Azithromycin decreases Chlamydia pneumoniae-mediated Interleukin-4 responses but not Immunoglobulin E responses.

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.

Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America.

Background: This document provides evidence-based clinical practice guidelines on the management of adult patients with community-acquired pneumonia.Methods: A multidisciplinary panel conducted pragmatic systematic reviews of the relevant research and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations.Results: The panel addressed 16 specific areas for recommendations spanning questions of diagnostic testing, determination of site of care, selection of initial empiric antibiotic therapy, and subsequent management decisions. Although some recommendations remain unchanged from the 2007 guideline, the availability of results from new therapeutic trials and epidemiological investigations led to revised recommendations for empiric treatment strategies and additional management decisions.Conclusions: The panel formulated and provided the rationale for recommendations on selected diagnostic and treatment strategies for adult patients with community-acquired pneumonia.

Low-Dose Aspirin May Prevent Trophoblast Dysfunction in Women With Chlamydia Pneumoniae Infection.

OBJECTIVE: Previously, we demonstrated that live Chlamydia pneumoniae (Cp) impaired extravillous trophoblast (EVT) viability and invasion and that Cp DNA was detected in placentas from cases with preeclampsia. We sought to elucidate whether (1) inactive forms of Cp also affect EVT function; (2) potential therapeutic interventions protect against the effects of Cp; and (3) anti-Cp antibodies are associated with preeclampsia. METHODS: Human first-trimester EVTs were infected with ultraviolet light-inactivated Cp. Subgroups of EVTs were pretreated with low-dose acetyl-salicylic acid (ASA), dexamethasone, heparin, and indomethacin. We conducted functional assays after infection with inactivated Cp and measured interleukin 8 (IL8), C-reactive protein (CRP), heat shock protein 60 (HSP60), and tumor necrosis factor-α (TNFα) in culture media. We measured anti-Cp IgG serum levels from women who developed preeclampsia (N = 105) and controls (N = 121). RESULTS: Inactivated Cp reduced EVT invasion when compared to noninfected cells (P < .00001) without adversely affecting cell viability. Increased levels of IL8, CRP, HSP60, and TNFα were detected in EVTs infected with inactivated Cp compared to noninfected cells (P < .0001). Only pretreatment with low-dose ASA prevented reduced EVT invasion and decreased release of inflammatory mediators (P < .01). Elevated anti-Cp IgG antibodies were more prevalent in serum from cases with preeclampsia compared to controls (67/105 vs 53/121; adjusted P = .013); elevated IgG correlated significantly with elevated serum CRP and elevated soluble fms-like tyrosine kinase-1-placental growth factor ratio. CONCLUSION: Inactivated Cp induces decreased EVT invasion and a proinflammatory response; these effects were abrogated by pretreatment with low-dose ASA. Our results suggest an association between Cp infection, trophoblast dysfunction, and preeclampsia.

In vitro efficacy of povidone iodine and hydroxyethyl cellulose, alone and in combination, against common feline ocular pathogens.

Infectious ocular disease, such as conjunctivitis, is common in cats and can be caused by several viruses and bacteria, either as a single infection or as co-infections. In this study, povidone-iodine (PVP-I), alone or compounded with hydroxyethyl cellulose (HEC), was investigated for its efficacy against these pathogens in vitro. Whilst PVP-I alone was effective at inhibiting feline herpesvirus type 1 (FHV-1), Chlamydia felis, and Mycoplasma felis, PVP-I with HEC exerted a synergistic inhibitory effect against FHV-1 and C. felis. In contrast, only minimal inhibition of feline calicivirus was observed. These results demonstrate that PVP-I, alone and in combination with HEC, is effective against some feline ocular pathogens when tested in cell lines in vitro. In vivo studies investigating the systemic safety, ocular tolerance, and clinical efficacy of this combination in cats would be necessary before it could be recommended as a therapy in affected cats.

Doxycycline suppresses Chlamydia pneumoniae induced interferon-gamma responses in peripheral blood mononuclear cells in children with allergic asthma.

Persistent respiratory infections caused by Chlamydia pneumoniae have been implicated in the pathogenesis of chronic diseases (e.g. asthma). Antibiotics are used to treat C. pneumoniae respiratory infections; however, the use of antibiotics as anti-inflammatory agents in treatment of asthma remains controversial. The current study investigated whether ciprofloxacin, azithromycin, or doxycycline can suppress C. pneumoniae-induced production of immunoglobulin (Ig) E or cytokines in peripheral blood mononuclear cells (PBMC) obtained from asthmatic children. Apart from blood, nasopharyngeal swab specimens were also collected to test for the presence of C. pneumoniae and/or M. pneumoniae (qPCR). PBMC (1.5 x 106) from asthmatic pediatric patients (N = 18) were infected or mock infected for 1 h ± C. pneumoniae AR-39 at a multiplicity of infection (MOI) = 0.1, and cultured ± ciprofloxacin, azithromycin, or doxycycline (0.1 or 1.0 µg/mLmL) for either 48 h (cytokines) or 10 days (IgE). Interleukin (IL)-4, interferon (IFN)-γ and IgE levels in supernatants were measured (ELISA). When PBMC were infected with C. pneumoniae, IL-4 and IFNγ production increased (p = 0.06 and 0.03, respectively); IgE levels were low. The now-elevated levels of IL-4 didn't decrease significantly after addition of ciprofloxacin, azithromycin, or doxycycline. However, infected PBMC IFNγ formation decreased significantly when 0.1 µg/mL doxycycline was employed (p = 0.04); no dose of ciprofloxacin or azithromycin had any impact. This inhibitory outcome with doxycycline lends support to the use of tetracyclines as immune modulators and anti-inflammatory medications in treatment of C. pneumoniae-infected asthma patients.

A prolonged antibiotic protocol to treat persistent Chlamydophila pneumoniae infection improves the extracranial venous circulation in multiple sclerosis.

Objective Chronic cerebrospinal venous insufficiency (CCSVI) is a condition associated with multiple sclerosis (MS). One mechanism that has been proposed is that the venous obstructions found in MS are due to a chronic persistent venulitis caused by the intra-cellular bacterial parasite, Chlamydophila pneumoniae (Cpn). The objective of the current study is to determine the effect of a combined antibiotic protocol (CAP) on the venous flow in MS patients as measured by a quantitative duplex ultrasound examination (QDUS). Method A non-randomised before-after cohort study was conducted to investigate differences in blood flow volumes pre and 6-months post antibiotic treatment for Cpn infection. Flow volume data were measured by QDUS across affected and unaffected sides from multiple veins segments, including internal jugular vein (IJV) segments J2 and J3, and vertebral vein (VV), as well as global arterial blood flow (GABF). Results 91 patients were included in the study. 64 (70%) were found to have positive Cpn serology. There was a statistically significant post-treatment difference seen for the affected side of Cpn infected patients (mean difference = 56 mL/min, p = 0.02). There was a non-significant increase seen for the affected side of uninfected patients (mean difference = 23 mL/min, p = 0.2). The difference in these effects (34 mL/min) was not statistically significant ( p = 0.3). The mean flow rate decreased in the unaffected side for both infected (-27 mL/min, p = 0.5) and uninfected patients (-69 mL/min, p = 0.01). There was a statistically significant post-treatment increase in GABF for the infected patients (mean difference = 90 mL/min, p = 0.02) and a difference of 76 mL/min for non-infected patients ( p = 0.01). Conclusion A CAP appears to improve the extra-cranial circulation in patients diagnosed with MS. This effect is statistically significant in patients with positive Cpn serology, although patients with negative Cpn serology also show some benefit, betraying a lack of specificity of this effect.

Serological Analysis and Drug Resistance of Chlamydia pneumoniae and Mycoplasma pneumoniae in 4500 Healthy Subjects in Shenzhen, China.

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.

Infection-mediated asthma: etiology, mechanisms and treatment options, with focus on Chlamydia pneumoniae and macrolides.

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.

Chlamydia Serine Protease Inhibitor, targeting HtrA, as a New Treatment for Koala Chlamydia infection.

The koala, an iconic marsupial native to Australia, is a threatened species in many parts of the country. One major factor in the decline is disease caused by infection with Chlamydia. Current therapeutic strategies to treat chlamydiosis in the koala are limited. This study examines the effectiveness of an inhibitor, JO146, which targets the HtrA serine protease for treatment of C. pecorum and C. pneumoniae in vitro and ex vivo with the aim of developing a novel therapeutic for koala Chlamydia infections. Clinical isolates from koalas were examined for their susceptibility to JO146. In vitro studies demonstrated that treatment with JO146 during the mid-replicative phase of C. pecorum or C. pneumoniae infections resulted in a significant loss of infectious progeny. Ex vivo primary koala tissue cultures were used to demonstrate the efficacy of JO146 and the non-toxic nature of this compound on peripheral blood mononuclear cells and primary cell lines established from koala tissues collected at necropsy. Our results suggest that inhibition of the serine protease HtrA could be a novel treatment strategy for chlamydiosis in koalas.

Amphipathic ß2,2-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae.

We demonstrate in the current work that small cationic antimicrobial ß2,2-amino acid derivatives (Mw < 500 Da) are highly potent against Chlamydia pneumoniae at clinical relevant concentrations (< 5 µM, i.e. < 3.4 µg/mL). C. pneumoniae is an atypical respiratory pathogen associated with frequent treatment failures and persistent infections. This gram-negative bacterium has a biphasic life cycle as infectious elementary bodies and proliferating reticulate bodies, and efficient treatment is challenging because of its long and obligate intracellular replication cycle within specialized inclusion vacuoles. Chlamydicidal effect of the ß2,2-amino acid derivatives in infected human epithelial cells was confirmed by transmission electron microscopy. Images of infected host cells treated with our lead derivative A2 revealed affected chlamydial inclusion vacuoles 24 hours post infection. Only remnants of elementary and reticulate bodies were detected at later time points. Neither the EM studies nor resazurin-based cell viability assays showed toxic effects on uninfected host cells or cell organelles after A2 treatment. Besides the effects on early intracellular inclusion vacuoles, the ability of these ß2,2-amino acid derivatives to suppress Chlamydia pneumoniae infectivity upon treatment of elementary bodies suggested also a direct interaction with bacterial membranes. Synthetic ß2,2-amino acid derivatives that target C. pneumoniae represent promising lead molecules for development of antimicrobial agents against this hard-to-treat intracellular pathogen.

Fever-triggered Brugada syndrome in an adult patient presenting with hemophagocytic syndrome induced by Chlamydophila pneumoniae.

A previously healthy 29-year-old man was admitted to our hospital, with a 4-day history of fever (>39°C), rigours, diaphoresis, fatigue and retro-orbital headache. On examination, he was febrile (37.8°C) and tachycardic (110 bpm). Laboratory work up revealed bicytopenia (white cell count 1.37×10(9)/L, platelets 60×10(9)/L) and an increase in C reactive protein (9 mg/dL). The ECG showed ST segment elevation in V1, V2 and V3 leads. The patient was admitted and investigation was initiated revealing prolonged fever (>7 days), pancytopenia, hepatosplenomegaly, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, elevated soluble CD25 and hemophagocytosis in bone marrow. Therefore, the patient presented 7 of the 8 diagnostic criteria of hemophagocytic syndrome. Laboratorial investigation for infectious causes was negative, except for IgA and IgG Chlamydophila pneumoniae. ECG re-evaluation on the day of discharge showed no ST segment elevation and no other abnormalities. Genetic testing for known mutations associated with hemophagocytic syndrome and Brugada syndrome did not show any mutations in these genes.

Detection of Chlamydia pneumoniae in a collection of captive snakes and response to treatment with marbofloxacin.

In a collection of 58 snakes comprising predominantly Eurasian vipers in Switzerland, five snakes died unexpectedly during hibernation from 2009 to 2012. In one snake, organisms resembling chlamydiae were detected by immunohistochemistry in multiple histiocytic granulomas. Real-time quantitative PCR and microarray analysis were used to determine the presence of Chlamydia pneumoniae in tissue samples and cloacal/choanal swabs from snakes in the collection; 8/53 (15.1%) of the remaining snakes were positive. Although one infected snake had suppurative periglossitis, infection with C. pneumoniae did not appear to be associated with specific clinical signs in snakes. Of seven snakes treated with 5 mg/kg marbofloxacin IM once daily, five became PCR negative for C. pneumoniae following treatment, whereas one animal remained positive and one snake was lost to follow-up.

Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma.

BACKGROUND: Steroid-insensitive endotypes of asthma are an important clinical problem and effective therapies are required. They are associated with bacterial infection and non-eosinophilic inflammatory responses in the asthmatic lung. Macrolide therapy is effective in steroid-insensitive endotypes, such as non-eosinophilic asthma. However, whether the effects of macrolides are due to antimicrobial or anti-inflammatory mechanisms is not known. OBJECTIVE: To determine and assess the efficacy of macrolide (ie, clarithromycin) and non-macrolide (ie, amoxicillin) antibiotic treatments in experimental models of infection-induced, severe, steroid-insensitive neutrophilic allergic airways disease (SSIAAD), compared with steroid-sensitive AAD and to delineate the antimicrobial and anti-inflammatory effects of macrolide therapy. METHODS: We developed and used novel mouse models of Chlamydia and Haemophilus lung infection-induced SSIAAD. We used these models to investigate the effects of clarithromycin and amoxicillin treatment on immune responses and airways hyper-responsiveness (AHR) in Ova-induced, T helper lymphocyte (Th) 2 -associated steroid-sensitive AAD and infection-induced Th1/Th17-associated SSIAAD compared with dexamethasone treatment. RESULTS: Clarithromycin and amoxicillin had similar antimicrobial effects on infection. Amoxicillin did attenuate some features, but did not broadly suppress either form of AAD. It did restore steroid sensitivity in SSIAAD by reducing infection. In contrast, clarithromycin alone widely suppressed inflammation and AHR in both steroid-sensitive AAD and SSIAAD. This occurred through reductions in Th2 responses that drive steroid-sensitive eosinophilic AAD and tumour necrosis factor α and interleukin 17 responses that induce SSIAAD. CONCLUSIONS: Macrolides have broad anti-inflammatory effects in AAD that are likely independent of their antimicrobial effects. The specific responses that are suppressed are dependent upon the responses that dominate during AAD.

Treatment of Chlamydial infections: 2014 update.

INTRODUCTION: Chlamydiae are obligate intracellular bacterial pathogens whose entry into mucosal epithelial cells is required for intracellular survival and subsequent growth. The life cycle of Chlamydia spp. and the ability to cause persistent, often subclinical infection, has major ramifications for diagnosis and treatment of Chlamydia trachomatis and C. pneumoniae infections in humans. AREAS COVERED: This paper reviews the current literature on the antimicrobial susceptibilities and treatment of genital infections due to C. trachomatis and respiratory infections due to C. pneumoniae published since 2011. EXPERT OPINION: Chlamydiae are susceptible to antibiotics that interfere with DNA and protein synthesis, including tetracyclines, macrolides and quinolones, which are the compounds that have been most extensively studied and used for treatment of human infection. Since our original review was published in 2011, there have been some major advances in diagnostic tests for C. trachomatis and the introduction of the first FDA-approved test for the detection of C. pneumoniae in respiratory samples. However, the options for treating chlamydial infections have largely remained the same. There are a small number of new drugs currently in preclinical development and early clinical trials that may have a role in the treatment of chlamydial infections.

Liver granulomatosis: a case of Chlamydophila pneumoniae infection.

An 18-year-old man was referred to the Internal Medicine ward because of a 2-week history of intermittent high fever, weight loss and cough. Clinical examination revealed hepato-splenomegaly and multiple lymph nodes swelling while laboratory tests showed elevated C-reactive protein, gamma glutamyl transferase and lactate dehydrogenase. All serologic testes for auto-immune antibodies, viruses and bacteria were negative except for Chlamydophila pneumoniae. An 18-FDG PET computed tomography scanner showed hypermetabolism in the liver, spleen and lymph nodes. We therefore conducted a liver biopsy that demonstrated non-necrotizing granulomas. We conclude to a C. pneumoniae infection associated with a granulomatous hepatitis. After treatment with Doxyciclin the patient had no more fever, hepatosplenomegaly resolved and blood testes normalized. This case report is to our knowledge the first report of a granulomatous hepatitis associated with C. pneumoniae respiratory infection.