Evaluation of antibiotic prescription for upper respiratory tract infections in the community pharmacy setting

This is an Open access article distributed under the terms of Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0/

Persistent chlamydial infections : role in inflammation and challenges for vaccine development.

The development of chlamydial vaccines continues to be a major challenge for researchers. While acute infections are the main target of vaccine development groups, Chlamydia is well known for its ability to establish chronic or persistent infections in its host. To date, little effort has focussed specifically on the challenges of vaccines to successfully combat the chronic or persistent phase of the disease and yet this will be a necessary aspect of any fully successful chlamydial vaccine. This short review specifically examines the phenomenon of chlamydial persistence and the unique challenges that this brings to vaccine development.

Development and evaluation of an integrated clinical learning model to inform continuing education for acute care nurses

Background Significant ongoing learning needs for nurses have occurred as a direct result of the continuous introduction of technological innovations and research developments in the healthcare environment. Despite an increased worldwide emphasis on the importance of continuing education, there continues to be an absence of empirical evidence of program and session effectiveness. Few studies determine whether continuing education enhances or develops practice and the relative cost benefits of health professionals’ participation in professional development. The implications for future clinical practice and associated educational approaches to meet the needs of an increasingly diverse multigenerational and multicultural workforce are also not well documented. There is minimal research confirming that continuing education programs contribute to improved patient outcomes, nurses’ earlier detection of patient deterioration or that standards of continuing competence are maintained. Crucially, evidence-based practice is demonstrated and international quality and safety benchmarks are adhered to. An integrated clinical learning model was developed to inform ongoing education for acute care nurses. Educational strategies included the use of integrated learning approaches, interactive teaching concepts and learner-centred pedagogies. A Respiratory Skills Update education (ReSKU) program was used as the content for the educational intervention to inform surgical nurses’ clinical practice in the area of respiratory assessment. The aim of the research was to evaluate the effectiveness of implementing the ReSKU program using teaching and learning strategies, in the context of organisational utility, on improving surgical nurses’ practice in the area of respiratory assessment. The education program aimed to facilitate better awareness, knowledge and understanding of respiratory dysfunction in the postoperative clinical environment. This research was guided by the work of Forneris (2004), who developed a theoretical framework to operationalise a critical thinking process incorporating the complexities of the clinical context. The framework used educational strategies that are learner-centred and participatory. These strategies aimed to engage the clinician in dynamic thinking processes in clinical practice situations guided by coaches and educators. Methods A quasi experimental pre test, post test non–equivalent control group design was used to evaluate the impact of the ReSKU program on the clinical practice of surgical nurses. The research tested the hypothesis that participation in the ReSKU program improves the reported beliefs and attitudes of surgical nurses, increases their knowledge and reported use of respiratory assessment skills. The study was conducted in a 400 bed regional referral public hospital, the central hub of three smaller hospitals, in a health district servicing the coastal and hinterland areas north of Brisbane. The sample included 90 nurses working in the three surgical wards eligible for inclusion in the study. The experimental group consisted of 36 surgical nurses who had chosen to attend the ReSKU program and consented to be part of the study intervention group. The comparison group included the 39 surgical nurses who elected not to attend the ReSKU program, but agreed to participate in the study. Findings One of the most notable findings was that nurses choosing not to participate were older, more experienced and less well educated. The data demonstrated that there was a barrier for training which impacted on educational strategies as this mature aged cohort was less likely to take up educational opportunities. The study demonstrated statistically significant differences between groups regarding reported use of respiratory skills, three months after ReSKU program attendance. Between group data analysis indicated that the intervention group’s reported beliefs and attitudes pertaining to subscale descriptors showed statistically significant differences in three of the six subscales following attendance at the ReSKU program. These subscales included influence on nursing care, educational preparation and clinical development. Findings suggest that the use of an integrated educational model underpinned by a robust theoretical framework is a strong factor in some perceptions of the ReSKU program relating to attitudes and behaviour. There were minimal differences in knowledge between groups across time. Conclusions This study was consistent with contemporary educational approaches using multi-modal, interactive teaching strategies and a robust overarching theoretical framework to support study concepts. The construct of critical thinking in the clinical context, combined with clinical reasoning and purposeful and collective reflection, was a powerful educational strategy to enhance competency and capability in clinicians.

Development of novel vaccine strategies to prevent genital tract chlamydial infections

Chlamydia trachomatis is the most prevalent bacterial sexually transmitted infection in the developed world and the leading cause of preventable blindness worldwide. As reported by the World Health Organization in 2001, there are approximately 92 million new infections detected annually, costing health systems billions of dollars to treat not only the acute infection, but also to treat infection-associated sequelae. The majority of genital infections are asymptomatic, with 50-70% going undetected. Genital tract infections can be easily treated with antibiotics when detected. Lack of treatment can lead to the development of pelvic inflammatory disease, ectopic pregnancies and tubal factor infertility in women and epididymitis and prostatitis in men. With infection rates on the continual rise and the large number of infections going undetected, there is a need to develop an efficacious vaccine which prevents not only infection, but also the development of infection-associated pathology. Before a vaccine can be developed and administered, the pathogenesis of chlamydial infections needs to be fully understood. This includes the kinetics of ascending infection and the effects of inoculating dose on ascension and development of pathology. The first aim in this study was to examine these factors in a murine model. Female BALB/c mice were infected intravaginally with varying doses of C. muridarum, the mouse variant of human C. trachomatis, and the ascension of infection along the reproductive tract and the time-course of infection-associated pathology development, including inflammatory cell infiltration, pyosalpinx and hydrosalpinx, were determined. It was found that while the inoculating dose did affect the rate and degree of infection, it did not affect any of the pathological parameters examined. This highlighted that the sexual transmission dose may have minimal effect on the development of reproductive sequelae. The results of the first section enabled further studies presented here to use an optimal inoculating dose that would ascend the reproductive tract and cause pathology development, so that vaccine efficacy could be determined. There has been a large amount of research into the development of an efficacious vaccine against genital tract chlamydial infections, with little success. However, there have been no studies examining the effects of the timing of vaccination, including the effects of vaccination during an active genital infection, or after clearance of a previous infection. These are important factors that need to be examined, as it is not yet known whether immunization will enhance not only the individual's immune response, but also pathology development. It is also unknown whether any enhancement of the immune responses will cause the Chlamydia to enter a dormant, persistent state, and possibly further enhance any pathology development. The second section of this study aimed to determine if vaccination during an active genital tract infection, or after clearance of a primary infection, enhanced the murine immune responses and whether any enhanced or reduced pathology occurred. Naïve, actively infected, or previously infected animals were immunized intranasally or transcutaneously with the adjuvants cholera toxin and CpG-ODN in combination with either the major outer membrane protein (MOMP) of C. muridarum, or MOMP and ribonucleotide reductase small chain protein (NrdB) of C. muridarum. It was found that the systemic immune responses in actively or previously infected mice were altered in comparison to animals immunized naïve with the same combinations, however mucosal antibodies were not enhanced. It was also found that there was no difference in pathology development between any of the groups. This suggests that immunization of individuals who may have an asymptomatic infection, or may have been previously exposed to a genital infection, may not benefit from vaccination in terms of enhanced immune responses against re-exposure. The final section of this study aimed to determine if the vaccination regimes mentioned above caused in vivo persistence of C. muridarum in the upper reproductive tracts of mice. As there has been no characterization of C. muridarum persistence in vitro, either ultrastructurally or via transcriptome analysis, this was the first aim of this section. Once it had been shown that C. muridarum could be induced into a persistent state, the gene transcriptional profiles of the selected persistent marker genes were used to determine if persistent infections were indeed present in the upper reproductive tracts of the mice. We found that intranasal immunization during an active infection induced persistent infections in the oviducts, but not the uterine horns, and that intranasal immunization after clearance of infection, caused persistent infections in both the uterine horns and the oviducts of the mice. This is a significant finding, not only because it is the first time that C. muridarum persistence has been characterized in vitro, but also due to the fact that there is minimal characterization of in vivo persistence of any chlamydial species. It is possible that the induction of persistent infections in the reproductive tract might enhance the development of pathology and thereby enhance the risk of infertility, factors that need to be prevented by vaccination, not enhanced. Overall, this study has shown that the inoculating dose does not affect pathology development in the female reproductive tract of infected mice, but does alter the degree and rate of ascending infection. It has also been shown that intranasal immunization during an active genital infection, or after clearance of one, induces persistent infections in the uterine horns and oviducts of mice. This suggests that potential vaccine candidates will need to have these factors closely examined before progressing to clinical trials. This is significant, because if the same situation occurs in humans, a vaccine administered to an asymptomatic, or previously exposed individual may not afford any extra protection and may in fact enhance the risk of development of infection-associated sequelae. This suggests that a vaccine may serve the community better if administered before the commencement of sexual activity.

Interleukin-13 promotes susceptibility to chlamydial infection of the respiratory and genital tracts

Chlamydiae are intracellular bacteria that commonly cause infections of the respiratory and genital tracts, which are major clinical problems. Infections are also linked to the aetiology of diseases such as asthma, emphysema and heart disease. The clinical management of infection is problematic and antibiotic resistance is emerging. Increased understanding of immune processes that are involved in both clearance and immunopathology of chlamydial infection is critical for the development of improved treatment strategies. Here, we show that IL-13 was produced in the lungs of mice rapidly after Chlamydia muridarum (Cmu) infection and promoted susceptibility to infection. Wild-type (WT) mice had increased disease severity, bacterial load and associated inflammation compared to IL-13 deficient (−/−) mice as early as 3 days post infection (p.i.). Intratracheal instillation of IL-13 enhanced bacterial load in IL-13−/− mice. There were no differences in early IFN-g and IL-10 expression between WT and IL-13−/− mice and depletion of CD4+ T cells did not affect infection in IL-13−/− mice. Collectively, these data demonstrate a lack of CD4+ T cell involvement and a novel role for IL-13 in innate responses to infection. We also showed that IL-13 deficiency increased macrophage uptake of Cmu in vitro and in vivo. Moreover, the depletion of IL-13 during infection of lung epithelial cells in vitro decreased the percentage of infected cells and reduced bacterial growth. Our results suggest that enhanced IL-13 responses in the airways, such as that found in asthmatics, may promote susceptibility to chlamydial lung infection. Importantly the role of IL-13 in regulating infection was not limited to the lung as we showed that IL-13 also promoted susceptibility to Cmu genital tract infection. Collectively our findings demonstrate that innate IL-13 release promotes infection that results in enhanced inflammation and have broad implications for the treatment of chlamydial infections and IL-13-associated diseases.

The open window of susceptibility to infection after acute exercise in healthy young male elite athletes

The 'open window' theory is characterised by short term suppression of the immune system following an acute bout of endurance exercise. This window of opportunity may allow for an increase in susceptibility to upper respiratory illness (URI). Many studies have indicated a decrease in immune function in response to exercise. However, many studies do not indicate changes in immune function past 2 hours after the completion of exercise, consequently failing to determine whether these immune cells numbers, or importantly their function, return to resting levels before the start of another bout of exercise. Ten male 'A' grade cyclists (age 24.2 +/- 5.3 years; body mass 73.8 +/- 6.5 kg; VO(2peak) 65.9 +/- 7.1 mL.kg(-1).min(-1)) exercised for two hours at 90% of their second ventilatory threshold. Blood samples were collected pre-, immediately post-, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours post-exercise. Immune variables examined included total leukocyte counts, neutrophil function (oxidative burst and phagocytic function), lymphocyte subset counts (CD4(+), CD8(+), and CD16(+)/56(+)), natural killer cell activity (NKCA), and NK phenotypes (CD56(dim)CD16(+), and CD56(bright)CD16(-)). There was a significant increase in total lymphocyte numbers from pre-, to immediately post-exercise (p<0.01), followed by a significant decrease at 2 hours post-exercise (p<0.001). CD4(+) T-cell counts significantly increased from pre-exercise, to 4 hours post- (p<0.05), and 6 hours post-exercise (p<0.01). However, NK (CD16(+)/56(+)) cell numbers decreased significantly from pre-exercise to 4 h post-exercise (p<0.05), to 6 h post-exercise (p<0.05), and to 8 h post-exercise (p<0.01). In contrast, CD56(bright)CD16- NK cell counts significantly increased from pre-exercise to immediately post-exercise (p<0.01). Neutrophil oxidative burst activity did not significantly change in response to exercise, while neutrophil cell counts significantly increased from pre-exercise, to immediately post-exercise (p<0.05), and 2 hours post-exercise (p<0.01), and remained significantly above pre-exercise levels to 8 hours post-exercise (p<0.01). Neutrophil phagocytic function significantly decreased from 2 hours post-exercise, to 6 hours post- (p<0.05), and 24 hours post-exercise (p<0.05). Finally, eosinophil cell counts significantly increased from 2 hours post to 6 hours post- (p<0.05), and 8 hours post-exercise (p<0.05). This is the first study to show changes in immunological variables up to 8 hours post-exercise, including significant NK cell suppression, NK cell phenotype changes, a significant increase in total lymphocyte counts, and a significant increase in eosinophil cell counts all at 8 hours post-exercise. Suppression of total lymphocyte counts, NK cell counts and neutrophil phagocytic function following exercise may be important in the increased rate of URI in response to regular intense endurance training.

Utility of an alternative bicycle commute route of lower proximity to motorised traffic in decreasing exposure to ultra-fine particles, respiratory symptoms and airway inflammation - a structured exposure experiment

Background: Bicycle commuting in an urban environment of high air pollution is known as a potential health risk, especially for susceptible individuals. While risk management strategies aimed to reduce motorised traffic emissions exposure have been suggested, limited studies have assessed the utility of such strategies in real-world circumstances. Objectives: The potential of reducing exposure to ultrafine particles (UFP; < 0.1 µm) during bicycle commuting by lowering interaction with motorised traffic was investigated with real-time air pollution and acute inflammatory measurements in healthy individuals using their typical, and an alternative to their typical, bicycle commute route. Methods: Thirty-five healthy adults (mean ± SD: age = 39 ± 11 yr; 29% female) each completed two return trips of their typical route (HIGH) and a pre-determined altered route of lower interaction with motorised traffic (LOW; determined by the proportion of on-road cycle paths). Particle number concentration (PNC) and diameter (PD) were monitored in real-time in-commute. Acute inflammatory indices of respiratory symptom incidence, lung function and spontaneous sputum (for inflammatory cell analyses) were collected immediately pre-commute, and one and three hours post-commute. Results: LOW resulted in a significant reduction in mean PNC (1.91 x e4 ± 0.93 x e4 ppcc vs. 2.95 x e4 ± 1.50 x e4 ppcc; p ≤ 0.001). Besides incidence of in-commute offensive odour detection (42 vs. 56 %; p = 0.019), incidence of dust and soot observation (33 vs. 47 %; p = 0.038) and nasopharyngeal irritation (31 vs. 41 %; p = 0.007), acute inflammatory indices were not significantly associated to in-commute PNC, nor were these indices reduced with LOW compared to HIGH. Conclusions: Exposure to PNC, and the incidence of offensive odour and nasopharyngeal irritation, can be significantly reduced when utilising a strategy of lowering interaction with motorised traffic whilst bicycle commuting, which may bring important benefits for both healthy and susceptible individuals.

Risk factors for impaired respiratory function during nurse-administered procedural sedation and analgesia in the cardiac catheterisation laboratory : a matched case-control study

Background: Side effects of the medications used for procedural sedation and analgesia in the cardiac catheterisation laboratory are known to cause impaired respiratory function. Impaired respiratory function poses considerable risk to patient safety as it can lead to inadequate oxygenation. Having knowledge about the conditions that predict impaired respiratory function prior to the procedure would enable nurses to identify at-risk patients and selectively implement intensive respiratory monitoring. This would reduce the possibility of inadequate oxygenation occurring. Aim: To identify pre-procedure risk factors for impaired respiratory function during nurse-administered procedural sedation and analgesia in the cardiac catheterisation laboratory. Design: Retrospective matched case–control. Methods: 21 cases of impaired respiratory function were identified and matched to 113 controls from a consecutive cohort of patients over 18 years of age. Conditional logistic regression was used to identify risk factors for impaired respiratory function. Results: With each additional indicator of acute illness, case patients were nearly two times more likely than their controls to experience impaired respiratory function (OR 1.78; 95% CI 1.19–2.67; p = 0.005). Indicators of acute illness included emergency admission, being transferred from a critical care unit for the procedure or requiring respiratory or haemodynamic support in the lead up to the procedure. Conclusion: Several factors that predict the likelihood of impaired respiratory function were identified. The results from this study could be used to inform prospective studies investigating the effectiveness of interventions for impaired respiratory function during nurse-administered procedural sedation and analgesia in the cardiac catheterisation laboratory.

The role of immunoglobulins and their transporters in urogenital Chlamydial infections

Chlamydia trachomatis infections of the male and female reproductive tracts are the world's leading sexually transmitted bacterial disease, and can lead to damaging pathology, scarring and infertility. The resolution of chlamydial infection requires the development of adaptive immune responses to infection, and includes cell-mediated and humoral immunity. Whilst cluster of differentiation (CD)4+ T cells are known to be essential in clearance of infection [1], they are also associated with immune cell infiltration, autoimmunity and infertility in the testes [2-3]. Conversely, antibodies are less associated with inflammation, are readily transported into the reproductive tracts, and can offer lumenal neutralization of chlamydiae prior to infection. Antibodies, or immunoglobulins (Ig), play a supportive role in the resolution of chlamydial infections, and this thesis sought to define the function of IgA and IgG, against a variety of chlamydial antigens expressed during the intracellular and extracellular stages of the chlamydial developmental cycle. Transport of IgA and IgG into the mucosal lumen is facilitated by receptor-mediated transcytosis yet the expression profile (under normal conditions and during urogenital chlamydial infection) of the polymeric immunoglobulin receptor (pIgR) and the neonatal Fc receptor (FcRn) remains unknown. The expression profile of pIgR and FcRn in the murine male reproductive tract was found to be polarized to the lower and upper reproductive tract tissues respectively. This demonstrates that the two receptors have a tissue tropism, which must be considered when targeting pathogens that colonize different sites. In contrast, the expression of pIgR and FcRn in the female mouse was found to be distributed in both the upper and lower reproductive tracts. When urogenitally infected with Chlamydia muridarum, both male and female reproductive tracts up-regulated expression of pIgR and down-regulated expression of FcRn. Unsurprisingly, the up-regulation of pIgR increased the concentration of IgA in the lumen. However, down-regulation of FcRn, prevented IgG uptake and led to an increase or pooling of IgG in lumenal secretions. As previous studies have identified the importance of pIgR-mediated delivery of IgA, as well as the potential of IgA to bind and neutralize intracellular pathogens, IgA against a variety of chlamydial antigens was investigated. The protection afforded by IgA against the extracellular antigen major outer membrane protein (MOMP), was found to be dependent on pIgR expression in vitro and in vivo. It was also found that in the absence of pIgR, no protection was afforded to mice previously immunized with MOMP. The protection afforded from polyclonal IgA against the intracellular chlamydial antigens; inclusion membrane protein A (IncA), inclusion membrane proteins (IncMem) and secreted chlamydial protease-like activity factor (CPAF) were produced and investigated in vitro. Antigen-specific intracellular IgA was found to bind to the respective antigen within the infected cell, but did not significantly reduce inclusion formation (p > 0.05). This suggests that whilst IgA specific for the selected antigens was transported by pIgR to the chlamydial inclusion, it was unable to prevent growth. Similarly, immunization of male mice with intracellular chlamydial antigens (IncA or IncMem), followed by depletion CD4+ T cells, and subsequent urogenital C. muridarum challenge, provided minimal pIgR-mediated protection. Wild type male mice immunized with IncA showed a 57 % reduction (p < 0.05), and mice deficient in pIgR showed a 35 % reduction (p < 0.05) in reproductive tract chlamydial burden compared to control antigen, and in the absence of CD4+ T cells. This suggests that pIgR and secretory IgA (SIgA) were playing a protective role (21 % pIgR-mediated) in unison with another antigen-specific immune mechanism (36 %). Interestingly, IgA generated during a primary respiratory C. muridarum infection did not provide a significant amount of protection to secondary urogenital C. muridarum challenge. Together, these data suggest that IgA specific for an extracellular antigen (MOMP) can play a strong protective role in chlamydial infections, and that IgA targeting intracellular antigens is also effective but dependent on pIgR expression in tissues. However, whilst not investigated here, IgA targeting and blocking other intracellular chlamydial antigens, that are more essential for replication or type III secretion, may be more efficacious in subunit vaccines. Recently, studies have demonstrated that IgG can neutralize influenza virus by trafficking IgG-bound virus to lysosomes [4]. We sought to determine if this process could also traffic chlamydial antigens for degradation by lysosomes, despite Chlamydia spp. actively inhibiting fusion with the host endocytic pathway. As observed in pIgR-mediated delivery of anti-IncA IgA, FcRn similarly transported IgG specific for IncA which bound the inclusion membrane. Interestingly, FcRn-mediated delivery of anti-IncA IgG significantly decreased inclusion formation by 36 % (p < 0.01), and induced aberrant inclusion morphology. This suggests that unlike IgA, IgG can facilitate additional host cellular responses which affect the intracellular niche of chlamydial growth. Fluorescence microscopy revealed that IgG also bound the inclusion, but unlike influenza studies, did not induce the recruitment of lysosomes. Notably, anti-IncA IgG recruited sequestosomes to the inclusion membrane, markers of the ubiquitin/proteasome pathway and major histocompatibility complex (MHC) class I loading. To determine if the protection against C. muridarum infection afforded by IncA IgG in vitro translated in vivo, wild type mice and mice deficient in functional FcRn and MHC-I, were immunized, depleted of CD4+, and urogenitally infected with C. muridarum. Unlike in pIgR-deficient mice, the protection afforded from IncA immunization was completely abrogated in mice lacking functional FcRn and MHC-I/CD8+. Thus, both anti-IncA IgA and IgG can bind the inclusion in a pIgR and FcRn-mediated manner, respectively. However, only IgG mediates a higher reduction in chlamydial infection in vitro and in vivo suggesting more than steric blocking of IncA had occurred. Unlike anti-MOMP IgA, which reduced chlamydial infection of epithelial cells and male mouse tissues, IgG was found to enhance infectivity in vitro, and in vivo. Opsonization of EBs with MOMP-IgG enhanced inclusion formation of epithelial cells in a MOMP-IgG dose-dependent and FcRn-dependent manner. When MOMP-IgG opsonized EBs were inoculated into the vagina of female mice, a small but non-significant (p > 0.05) enhancement of cervicovaginal C. muridarum shedding was observed three days post infection in mice with functional FcRn. Interestingly, infection with opsonized EBs reduced the intensity of the peak of infection (day six) but protracted the duration of infection by 60 % in wild type mice only. Infection with EBs opsonized in IgG also significantly increased (p < 0.05) hydrosalpinx formation in the oviducts and induced lymphocyte infiltration uterine horns. As MOMP is an immunodominant antigen, and is widely used in vaccines, the ability of IgG specific to extracellular chlamydial antigens to enhance infection and induce pathology needs to be considered. Together, these data suggest that immunoglobulins play a dichotomous role in chlamydial infections, and are dependent on antigen specificity, FcRn and pIgR expression. FcRn was found to be highly expressed in upper male reproductive tract, whilst pIgR was dominantly expressed in the lower reproductive tract. Conversely, female mice expressed FcRn and pIgR in both the lower and upper reproductive tracts. In response to a normal chlamydial infection, pIgR is up-regulated increasing secretory IgA release, but FcRn is down-regulated preventing IgG uptake. Similarly to other studies [5-6], we demonstrate that IgA and IgG generated during primary chlamydial infections plays a minor role in recall immunity, and that antigen-specific subunit vaccines can offer more protection. We also show that both IgA and IgG can be used to target intracellular chlamydial antigens, but that IgG is more effective. Finally, IgA against the extracellular antigen MOMP can afford protection, whist IgG plays a deleterious role by increasing infectivity and inducing damaging immunopathology. Further investigations with additional antigens or combination subunit vaccines will enhance our understanding the protection afforded by antibodies against intracellular and extracellular pathogenic antigens, and help improve the development of an efficacious chlamydial vaccine.

Respiratory illness during winter : a cohort study of urban children from temperate Australia

Objective: To examine the epidemiology and burden of respiratory illness during winter in urban children from temperate Australia. Methods: We conducted a cohort study of healthy Melbourne children, aged from 12 to 71 months. Parents kept a daily respiratory symptom diary and recorded resource use when an influenza-like illness (ILI) occurred. Results: One-hundred and eighteen children had 137 ILI episodes over 12 weeks for a rate of 0.53 ILI episodes per child-month (95% CI 0.44-0.61). Risk factors for ILI included younger age, fewer people residing in the household, structured exposure to other children outside the home, and a higher household income. Episodes had a mean duration of 10.4 days with 64 visits to a general practitioner (46.7 GP visits per 100 episodes), 27 antibiotic courses prescribed (19.7 antibiotic courses per 100 episodes), and three overnight hospitalizations (2.2 admissions per 100 episodes). Parents reported an average of 11.7 h excess time spent caring for a child per episode. Conclusions: Respiratory illnesses are a common and largely neglected cause of illness in Australian children. Pathogen-specific data are required to better assess the likely impact of available and developing vaccines and other treatment options.

Acute poststreptococcal glomerulonephritis : public health implications of recent clusters in New South Wales and epidemiology of hospital admissions

Acute poststreptococcal glomerulonephritis (APSGN) is an inflammatory kidney condition that can complicate Group A streptococcal infections. Two clusters of APSGN occurred recently in New South Wales (NSW), Australia; one in a rural town in December 1999 and the other in a Sydney suburb in January 2000. We interviewed carers of the affected children but found no common exposures except three of the Sydney cases were cousins in frequent contact. To assess the probability of these clusters occurring, we analysed hospital admissions for acute glomerulonephritis, as a proxy for APSGN in younger patients. The incidence of acute glomerulonephritis in NSW during 1989/90-1997/8 in residents aged under 20 years was 2(.)2/100000/year (95% CI 2(.)0-2(.)5). Incidence was highest in children aged 5-9 years, boys and Aboriginal children. We found no evidence for other clusters during that period. The recent clusters highlight the continued potential for unexpected future outbreaks of APSGN.

Does a 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine prevent respiratory exacerbations in children with recurrent protracted bacterial bronchitis, chronic suppurative lung disease and bronchiectasis : protocol for a randomised controlled trial

Background Recurrent protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) and bronchiectasis are characterised by a chronic wet cough and are important causes of childhood respiratory morbidity globally. Haemophilus influenzae and Streptococcus pneumoniae are the most commonly associated pathogens. As respiratory exacerbations impair quality of life and may be associated with disease progression, we will determine if the novel 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) reduces exacerbations in these children. Methods A multi-centre, parallel group, double-blind, randomised controlled trial in tertiary paediatric centres from three Australian cities is planned. Two hundred six children aged 18 months to 14 years with recurrent PBB, CSLD or bronchiectasis will be randomised to receive either two doses of PHiD-CV or control meningococcal (ACYW(135)) conjugate vaccine 2 months apart and followed for 12 months after the second vaccine dose. Randomisation will be stratified by site, age (<6 years and >= 6 years) and aetiology (recurrent PBB or CSLD/bronchiectasis). Clinical histories, respiratory status (including spirometry in children aged >= 6 years), nasopharyngeal and saliva swabs, and serum will be collected at baseline and at 2, 3, 8 and 14 months post-enrolment. Local and systemic reactions will be recorded on daily diaries for 7 and 30 days, respectively, following each vaccine dose and serious adverse events monitored throughout the trial. Fortnightly, parental contact will help record respiratory exacerbations. The primary outcome is the incidence of respiratory exacerbations in the 12 months following the second vaccine dose. Secondary outcomes include: nasopharyngeal carriage of H. influenzae and S. pneumoniae vaccine and vaccine-related serotypes; systemic and mucosal immune responses to H. influenzae proteins and S. pneumoniae vaccine and vaccine-related serotypes; impact upon lung function in children aged >= 6 years; and vaccine safety. Discussion As H. influenzae is the most common bacterial pathogen associated with these chronic respiratory diseases in children, a novel pneumococcal conjugate vaccine that also impacts upon H. influenzae and helps prevent respiratory exacerbations would assist clinical management with potential short- and long-term health benefits. Our study will be the first to assess vaccine efficacy targeting H. influenzae in children with recurrent PBB, CSLD and bronchiectasis.

Cough formation in viral infections in children

Using a multidisciplinary approach, Human Respiratory Viral Infections is set at the level between the definitive reference work and an essential clinical manual. Exploring recent advances in human respiratory viral research, the text builds on the basic sciences of epidemiology, virology, molecular biology, and immunology to cover clinical diagnosis, mechanism of pathogenesis, manifestations of disease, impact, treatment, and management strategies.

A FimH inhibitor prevents acute bladder infection and treats chronic cystitis caused by multidrug-resistant uropathogenic Escherichia coli ST131

Background. Escherichia coli O25b:H4-ST131 represents a predominant clone of multidrug-resistant uropathogens currently circulating worldwide in hospitals and the community. Urinary tract infections (UTIs) caused by E. coli ST131 are typically associated with limited treatment options and are often recurrent. Methods. Using established mouse models of acute and chronic UTI, we mapped the pathogenic trajectory of the reference E. coli ST131 UTI isolate, strain EC958. Results. We demonstrated that E. coli EC958 can invade bladder epithelial cells and form intracellular bacterial communities early during acute UTI. Moreover, E. coli EC958 persisted in the bladder and established chronic UTI. Prophylactic antibiotic administration failed to prevent E. coli EC958–mediated UTI. However, 1 oral dose of a small-molecular-weight compound that inhibits FimH, the type 1 fimbriae adhesin, significantly reduced bacterial colonization of the bladder and prevented acute UTI. Treatment of chronically infected mice with the same FimH inhibitor lowered their bladder bacterial burden by >1000-fold. Conclusions. In this study, we provide novel insight into the pathogenic mechanisms used by the globally disseminated E. coli ST131 clone during acute and chronic UTI and establish the potential of FimH inhibitors as an alternative treatment against multidrug-resistant E. coli.