Antibiotic use in early life and development of allergic diseases: respiratory infection as the explanation

Background Early antibiotic use has been postulated to increase the development of allergic disease. Antibiotic use results from infection. Early infection may play a confounding role in the relationship between antibiotic use and allergic disease. Objective We aimed to investigate the relationship between antibiotic use during the first year of life and the development of allergic diseases in a birth cohort study, and also to carefully address the confounding effect of early respiratory infection. Methods Three thousand three hundred and six children were included in this study who participated in investigations at all occasions of 2 months, 1, 4 and 8 years of age. Data on antibiotic use and respiratory infections were collected at the age of 1 year. Diagnoses of allergic diseases at 4 and 8 years of age were derived from the follow‐up questionnaires. Results During the first year of life, 43% (n=1420) of the children received antibiotics and 32% (n=1046) of the children had at least one type of respiratory infection among pneumonia, bronchitis and otitis. In univariate logistic regression analysis and after adjustment for early life factors, antibiotic use during the first year of life was associated with wheeze, asthma, eczema and food hypersensitivity at 4 years of age. After adjustment for the above respiratory infections during the first year of life, only the associations with wheeze and asthma at age 4 years remained statistically significant. These associations became non‐significant in a subgroup analysis in children without early allergic signs. At age 8 years, antibiotic use during the first year of life was significantly associated with wheeze and eczema after adjustment for early life factors. The significant associations at age 8 years faded away following further adjustment for the respiratory infections. Conclusion Our study indicated that the association between early antibiotic use and later allergic disease could at least partially be explained by early respiratory infection. Cite this as: X.‐M. Mai, I. Kull, M. Wickman and A. Bergström, Clinical & Experimental Allergy, 2010 (40) 1230–1237.     

Perioperative variation in phagocytic activity against Candida albicans measured by a flow-cytometric assay in cardiovascular-surgery patients.

Candidiasis is an opportunistic fungal infection that frequently occurs following modifications of host defenses. Major surgery can be responsible for such alterations, and therefore it increases the risk of fungal infection. The purpose of this study was to evaluate the perioperative impairment of leukocyte function in patients after cardiovascular surgery by measuring the phagocytic activity against Candida albicans by a flow-cytometric method. The average postsurgical decrease in phagocytosis in our patients was 11.4%. By univariate analysis, three factors, all related to antibiotic therapy, were significantly associated with an important decrease in phagocytosis; the use of antimicrobial therapy before surgery, the number of different antibiotics taken, and the length of antibiotic treatment. The results of our study showed that the use of antibiotics in patients undergoing cardiovascular surgery alters the normal phagocytic activity of the host immune system against C. albicans and that flow cytometry is a rapid and simple technique that helps in early identification of patients at high risk for Candida infections. The mechanisms by which surgery and antibiotics decrease phagocytosis remain to be elucidated.     

Prevalence of allergy, patterns of allergic sensitization and allergy risk factors in rural and urban children

BACKGROUND: We aimed to compare the prevalence of allergic diseases and sensitization in children living in urban and rural areas and to identify potential risk/protection factors associated with allergy. METHODS: School children 12-16 years old, from urban community (n = 201) and rural area (n = 203) were recruited. The data obtained by questionnaire were referred to doctors' diagnosis, skin prick tests (SPTs), and serum specific and total IgE assessment. RESULTS: The prevalence of allergic diseases in urban children was significantly higher as compared with rural children [asthma 16.42%vs 1.97% (P < 0.001) allergic rhinitis 38.81%vs 10.84% (P < 0.001)]. Positive SPTs to at least one allergen was found in 63.7% of urban and 22.7% rural children (P < 0.001). Significantly higher percentage of allergic rural than urban children were monosensitized or sensitized to 2-4 allergens, but almost a fourfold higher percentage of allergic urban children was found to be sensitized to five or more allergens (P < 0.0001). The history of frequent upper respiratory factor (URT) infections, antibiotic therapy, tonsiltectomy/adenoidectomy were positively associated with development of atopy and sensitization. CONCLUSION: Our findings confirm that residence of rural area is associated with a significant lower prevalence of allergic sensitization and symptoms in school children. Several risk and protective factors related to environment and style of life could be identified in both environments.     

Bacteriophages: Potential Biocontrol Agents and Treatment Options for Bacterial Pathogens

The global report on antibiotic resistance by the World Health Organization features the burden of antimicrobial resistance and the emerging risk of a post-antibiotic era, where therapeutic options will no longer exist for previously treatable diseases. The search for alternative avenues to combat multidrug-resistant (MDR) pathogens has sparked interest in the use of bacteriophages for the treatment of bacterial infections. The unique ability of bacteriophages to infect and kill bacteria without affecting mammalian cells makes them a promising avenue as biocontrol agents against bacterial pathogens. Phage therapy in both animal and human models has shown promising results. Further, the phage-derived proteins (lytic enzymes), such as endolysins, that are the key weapons used by phages to degrade the bacterial cell have been explored by the scientific community as viable therapeutic options themselves. This review focuses on the prospects of phage therapy; an overview of diverse phages isolated against MDR pathogens; phage-derived proteins as antibacterial agents; phage cocktail development; phage and antibiotic combinational therapy; and the application of phages as biocontrol agents in agriculture, veterinary science, synthetic biology, and aquaculture. The review emphasizes the therapeutic use of phages and how they might be applied on a large scale if certain limitations and challenges can be overcome.     

Thinking bigger: How early‐life environmental exposures shape the gut microbiome and influence the development of asthma and allergic disease

Imbalance, or dysbiosis, of the gut microbiome of infants has been linked to an increased risk of asthma and allergic diseases. Most studies to date have provided a wealth of data showing correlations between early‐life risk factors for disease and changes in the structure of the gut microbiome that disrupt normal immunoregulation. These studies have typically focused on one specific risk factor, such as mode of delivery or early‐life antibiotic use. Such “micro‐level” exposures have a considerable impact on affected individuals but not necessarily the whole population. In this review, we place these mechanisms under a larger lens that takes into account the influence of upstream “macro‐level” environmental factors such as air pollution and the built environment. While these exposures likely have a smaller impact on the microbiome at an individual level, their ubiquitous nature confers them with a large influence at the population level. We focus on features of the indoor and outdoor human‐made environment, their microbiomes and the research challenges inherent in integrating the built environment microbiomes with the early‐life gut microbiome. We argue that an exposome perspective integrating internal and external microbiomes with macro‐level environmental factors can provide a more comprehensive framework to define how environmental exposures can shape the gut microbiome and influence the development of allergic disease.     

Evaluation of clinical, laboratory, and therapeutic features of 145 tularemia cases: the role of quinolones in oropharyngeal tularemia

Tularemia outbreaks have occurred in various regions of Turkey in recent years. In this study, clinical (145 patients) and laboratory (97 patients) features of patients with oropharyngeal tularemia were evaluated during the tularemia outbreak in the district of Gölcük in Kocaeli, Turkey. We analyzed the risk factors for therapeutic failure and prolonged recovery time, and compared the efficacy of three antibiotic groups, namely aminoglycoside, tetracycline and quinolone. The most common physical sign and laboratory findings in patients were lymphadenopathy (LAP) and increased erythrocyte sedimentation rate, respectively. Treatment failure was observed in 55 of the 145 (38%) patients during one‐year follow‐up and the most successful results were obtained in the quinolone group. It was determined that antimicrobial therapy initiated 14 days after onset of symptoms was a statistically significiant risk factor, reducing the success rate (p=0.0001, OR=13.10, 95% CI=5.69–30.15) and prolonging the recovery period (p=0.001, OR=3.23, 95% CI=1.63–6.40) in oropharyngeal tularemia cases. These results suggest that antimicrobial treatment should be started early, and quinolones such as moxifloxacin and ciprofloxacin seem to be new alternatives in the treatment of oropharyngeal tularemia.     

Rates,predictors and mortality of community-onset bloodstream infections due to Pseudomonas aeruginosa: systematic review and meta-analysis

BackgroundPseudomonas aeruginosa is mostly a nosocomial pathogen affecting predisposed patients. However, community-onset bloodstream infections (CO-BSI) caused by this organism are not exceptional.ObjectivesTo assess the predisposing factors for CO-BSI due to P. aeruginosa (CO-BSI-PA) and the impact in mortality of inappropriate empirical antimicrobial therapy.Data sourceA systematic literature search was performed in the Medline, Embase, Cochrane Library, Scopus and Web of Science databases.Study eligibility criteria and participants: Articles published between 1 January 2002 and 31 January 2018 reporting at least of 20 adult patients with CO-BSI due to P. aeruginosa were considered.InterventionEmpiric antimicrobial therapy for CO-BSI-PA.MethodsA systematic review and a meta-analysis were conducted for risk factors and to evaluate if inappropriate empiric antimicrobial therapy increased mortality in CO-BSI-PA using a Mantel-Haenszel effects model.ResultsTwelve studies assessing data of 1120 patients were included in the systematic review. Solid tumour (33.1%), haematologic malignancy (26.4%), neutropenia (31.7%) and previous antibiotic use (44.8%) were the most prevalent predisposing factors. Septic shock was present in 42.3% of cases, and 30-day crude mortality was 33.8%. Mortality in meta-analysis (four studies) was associated with septic shock at presentation (odds ratio, 22.31; 95% confidence interval, 3.52–141.35; p 0.001) and with inappropriate empiric antibiotic therapy (odds ratio, 1.83; 95% confidence interval, 1.12–2.98l p 0.02).ConclusionsCO-BSI-PA mostly occurred in patients with predisposing factors and had a 30-day mortality comparable to hospital-acquired cases. Inappropriate empirical antibiotic therapy was associated with increased mortality. Appropriate identification of patients at risk for CO-BSI-PA is needed for empirical treatment decisions.     

Biofilm related infections: is there a place for conservative treatment of port-related bloodstream infections?

Vascular catheters are the most frequently used indwelling medical devices and have become necessary tools for patients with chronic or critical illness. Surgically or percutaneously placed venous access ports are used to facilitate long-term intravenous therapy. The widespread use of these devices has resulted in a dramatic increase in catheter-related infections. It implies considerable morbidity, occasional mortality, and an increase in medical costs derived from its diagnosis, treatment, and mainly, prolongation of the patient's in-hospital stay. Treatment of such infections is often difficult due to the presence of biofilms on the port inner surface; inside the biofilms, bacteria are less vulnerable to antimicrobial agents. Current diagnostic strategies are suboptimal, and most successful treatment options require removal of the infected device followed by a course of antimicrobial therapy. There are limited data concerning the efficacy of antibiotic treatment of port-related bloodstream infections without catheter removal.     

Antibiotic use in the first year of life and risk of atopic disease in early childhood

Background Reduced post‐natal microbial stimulation resulting from improvements in public health measures, smaller family size, and through increased antibiotic use has been postulated to account for the increasing prevalence of atopic diseases seen predominantly in developed countries. Objective To investigate use of antibiotics in the first year of life and subsequent development of atopic disease in early childhood. Methods A prospective birth cohort of 198 children at high atopic risk was recruited prenatally and followed for 5 years. Illnesses and antibiotic use were ascertained through daily diaries, and diagnoses of asthma and hayfever were collected by questionnaire interviews. The children were examined regularly for eczema, and atopic status was defined by skin prick tests and serum total IgE. The effect of antibiotic use on subsequent atopic disease was examined using logistic regression with propensity score adjustment. Results 54.0% (107/198) of children received at least one course of antibiotics, mainly for acute respiratory illnesses (ARI). Thirty‐three percent (329/984) of the ARI involved the lower respiratory tract (LRI). Twenty‐three percent (222/984) of ARI were treated with antibiotics, with LRI significantly more likely to receive antibiotics. Antibiotic use was associated with asthma (unadjusted odds ratio 2.3; 95% confidence interval 1.2–4.5; P=0.01) but this association was reduced after propensity score adjustment. No associations were found between antibiotic use and eczema, current wheeze, current asthma, atopic asthma, allergic rhinoconjunctivitis or atopy. Conclusion Although this was a small study, systematic and careful monitoring of ARI, antibiotic use, and asthma and atopic diseases did not indicate that receipt of antibiotics early in life led to subsequent asthma or atopy at 5 years.     

Catheter-related infections in pediatric patients with cancer

Central venous catheters (CVCs) are essential in the management of pediatric patients receiving antineoplastic therapy or bone marrow transplants, and have significantly improved their quality of life, but CVC-related infectious complications are a major source of morbidity. It has been estimated that 14–51 % of the CVCs implanted in children with malignancies may be complicated by bacteremia, and that the incidence of infections is 1.4–1.9 episodes per 1,000 CVC days. However, there are few recent data concerning the epidemiology of CVC-related infections, the prevalence of antimicrobial resistance in their etiology, or the main factors associated with an increased risk of infection by type of catheter, patient age, the type of cancer, or the presence of neutropenia. Moreover, although various new strategies have been proposed in an attempt to reduce the risk of CVC-related infections, such as catheters impregnated with antiseptics/antibiotics, lock antibiotic prophylaxis, the use of ointments at the exit site, and antithrombotic prophylaxis, their real efficacy in children has not yet been demonstrated. The management of CVC-related infections remains difficult, mainly because of the number of still open questions (including the choice of optimal antimicrobial therapy because of the increasing isolation of multiresistant bacterial strains, treatment duration, whether catheters should be removed or not, the feasibility of guidewire exchange, and the usefulness of antibiotic lock therapy) and the lack of studies of children with cancer. Only well-designed, prospective clinical trials involving pediatric cancer patients can clarify optimal prevention and treatment strategies for CVC-related infections in this population.     

Environmental Changes,Microbiota, and Allergic Diseases

During the last few decades, the prevalence of allergic disease has increased dramatically. The development of allergic diseases has been attributed to complex interactions between environmental factors and genetic factors. Of the many possible environmental factors, most research has focused on the most commonly encountered environmental factors, such as air pollution and environmental microbiota in combination with climate change. There is increasing evidence that such environmental factors play a critical role in the regulation of the immune response that is associated with allergic diseases, especially in genetically susceptible individuals. This review deals with not only these environmental factors and genetic factors but also their interactions in the development of allergic diseases. It will also emphasize the need for early interventions that can prevent the development of allergic diseases in susceptible populations and how these interventions can be identified.     

Proteomics progresses in microbial physiology and clinical antimicrobial therapy

Clinical microbial identification plays an important role in optimizing the management of infectious diseases and provides diagnostic and therapeutic support for clinical management. Microbial proteomic research is aimed at identifying proteins associated with microbial activity, which has facilitated the discovery of microbial physiology changes and host–pathogen interactions during bacterial infection and antimicrobial therapy. Here, we summarize proteomic-driven progresses of host–microbial pathogen interactions at multiple levels, mass spectrometry-based microbial proteome identification for clinical diagnosis, and antimicrobial therapy. Proteomic technique progresses pave new ways towards effective prevention and drug discovery for microbial-induced infectious diseases.     

How to: implement procalcitonin testing in my practice

BackgroundAdding procalcitonin (PCT) to antibiotic stewardship algorithms may improve antibiotic use. However, PCT protocols need to be adapted to clinical settings and patient populations.ObjectivesTo review PCT use in different medical settings and patient populations.SourcesMost recent trials and meta-analyses investigating PCT for antibiotic stewardship were reviewed.ContentSeveral trials found PCT-guided antibiotic stewardship to reduce antibiotic exposure and associated side-effects among patients with respiratory infection and sepsis. Decisions regarding antibiotic use in an individual patient are complex and should be based on the pre-test probability for bacterial infection, the severity of presentation and the results of PCT. In the context of a low pre-test probability for bacterial infections and a low-risk patient, a low PCT level helps to rule out bacterial infection and empiric antibiotic therapy can be avoided. In the context of a high pre-test probability for bacterial infections and/or a high-risk patient with sepsis, monitoring of PCT over time helps to track the resolution of infection and decisions regarding early stop of antibiotic treatment. Although these concepts have been successful in several respiratory infection and sepsis trials, some studies failed to show an added benefit of PCT due to factors such as low protocol adherence and relying on single rather than repeat PCT measurements.ImplicationAs an adjunct to other clinical and laboratory parameters, PCT provides information about risk for bacterial infection and resolution of infection, and improves antibiotic stewardship decisions, thereby offering more individualized treatment courses with overall reduced antibiotic exposure.     

Influences of environmental bacteria and their metabolites on allergies,asthma, and host microbiota

The prevalence of allergic diseases and asthma has dramatically increased over the last decades, resulting in a high burden for patients and healthcare systems. Thus, there is an unmet need to develop preventative strategies for these diseases. Epidemiological studies show that reduced exposure to environmental bacteria in early life (eg, birth by cesarean section, being formula‐fed, growing up in an urban environment or with less contact to various persons) is associated with an increased risk to develop allergies and asthma later in life. Conversely, a reduced risk for asthma is consistently found in children growing up on traditional farms, thereby being exposed to a wide spectrum of microbes. However, clinical studies with bacteria to prevent allergic diseases are still rare and to some extent contradicting. A detailed mechanistic understanding of how environmental microbes influence the development of the human microbiome and the immune system is important to enable the development of novel preventative approaches that are based on the early modulation of the host microbiota and immunity. In this mini‐review, we summarize current knowledge and experimental evidence for the potential of bacteria and their metabolites to be used for the prevention of asthma and allergic diseases.     

Six weeks antibiotic therapy for all bone infections: results of a cohort study

There is no consensus on the antibiotic therapy for bone infection due to the heterogeneous spectrum of diseases. Most authors suggest different durations of treatment based on pathophysiological considerations. However, adverse effects are related, at least in part, to the duration of treatment. We, therefore, investigated a 6 weeks antibiotic combination therapy for all cases of bone infection. Herewith, we report the results of this therapeutic approach. This is a cohort study including all patients presenting with bone infection, regardless of the mechanism involved. The diagnosis was based on bone biopsy obtained through invasive procedures. Chronic bone infection was defined as a history of disease of over 1 month duration. The duration of clinical follow-up following treatment discontinuation was at least 6 months. Cured bone infection was defined as the absence of relapse after antibiotic discontinuation. One hundred and eighteen patients were included between July 2005 and March 2009; 61 presented with bone infection following prosthetic implant (52%) and the 57 remaining patients had bone infection without foreign material (48%). Surgery was required for 80 patients (68%). Microbial agents were identified in 116/118 patients, with 24 patients presenting with polymicrobial sepsis (20%). The mean duration of antibiotic treatment was 42 ± 0.2 days and the mean clinical follow-up was 27 ± 14 months. The treatment success rate was 91.5% (108/118). Six weeks of antimicrobial therapy appears to be effective for nearly all bone infections, regardless of the pathophysiology. These results encourage us to pursue attempts to simplify the management of bone infection without obvious prejudice to the patient.     

Microbial exposure, interferon gamma gene demethylation in naïve T-cells, and the risk of allergic disease

The period of immune programming during early life presents a critical window of opportunity for the prevention of allergic diseases. There is mounting evidence that inappropriate immune programming may involve disruption of specific epigenetic modifications (switches) at immune-related genes. This novel area of research has great potential, as epigenetic changes are known to be sensitive to environmental factors and may therefore provide a mechanistic link for the observed association between specific environmental cues, faulty immune development, and the risk of allergic disease. In addition, the dynamic and potentially reversible nature of epigenetic modifications offers potentially novel targets for therapeutic and/or preventative interventions. We review the evidence that (1) failure to up-regulate the interferon gamma (IFNγ) response during infancy is an important determinant of the risk of allergic disease, (2) expression of the IFNγ gene in naïve T-cells is regulated by epigenetic mechanisms, and (3) failure to up-regulate IFNγ gene expression of naïve T-cells associated with low early life microbial exposure. Taken together, these lines of evidence suggest that low microbial exposure during early life increases the risk of allergic disease by reducing demethylation (activation) of the IFNγ gene of naive T-cells.     

Allergic conjunctivitis: update on pathophysiology and prospects for future treatment

Allergic conjunctivitis is in actuality a group of diseases affecting the ocular surface and is usually associated with type 1 hypersensitivity reactions. Two acute disorders, seasonal allergic conjunctivitis and perennial allergic conjunctivitis, exist, as do 3 chronic diseases, vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis. The ocular surface inflammation (usually mast cell driven) results in itching, tearing, lid and conjunctival edema-redness, and photophobia during the acute phase and can lead to a classic late-phase response (with associated eosinophilia and neutrophilia) in a subset of individuals. As is the case in other allergic diseases, a chronic disease can also develop, accompanied by remodeling of the ocular surface tissues. In severe cases the patient experiences extreme discomfort and sustains damage to the ocular surface. For such cases, there is no highly effective and safe treatment regimen. Topical administration of corticosteroids is used in severe cases but is associated with an increased risk for the development of cataracts and glaucoma. Thus there is a worldwide search for new biotargets for the treatment of these diseases. Here we provide a brief update of the clinical symptoms associated with these diseases, the rationale for disease classification, recent advances in our understanding of the pathogenesis of the diseases, and an update on both preclinical and clinical advances toward refined therapies for these diseases.     

The use of a feather quilt, childhood asthma and allergic rhinitis: a prospective cohort study

BACKGROUND: Feather bedding has long been considered as a potential source of allergen exposure and thus a potential risk factor for allergic diseases. However, recent cross-sectional studies have reported a higher risk of allergic diseases among users of synthetic bedding compared with feather-bedding users. OBJECTIVE: To explore associations between early life exposure to feather bedding and the risk of developing asthma allergic rhinitis in childhood. METHODS: We assessed the association between early life exposure to feather quilts and the risk of bronchial obstruction during the first 2 years of life and asthma and allergic rhinitis in a prospective 4-year cohort study of 2531 Norwegian children. RESULTS: At the age of 6 months, 24% of the children had a quilt with feathers, decreasing to 20% at the age of 2 years. The adjusted odds ratio for bronchial obstruction 0 to 2 years by exposure to a feather quilt at the age of 6 months was 0.59, 95% confidence interval 0.41 to 0.86, for asthma at the age of 4 years 0.38, 0.23 to 0.64 and for allergic rhinitis at the age of 4 years 0.73, 0.43 to 1.18. CONCLUSION: The use of a feather quilt in early life does not seem to increase the risk of asthma and allergic rhinitis later in childhood.     

Severe chronic allergic (and related) diseases: a uniform approach--a MeDALL--GA2LEN--ARIA position paper

Concepts of disease severity, activity, control and responsiveness to treatment are linked but different. Severity refers to the loss of function of the organs induced by the disease process or to the occurrence of severe acute exacerbations. Severity may vary over time and needs regular follow-up. Control is the degree to which therapy goals are currently met. These concepts have evolved over time for asthma in guidelines, task forces or consensus meetings. The aim of this paper is to generalize the approach of the uniform definition of severe asthma presented to WHO for chronic allergic and associated diseases (rhinitis, chronic rhinosinusitis, chronic urticaria and atopic dermatitis) in order to have a uniform definition of severity, control and risk, usable in most situations. It is based on the appropriate diagnosis, availability and accessibility of treatments, treatment responsiveness and associated factors such as comorbidities and risk factors. This uniform definition will allow a better definition of the phenotypes of severe allergic (and related) diseases for clinical practice, research (including epidemiology), public health purposes, education and the discovery of novel therapies.