Robert Wilson's research while affiliated with Royal Brompton and Harefield NHS Foundation Trust and other places

To compare the effectiveness of oral moxifloxacin with standard antibiotic therapy in acute exacerbation of chronic bronchitis (AECB). Multicenter, multinational, randomized, double-blind study of two parallel treatment arms. Outpatients >or= 45 years old with stable chronic bronchitis, smoking history of >or= 20 pack-years, two or more AECBs in the previous year, and FEV(1) < 85% of predicted value. Patients were enrolled when in a stable condition, and patients with exacerbations within 12 months of enrollment were randomized. Randomization (stratified on steroid use) between moxifloxacin (400 mg qd for 5 days) and standard therapy (amoxicillin [500 mg tid for 7 days], clarithromycin [500 mg bid for 7 days], or cefuroxime-axetil [250 mg bid for 7 days]). Assessment at enrollment, randomization (Anthonisen type 1 exacerbation), 7 to 10 days after treatment, and monthly until next AECB or up to 9 months. The primary efficacy variable was clinical success (sufficient improvement, no alternative antimicrobial therapy required) 7 to 10 days after therapy. Secondary predefined end points were clinical cure (return to pre-exacerbation status), further antimicrobial use, time to next AECB, and bacteriologic success. Three hundred fifty-four patients received moxifloxacin, and 376 patients received standard therapy. At 7 to 10 days after therapy, clinical success rates were similar in intention-to-treat (ITT) patients (95% confidence interval [CI], - 0.7 to 9.5) and per-protocol (PP) patients (95% CI, - 3.0 to 8.5). Moxifloxacin showed superior clinical cure rates over standard therapy in both ITT patients (95% CI, 1.4 to 14.9) and PP patients (95% CI, 0.3 to 15.6), and higher bacteriologic success in microbiologically valid patients (95% CI, 0.4 to 22.1). Fewer ITT patients required antimicrobials after treatment with moxifloxacin than standard therapy (p < 0.01). Time to next exacerbation was longer with moxifloxacin; median and mean times to new AECBs in ITT patients who did not require any further antibiotics were 131.0 days and 132.8 days in moxifloxacin, and 103.5 days and 118.0 days in standard therapy, respectively (p = 0.03). The occurrence of failure, new exacerbation, or any further antibiotic was less frequent in moxifloxacin-treated patients for up to 5 months of follow-up (p = 0.03). Moxifloxacin was equivalent to standard therapy for clinical success and showed superiority over standard therapy in clinical cure, bacteriologic eradication, and long-term outcomes.

Gemifloxacin is an enhanced-affinity quinolone with potent activity against lower respiratory tract pathogens. The efficacy and safety of a 5-day course of gemifloxacin were compared with those of a standard 7-day regimen of clarithromycin in patients with an acute exacerbation of chronic bronchitis (AECB). The impact of treatment on the long-term (26 weeks) clinical outcome was also assessed. The acute phase of this randomized, double-blind study was performed in 93 centers in 7 countries. Adult patients (age >40 years) with a history of chronic bronchitis and an Anthonisen type 1 acute exacerbation (increased dyspnea, cough, and sputum purulence) were eligible. Patients receiving systemic steroids at a dose of >10 mg prednisone or the equivalent were excluded. Patients were randomized to receive gemifloxacin 320 mg once daily for 5 days or clarithromycin 500 mg twice daily for 7 days. Clinical and bacteriologic response rates were assessed at the end-of-therapy visit (days 8-12), the week 2-3 follow-up visit (days 13-24), and the week 4-5 follow-up visit (days 25-38). The long-term phase (26 weeks), which included US and Canadian participants only, evaluated the proportion of patients who remained free of a recurrence of AECB requiring additional antimicrobial therapy after resolution of the initial episode. Seven hundred twelve patients were randomized to treatment, 351 to gemifloxacin and 361 to clarithromycin. The long-term study included 438 patients, 214 receiving gemifloxacin and 224 receiving clarithromycin. Clinical success rates at the 2-3 week follow-up visit were 85.4% for gemifloxacin and 84.6% for clarithromycin. Bacteriologic success rates were 86.7% for gemifloxacin and 73.1% for clarithromycin. Significantly more patients receiving gemifloxacin than clarithromycin remained free of AECB recurrences (71.0% vs 58.5%, respectively; P = 0.016). Both treatments were well tolerated. In the acute treatment of Anthonisen type 1 AECB, a 5-day course of gemifloxacin was at least as effective as a 7-day regimen of clarithromycin. In this population, significantly more patients receiving gemifloxacin remained free of AECB recurrence after 26 weeks compared with those receiving clarithromycin.

EXECUTIVE SUMMARY This document is an update of the original 1993 statement on community-acquired pneumonia, incorporating new information about bacteriology, patient stratification, diagnostic evaluation , antibiotic therapy, and prevention. The statement includes a summary of the available literature, as well as evidence-based recommendations for patient management, developed by a multidisciplinary group composed of pulmonary, critical care, general internal medicine, and infectious disease specialists. The sections of this document are as follows: an overview of the purpose of our efforts and the methodology used to collect and grade the available data; a review of the likely etiologic pathogens causing community-acquired pneumonia (CAP), including a discussion of drug-resistant Streptococcus pneumoniae (DRSP); a proposed approach to patient stratification for the purpose of predicting the likely etiologic pathogens of different patient populations with CAP; a summary of available and recommended diagnostic studies; suggestions on how to define the need for hospitalization and admission to the intensive care unit (ICU) for patients with CAP; guidelines for antibiotic therapy of CAP, including principles of therapy and specific recommendations for each patient category; an approach to the nonre-sponding patient, as well as a discussion of when to switch to oral therapy and when to discharge an admitted patient with CAP who is responding to initial therapy; and recommendations for the use of pneumococcal and influenza vaccines.

The effects of pathologically relevant concentrations (0.38 to 12.5 microM) of the proinflammatory, Pseudomonas aeruginosa-derived pigment 1-hydroxyphenazine (1-hp) on Ca2+ metabolism and intracellular cyclic AMP (cAMP) in N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP; 1 microM)-activated human neutrophils, as well as on the release of myeloperoxidase (MPO) and elastase from these cells, have been investigated in vitro. Ca2+ fluxes were measured by the combination of a fura-2/AM-based spectrofluorimetric method and radiometric procedures, which together enable distinction between net efflux and influx of the cation, while radioimmunoassay and colorimetric methods were used to measure cAMP and granule enzymes, respectively. Coincubation of neutrophils with 1-hp did not affect intracellular cAMP levels or the FMLP-activated release of Ca2+ from intracellular stores but did retard the subsequent decline in the chemoattractant-induced increase in the concentration of cytosolic free Ca2+. These effects of 1-hp on the clearance of Ca2+ from the cytosol of activated neutrophils were associated with decreased efflux of the cation from the cells and increased release of MPO and elastase, while the delayed store-operated influx of the cation into the cells was unaffected by the pigment. The plasma membrane Ca2+-ATPase rather than a Na+-Ca2+ exchanger appeared to be the primary target of 1-hp. These observations suggest that the proinflammatory interactions of 1-hp with activated human neutrophils are a consequence of interference with the efflux of cytosolic Ca2+ from these cells.

Pseudomonas aeruginosa: is an aerobic Gram-negative rod; it is an opportunistic pathogen that causes disease in patients with impaired host defenses. The defenses may be generally weakened by debility or cancer, or there may be an artificial breach in the defenses, such as an endotracheal tube, or specific humoral or cellular defects, such as seen in cystic fibrosis (CF). P aeruginosa is particularly associated with progressive and ultimately fatal chronic respiratory infection in CF; patients with other forms of bronchiectasis may contract chronic infection that may be impossible to eradicate despite vigorous treatment. P aeruginosa is a significant cause of nosocomial pneumonia, and several risk factors have been identified. Various bacterial products contribute to the pathogenicity of the bacterium. An exuberant chronic inflammatory response causes lung damage in bronchiectasis, whereas the acute inflammatory response may be inadequate in pneumonia, which is associated with bacteremia and high mortality. P aeruginosa is inherently resistant to many antibiotics at concentrations that can be achieved in vivo, and with the exception of some quinolones, the antibiotics to which it is sensitive need to be given intravenously. A semisynthetic penicillin or third-generation cephalosporin is commonly used together with an aminoglycoside. In bronchiectasis, barriers to antibiotic penetration to the site of infection may reduce efficacy, and the use of nebulized antibiotics is an approach that attempts to overcome this. Future research will concentrate on preventative strategies and adjunct therapies to improve outcome. (C) 1999 Lippincott Williams & Wilkins, Inc.

This chapter discusses the interaction of bacteria and their products with tissues in organ culture. Bacterial interactions with mucosal surfaces are thought to be critical in the pathogenesis of infectious disease. In order to colonize a mucosal surface the potential pathogen must overcome local defenses, which might include physical barriers, antibacterial substances, and resident phagocytes. Bacterial products also facilitate the colonization process by compromising mucosal defenses. Bacterial adherence involves specific interactions between structures on the bacterial surface and receptors on the mucosa, although non-specific interactions between bacteria and host cells involving charge and hydrophobicity are also likely. Further, the chapter explains the advantages of organ cultures. Organ cultures maintain the three-dimensional arrangement of folds and grooves present on some epithelial surfaces in vivo and possess a population of leukocytes, which may be important during bacterial infection, although the longevity of this cell population is limited. Organ cultures are sufficiently sensitive to discriminate between the interactions of closely related bacterial strains and hence provide a powerful tool for investigating the effects of bacterial toxins or the importance of bacterial surface structures. The number of bacteria infecting an organ culture can be estimated by culturing homogenates of tissue on agar or by radioisotope techniques. Organ cultures provide a useful method for examining complex bacterial interactions with mucosal surfaces under controlled conditions.

We studied the effect of the nitric oxide synthase (NOS) inhibitor asymmetric dimethyl arginine (ADMA) and the inactive enantiomer N G-methyl-D-arginine (D-NMMA) on Pseudomonas aeruginosa infection of the respiratory mucosa in nasal turbinate organ cultures. We also investigated the effect of P. aeruginosa culture filtrate on the expression of inducible NOS (iNOS) messenger RNA (mRNA) by an epithelial cell line (A549). Organ cultures were preincubated with ADMA (0.1 to 4 x 10(-4) M) or D-NMMA (2 x 10(-4) M) for 30 min prior to bacterial infection. Infected organ cultures (8 h) had significantly (P <= 0.05) greater epithelial damage and fewer ciliated and unciliated cells than did control cultures. There was an increased level of nitrite in the medium feeding infected organ cultures as compared with control cultures. ADMA significantly (P <= 0.05) reduced both bacterially induced epithelial damage and loss of ciliated cells in a concentration-dependent manner. D-NMMA did not influence the effect of P. aeruginosa infection of the mucosa. ADMA, but not D-NMMA, significantly (P <= 0.04) reduced total bacterial numbers adherent to the respiratory mucosa. P. aeruginosa culture filtrates (24 h and 36 h) significantly (P = 0.02) increased iNOS with respect to glyceraldehyde-3-phosphate dehydrogenase mRNA expression. These results show that P. aeruginosa stimulates iNOS expression by a cell line and NO production by an organ culture. ADMA reduces mucosal damage and loss of ciliated cells, which suggests that NO may be a mediator of epithelial damage caused by P. aeruginosa.

Macrolides have properties other than their antibiotic action which may benefit patients with airway infections. We have investigated the effect of dirithromycin (0.125 to 8.0 μg/ml) on the interaction of Haemophilus influenzae with respiratory mucosa in vitro using human nasal epithelium, adenoid tissue, and bovine trachea. Dirithromycin did not affect the ciliary beat frequency of the nasal epithelium or the transport of mucus on bovine trachea, but dirithromycin (1 μg/ml) did reduce the slowing of the ciliary beat frequency and the damage to the nasal epithelium caused by H. influenzae broth culture filtrate. Amoxicillin (2 μg/ml) did not reduce the effects of the H. influenzae broth culture filtrate. H. influenzae infection of the organ cultures for 24 h caused mucosal damage and the loss of ciliated cells. Bacteria adhered to damaged epithelium and to a lesser extent to mucus and unciliated cells. Incubation of H. influenzae with dirithromycin at sub-MICs (0.125 and 0.5 μg/ml) prior to infection of the organ cultures did not reduce the mucosal damage caused by bacterial infection. By contrast, incubation of adenoid tissue with dirithromycin (0.125 to 1.0 μg/ml) for 4 h prior to assembling the organ culture reduced the mucosal damage caused by subsequent H. influenzae infection by as much as 50%. The number of bacteria adherent to the mucosa was reduced, although the tissue that had been incubated with dirithromycin (0.125 and 0.5 μg/ml) did not inhibit bacterial growth. This was achieved by a reduction in the amount of damaged epithelium to which H. influenzae adhered and a reduction in the density of bacteria adhering to mucus. We conclude that dirithromycin at concentrations achievable in vivo markedly reduces the mucosal damage caused by H. influenzae infection due to a cytoprotective effect.

Clinical studies of acute exacerbations of COPD are difficult because of the heterogeneous nature of COPD, diffuse symptoms that can vary spontaneously, and difficulties in defining clinical response both in the short and long term. The role of bacterial infection, and thus use of antibiotics, in COPD is controversial. The available evidence shows that bacterial infection has a significant role in acute exacerbations, but its role in disease progression is less certain. Upper respiratory tract commensals, such as nontypable Haemophilus influenzae, cause most bronchial infections by exploiting deficiencies in the host defenses. Some COPD patients are chronically colonized by bacteria between exacerbations, which represents an equilibrium in which the numbers of bacteria are contained by the host defenses but not eliminated. When an exacerbation occurs, this equilibrium is upset and bacterial numbers increase, which incites an inflammatory response. Neutrophil products can further impair the mucosal defenses, favoring the bacteria, but if the infection is overcome, symptoms resolve. However, if the infection persists, chronic inflammation may cause lung damage. About half of exacerbations involve bacterial infection, but these patients are not easy to differentiate from those who are uninfected, which means that antibiotics have to be given more often than is strictly necessary. Further research is needed to characterize those patients in whom bacterial infection has a more important role.