RESUMO
The fading efficacy of antibiotics is a growing global health concern due to its life-threatening consequences and increased healthcare costs. Non-genetic mechanisms of antimicrobial resistance, such as those employed by Chlamydia pneumoniae and Chlamydia trachomatis, complicate treatment as these bacteria can enter a non-replicative, persistent state under stress, evading antibiotics and linking to inflammatory conditions. Understanding chlamydial persistence at the molecular level is challenging, and new models for studying Chlamydia-host interactions in vivo are urgently needed. Caenorhabditis elegans offers an alternative given its immune system and numerous orthologues of human genes. This study established C. elegans as an in vivo model for chlamydial infection. Both Chlamydia species reduced the worm's lifespan, their DNA being detectable at three- and six-days post-infection. Azithromycin at its MIC (25â¯nM) failed to prevent the infection-induced lifespan reduction, indicating a persister phenotype. In contrast, the methanolic extract of Schisandra chinensis berries showed anti-chlamydial activity both in vitro (in THP-1 macrophages) and in vivo, significantly extending the lifespan of infected C. elegans and reducing the bacterial load. Moreover, S. chinensis increased the transcriptional activity of SKN-1 in the worms, but was unable to impact the bacterial load or lifespan in a sek-1 defective C. elegans strain. In summary, this study validated C. elegans as a chlamydial infection model and showcased S. chinensis berries' in vivo anti-chlamydial potential, possibly through SEK/SKN-1 signaling modulation.
Assuntos
Antibacterianos , Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Infecções por Chlamydia , Caenorhabditis elegans/microbiologia , Caenorhabditis elegans/efeitos dos fármacos , Animais , Humanos , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Infecções por Chlamydia/microbiologia , Infecções por Chlamydia/tratamento farmacológico , Antibacterianos/farmacologia , Chlamydia trachomatis/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Extratos Vegetais/farmacologia , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Células THP-1 , Azitromicina/farmacologia , Longevidade/efeitos dos fármacos , Chlamydophila pneumoniae/efeitos dos fármacosRESUMO
Community-acquired pneumonia (CAP) is a common illness that can lead to mortality. ß-lactams are ineffective against atypical pathogen including Mycoplasma pneumoniae. We used molecular examinations to develop a decision tree to predict atypical pathogens with CAP and to examine the prevalence of macrolide resistance in Mycoplasma pneumoniae. We conducted a prospective observational study of patients aged ≥ 18 years who had fever and respiratory symptoms and were diagnosed with CAP in one of two community hospitals between December 2016 and October 2018. We assessed combinations of clinical variables that best predicted atypical pathogens with CAP by classification and regression tree (CART) analysis. Pneumonia was defined as respiratory symptoms and new infiltration recognized on chest X-ray or chest computed tomography. We analyzed 47 patients (21 females, 44.7%, mean age: 47.6 years). Atypical pathogens were detected in 15 patients (31.9%; 12 Mycoplasma pneumoniae, 3 Chlamydophila pneumoniae). Ten patients carried macrolide resistant Mycoplasma pneumoniae (macrolide resistant rate 83.3%). CART analysis suggested that factors associated with presence of atypical pathogens were absence of crackles, age < 45 years, and LD ≥ 183 U/L (sensitivity 86.7% [59.5, 98.3], specificity 96.9% [83.8, 99.9]). ur simple clinical decision rules can be used to identify primary care patients with CAP that are at risk for atypical pathogens. Further research is needed to validate its usefulness in various populations.Trial registration Clinical Trial (UMIN trial ID: UMIN000035346).
Assuntos
Pneumonia/etiologia , Infecções Respiratórias/complicações , Adulto , Idoso , Antibacterianos/uso terapêutico , Área Sob a Curva , Chlamydophila pneumoniae/efeitos dos fármacos , Chlamydophila pneumoniae/patogenicidade , Infecções Comunitárias Adquiridas/complicações , Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/microbiologia , Estudos Epidemiológicos , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Mycoplasma pneumoniae/efeitos dos fármacos , Mycoplasma pneumoniae/patogenicidade , Pneumonia/epidemiologia , Pneumonia/microbiologia , Reação em Cadeia da Polimerase/métodos , Prevalência , Estudos Prospectivos , Curva ROC , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/microbiologiaRESUMO
From a microbiological point of view, both empirical and targeted antimicrobial treatment in respiratory infection is based on the sensitivity profile of isolated microorganisms and the possible resistance mechanisms that they may present. The latter may vary in different geographic areas according to prescription profiles and vaccination programs. Beta-lactam antibiotics, fluoroquinolones, and macrolides are the most commonly used antimicrobials during the exacerbations of chronic obstructive pulmonary disease and community-acquired pneumonia. In their prescription, different aspects such as intrinsic activity, bactericidal effect or their ability to prevent the development of resistance must be taken into account. The latter is related to the PK/PD parameters, the mutant prevention concentration and the so-called selection window. More recently, the potential ecological impact has grown in importance, not only on the intestinal microbiota, but also on the respiratory one. Maintaining the state of eubiosis requires the use of antimicrobials with a low profile of action on anaerobic bacteria. With their use, the resilience of the bacterial populations belonging to the microbiota, the state of resistance of colonization and the collateral damage related to the emergence of resistance to the antimicrobials in pathogens causing the infections and in the bacterial populations integrating the microbiota.
Assuntos
Antibacterianos/farmacologia , COVID-19/epidemiologia , Farmacorresistência Bacteriana , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Administração Oral , Antibacterianos/administração & dosagem , Chlamydophila pneumoniae/efeitos dos fármacos , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Progressão da Doença , Microbioma Gastrointestinal/efeitos dos fármacos , Haemophilus influenzae/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Moraxella catarrhalis/efeitos dos fármacos , Mycoplasma pneumoniae/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/microbiologia , Infecções Respiratórias/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacosRESUMO
BACKGROUND: Chlamydia pneumoniae is an obligate intracellular bacterium that causes respiratory infection. There may exist an association between C. pneumoniae, asthma, and production of immunoglobulin (Ig) E responses in vitro. Interleukin (IL-4) is required for IgE production. OBJECTIVE: We previously demonstrated that doxycycline suppresses C. pneumoniae-induced production of IgE and IL-4 responses in peripheral blood mononuclear cells (PBMC) from asthmatic subjects. Whereas macrolides have anti-chlamydial activity, their effect on in vitro anti-inflammatory (IgE) and IL-4 responses to C. pneumoniae have not been studied. METHODS: PBMC from IgE- adult atopic subjects (N = 5) were infected +/- C. pneumoniae BAL69, +/- azithromycin (0.1, 1.0 ug/mL) for 10 days. IL-4 and IgE levels were determined in supernatants by ELISA. IL-4 and IgE were detected in supernatants of PBMC (day 10). RESULTS: When azithromycin (0.1, 1.0 ug/ml) was added, IL-4 levels decreased. At low dose, IgE levels increased and at high dose, IgE levels decreased. When PBMC were infected with C. pneumoniae, both IL-4 and IgE levels decreased. Addition of azithromycin (0.1, 1.0 ug/mL) decreased IL-4 levels and had no effect on IgE levels. CONCLUSIONS: These findings indicate that azithromycin decreases IL-4 responses but has a bimodal effect on IgE responses in PBMC from atopic patients in vitro.
Assuntos
Azitromicina/farmacologia , Chlamydophila pneumoniae/imunologia , Imunoglobulina E/biossíntese , Interleucina-4/biossíntese , Idoso , Antibacterianos/farmacologia , Asma/complicações , Asma/tratamento farmacológico , Asma/imunologia , Infecções por Chlamydophila/complicações , Infecções por Chlamydophila/tratamento farmacológico , Infecções por Chlamydophila/imunologia , Chlamydophila pneumoniae/efeitos dos fármacos , Chlamydophila pneumoniae/patogenicidade , Feminino , Humanos , Hipersensibilidade Imediata/complicações , Hipersensibilidade Imediata/imunologia , Hipersensibilidade Imediata/microbiologia , Imunoglobulina E/sangue , Técnicas In Vitro , Interleucina-4/sangue , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/microbiologia , Masculino , Pessoa de Meia-Idade , Infecções Respiratórias/complicações , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/imunologia , Adulto JovemRESUMO
Antibiotic-tolerant persister bacteria involve frequent treatment failures, relapsing infections and the need for extended antibiotic treatment. The virulence of an intracellular human pathogen C. pneumoniae is tightly linked to its propensity for persistence and means for its chemosensitization are urgently needed. In the current work, persistence of C. pneumoniae clinical isolate CV6 was studied in THP-1 macrophages using quantitative PCR and quantitative culture. A dibenzocyclooctadiene lignan schisandrin reverted C. pneumoniae persistence and promoted productive infection. The concomitant administration of schisandrin and azithromycin resulted in significantly improved bacterial eradication compared to sole azithromycin treatment. In addition, the closely related lignan schisandrin C was superior to azithromycin in eradicating the C. pneumoniae infection from the macrophages. The observed chemosensitization of C. pneumoniae was associated with the suppression of cellular glutathione pools by the lignans, implying to a previously unknown aspect of chlamydia-host interactions. These data indicate that schisandrin lignans induce a phenotypic switch in C. pneumoniae, promoting the productive and antibiotic-susceptible phenotype instead of persistence. By this means, these medicinal plant -derived compounds show potential as adjuvant therapies for intracellular bacteria resuscitation.
Assuntos
Bioensaio/métodos , Chlamydophila pneumoniae/fisiologia , Ciclo-Octanos/farmacologia , Lignanas/farmacologia , Macrófagos/microbiologia , Azitromicina/administração & dosagem , Azitromicina/farmacologia , Chlamydophila pneumoniae/efeitos dos fármacos , Chlamydophila pneumoniae/crescimento & desenvolvimento , Ciclo-Octanos/administração & dosagem , Ciclo-Octanos/química , Glutationa/metabolismo , Humanos , Cinética , Lignanas/administração & dosagem , Lignanas/química , Macrófagos/efeitos dos fármacos , Oxirredução , Fenótipo , Compostos Policíclicos/administração & dosagem , Compostos Policíclicos/química , Compostos Policíclicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Células THP-1RESUMO
Chlamydia trachomatis is the leading cause of bacterial sexually transmitted infections, and Chlamydia pneumoniae causes community-acquired respiratory infections. In vivo, the host immune system will release gamma interferon (IFN-γ) to combat infection. IFN-γ activates human cells to produce the tryptophan (Trp)-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). Consequently, there is a reduction in cytosolic Trp in IFN-γ-activated host cells. In evolving to obligate intracellular dependence, Chlamydia has significantly reduced its genome size and content, as it relies on the host cell for various nutrients. Importantly, C. trachomatis and C. pneumoniae are Trp auxotrophs and are starved for this essential nutrient when the human host cell is exposed to IFN-γ. To survive this, chlamydiae enter an alternative developmental state referred to as persistence. Chlamydial persistence is characterized by a halt in the division cycle, aberrant morphology, and, in the case of IFN-γ-induced persistence, Trp codon-dependent changes in transcription. We hypothesize that these changes in transcription are dependent on the particular amino acid starvation state. To investigate the chlamydial response mechanisms acting when other amino acids become limiting, we tested the efficacy of prokaryote-specific tRNA synthetase inhibitors, indolmycin and AN3365, to mimic starvation of Trp and leucine, respectively. We show that these drugs block chlamydial growth and induce changes in morphology and transcription consistent with persistence. Importantly, growth inhibition was reversed when the compounds were removed from the medium. With these data, we find that indolmycin and AN3365 are valid tools that can be used to mimic the persistent state independently of IFN-γ.
Assuntos
Adaptação Fisiológica , Aminoacil-tRNA Sintetases/antagonistas & inibidores , Infecções por Chlamydia/microbiologia , Chlamydia trachomatis/crescimento & desenvolvimento , Chlamydophila pneumoniae/crescimento & desenvolvimento , Regulação Bacteriana da Expressão Gênica , Triptofano/metabolismo , Linhagem Celular , Chlamydia trachomatis/citologia , Chlamydia trachomatis/efeitos dos fármacos , Chlamydia trachomatis/enzimologia , Chlamydophila pneumoniae/citologia , Chlamydophila pneumoniae/efeitos dos fármacos , Chlamydophila pneumoniae/enzimologia , Inibidores Enzimáticos/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Indóis/metabolismo , Leucina/metabolismo , Modelos Biológicos , Transcrição GênicaRESUMO
BACKGROUND: In the past century, many phenazines were isolated from the marine microorganism, and some of these phenazines possessed potent antibacterial activities. We found that a few of the synthesized 4-substituted phenazines could block the infectivity of chlamydiae without host cell toxicity. OBJECTIVE: The aim of this study was to design and synthesize two series of novel 3-substituted phenazines to find novel antichlamydial agents. METHODS: The 3-substituted phenazines were synthesized via Buchwald-Hartwig cross coupling reaction and Suzuki reaction from 3-bromo-1-methoxyphenazine. The antichlamydial activity of these synthesized compounds was evaluated by determining their effect on the yield of infectious progeny EBs. Cytotoxicity of these compounds on host cells was assessed by the treatment of uninfected HeLa cells using WST-1 method. RESULTS: Most of the 3-substituted phenazines possessed potent antichlamydial activity with IC50 values from 0.15 to 12.08 µM against Chlamydia trachomatis L2, C. muridarum MoPn and C. pneumoniae AR39. Among them, 7d and 9a exhibited better antichlamydial activity with IC50 values from 0.20 to 1.01 µM while they have no apparent cytotoxicity to host cells. Biological assay disclosed that both 7d and 9a inhibited chlamydial infection by reducing elementary body infectivity and disturbing chlamydial growth during the whole chlamydial developmental cycle. CONCLUSION: Our findings suggested that 3-substituted phenazine derivatives might be a promising class of therapeutic agents for chlamydial infections. More effective phenazines with low toxicity could be acquired through further chemical modification on C-3 position rather than C-4 position of phenazine.
Assuntos
Antibacterianos/farmacologia , Fenazinas/farmacologia , Antibacterianos/síntese química , Antibacterianos/toxicidade , Chlamydia trachomatis/efeitos dos fármacos , Chlamydophila pneumoniae/efeitos dos fármacos , Desenho de Fármacos , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Fenazinas/síntese química , Fenazinas/toxicidadeAssuntos
Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções por Chlamydia/tratamento farmacológico , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Animais , Infecções por Chlamydia/microbiologia , Chlamydophila pneumoniae/efeitos dos fármacos , Chlamydophila pneumoniae/patogenicidade , Humanos , Testes de Sensibilidade MicrobianaRESUMO
Chlamydia trachomatis infections are the most prevalent sexually transmitted infections with potentially debilitating sequelae, such as infertility. Mouse models are generally used for vaccine development, to study the immune response and histopathology associated with Chlamydia infection. An important question regarding murine models is the in vivo identification of murine host genes responsible for the elimination of the murine and human Chlamydia strains. RNA sequencing of the Chlamydia muridarum infected BALB/c lung transcriptome revealed that several genes with direct antichlamydial functions were induced at the tissue level, including the already described and novel members of the murine interferon-inducible GTPase family, the CXCL chemokines CXCL9, CXCL11, immunoresponsive gene 1, nitric oxide synthase-2 (iNOS), and lipocalin-2. Indoleamine 2,3-dioxygenase 1-2 (IDO1-2) previously described potent antichlamydial host enzymes were also highly expressed in the infected murine lungs. This finding was novel, since IDO was considered as a unique human antichlamydial defense gene. Besides a lower level of epithelial cell positivity, immunohistochemistry showed that IDO1-2 proteins were expressed prominently in macrophages. Detection of the tryptophan degradation product kynurenine and the impact of IDO inhibition on Chlamydia muridarum growth proved that the IDO1-2 proteins were functionally active. IDO1-2 activity also increased in Chlamydia muridarum infected C57BL/6 lung tissues, indicating that this phenomenon is not mouse strain specific. Our study shows that the murine antichlamydial response includes a variety of highly up-regulated defense genes in vivo. Among these genes the antichlamydial effectors IDO1-2 were identified. The potential impact of murine IDO1-2 expression on Chlamydia propagation needs further investigation.
Assuntos
Infecções por Chlamydia/metabolismo , Chlamydia muridarum/efeitos dos fármacos , Chlamydia muridarum/metabolismo , Chlamydophila pneumoniae/efeitos dos fármacos , Chlamydophila pneumoniae/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/farmacologia , Pulmão/metabolismo , Animais , Quimiocina CXCL11/genética , Quimiocina CXCL11/metabolismo , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Infecções por Chlamydia/genética , Infecções por Chlamydia/microbiologia , Infecções por Chlamydia/patologia , Modelos Animais de Doenças , Inibidores Enzimáticos/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Expressão Gênica , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/efeitos dos fármacos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Cinurenina , Lipocalina-2/genética , Lipocalina-2/metabolismo , Pulmão/patologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro/metabolismo , Transcriptoma , Triptofano/análogos & derivados , Triptofano/antagonistas & inibidores , Triptofano/metabolismoRESUMO
Obligate intracellular bacterium Chlamydia pneumoniae causes respiratory tract infections such as community-acquired pneumonia. During infection, C. pneumoniae induces inflammatory responses in host cells and the oxygen concentration at the infection sites subsequently decreases. Because hypoxic conditions influence further inflammatory responses and reduced antibacterial effects, this may exacerbate the C. pneumoniae infection. Here, we show inflammatory responses and drug sensitivity in C. pneumoniae-infected cells under hypoxic conditions. First, we confirmed the enhanced growth of C. pneumoniae under hypoxia, which indicates that the hypoxic condition we used could adequately reproduce past reports. We then demonstrated a significant increase in production of the pro-inflammatory cytokine Interleukin 8 (IL-8) in C. pneumoniae-infected cells under hypoxic conditions. Furthermore, hypoxia decreased the antibacterial effects of azithromycin against C. pneumoniae compared with normoxic conditions. Together, our data suggest that inflammatory responses and drug sensitivity may have been underestimated in C. pneumoniae infection in previous studies. Thus, to accurately understand the Chlamydia infection, it may be necessary to perform in vitro experiments under hypoxic conditions.
Assuntos
Azitromicina/farmacologia , Hipóxia Celular/imunologia , Infecções por Chlamydophila , Chlamydophila pneumoniae/efeitos dos fármacos , Chlamydophila pneumoniae/fisiologia , Interações Hospedeiro-Patógeno , Interleucina-8/metabolismo , Antibacterianos/farmacologia , Linhagem Celular , Infecções por Chlamydophila/imunologia , Infecções por Chlamydophila/microbiologia , Chlamydophila pneumoniae/crescimento & desenvolvimento , Farmacorresistência Bacteriana/fisiologia , Humanos , Testes de Sensibilidade MicrobianaRESUMO
INTRODUCTION: Chlamydia pneumoniae (Cp) is a bacterium that causes pneumonia and other respiratory diseases. Fever may be present early but absent by time of presentation to clinic. Increases in X-ray-confirmed pneumonia (XCP) and laboratory-confirmed Cp infections were observed in new soldiers in training at Fort Leonard Wood (FLW), Missouri, early in 2014. These findings prompted a site assistance visit from the U.S. Army Public Health Command, Aberdeen Proving Ground, Maryland, with a review of available data and information to describe the outbreak, and inspections of barracks and training facilities and review of training practices to identify opportunities for interventions to reduce the risk of respiratory disease agent transmission. MATERIALS AND METHODS: The study population was trainee soldiers at FLW in 2013-2014. Data from two acute respiratory disease surveillance systems were studied. A local surveillance system operated by the FLW General Leonard Wood Army Community Hospital Preventive Medicine Department tracked weekly chest X-rays taken and the numbers positive for pneumonia. A Naval Health Research Center, San Diego, California, laboratory-based Febrile Respiratory Illness Surveillance Program collected clinical data and nasal, or nasal and pharyngeal swabs, for nucleic acid amplification testing from up to 15 trainees/week with fever and either cough or sore throat. Up to 4 of the 15 specimens could be from afebrile patients with XCP. Specimens were tested for a variety of agents. RESULTS: Monthly rates of XCP rose quickly in 2014 and peaked at 0.9/100 trainees in May. The percentage of the San Diego surveillance system specimens that were positive for Cp also increased quickly in 2014, peaking at 54% in May. During the first half of 2014, the San Diego program studied specimens from 141 ill trainees; 37% (52/141) were positive for Cp, making it the most common organism identified, followed by rhinoviruses (8%), influenza viruses (4%), Mycoplasma pneumoniae (2%), and adenoviruses (1%). The remaining specimens (48%) were negative for all respiratory pathogens. Only 12% (6/52) of Cp positive patients were febrile. Facilities inspections and review of training practices failed to identify variables that might be contributing to an increased risk of respiratory agent transmission. CONCLUSION: The XCP rate and the percentage of specimens positive for Cp increased in early 2014, peaking in May. Only 12% of trainees with laboratory-confirmed Cp were febrile. Historically, acute respiratory disease surveillance at military training centers focused on febrile diseases, particularly those caused by adenoviruses. With introduction of an adenovirus vaccine in late 2011, respiratory disease rates dropped with only sporadic occurrences of adenovirus-associated disease. In 2012, the San Diego surveillance program began providing data on multiple respiratory disease agents, in addition to adenoviruses and influenza viruses. Since then, Cp, rhinoviruses and Mycoplasma pneumoniae have frequently been detected in trainees with acute respiratory disease. Respiratory surveillance programs supporting Army training centers should be re-evaluated in this post-adenovirus vaccine era, to include assessment of the fever criterion for selecting patients for study, the value of chest X-ray surveillance and the value of rapidly providing laboratory results to inform provider decisions regarding antibiotic use.
Assuntos
Infecções por Chlamydophila/complicações , Militares/estatística & dados numéricos , Pneumonia/etiologia , Infecções por Chlamydophila/epidemiologia , Chlamydophila pneumoniae/efeitos dos fármacos , Chlamydophila pneumoniae/patogenicidade , Surtos de Doenças , Feminino , Humanos , Masculino , Missouri/epidemiologia , Pneumonia/epidemiologia , Vigilância da População/métodos , Radiografia/métodos , Radiografia/estatística & dados numéricos , Estudantes/estatística & dados numéricos , Ensino/estatística & dados numéricos , Adulto JovemRESUMO
The in vitro activities of omadacycline, azithromycin, doxycycline, moxifloxacin, and levofloxacin were tested against 15 isolates of Chlamydia pneumoniae The minimum inhibitory concentration at which 90% of the isolates of C. pneumoniae were inhibited by omadacycline was 0.25 µg/ml (range, 0.03 to 0.5 µg/ml).
Assuntos
Antibacterianos/farmacologia , Chlamydophila pneumoniae/efeitos dos fármacos , Tetraciclinas/farmacologia , Azitromicina/farmacologia , Linhagem Celular , Pneumonia por Clamídia/tratamento farmacológico , Pneumonia por Clamídia/microbiologia , Chlamydophila pneumoniae/isolamento & purificação , Doxiciclina/farmacologia , Humanos , Levofloxacino/farmacologia , Testes de Sensibilidade Microbiana , Moxifloxacina/farmacologiaRESUMO
PURPOSE: The antimicrobial activity of N-chlorotaurine (NCT), an endogenous long-lived oxidant applied topically, was tested against Chlamydiae in vitro. METHODOLOGY: Elementary bodies of Chlamydia pneumoniae strain CV-6 and Chlamydia trachomatis serovars A and D were incubated in 0.01, 0.1 and 1â% (w/v) NCT solution at pH 7.1 and 37 °C. After different incubation times, aliquots were removed and grown in cell culture. The number of inclusion forming units was quantified by immunofluorescence and real-time qPCR.Results/Key findings.Chlamydia pneumoniae and Chlamydia trachomatis were inactivated by 1 and 0.1â% NCT within 1 min. Moreover, 0.025-0.1â% NCT significantly reduced the number of intracellularly growing C. pneumoniae within 30 min. CONCLUSIONS: This is the first study demonstrating the antimicrobial activity of NCT against Chlamydiae. Clinical implications of these findings have to be investigated in further trials.
Assuntos
Anti-Infecciosos Locais/farmacologia , Chlamydia trachomatis/efeitos dos fármacos , Infecções por Chlamydophila/microbiologia , Chlamydophila pneumoniae/efeitos dos fármacos , Taurina/análogos & derivados , Infecções por Chlamydia , Chlamydia trachomatis/crescimento & desenvolvimento , Chlamydophila pneumoniae/genética , Chlamydophila pneumoniae/crescimento & desenvolvimento , Chlamydophila pneumoniae/metabolismo , Humanos , Taurina/farmacologiaRESUMO
Chlamydia trachomatis is the leading cause of sexually transmitted infections worldwide. Capsaicin, a component of chili pepper, which can stimulate actin remodeling via capsaicin receptor TRPV1 (transient receptor potential vanilloid 1) and anti-inflammatory effects via PPARγ (peroxisome proliferator-activated receptor-γ) and LXRα (liver X receptor α), is a potential candidate to control chlamydial growth in host cells. We examined whether capsaicin could inhibit C. trachomatis growth in immortal human epithelial HeLa cells. Inclusion forming unit and quantitative PCR assays showed that capsaicin significantly inhibited bacterial growth in cells in a dose-dependent manner, even in the presence of cycloheximide, a eukaryotic protein synthesis inhibitor. Confocal microscopic and transmission electron microscopic observations revealed an obvious decrease in bacterial numbers to inclusions bodies formed in the cells. Although capsaicin can stimulate the apoptosis of cells, no increase in cleaved PARP (poly (ADP-ribose) polymerase), an apoptotic indicator, was observed at a working concentration. All of the drugs tested (capsazepine, a TRPV1 antagonist; 5CPPSS-50, an LXRα inhibitor; and T0070907, a PPARγ inhibitor) had no effect on chlamydial inhibition in the presence of capsaicin. In addition, we also confirmed that capsaicin inhibited Chlamydia pneumoniae growth, indicating a phenomena not specific to C. trachomatis. Thus, we conclude that capsaicin can block chlamydial growth without the requirement of host cell protein synthesis, but by another, yet to be defined, mechanism.
Assuntos
Capsaicina/farmacologia , Chlamydia trachomatis/efeitos dos fármacos , Chlamydophila pneumoniae/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chlamydia trachomatis/crescimento & desenvolvimento , Chlamydophila pneumoniae/crescimento & desenvolvimento , Cicloeximida/farmacologia , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Corpos de Inclusão/efeitos dos fármacos , Receptores X do Fígado/antagonistas & inibidores , PPAR gama/antagonistas & inibidores , Inibidores da Síntese de Proteínas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidoresRESUMO
OBJECTIVE: To understand the prevalence and distribution of Chlamydia pneumoniae (CP) and Mycoplasma pneumoniae (MP) in the population and to provide a basis for the prevention and treatment of respiratory tract infection. METHODS: This study included a total of 4500 healthy subjects who were given physical examination in Shenzhen People's Hospital from January to December in 2016. Venous blood was drawn from people to detect the MP- and CP-specific IgG and IgM in the serum using chemiluminescence immunoassay (CLIA). The relationship of MP and CP infections with patient age, seasons, and percentage of infections was analyzed. CONCLUSION: CP and MP cause high rate of asymptomatic infection, which may be associated with the high incidence of CP and MP infection, especially in children and the elderly population. Therefore, the implementation of effective and practical prevention measures has become an urgent need. MP culture and drug sensitivity test should be performed as early as possible in patients with manifested MP infections in order to ensure timely and proper treatment and to reduce the emergence of drug-resistant strains.
Assuntos
Infecções por Chlamydophila/sangue , Chlamydophila pneumoniae/isolamento & purificação , Mycoplasma pneumoniae/isolamento & purificação , Pneumonia por Mycoplasma/sangue , Adolescente , Adulto , Idoso , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/isolamento & purificação , Criança , Pré-Escolar , China/epidemiologia , Infecções por Chlamydophila/tratamento farmacológico , Infecções por Chlamydophila/microbiologia , Chlamydophila pneumoniae/efeitos dos fármacos , Chlamydophila pneumoniae/patogenicidade , Farmacorresistência Bacteriana/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mycoplasma pneumoniae/efeitos dos fármacos , Mycoplasma pneumoniae/patogenicidade , Pneumonia por Mycoplasma/tratamento farmacológico , Pneumonia por Mycoplasma/microbiologia , Infecções Respiratórias/sangue , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Testes SorológicosRESUMO
The obligate intracellular pathogen Chlamydia pneumoniae remains a difficult target for antimicrobial therapy. Owing to the permeability barrier placed by bacterial and host vacuolar membranes, as well as the propensity of the bacterium for persistent infections, treatment failures are common. Despite the urgent need for new antichlamydial compounds, their discovery is challenged by the technically demanding assay procedures and lack of validated targets. An alternative strategy of using naturally occurring compounds and their derivatives against C. pneumoniae is presented. The strategy consists of the application of ligand-based virtual screening to a natural product library of 502 compounds with the ChemGPS-NP chemography tool followed by in vitro antichlamydial assays. The reference set used for the 2D similarity search was constructed of 19 known antichlamydial compounds of plant origin. Based on the similarity screen, 53 virtual hits were selected for in vitro testing. Six compounds (leads) were identified that cause ≥50% C. pneumoniae growth inhibition and showed no impact on host cell viability. The leads fall into completely new antichlamydial chemotypes, one of them being mycophenolic acid (IC50 value 0.3 µM). The outcome indicates that using this flipped, target-independent strategy is useful for facilitating the antimicrobial lead discovery against challenging microbes.
Assuntos
Antibacterianos/farmacologia , Produtos Biológicos/farmacologia , Chlamydophila pneumoniae/efeitos dos fármacos , Antibacterianos/química , Azitromicina/farmacologia , Produtos Biológicos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas , Humanos , Ligantes , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
The antimicrobial activity of bitespiramycin (BT) against Chlamydia trachomatis (Ct), Chlamydia pneumoniae (Cp), Ureaplasma urealyticum (Uu), and Mycoplasma pneumoniae (Mp), was compared with those of azithromycin (AZM) and acetylspiramycin (AT-SP) in vitro. Furthermore, the anti-Mp activities of BT and AZM were evaluated in a hamster model. The activities of BT in vitro were similar to those of AZM but were more effective than those of AT-SP. BT effectively inhibited Mp infection at a dose of 200mg/kg in a hamster model.
Assuntos
Antibacterianos/farmacologia , Chlamydia trachomatis/efeitos dos fármacos , Chlamydophila pneumoniae/efeitos dos fármacos , Mycoplasma pneumoniae/efeitos dos fármacos , Espiramicina/análogos & derivados , Ureaplasma urealyticum/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Espiramicina/síntese química , Espiramicina/química , Espiramicina/farmacologia , Relação Estrutura-AtividadeRESUMO
The nafithromycin concentrations in the plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) of 37 healthy adult subjects were measured following repeated dosing of oral nafithromycin at 800 mg once daily for 3 days. The values of noncompartmental pharmacokinetic (PK) parameters were determined from serial plasma samples collected over a 24-h interval following the first and third oral doses. Each subject underwent one standardized bronchoscopy with bronchoalveolar lavage (BAL) at 3, 6, 9, 12, 24, or 48 h after the third dose of nafithromycin. The mean ± standard deviation values of the plasma PK parameters after the first and third doses included maximum plasma concentrations (Cmax) of 1.02 ± 0.31 µg/ml and 1.39 ± 0.36 µg/ml, respectively; times to Cmax of 3.97 ± 1.30 h and 3.69 ± 1.28 h, respectively; clearances of 67.3 ± 21.3 liters/h and 52.4 ± 18.5 liters/h, respectively, and elimination half-lives of 7.7 ± 1.1 h and 9.1 ± 1.7 h, respectively. The values of the area under the plasma concentration-time curve (AUC) from time zero to 24 h postdosing (AUC0-24) for nafithromycin based on the mean or median total plasma concentrations at BAL fluid sampling times were 16.2 µg · h/ml. For ELF, the respective AUC0-24 values based on the mean and median concentrations were 224.1 and 176.3 µg · h/ml, whereas for AM, the respective AUC0-24 values were 8,538 and 5,894 µg · h/ml. Penetration ratios based on ELF and total plasma AUC0-24 values based on the mean and median concentrations were 13.8 and 10.9, respectively, whereas the ratios of the AM to total plasma concentrations based on the mean and median concentrations were 527 and 364, respectively. The sustained ELF and AM concentrations for 48 h after the third dose suggest that nafithromycin has the potential to be a useful agent for the treatment of lower respiratory tract infections. (This study has been registered at ClinicalTrials.gov under registration no. NCT02453529.).
Assuntos
Antibacterianos/sangue , Antibacterianos/farmacocinética , Líquido da Lavagem Broncoalveolar/química , Cetolídeos/sangue , Cetolídeos/farmacocinética , Lactonas/farmacologia , Pneumonia Bacteriana/tratamento farmacológico , Adulto , Antibacterianos/efeitos adversos , Lavagem Broncoalveolar , Broncoscopia , Chlamydophila pneumoniae/efeitos dos fármacos , Feminino , Haemophilus influenzae/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Cetolídeos/química , Cetolídeos/farmacologia , Lactonas/química , Legionella pneumophila/efeitos dos fármacos , Macrófagos Alveolares/citologia , Masculino , Pessoa de Meia-Idade , Moraxella catarrhalis/efeitos dos fármacos , Mycoplasma pneumoniae/efeitos dos fármacos , Pneumonia Bacteriana/microbiologia , Alvéolos Pulmonares/química , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Adulto JovemRESUMO
Asthma is a chronic respiratory disease characterized by reversible airway obstruction and airway hyperresponsiveness to non-specific bronchoconstriction agonists as the primary underlying pathophysiology. The worldwide incidence of asthma has increased dramatically in the last 40 years. According to World Health Organization (WHO) estimates, over 300 million children and adults worldwide currently suffer from this incurable disease and 255,000 die from the disease each year. It is now well accepted that asthma is a heterogeneous syndrome and many clinical subtypes have been described. Viral infections such as respiratory syncytial virus (RSV) and human rhinovirus (hRV) have been implicated in asthma exacerbation in children because of their ability to cause severe airway inflammation and wheezing. Infections with atypical bacteria also appear to play a role in the induction and exacerbation of asthma in both children and adults. Recent studies confirm the existence of an infectious asthma etiology mediated by Chlamydia pneumoniae (CP) and possibly by other viral, bacterial and fungal microbes. It is also likely that early-life infections with microbes such as CP could lead to alterations in the lung microbiome that significantly affect asthma risk and treatment outcomes. These infectious microbes may exacerbate the symptoms of established chronic asthma and may even contribute to the initial development of the clinical onset of the disease. It is now becoming more widely accepted that patterns of airway inflammation differ based on the trigger responsible for asthma initiation and exacerbation. Therefore, a better understanding of asthma subtypes is now being explored more aggressively, not only to decipher pathophysiologic mechanisms but also to select treatment and guide prognoses. This review will explore infection-mediated asthma with special emphasis on the protean manifestations of CP lung infection, clinical characteristics of infection-mediated asthma, mechanisms involved and antibiotic treatment outcomes.
Assuntos
Asma/tratamento farmacológico , Asma/imunologia , Infecções por Chlamydophila/tratamento farmacológico , Infecções por Chlamydophila/imunologia , Chlamydophila pneumoniae/imunologia , Macrolídeos/imunologia , Antibacterianos/uso terapêutico , Asma/epidemiologia , Infecções por Chlamydophila/epidemiologia , Chlamydophila pneumoniae/efeitos dos fármacos , Chlamydophila pneumoniae/isolamento & purificação , Humanos , Macrolídeos/isolamento & purificação , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/epidemiologia , Pneumonia Bacteriana/imunologia , Resultado do TratamentoRESUMO
The present study included 201 adult patients presenting with exacerbation of chronic maxillary sinusitis. The presence of Chlamydia trachomatis and Chl. pneumoniae was verified by the direct immunofluorescencetechnique and polymerase chain reaction. The study material consisted of swipes und swabs from the mucous membrane of the middle nasal passage. The information from the patients was collected with the use of a questionnaire specially elaborated for the purpose of this study. The correlation relationships were established by means of gamma-statistics. The method is based on the calculation of the integral index characterizing the risk of development of chlamydial infection using the scoring scale for the evaluation of the clinical and anamnestic characteristics of the patients. The assessment of the risk of chlamydial colonization by the anamnestic method makes it possible to enhance the effectiveness of clinical diagnostics of chlamydial infection and thereby provides a basis for the prescription of the adequate anti-chlamydial treatment facilitating reduction of the frequency of complications and preventing dissemination of the causative factor of the disease. Moreover, this approach creates the conditions for the targeted selection of the patients to be referred to the laboratory verification of Chlamydia. Highoperating performance and effectiveness characteristics of the clinic-anamnestic diagnostics make it a method of choice for the wide application in the clinical practice.