respiratory failure were at increased risk of death. In conclusion, recent surgery, respiratory failure, shock, indwelling catheterization, and disturbance of consciousness are risk factors for carbapenem-resistant Gram-negative bacteria pneumonia. Coronary heart disease, diabetes mellitus, shock, renal insufficiency, deep venous catheterization and respiratory failure are risk factors for death from carbapenem-resistant gram-negative bacteria pneumonia.