Acute Infectious Exacerbations Research Articles

Measurement of parasternal intercostal electromyogram during an infective exacerbation in patients with cystic fibrosis.

The parasternal intercostal muscle electromyogram (sEMGpara) is a measure of neural respiratory drive and reflects lung disease severity in stable cystic fibrosis (CF). The aim of the study was to measure sEMGpara in acute infective exacerbations of CF and compare changes in sEMGpara with those in conventional lung function measures. 12 patients with CF admitted to hospital with an acute chest infection were studied. There was a significant reduction in mean ± SD sEMGpara (ΔsEMGpara -38 ± 19%, p<0.001) between admission and discharge. Spirometery also improved significantly from admission to discharge; Δforced expiratory volume in 1 s % predicted 39 ± 30%, p<0.001 and Δvital capacity % pred 22 ± 18%, p<0.001. sEMGpara has potential value as a nonvolitional measure of change in respiratory function in CF.

Effects of therapy with systemic glucocorticosteroids on endothelial function and hemostasis in patients with infective exacerbation of chronic obstructive pulmonary disease

Summary. Changes in basic parameters of vascular endothelial function and thrombinaemia were analyzed in 111 patients with acute infective exacerbation of COPD upon therapy with systemic steroids. In acute infective exacerbation of COPD, increased levels of endotelin-1 and homocysteine as endothelial dysfunction markers, substantial increase in plasma D-dimer level and changes in thrombocyte aggregation were found. Treatment with systemic steroids led to decreasing in endotelium-1 and D-dimer levels which directly related to C-reactive protein. In stable COPD, high D-dimer level persisted that was considered as thrombogenic and thromboembolic risks in COPD patients with cardiovascular comorbidity.

Treatment of Chronic Rhinosinusitis With Antibiotics

Chronic rhinosinusitis is among the most common chronic diseases. It presents a major financial burden to the health care system [1], not to mention the burden of personal suffering and morbidity to the patient with debilitating chronic rhinosinusitis. Chronic rhinosinusitis is not a uniform entity, and its clinical presentations and etiologies may vary. Environmental factors predispose patients to chronic rhinosinusitis, but allergens for allergic patients or other environmental irritants may be ill defined. Chronic rhinosinusitis may present with nasal polyposis that sometimes occurs in conjunction with asthma and aspirin insensitivity. Traditionally, the disease is classified as chronic rhinosinusitis either with or without polyposis, a distinction that may reflect differences in the cytokines between the 2 conditions. However, the difference between these 2 may not always be clinically obvious because some patients present with polypoid thickening of the mucosa in the middle nasal meatus without obvious nasal polyps. Chronic rhinosinusitis may also occur with comorbidities other than allergy and asthma, such as immune deficiencies and disorders of the mucociliary clearance. Because of the variability of the etiology of chronic rhinosinusitis, it is challenging to define. The American Academy of Otolaryngology—Head and Neck Surgery published in 2007 a clinical practice guideline that defines chronic rhinosinusitis by clinical signs, symptoms, and objective findings [2]. According to the guideline, chronic rhinosinusitis is defined by having for 12 weeks or longer$2 of the following signs and symptoms: (1) mucopurulent drainage (anterior, posterior, or both); (2) nasal obstruction (congestion); (3) facial pain, pressure, or fullness; or (4) decreased sense of smell. In addition, objective findings of nasal inflammation are needed for the diagnosis. These are $1 of the following: (1) purulent (not clear) mucus or edema in the middle meatus or ethmoid region, (2) polyps in the nasal cavity or the middle meatus, or (3) radiographic imaging showing inflammation of the paranasal sinuses. In an office setting, the first 2 findings can be evaluated by nasal endoscopy. The preceding definition of chronic rhinosinusitis requires neither a microbiologic diagnosis nor the isolation of a pathogen in the nasal sinuses. For example, at present it is often unknown in a given patient whether nasal polyposis is actually triggered by a microbe, microbial superantigen, or an environmental agent, or whether there is any foreign triggering agent in the first place. Nevertheless, chronic rhinosinusitis may involve biofilm formation that is accompanied by acute exacerbations of sinus infection [3]. The cornerstones of treatment of chronic rhinosinusitis are relief of inflammation of the nasal mucosa, facilitation of drainage of secretions, and if possible, restoration of mucociliary clearance within the sinuses [4]. The rationale in relieving inflammation is to reduce swelling of the mucosa, which may then open obstructed sinus cavities and improve drainage. Topical corticosteroids are widely used for this purpose. Short courses of oral steroids are used to reduce the size of nasal polyps and in selected cases to relieve overt inflammation in the nasal mucosa. Saline nasal irrigation is also widely used in patients with chronic rhinosinusitis [5]. Self-administered saline irrigation helps to remove crusts, mucus, and irritants. Many patients report that saline irrigation improves their symptoms. It follows that an ideal treatment for a biofilm disease would be to remove the biofilm mechanically, which could at least to some extent be accomplished by saline irrigation. Endoscopic sinus surgery is reserved for patients who fail to benefit from medical therapy. Here again the aim is often to improve drainage from the nasal sinuses. A common reason for surgery is to remove nasal polyps that do not respond to medical therapy. Received 31 August 2011; accepted 6 September 2011; electronically published 22 November 2011. Correspondence: Petri Mattila, MD, PhD, Department of Otorhinolaryngology, Helsinki University Central Hospital, PO Box 220, FI-00029 HUS, Helsinki, Finland (petri.mattila@hus.fi). Clinical Infectious Diseases 2012;54(1):69–70 The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@ oup.com. DOI: 10.1093/cid/cir757

Comparison of Methods To Test Antibiotic Combinations against Heterogeneous Populations of Multiresistant Pseudomonas aeruginosa from Patients with Acute Infective Exacerbations in Cystic Fibrosis

Multiresistant Pseudomonas aeruginosa isolates can chronically infect patients with cystic fibrosis. Acute infective exacerbations are treated with combinations of two antipseudomonal antibiotics. Patients may respond clinically even if the bacteria are resistant, possibly due to antimicrobial synergy. The challenge for testing for synergy in vitro is that there is no standardized method, and the antibiotic susceptibility in a population of P. aeruginosa isolates in a single sputum sample can vary. We therefore compared (i) antibiotic combinations with different examples of resistant bacteria from the same sputum sample and (ii) the results of synergy testing by different methods. Antibiotic synergy was tested by using resistant P. aeruginosa isolates recovered from sputum samples taken just before the start of treatment for an acute infective exacerbation. Several examples of each morphotype of P. aeruginosa were tested by cidal checkerboard, time-kill curve, and multiple-combination bactericidal testing. The isolates were typed by pulsed-field gel electrophoresis (PFGE). The results were compared with the clinical and microbiological responses to 14 days of antibiotic treatment. Forty-four resistant isolates from nine patients were tested. Some P. aeruginosa isolates with the same morphotype and PFGE pulsotype had different results by synergy testing. There was a poor correlation between the results of the different methods of synergy testing, and no one method would have predicted the response to treatment in all patients. The in vitro effects of antibiotic combinations against different isolates from the same sputum sample can vary, and the results depend on the methodology used. The role of combination testing for the treatment of antibiotic-resistant P. aeruginosa in acute exacerbations of chronic infection in patients with cystic fibrosis needs to be reviewed.

Pneumococcal vaccines for children and adults with bronchiectasis.

Bronchiectasis is increasingly recognized as a major cause of respiratory morbidity especially in developing countries. Even in affluent countries, bronchiectasis is increasingly seen in some community subsections (e.g. Aboriginal communities) and occurs as a comorbidity and disease modifier in respiratory diseases such as chronic obstructive pulmonary disease (COPD). Respiratory exacerbations in people with bronchiectasis are associated with reduced quality of life, accelerated pulmonary decline, hospitalisation and even death. Conjugate pneumococcal vaccine is part of the routine infant immunisation schedule in many countries. Current recommendations for additional pneumococcal vaccination include children and adults with chronic suppurative disease. To evaluate the effectiveness of pneumococcal vaccine as routine management in children and adults with bronchiectasis in (a) reducing the severity and frequency of respiratory exacerbations and (b) pulmonary decline. The Cochrane Register of Controlled Trials (CENTRAL), the Cochrane Airways Group Specialised Register, MEDLINE and EMBASE databases were searched by the Cochrane Airways Group. Pharmaceutical manufacturers of pneumococcal vaccines were also contacted. The latest searches were performed in November 2008. All randomised controlled trials that utilised pneumococcal vaccine on children and adults with bronchiectasis. All types of pneumococcal vaccines were included. Results of searches were reviewed against pre-determined criteria for inclusion. No eligible trials were identified and thus no data was available for analysis. One small non-randomised controlled trial in children was reported. One randomised controlled open label study in 167 adults with chronic lung disease (bronchiectasis and other diseases associated with bronchiectasis) compared 23-valent pneumococcal (PV) and influenza vaccine with influenza vaccine alone (control group). The study found a significant reduction in acute infective respiratory exacerbations in the PV group compared to the control group, OR=0.48 (95%CI 0.26, 0.88); number needed to treat to benefit = 6 (95%CI 4, 32) over 2-years. There was however no difference in episodes of pneumonia between groups and no data on pulmonary decline was available. In another study, a benefit in elimination of Strep. pneumoniae in the sputum was found in a non-randomised trial in children but no clinical effect was described. Current but limited evidence support the use of 23-valent pneumococcal vaccine as routine management in adults with bronchiectasis. Circumstantial evidence also support the use of routine 23-valent pneumococcal vaccination in children with bronchiectasis. Further randomised controlled trials examining the efficacy of this intervention using various vaccine types in different age groups are needed. There is no data on the efficacy of pneumococcal vaccine on pulmonary decline. With the lack of evidence in how often the vaccine should be given, it is recommended that health providers adhere to national guidelines.

ORAL IMMUNOTHERAPY IN PREVENTING INFECTIVE EXACERBATIONS OF COPD

PURPOSE: Respiratory tract infection is the commonest cause of exacerbation of COPD. It is necessary to explore new alternatives for the prevention of infection responsible for acute exacerbations. Our aim was to study the role of oral immunostimulating therapy (OIST) in acute infective exacerbations of COPD. OIST is the product of alkaline proteolysis from lysates of six common bacteria implicated in infective exacerbations of COPD.

Clinical studies of garenoxacin

Garenoxacin mesylate hydrate (GRN) is a novel oral des-fluoro(6) quinolone with potent antimicrobial activity against common respiratory pathogens, including resistant strains. It has favourable pharmacokinetic profiles for maximum plasma concentration ( C max) and area under the plasma concentration–time curve (AUC), with good penetration into sputum and otorhinolaryngological tissues. In clinical studies, the efficacy of GRN ranged from 92% to 96% in patients with bacterial pneumonia, mycoplasma pneumonia, chlamydial pneumonia and acute bronchitis. Efficacy was 85% in acute infectious exacerbations of chronic respiratory disease and ranged from 81% to 95% in otorhinolaryngological infections. Bacterial eradication was 90.9% for Staphylococcus aureus, 99.2% for Streptococcus pneumoniae, 98.2% for Haemophilus influenzae, 96.6% for Moraxella catarrhalis, 100% for penicillin-resistant S. pneumoniae, 100% for β-lactamase-negative ampicillin-resistant H. influenzae and β-lactamase-positive H. influenzae, and 96.2% for β-lactamase-positive M. catarrhalis. Garenoxacin concentrations in plasma and tissues using GRN 400 mg once a day were higher than the MIC 90 (minimum inhibitory concentration for 90% of the organisms) of major causative pathogens. The trough concentration ( C min) in plasma was 1.92 μg/mL, a level that was higher than the mutant prevention concentration, suggesting that GRN is unlikely to induce the selection of resistant strains during treatment. In clinical studies, GRN did not produce class adverse effects of fluoroquinolones such as QTc prolongation, blood glucose abnormality or severe liver damage. No serious adverse events were observed during the trials. The results indicate that GRN is very effective in treating patients with upper and lower respiratory tract infections.

Pharmacology and clinical efficacy of erdosteine in chronic obstructive pulmonary disease

Erdosteine is a multimechanism, mucolytic agent that decreases the sputum viscoelastic properties and bacterial adhesion to the cell membrane, endowed with bronchial anti-inflammatory activity and a scavenging effect on free oxidant radicals. Erdosteine is a prodrug and metabolite I is the active metabolite of erdosteine owing to its free thiol group. In acute infective exacerbation of chronic bronchitis or chronic obstructive pulmonary disease (COPD), adding erdosteine to standard treatment significantly modified the outcome by improving the symptoms and reducing the length of disease. Furthermore, erdosteine has shown a synergism with antibiotic therapy. In stable COPD patients, long-term treatment with erdosteine had a protective effect against exacerbations by reducing the rate of exacerbations and hospitalizations in the study period. A total of 8 months of treatment with erdosteine significantly improved the patients’ health status and preserved lung function. Erdosteine has a scavenging effect on free oxidant radicals by a direct and indirect antioxidative effect and the final result is a protective effect against tissue damage, as demonstrated in animal studies. In view of the persuasive evidence that oxidative stress is important in the pathophysiology of COPD, erdosteine appears to be a logical approach to therapy.

Acute cough

Acute cough

Evaluation of Once Daily Tobramycin Versus the Traditional Three Time Daily for the Treatment of Acute Pulmonary Exacerbations in Adult Cystic Fibrosis Patients

Once daily tobramycin is convenient to use and achieves higher tissue levels that should kill Pseudomonas aeruginosa more rapidly. Small trials of OD compared with TDS aminoglycosides in CF patients have shown no dif-ference in efficacy or toxicity. No one has looked in detail at the impact on sputum microbiology. In a prospective, randomized study at Papworth Hospital, UK, we compared OD with TDS tobramycin, each plus a second anti-pseudomonal, for the treatment of acute infective exacer-bation in 15 adult cystic fibrosis patients colonized with Pseudomonas aeruginosa. Using the patients as their own control, the same individuals received the alternate treat-ment regime for the next exacerbation. We aimed to com-pare the clinical and bacteriological efficacy, toxicity&gt;, and the effects on susceptibility of the organism among patients in both treatment groups. Isolates were identified, and the Minimum Inhibitory Concentration (MIC) of the antibi-otic in each patient was performed. Patients were assessed for clinical improvement, toxicity and the total viable count in their sputum on days 0\ 7 and 14. In both treatment groups there was a significant clinical improvement, and toxicity did not occur in either group. There was no differ-ence in clinical outcome, adverse events, or time to the next exacerbation. No difference was seen in the selection of antibiotic resistance. OD tobramycin appeared more ef-fective in reducing the number of bacteria in the group overall at day 7 and in two individuals, at day 14.

Twice-weekly azithromycin reduces the incidence of acute infectious respiratory exacerbations in patients with bronchiectasis,

Twice-weekly azithromycin reduces the incidence of acute infectious respiratory exacerbations in patients with bronchiectasis,

Phenotypic variability of Pseudomonas aeruginosa in sputa from patients with acute infective exacerbation of cystic fibrosis and its impact on the validity of antimicrobial susceptibility testing

To investigate the variability in antimicrobial susceptibility of Pseudomonas aeruginosa from sputa of patients with cystic fibrosis, to compare testing individual colonies of the same morphotype either separately or combined and to study the reproducibility of testing antimicrobial susceptibility within and between laboratories. One hundred and one sputa were cultured. Four colonies of each P. aeruginosa morphotype were suspended. Susceptibility to 12 agents by disc diffusion was tested individually or by pooling the four suspensions. A sputum sample containing four morphotypes of one genotype of P. aeruginosa was used to study reproducibility. Susceptibility was tested in duplicate by eight biomedical scientists in one laboratory and by routine procedures in seven different laboratories. There was a mean of four morphotypes of P. aeruginosa per sputum and three antibiograms per morphotype. In some cases, all four colonies of a single morphotype had different antibiograms. The susceptibility profiles of single isolates of P. aeruginosa correlated poorly with pooled cultures, with the pooled tests missing resistance. Results from one sample tested in duplicate by eight biomedical scientists in one laboratory and in seven other laboratories did not correlate well. The wide range of zone sizes in disc diffusion tests illustrated the variation in susceptibility of 48 colonies from one sputum sample. The role of conventional antimicrobial susceptibility testing is questionable once P. aeruginosa chronically infects the cystic fibrosis lung. A range of susceptibility patterns is seen, even within a morphotype. Routine test results are not reproducible and underestimate resistance.

Role of oral fluoroquinolones in patients with respiratory diseases

The characteristics of recently developed oral fluoroquinolones include their broad spectrum involving gram-positive/gram-negative bacteria and atypical pathogens, potent antimicrobial activity against Pneumococcus, rapid tissue/sputum transfer, prolonged half-life, and reduction of their interaction with other agents. However, it has been reported that the common use of oral fluoroquinolones increases the number of fluoroquinolone-resistant bacterial strains. We review the appropriate use of these agents in patients with respiratory infections. In most cases, upper respiratory inflammation is a viral infection. Generally, antimicrobial agents are not necessary, and should not be administered. In Japan, a large number of antimicrobial agents, especially quinolones, are frequently prescribed to treat upper respiratory infection. This tendency must not be corrected. With respect to treatment for community-acquired pneumonia, it is controversial whether oral fluoroquinolones should be prescribed under various guidelines. In elderly patients and those with an underlying disease, oral fluoroquinolones may be a first-choice treatment at the outpatient clinic, because it is difficult to differentiate atypical pneumonia from bacterial pneumonia, and because the risk of drug-resistant Pneumococcus or gram-negative bacteria is high. With respect to treatment for hospital-acquired pneumonia, oral fluoroquinolones are recommended for patients with moderate or mild conditions without risk factors under the Guidelines established by the Japanese Respiratory Society. Bacteria causing acute infectious exacerbation in patients with chronic pulmonary diseases include gram-positive/gram-negative bacteria and anaerobic bacteria. Therefore, oral fluoroquinolones may be the most appropriate treatment for such patients. New oral fluoroquinolones show potent antimicrobial activity against tubercle bacillus, and may also be effective for infection with bacteria resistant to standard antitubercular agents. It may be controversial whether these agents should be indicated for atypical acid-fast bacterial infection.

The MOSAIC Study: Redefining Clinical Success in Patients With AECB

PURPOSE: The MOSAIC study: A multicenter, multinational, randomized, double-blind study to compare moxifloxacin oral tablets to standard oral antibiotic regimen given as first-line therapy in outpatients with acute infective exacerbations of chronic bronchitis. The MOSAIC study is unique and improved in its design. Specifically, it includes: established pre-exacerbation baseline; multicomparator, randomized, double-blind study; and short- and long-term follow-up. MOSAIC has been submitted to CHEST for publication and is currently under review.

Dornase alfa in early cystic fibrosis lung disease.

Leukocytes that infiltrate cystic fibrosis (CF) sputum as a result of infection have long been known to liberate large amounts of DNA, which increases sputum viscosity and promotes the cycle of chronic lung infection and inflammation that ultimately leads to respiratory failure and death. It was only recently recognized that this vicious cycle begins in infancy, and that architectural damage to CF lungs is detectable even in children with normal pulmonary function tests. Dornase alfa cleaves DNA and improves sputum viscosity in CF. Although its efficacy in reducing the risk of acute infectious exacerbations and improving pulmonary function has been recognized for a decade, there is growing interest in its potential for long-term benefit in young patients with mild lung function abnormalities. The Pulmozyme Early Intervention Trial (PEIT) study demonstrated that dornase alfa reduces the risk of pulmonary exacerbations requiring i.v. antibiotic treatment by 34% and improves forced expiratory flow at 25-75% of forced vital capacity (FEF(25-75)), mid-expiratory flow at 50% of forced vital capacity (MEF), and forced expired volume in 1 sec (FEV(1)) over a 2-year period in CF patients with almost normal lung function. A post hoc subgroup analysis suggests that the magnitude of pulmonary function test (PFT) changes may vary, depending on the initial degree of lung function impairment, but that the reduction in exacerbations appears to be a consistent benefit. These results support the current view that CF patients benefit from intervention early in the course of their lung disease.

Iron and Its Relation to Immunity and Infectious Disease

The continuing unresolved debate over the interaction of iron and infection indicates a need for quantitative review of clinical morbidity outcomes. Iron deficiency is associated with reversible abnormalities of immune function, but it is difficult to demonstrate the severity and relevance of these in observational studies. Iron treatment has been associated with acute exacerbations of infection, in particular, malaria. Oral iron has been associated with increased rates of clinical malaria (5 of 9 studies) and increased morbidity from other infectious disease (4 of 8 studies). In most instances, therapeutic doses of oral iron were used. No studies in malarial regions showed benefits. Knowledge of local prevalence of causes of anemia including iron deficiency, seasonal malarial endemicity, protective hemoglobinopathies and age-specific immunity is essential in planning interventions. A balance must be struck in dose of oral iron and the timing of intervention with respect to age and malaria transmission. Antimalarial intervention is important. No studies of oral iron supplementation clearly show deleterious effects in nonmalarious areas. Milk fortification reduced morbidity due to respiratory disease in two very early studies in nonmalarious regions, but this was not confirmed in three later fortification studies, and better morbidity rates could be achieved by breast-feeding alone. One study in a nonmalarious area of Indonesia showed reduced infectious outcome after oral iron supplementation of anemic schoolchildren. No systematic studies report oral iron supplementation and infectious morbidity in breast-fed infants in nonmalarious regions.

Hydrogen peroxide and nitric oxide in exhaled air of children with cystic fibrosis during antibiotic treatment

Cystic fibrosis (CF) patients characteristically have severe chronic airway inflammation associated with bacterial infection. A noninvasive marker of airway inflammation could be a useful guide to treatment of CF lung disease. The aim of this study was to assess whether measurement of hydrogen peroxide (H2O2) and nitric oxide (NO) in exhaled air can serve to monitor the effect of treatment with antibiotics in CF-children with acute infective pulmonary exacerbations. Sixteen CF-patients (mean age 12.3 yrs) with exacerbation of their lung infection were treated with intravenous antibiotics in an uncontrolled study. During treatment, H2O2 in exhaled air condensate was measured twice a week. In addition, serial NO measurements were performed in nine patients. During antibiotic treatment the median H2O2 concentration in exhaled air condensate decreased significantly from 0.28 microM (range 0.07-1.20 microM) to 0.16 microM (range 0.05-0.24 microM, p=0.002) and the mean forced expiratory volume in one second significantly increased from 55% predicted to 75% pred (p=0.001). In individual subjects, changes of H2O2 and FEV1 between pairs of serial measurements correlated weakly (p=0.08). Data on exhaled NO were inconclusive; exhaled NO did not change systematically during treatment. It is concluded that cystic fibrosis patients with an acute pulmonary exacerbation have abnormally high concentrations of hydrogen peroxide, but not of nitric oxide, in exhaled air, which decrease during intravenous antibiotic treatment. Further controlled studies should establish if exhaled hydrogen peroxide, may serve as a noninvasive parameter of airway inflammation to guide antibiotic treatment in cystic fibrosis lung disease.

Epidemiology of Chronic Bronchitis and Acute Infective Exacerbations of Chronic Bronchitis

Acute exacerbations of chronic bronchitis (AECBs) are one of the major causes of morbidity and mortality in the United States, resulting in significant cost to the health care system. Epidemiological information on chronic bronchitis is abundant and has been collected in most industrialized countries. The epidemiology of AECB, however, is less forthcoming. The causes of AECB are multifactorial and include environmental pollutants, allergic responses, and viral and bacterial infections. The role of bacterial infection in AECB is controversial but is believed to account for half of AECB. Because the medical and economic implications of treatment failure in these patients are substantial, an aggressive approach to stratify and treat these patients is necessary. Epidemiological data on chronic bronchitis and acute infective exacerbations of chronic bronchitis will allow us to more precisely define the role of bacterial infection in AECB, and this information may help guide antimicrobial therapy.

Chronic Obstructive Pulmonary Disease and Infection

Patients with chronic obstructive pulmonary disease (COPD) are especially prone to bronchial colonization and acute infection, including acute infectious exacerbations and community-acquired as well as nosocomial pneumonia. Bacterial colonization may promote bronchial inflammation, predispose to acute exacerbations, and thereby contribute to respiratory decline. Haemophilus influenzae and Streptococcus pneumoniae are the most frequently encountered pathogens in both stable disease as well as acute exacerbations. The role of bacterial infection in acute exacerbations remains subject to controversy; however, evidence is in favor of regular antimicrobial treatment in patients with severe exacerbations. COPD represents an important risk factor for community-acquired pneumonia (CAP). Microbial patterns for CAP differ from exacerbations in that S. pneumoniae and “atypical” bacterial pathogens predominate. Similarly, COPD has been recognized as an important risk factor for nosocomial pneumonia. Initial empiric antimicrobial treatment of both severe acute exacerbations and pneumonia should take into account regional drug resistance rates to penicillin of S. pneumoniae and should cover Gram-negative enteric bacilli. The additional treatment of atypical bacterial pathogens and Pseudomonas aeruginosa should be considered individually.

Exhaled nitric oxide is not elevated in the inflammatory airways diseases of cystic fibrosis and bronchiectasis.

Airways inflammation has been associated with increased nitric oxide (NO) in the exhaled breath. It was, therefore, questioned whether exhaled NO could act as an indicator of the severity of airways inflammation in the chronic suppurative lung diseases cystic fibrosis (CF) and bronchiectasis. NO levels in a single exhalation were measured using a chemiluminescence analyser. Thirty-six patients with CF and 16 with bronchiectasis were studied and compared with 22 normal subjects and 35 asthmatic patients. All subjects were nonsmokers and all measurements were made when patients were clinically stable. In addition, exhaled NO was measured in 10 CF patients at the time of onset of an acute infective exacerbation and followed for 7 days during the treatment of the exacerbation in eight of the 10 patients. No significant differences were found in NO levels in patients with CF or bronchiectasis compared with normals (median 4.0, 5.5 and 4.4 parts per billion (ppb), respectively), but all were lower than in asthma patients (10.4 ppb). The NO levels in the CF patients at time of exacerbation were not increased and did not change during treatment. These data show that nitric oxide levels in the exhaled breath of patients with chronic suppurative lung diseases, in contrast to asthma, are not elevated, despite the presence of substantial airways inflammation. Possible explanations include poor diffusion of nitric oxide across increased and viscous airway secretions, removal of nitric oxide by reaction with reactive oxygen species in the inflamed environment and failure of upregulation of epithelial inducible nitric oxide synthase in chronic suppurative conditions.