RESUMEN
Carbapenem-resistant Klebsiella pneumoniae (CRKP) causes Gram-negative lung infections and fatal pneumonic sepsis for which limited therapeutic options are available. The lungs are densely innervated by nociceptor sensory neurons that mediate breathing, cough, and bronchoconstriction. The role of nociceptors in defense against Gram-negative lung pathogens is unknown. Here, we found that lung-innervating nociceptors promote CRKP pneumonia and pneumonic sepsis. Ablation of nociceptors in mice increased lung CRKP clearance, suppressed trans-alveolar dissemination of CRKP, and protected mice from hypothermia and death. Furthermore, ablation of nociceptors enhanced the recruitment of neutrophils and Ly6Chi monocytes and cytokine induction. Depletion of Ly6Chi monocytes, but not of neutrophils, abrogated lung and extrapulmonary CRKP clearance in ablated mice, suggesting that Ly6Chi monocytes are a critical cellular population to regulate pneumonic sepsis. Further, neuropeptide calcitonin gene-related peptide suppressed the induction of reactive oxygen species in Ly6Chi monocytes and their CRKP-killing abilities. Targeting nociceptor signaling could be a therapeutic approach for treating multidrug-resistant Gram-negative infection and pneumonic sepsis.
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Péptido Relacionado con Gen de Calcitonina , Carbapenémicos , Infecciones por Klebsiella , Klebsiella pneumoniae , Pulmón , Nociceptores , Sepsis , Animales , Klebsiella pneumoniae/fisiología , Ratones , Infecciones por Klebsiella/microbiología , Sepsis/metabolismo , Sepsis/microbiología , Pulmón/microbiología , Pulmón/metabolismo , Carbapenémicos/farmacología , Péptido Relacionado con Gen de Calcitonina/metabolismo , Nociceptores/metabolismo , Monocitos/metabolismo , Células Receptoras Sensoriales/metabolismo , Neutrófilos/metabolismo , Modelos Animales de Enfermedad , Antígenos Ly/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/metabolismo , Neumonía Bacteriana/patología , Ratones Endogámicos C57BLRESUMEN
Alcohol use is an independent risk factor for the development of bacterial pneumonia due, in part, to impaired mucus-facilitated clearance, macrophage phagocytosis, and recruitment of neutrophils. Alcohol consumption is also known to reduce peripheral natural killer (NK) cell numbers and compromise NK cell cytolytic activity, especially NK cells with a mature phenotype. However, the role of innate lymphocytes, such as NK cells during host defense against alcohol-associated bacterial pneumonia is essentially unknown. We have previously shown that indole supplementation mitigates increases in pulmonary bacterial burden and improves pulmonary NK cell recruitment in alcohol-fed mice, which were dependent on aryl hydrocarbon receptor (AhR) signaling. Employing a binge-on-chronic alcohol-feeding model we sought to define the role and interaction of indole and NK cells during pulmonary host defense against alcohol-associated pneumonia. We demonstrate that alcohol dysregulates NK cell effector function and pulmonary recruitment via alterations in two key signaling pathways. We found that alcohol increases transforming growth factor beta (TGF-ß) signaling while suppressing AhR signaling. We further demonstrated that NK cells isolated from alcohol-fed mice have a reduced ability to kill Klebsiella pneumoniae. NK cell migratory capacity to chemokines was also significantly altered by alcohol, as NK cells isolated from alcohol-fed mice exhibited preferential migration in response to CXCR3 chemokines but exhibited reduced migration in response to CCR2, CXCR4, and CX3CR1 chemokines. Together this data suggests that alcohol disrupts NK cell-specific TGF-ß and AhR signaling pathways leading to decreased pulmonary recruitment and cytolytic activity thereby increasing susceptibility to alcohol-associated bacterial pneumonia.
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Células Asesinas Naturales , Ratones Endogámicos C57BL , Neumonía Bacteriana , Receptores de Hidrocarburo de Aril , Transducción de Señal , Animales , Células Asesinas Naturales/inmunología , Neumonía Bacteriana/inmunología , Neumonía Bacteriana/microbiología , Ratones , Receptores de Hidrocarburo de Aril/metabolismo , Pulmón/inmunología , Pulmón/microbiología , Factor de Crecimiento Transformador beta/metabolismo , Etanol , Receptores CCR2/metabolismo , Receptores CCR2/genética , Modelos Animales de Enfermedad , Indoles/farmacología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Masculino , Klebsiella pneumoniae , Receptores CXCR3/metabolismoRESUMEN
PURPOSE: Patients with bacterial, fungal, and viral community-acquired pneumonia (CAP) were studied to determine their metabolic profiles. METHODS: Loop-mediated isothermal amplification technology and nucleic acid sequence-dependent amplification combined with microfluidic chip technology were applied to screen multiple pathogens from respiratory tract samples. Eighteen patients with single bacterial infection (B-CAP), fifteen with single virus infection (V-CAP), twenty with single fungal infection (F-CAP), and twenty controls were enrolled. UHPLC-MS/MS analysis of untargeted serum samples for metabolic profiles. Multiple linear regression and Spearman's rank correlation analysis were used to determine associations between metabolites and clinical parameters. The sensitivity and specificity of the screened metabolites were also examined, along with their area under the curve. RESULTS: The metabolic signatures of patients with CAP infected by bacteria, viruses, and fungi were markedly different from those of controls. The abundances of 45, 56, and 79 metabolites were significantly unbalanced. Among these differential metabolites, 11, 13, and 29 were unique to the B-CAP, V-CAP, and F-CAP groups, respectively. Bacterial infections were the only known causes of disturbances in the pentose and glucuronate and aldarate and ascorbate metabolism interconversions metabolic pathway. CONCLUSIONS: Serum metabolomic techniques based on UHPLC-MS/MS may identify differences between individuals with CAP who have been infected by various pathogens, and they can also build a metabolite signature for early detection of the origin of infection and prompt care.
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Infecciones Comunitarias Adquiridas , Metabolómica , Humanos , Femenino , Masculino , Persona de Mediana Edad , Infecciones Comunitarias Adquiridas/sangre , Infecciones Comunitarias Adquiridas/microbiología , Infecciones Comunitarias Adquiridas/diagnóstico , Metabolómica/métodos , Anciano , Neumonía Bacteriana/sangre , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/diagnóstico , Espectrometría de Masas en Tándem/métodos , Neumonía Viral/sangre , Neumonía Viral/diagnóstico , Neumonía Viral/microbiología , Neumonía Viral/virología , Adulto , Estudios de Casos y Controles , Cromatografía Líquida de Alta Presión/métodos , Metaboloma , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: The 2016 IDSA guideline recommends a treatment duration of at least 7 days for hospital-acquired (HAP)/ventilator-associated pneumonia (VAP). The limited literature has demonstrated higher rates of recurrence for non-glucose fermenting gram-negative bacilli with short course therapy, raising the concern of optimal treatment duration for these pathogens. Therefore, we aimed to compare the outcomes for patients receiving shorter therapy treatment (≤ 8 days) versus longer regimen (> 8 days) for the treatment of multidrug resistant (MDR) Pseudomonas pneumonia. METHODS: A single-center, retrospective cohort study was conducted to evaluate adult patients receiving an antimicrobial regimen with activity against MDR Pseudomonas aeruginosa in respiratory culture between 2017 and 2020 for a minimum of 6 consecutive days. Exclusion criteria were inmates, those with polymicrobial pneumonia, community-acquired pneumonia, and infections requiring prolonged antibiotic therapy. RESULTS: Of 427 patients with MDR P. aeruginosa respiratory isolates, 85 patients were included. Baseline characteristics were similar among groups with a median age of 65.5 years and median APACHE 2 score of 20. Roughly 75% had ventilator-associated pneumonia. Compared to those who received ≤ 8 days of therapy, no difference was seen for clinical success in patients treated for more than 8 days (80% vs. 65.5%, p = 0.16). The number of 30-day and 90-day in-hospital mortality, 30-days relapse, and other secondary outcomes did not significantly differ among the treatment groups. CONCLUSIONS: Prolonging treatment duration beyond 8 days did not improve patient outcomes for MDR P. aeruginosa HAP/VAP.
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Antibacterianos , Farmacorresistencia Bacteriana Múltiple , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Humanos , Masculino , Femenino , Pseudomonas aeruginosa/efectos de los fármacos , Estudios Retrospectivos , Antibacterianos/uso terapéutico , Antibacterianos/administración & dosificación , Anciano , Persona de Mediana Edad , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/mortalidad , Neumonía Asociada al Ventilador/tratamiento farmacológico , Neumonía Asociada al Ventilador/microbiología , Neumonía Asociada al Ventilador/mortalidad , Resultado del Tratamiento , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/mortalidad , Duración de la TerapiaRESUMEN
BACKGROUND: The incidence of hypermucoviscous Klebsiella pneumoniae (hmvKp), which complicates community-acquired pneumonia, has been increasing recently. This study aimed to detect hypermucoviscous K. pneumoniae and determine its antimicrobial susceptibility pattern in adult patients with community-acquired pneumonia in Northwest Ethiopia. METHODS: This cross-sectional study included 39 K. pneumoniae isolates identified by using Gram stain, culture, and biochemical tests from 312 adult patients with community-acquired pneumonia at the University of Gondar Comprehensive Specialized Referral Hospital from April to June 2021. The hypermucoviscous strains were identified by using the string test. Antimicrobial susceptibility testing was performed by using the Kirby-Bauer disk dif-fusion method. Data were entered by using EPI data version 4.6 and were analyzed by using SPSS version 20. A p-value ≤ 0.05 at a 95% confidence interval was considered statistically significant. RESULTS: Overall, 35.9% (n = 14) of the 39 K. pneumoniae isolates were hypermucoviscous phenotype. The mean age of the hmvKp group was lower than of the cKp group (36.93 ± 12.573 vs. 53.52 ± 19.556 years, p = 0.007). All hmvKp isolates were resistant to amoxicillin-clavulanic acid and trimethoprim-sulfamethoxazole. Azithromycin resistance in the hmvKp strains was significantly higher than in the cKp group (p = 0.012). CONCLUSIONS: This study demonstrates that the hmvKp phenotype causes community-acquired pneumonia and a full resistance to amoxicillin-clavulanic acid and trimethoprim-sulfamethoxazole. Antimicrobial resistance was higher in the hmvKp strain than in the classic strains. Further detection of resistance genes, capsular serotypes, hypermucoviscosity-related genes, and virulence genes is necessary.
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Antibacterianos , Infecciones Comunitarias Adquiridas , Infecciones por Klebsiella , Klebsiella pneumoniae , Pruebas de Sensibilidad Microbiana , Humanos , Infecciones Comunitarias Adquiridas/microbiología , Infecciones Comunitarias Adquiridas/epidemiología , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/aislamiento & purificación , Klebsiella pneumoniae/genética , Etiopía/epidemiología , Adulto , Masculino , Femenino , Persona de Mediana Edad , Estudios Transversales , Infecciones por Klebsiella/epidemiología , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/diagnóstico , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Anciano , Adulto Joven , Farmacorresistencia Bacteriana Múltiple , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/epidemiología , Neumonía Bacteriana/diagnósticoRESUMEN
PURPOSE: Infection by carbapenem-resistant Klebsiella pneumoniae (CRKP) has high mortality. There is no clear optimal therapeutic choice for pneumonia caused by CRKP. The aim of this study was to compare the clinical outcomes and safety of the standard doses of polymyxin B-based regimens vs tigecycline-based regimens and to identify risk factors for mortality. METHODS: This retrospective cohort study included patients with pneumonia caused by CRKP between January 1, 2020 and December 31, 2022. The primary outcomes were 7-day bacterial eradication rate and 14- and 28-day all-cause mortality. The secondary outcome was incidence of acute kidney injury. RESULTS: Seventy-three patients were included in this study, 29 in the polymyxin B-based combination therapy group and 44 in tigecycline-based combination therapy group. There were no significant differences between the two groups in terms of the 7-day bacterial eradication rate (31.03% vs 20.45%, p = 0.409), the 14-day all-cause mortality (37.93% vs 22.73%, p = 0.160), and the incidence of acute kidney injury (14.29% vs 6.82%, p = 0.526). The 28-day all-cause mortality in the polymyxin B-based therapy group was higher than in the tigecycline-based group (75.86% vs 45.45%, p = 0.010). Binary logistic regression analysis revealed that male and previous use of carbapenems were independent factors associated with 28-day all-cause mortality for patients treated with polymyxin B (p < 0.05). CONCLUSIONS: Polymyxin B-based combination therapy at the standard dose should be used with caution for patients with CRKP-induced pneumonia, especially for men who used carbapenems prior to CRKP detection.
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Antibacterianos , Quimioterapia Combinada , Infecciones por Klebsiella , Klebsiella pneumoniae , Polimixina B , Tigeciclina , Humanos , Polimixina B/administración & dosificación , Polimixina B/uso terapéutico , Polimixina B/efectos adversos , Masculino , Estudios Retrospectivos , Tigeciclina/administración & dosificación , Tigeciclina/uso terapéutico , Tigeciclina/efectos adversos , Femenino , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/mortalidad , Infecciones por Klebsiella/epidemiología , Infecciones por Klebsiella/microbiología , Anciano , Klebsiella pneumoniae/efectos de los fármacos , Persona de Mediana Edad , Carbapenémicos/uso terapéutico , Carbapenémicos/efectos adversos , Carbapenémicos/administración & dosificación , Resultado del Tratamiento , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiología , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/mortalidadRESUMEN
Pseudomonas aeruginosa is a frequent cause of antimicrobial-resistant hospital-acquired pneumonia, especially in critically ill patients. Inflammation triggered by P. aeruginosa infection is necessary for bacterial clearance but must be spatially and temporally regulated to prevent further tissue damage and bacterial dissemination. Emerging data have shed light on the pro-resolving actions of angiotensin-(1-7) [Ang-(1-7)] signaling through the G protein-coupled receptor Mas (MasR) during infections. Herein, we investigated the role of the Ang-(1-7)/Mas axis in pneumonia caused by P. aeruginosa by using genetic and pharmacological approach and found that Mas receptor-deficient animals developed a more severe form of pneumonia showing higher neutrophilic infiltration into the airways, bacterial load, cytokines, and chemokines production and more severe pulmonary damage. Conversely, treatment of pseudomonas-infected mice with Ang-(1-7) was able to decrease neutrophilic infiltration in airways and lungs, local and systemic levels of pro-inflammatory cytokines and chemokines, and increase the efferocytosis rates, mitigating lung damage/dysfunction caused by infection. Notably, the therapeutic association of Ang-(1-7) with antibiotics improved the survival rates of mice subjected to lethal inoculum of P. aeruginosa, extending the therapeutic window for imipenem. Mechanistically, Ang-(1-7) increased phagocytosis of bacteria by neutrophils and macrophages to accelerate pathogen clearance. Altogether, harnessing the Ang-(1-7) pathway during infection is a potential strategy for the development of host-directed therapies to promote mechanisms of resistance and resilience to pneumonia.
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Angiotensina I , Antibacterianos , Ratones Endogámicos C57BL , Fragmentos de Péptidos , Proto-Oncogenes Mas , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Receptores Acoplados a Proteínas G , Animales , Angiotensina I/metabolismo , Pseudomonas aeruginosa/efectos de los fármacos , Ratones , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/metabolismo , Infecciones por Pseudomonas/microbiología , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/farmacología , Receptores Acoplados a Proteínas G/metabolismo , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/patología , Neumonía Bacteriana/metabolismo , Citocinas/metabolismo , Ratones Noqueados , Neumonía/tratamiento farmacológico , Neumonía/metabolismo , Neumonía/microbiología , Masculino , Pulmón/microbiología , Pulmón/metabolismo , Pulmón/patología , Transducción de Señal/efectos de los fármacos , Infiltración Neutrófila/efectos de los fármacosRESUMEN
RATIONALE: Shewanella algae are Gram-negative bacteria that are widely found in aquatic habitats and rarely cause lung infections in inland areas. PATIENT CONCERNS: Cough with light-yellow phlegm for 2 weeks. DIAGNOSES: The final diagnosis was bacterial pneumonia. INTERVENTIONS: The patient was treated with ceftazidime (2 g, every 12 h) for 1 week. OUTCOMES: The patient's lung infection improved and he was discharged. LESSONS: This case highlights a rare occurrence of lung infection caused by Shewanella algae in elderly Tibetan men residing in non-marine environments.
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Antibacterianos , Infecciones por Bacterias Gramnegativas , Neumonía Bacteriana , Shewanella , Humanos , Masculino , Shewanella/aislamiento & purificación , Infecciones por Bacterias Gramnegativas/diagnóstico , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/microbiología , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/diagnóstico , Neumonía Bacteriana/complicaciones , Antibacterianos/uso terapéutico , Tibet , Ceftazidima/uso terapéutico , Ceftazidima/administración & dosificación , AncianoRESUMEN
Carbapenem-resistant Acinetobacter baumannii (CRAB) pneumonia has been a serious problem in the intensive care unit (ICU). However, defined characteristics of respiratory microbiome in CRAB pneumonia are lacking nowadays. This study aimed to analyze respiratory microbiome of CRAB pneumonia compared to non-CRAB pneumonia and reveal the clinical significance of respiratory microbiome data in these patients. Patients diagnosed with severe pneumonia with mechanical ventilation were enrolled in the ICU of a tertiary care hospital. Respiratory specimens were collected on days 1, 4, 7, and 14 in each participant via tracheal aspiration. Clinical data and outcomes of each enrolled patient were collected via electronic medical records. Microbiome analysis was conducted with collected respiratory specimens undergone by next-generation sequencing of microbial 16S ribosomal DNA. Six CRAB pneumonia, 4 non-CRAB pneumonia and 5 healthy controls were enrolled. In CRAB pneumonia, CRAB was detected in 3 patients by sputum culture at day 1, while it was negative at day 1 and detected later in the others by follow-up sputum culture. Beta diversity plot analysis showed differences between each group. Shannon index was decreased markedly at day 4 in CRAB pneumonia compared to the others. Among CRAB pneumonia cases, 3 respiratory specimens were culture-negative, but positive by microbiome analysis. Lower respiratory microbiome in CRAB pneumonia had distinct characteristics and early loss of diversity compared to non-CRAB pneumonia, which might be related to poor clinical course. Moreover, CRAB acquisition and colonization would be predicted by preemptive microbiome analysis, which will contribute to effective infection control in the ICU.
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Infecciones por Acinetobacter , Acinetobacter baumannii , Carbapenémicos , Enfermedad Crítica , Microbiota , Humanos , Acinetobacter baumannii/aislamiento & purificación , Acinetobacter baumannii/efectos de los fármacos , Masculino , Carbapenémicos/farmacología , Carbapenémicos/uso terapéutico , Femenino , Persona de Mediana Edad , Infecciones por Acinetobacter/microbiología , Infecciones por Acinetobacter/tratamiento farmacológico , Microbiota/efectos de los fármacos , Anciano , Unidades de Cuidados Intensivos/estadística & datos numéricos , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/tratamiento farmacológico , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Esputo/microbiología , Respiración Artificial/efectos adversosRESUMEN
Pediatric pneumonia can be severe and result in empyema. Next-generation sequencing (NGS) may broadly detect pathogens though, optimal timing and impact of sample type on diagnostic yield is unknown. This is a prospective, single-center pilot study of children aged 3 months through 17 years admitted to the PICU with a primary diagnosis of complicated pneumonia. Plasma, endotracheal, nasopharyngeal, and pleural fluid samples were collected at three time points during hospitalization. After nucleic acid extraction, combined libraries were enriched with an NGS enrichment panel kit (RPIP, Illumina), sequenced and quantitative organism detections were analyzed. NGS identified the same bacterial pathogen as traditional testing in all samples, regardless of antibiotic pre-treatment or time collected. Conventional culture methods only identified the pathogen reliably in invasively obtained pleural fluid or endotracheal aspirates. Future application of NGS may allow for non-invasive pathogen detection at a broader range of time points and more targeted antibiotic coverage.
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Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Niño , Lactante , Preescolar , Estudios Prospectivos , Adolescente , Proyectos Piloto , Masculino , Femenino , Bacterias/genética , Bacterias/aislamiento & purificación , Bacterias/clasificación , Neumonía Bacteriana/diagnóstico , Neumonía Bacteriana/microbiología , Nasofaringe/microbiología , Neumonía/microbiología , Neumonía/diagnósticoRESUMEN
Antimicrobial peptides (AMPs) possess strong antibacterial activity and low drug resistance, making them ideal candidates for bactericidal drugs for addressing the issue of traditional antibiotic resistance. In this study, a template (G(XXKK)nI, G = Gly; X = Leu, Ile, Phe, or Trp; n = 2, 3, or 4; K = Lys; I = Ile.) was employed for the devised of a variety of novel α-helical AMPs with a high therapeutic index. The AMP with the highest therapeutic index, WK2, was ultimately chosen following a thorough screening process. It demonstrates broad-spectrum and potent activity against both standard and multidrug-resistant bacteria, while also showing low hemolysis and rapid and efficient time-kill kinetics. Additionally, WK2 exhibits excellent efficacy in treating mouse models of Klebsiella pneumonia-induced lung infections and methicillin-resistant Staphylococcus aureus (MRSA)-induced skin wound infections while demonstrating good safety profiles in vivo. In conclusion, the template-based design methodology for novel AMPs with high therapeutic indices offers new insights into addressing antibiotic resistance problems. WK2 represents a promising antimicrobial agent.
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Antibacterianos , Péptidos Antimicrobianos , Klebsiella pneumoniae , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Infección de Heridas , Animales , Ratones , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/uso terapéutico , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Infección de Heridas/tratamiento farmacológico , Infección de Heridas/microbiología , Klebsiella pneumoniae/efectos de los fármacos , Péptidos Antimicrobianos/farmacología , Péptidos Antimicrobianos/química , Péptidos Antimicrobianos/uso terapéutico , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/microbiología , Femenino , Modelos Animales de Enfermedad , Humanos , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Enfermedades Cutáneas Bacterianas/microbiologíaAsunto(s)
Biopelículas , Pulmón , Pseudomonas aeruginosa , Animales , Humanos , Biopelículas/crecimiento & desarrollo , Encéfalo/inmunología , Encéfalo/microbiología , Encéfalo/patología , Evasión Inmune , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Neumonía Bacteriana/inmunología , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/genética , Neumonía Bacteriana/patología , Polisacáridos Bacterianos/inmunología , Polisacáridos Bacterianos/genética , Pseudomonas aeruginosa/inmunología , Pseudomonas aeruginosa/patogenicidad , Pseudomonas aeruginosa/genética , Infecciones por Pseudomonas/inmunología , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/genética , Transducción de Señal/inmunologíaRESUMEN
BACKGROUND: Pneumonia due to typical bacterial, atypical bacterial and viral pathogens can be difficult to clinically differentiate. Host response-based diagnostics are emerging as a complementary diagnostic strategy to pathogen detection. METHODS: We used murine models of typical bacterial, atypical bacterial and viral pneumonia to develop diagnostic signatures and understand the host's response to these types of infections. Mice were intranasally inoculated with Streptococcus pneumoniae, Mycoplasma pneumoniae, influenza or saline as a control. Peripheral blood gene expression analysis was performed at multiple time points. Differentially expressed genes were used to perform gene set enrichment analysis and generate diagnostic signatures. These murine-derived signatures were externally validated in silico using human gene expression data. The response to S. pneumoniae was the most rapid and robust. RESULTS: Mice infected with M. pneumoniae had a delayed response more similar to influenza-infected animals. Diagnostic signatures for the three types of infection had 0.94-1.00 area under the receiver operator curve (auROC). Validation in five human gene expression datasets revealed auROC of 0.82-0.96. DISCUSSION: This study identified discrete host responses to typical bacterial, atypical bacterial and viral aetiologies of pneumonia in mice. These signatures validated well in humans, highlighting the conserved nature of the host response to these pathogen classes.
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Modelos Animales de Enfermedad , Mycoplasma pneumoniae , Neumonía por Mycoplasma , Streptococcus pneumoniae , Animales , Humanos , Ratones , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/aislamiento & purificación , Neumonía por Mycoplasma/diagnóstico , Mycoplasma pneumoniae/genética , Mycoplasma pneumoniae/aislamiento & purificación , Femenino , Neumonía Neumocócica/microbiología , Infecciones por Orthomyxoviridae/inmunología , Curva ROC , Perfilación de la Expresión Génica , Neumonía Viral/diagnóstico , Neumonía Viral/inmunología , Ratones Endogámicos C57BL , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/diagnóstico , Interacciones Huésped-PatógenoRESUMEN
Introduction. The frequency of multidrug-resistant organisms (MDROs) in hospitals and the risk of delaying effective treatment result in the culture of respiratory secretions for nearly all patients with suspected pneumonia. Culture delays contribute to over prescribing and use of broader spectrum antibiotics.Gap statement. The need for improved rapid diagnostics for early assessment of suspected hospital pneumonia.Aim. To validate a new metric, enhanced Gram stain (EGS), to provide a rapid diagnostic test of high diagnostic accuracy that could be assessed in clinical trials of the use of antibiotics in suspected pneumonia.Methodology. Ninety-two residual lower respiratory samples previously tested by culture and Gram stain were re-tested by 16S ribosomal DNA real-time polymerase chain reaction (16S qPCR) and reported as a combined metric with Gram stain termed EGS. The EGS was assessed for diagnostic accuracy, standard performance measurements and correlation against culture. For samples with discordance between culture and EGS, 16S ribosomal DNA whole operon sequencing (16S rDNA WOS) was used for test resolution. An amended EGS (A-EGS was reassessed against culture.Results. Gram stain, 16S qPCR, EGS and A-EGS had respective diagnostic accuracies of 77.01â%, 82.76â%, 84.04â% and 94.19â%. The same platforms had respective correlation with culture of r = 0.67, r = 0.71, r = 0.81 and r = 0.89. EGS had the highest negative predictive value (NPV) of 93.18â% (81.99â%-97.62â%). Adding an 16S qPCR result is achievable in most routine laboratories and, combined with Gram stain, could improve early decision-making in patients with suspected hospital pneumonia.Conclusion. EGS could improve early decision-making in patients with suspected hospital pneumonia and could be assessed in clinical trials. The 16S rDNA WOS results in the A-EGS also supported the use of pathogen genomic sequencing in early decision making of suspected pneumonia.
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Violeta de Genciana , Fenazinas , ARN Ribosómico 16S , Reacción en Cadena en Tiempo Real de la Polimerasa , Humanos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , ARN Ribosómico 16S/genética , ADN Bacteriano/genética , Sensibilidad y Especificidad , Neumonía Bacteriana/diagnóstico , Neumonía Bacteriana/microbiología , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/microbiología , Neumonía/diagnóstico , Neumonía/microbiología , Bacterias/aislamiento & purificación , Bacterias/genética , Bacterias/clasificación , MasculinoRESUMEN
Respiratory viral infections, including respiratory syncytial virus (RSV), parainfluenza viruses and type A and B influenza viruses, can have severe outcomes. Bacterial infections frequently follow viral infections, and influenza or other viral epidemics periodically have higher mortalities from secondary bacterial pneumonias. Most secondary bacterial infections can cause lung immunosuppression by fatty acid mediators which activate cellular receptors to manipulate neutrophils, macrophages, natural killer cells, dendritic cells and other lung immune cells. Bacterial infections induce synthesis of inflammatory mediators including prostaglandins and leukotrienes, then eventually also special pro-resolving mediators, including lipoxins, resolvins, protectins and maresins, which normally resolve inflammation and immunosuppression. Concurrent viral and secondary bacterial infections are more dangerous, because viral infections can cause inflammation and immunosuppression before the secondary bacterial infections worsen inflammation and immunosuppression. Plausibly, the higher mortalities of secondary bacterial pneumonias are caused by the overwhelming inflammation and immunosuppression, which the special pro-resolving mediators might not resolve.
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Neumonía Bacteriana , Humanos , Neumonía Bacteriana/mortalidad , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/inmunología , Mediadores de Inflamación/metabolismo , Coinfección/microbiología , Coinfección/mortalidad , Coinfección/inmunología , Coinfección/virología , Pulmón/microbiología , Pulmón/virología , Pulmón/patología , Ácidos Docosahexaenoicos , Tolerancia Inmunológica , Prostaglandinas/metabolismo , Lipoxinas/metabolismo , Inflamación , Leucotrienos/metabolismoRESUMEN
OBJECTIVES: We evaluated the efficacies of human-simulated regimens (HSRs) of two clinically utilized sulbactam regimens: 1 g q6h 0.5 h infusion (maximum FDA-approved dosage) and 3 g q8h 4 h infusion (high-dose, prolonged-infusion regimen), against Acinetobacter baumannii in a translational murine model. METHODS: Thirty-two clinical A. baumannii isolates were investigated, of which 16 were sulbactam resistant (MICâ≥â16 mg/L), 6 were sulbactam intermediate (MICâ=â8 mg/L) and 10 were sulbactam susceptible (MICâ≤â4 mg/L). Efficacies of the two sulbactam HSRs were assessed in the neutropenic murine pneumonia model. Changes in log10 cfu/lungs at 24 h compared with 0 h controls were measured, and efficacy was defined as achieving 1 log kill relative to baseline. WGS of the isolates and bioinformatics analysis were performed to explore potential associations between the genomic backgrounds and the in vivo responses. RESULTS: Eleven isolates harboured blaOXA-23, of which 10 were sulbactam resistant, 1 was sulbactam intermediate while none was sulbactam susceptible. Both sulbactam HSRs achieved >1 log kill against sulbactam-susceptible isolates. Against sulbactam-intermediate and sulbactam-resistant isolates, lack of efficacy correlated with the presence of the blaOXA-23 gene; sulbactam 1 g HSR and 3 g HSR did not show efficacy against 11/11 and 9/11 blaOXA-23-positive isolates, respectively, while efficacy was observed against all 11 blaOXA-23-negative sulbactam-intermediate and sulbactam-resistant isolates (i.e. harbouring other resistance genes). CONCLUSIONS: A sulbactam high-dose prolonged-infusion regimen provides comparable activity to the standard dose against isolates currently considered sulbactam susceptible. However, the activity against isolates with intermediate and resistant susceptibility could be predicted by the detection of blaOXA-23. Enhancing detection capabilities of common diagnostic modalities to include OXA-23 can improve patient outcome.
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Infecciones por Acinetobacter , Acinetobacter baumannii , Antibacterianos , Pruebas de Sensibilidad Microbiana , Sulbactam , beta-Lactamasas , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/genética , Sulbactam/administración & dosificación , Sulbactam/uso terapéutico , Sulbactam/farmacología , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Animales , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Ratones , beta-Lactamasas/genética , Humanos , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Modelos Animales de Enfermedad , Femenino , Resultado del Tratamiento , Farmacorresistencia BacterianaRESUMEN
BACKGROUND: Fosfomycin is gaining increasing attention for its activity against MDR or XDR pathogens. Currently, IV fosfomycin is a potential option for treating various infections, including urinary tract infections, pneumonia and skin infections when first-line treatments fail. OBJECTIVES: To evaluate the demographic, clinical, microbiological and treatment modality of children received IV fosfomycin to treat infections caused by MDR pathogens since there are few data on the use of fosfomycin in children. METHODS: This study was conducted retrospectively with patients under 18 years of age who were treated with IV fosfomycin for at least 72 h due to infections caused by MDR pathogens between January 2019 and October 2023 at Marmara University Pendik Training and Research Hospital, Istanbul, Türkiye. Data on demographic and clinical features, microbiological findings, treatment modalities and side effects were evaluated. RESULTS: Twenty-five children, for a total of 32 cases of infection episodes, with a mean age of 11.4â±â3.92 years who received IV fosfomycin were included. The most frequent comorbidity was chronic pulmonary diseases, and the most common infection needed for IV fosfomycin was MDR Pseudomonas aeruginosa pneumonia. In all cases, fosfomycin was administered in combination with other antibiotics, mainly meropenem-colistin (68.7%) or meropenem (15.6%). Twenty-two (71.9%) cases had favourable clinical responses at the end of therapy. CONCLUSIONS: Our results suggest that IV fosfomycin may be an effective treatment option for MDR pathogens in the paediatric population. Nevertheless, careful stewardship is necessary to maintain efficacy and reduce antimicrobial resistance selection risk.
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Antibacterianos , Farmacorresistencia Bacteriana Múltiple , Fosfomicina , Humanos , Fosfomicina/uso terapéutico , Estudios Retrospectivos , Niño , Femenino , Masculino , Antibacterianos/uso terapéutico , Adolescente , Preescolar , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/microbiología , Lactante , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Turquía , Pruebas de Sensibilidad Microbiana , Neumonía/tratamiento farmacológico , Neumonía/microbiologíaRESUMEN
BACKGROUND: Sulbactam dosing for Acinetobacter baumannii infections has not been standardized due to limited available pharmacokinetics/pharmacodynamics (PK/PD) data. Herein, we report a comprehensive PK/PD analysis of ampicillin-sulbactam against A. baumannii pneumonia. METHODS: Twenty-one A. baumannii clinical isolates were tested in the neutropenic murine pneumonia model. For dose-ranging studies, groups of mice were administered escalating doses of ampicillin-sulbactam. Changes in log10cfu/lungs relative to 0 h were assessed. Dose-fractionation studies were performed. Estimates of the percentage of of time during which the unbound plasma sulbactam concentrations exceeded the MIC (%fTâ>âMIC) required for different efficacy endpoints were calculated. The probabilities of target attainment (PTA) for the 1-log kill plasma targets were estimated following clinically utilized sulbactam regimens. RESULTS: Dose-fractionation studies demonstrated time-dependent kill. Isolates resistant to both sulbactam and meropenem required three times the exposures to achieve 1-log kill; median [IQR] %fTâ>âMIC of 60.37% [51.6-66.8] compared with other phenotypes (21.17 [16.0-32.9] %fTâ>âMIC). Sulbactam standard dose (1 g q6h, 0.5 h infusion) provided >90% PTA up to MIC of 4 mg/L. Sulbactam 3 g q8h, 4 h inf provided greater PTA for isolates with sulbactam-intermediate susceptibility (8 mg/L, 100% versus 86% following the standard dose). Despite the higher exposure following 3 g q8h, 4 h inf, PTA was ≤57% among sulbactam-resistant/meropenem-resistant isolates. CONCLUSION: Sulbactam standard dose is a valuable regimen across sulbactam-susceptible isolates while the high-dose extended-infusion provides additional benefit against sulbactam-intermediate isolates. Given that most of the sulbactam-resistant A. baumannii isolates are meropenem-resistant, high-dose prolonged-infusion regimens are not expected to be effective as monotherapy against infections due to these isolates.
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Infecciones por Acinetobacter , Acinetobacter baumannii , Ampicilina , Antibacterianos , Pruebas de Sensibilidad Microbiana , Sulbactam , Acinetobacter baumannii/efectos de los fármacos , Sulbactam/farmacocinética , Sulbactam/administración & dosificación , Sulbactam/farmacología , Sulbactam/uso terapéutico , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Animales , Ampicilina/farmacocinética , Ampicilina/administración & dosificación , Ampicilina/farmacología , Ratones , Femenino , Modelos Animales de Enfermedad , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , HumanosRESUMEN
BACKGROUND: Most of the current bacteriophages (phages) are mostly isolated from environments. However, phages isolated from feces might be more specific to the bacteria that are harmful to the host. Meanwhile, some phages from the environment might affect non-pathogenic bacteria for the host. METHODS: Here, bacteriophages isolated from mouse feces were intratracheally (IT) or intravenously (IV) administered in pneumonia mice caused by Pseudomonas aeruginosa at 2 hours post-intratracheal bacterial administration. As such, the mice with phage treatment, using either IT or IV administration, demonstrated less severe pneumonia as indicated by mortality, serum cytokines, bacteremia, bacterial abundance in bronchoalveolar lavage fluid (BALF), and neutrophil extracellular traps (NETs) in lung tissue (immunofluorescence of neutrophil elastase and myeloperoxidase). RESULTS: Interestingly, the abundance of phages in BALF from the IT and IV injections was similar, supporting a flexible route of phage administration. With the incubation of bacteria with neutrophils, the presence of bacteriophages significantly improved bactericidal activity, but not NETs formation, with the elevated supernatant IL-6 and TNF-α, but not IL-1ß. In conclusion, our findings suggest that bacteriophages against Pseudomonas aeruginosa can be discovered from feces of the host. CONCLUSIONS: The phages attenuate pneumonia partly through an enhanced neutrophil bactericidal activity, but not via inducing NETs formation. The isolation of phages from the infected hosts themselves might be practically useful for future treatment. More studies are warranted.
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Heces , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Animales , Pseudomonas aeruginosa/virología , Heces/microbiología , Heces/virología , Ratones , Infecciones por Pseudomonas/terapia , Infecciones por Pseudomonas/microbiología , Líquido del Lavado Bronquioalveolar/microbiología , Líquido del Lavado Bronquioalveolar/virología , Neutrófilos/inmunología , Bacteriófagos/aislamiento & purificación , Bacteriófagos/fisiología , Trampas Extracelulares , Neumonía/microbiología , Neumonía/terapia , Neumonía/virología , Citocinas/metabolismo , Citocinas/sangre , Terapia de Fagos/métodos , Femenino , Pulmón/microbiología , Pulmón/virología , Neumonía Bacteriana/terapia , Neumonía Bacteriana/microbiologíaRESUMEN
BACKGROUND: Stroke-associated pneumonia (SAP) considerably burden healthcare systems. This study aimed to identify predictors of developing SAP in acute ischemic stroke patients admitted to the Stroke Unit at Manial Specialized Hospital factors with microbiological causality and impact on 30-day mortality. METHODS: This was a retrospective cohort study. All patients with acute ischemic stroke admitted to the Stroke Unit at Manial Specialized Hospital (from February 2021 to August 2023) were divided into the SAP and non-SAP groups. Detailed clinical characteristics and microbiological results were recorded. RESULTS: Five hundred twenty-two patients diagnosed with acute ischemic stroke (mean age of 55 ± 10) were included. One hundred sixty-nine (32.4%) of stroke patients developed SAP; Klebsiella pneumoniae was the most commonly detected pathogen (40.2%), followed by Pseudomonas aeruginosa (20.7%). Bacteremia was identified in nine cases (5.3%). The number of deaths was 11, all of whom were diagnosed with SAP, whereas none from the non-SAP group died (P < 0.001). The binary logistic regression model identified three independent predictors of the occurrence of SAP: previous history of TIA/stroke (OR = 3.014, 95%CI = 1.281-7.092), mechanical ventilation (OR = 4.883, 95%CI = 1.544-15.436), and bulbar dysfunction (OR = 200.460, 95%CI = 80.831-497.143). CONCLUSIONS: Stroke-associated pneumonia was reported in one-third of patients with acute ischemic stroke, adversely affecting mortality outcomes. Findings showed that the main predictors of SAP were bulbar dysfunction, the use of mechanical ventilation and previous history of TIA/stroke. More attention to these vulnerable patients is necessary to reduce mortality.