Effects of Tham Nasal Alkalinization on Airway Microbial Communities: A Pilot Study in Non-CF and CF Adults.

OBJECTIVES: In cystic fibrosis (CF), loss of CFTR-mediated bicarbonate secretion reduces the airway surface liquid (ASL) pH causing airway host defense defects. Aerosolized sodium bicarbonate can reverse these defects, but its effects are short-lived. Aerosolized tromethamine (THAM) also raises the ASL pH but its effects are much longer lasting. In this pilot study, we tested the hypothesis that nasally administered THAM would alter the nasal bacterial composition in adults with and without CF. METHODS: Subjects (n = 32 total) received intranasally administered normal saline or THAM followed by a wash out period prior to receiving the other treatment. Nasal bacterial cultures were obtained prior to and after each treatment period. RESULTS: At baseline, nasal swab bacterial counts were similar between non-CF and CF subjects, but CF subjects had reduced microbial diversity. Both nasal saline and THAM were well-tolerated. In non-CF subjects, nasal airway alkalinization decreased both the total bacterial density and the gram-positive bacterial species recovered. In both non-CF and CF subjects, THAM decreased the amount of Corynebacterium accolens detected, but increased the amount of Corynebacterium pseudodiphtheriticum recovered on nasal swabs. A reduction in Staphylococcus aureus nasal colonization was also found in subjects who grew C. pseudodiphtheriticum. CONCLUSIONS: This study shows that aerosolized THAM is safe and well-tolerated and that nasal airway alkalinization alters the composition of mucosal bacterial communities. CLINICAL TRIAL REGISTRATION: NCT00928135 (https://clinicaltrials.gov/ct2/show/NCT00928135).

Randomized controlled study of aerosolized hypertonic xylitol versus hypertonic saline in hospitalized patients with pulmonary exacerbation of cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) lung disease is characterized by chronic bacterial infection and recurrent pulmonary exacerbations. Xylitol is a 5-carbon sugar that can lower the airway surface salt concentration and augment innate immunity. We examined the safety and efficacy of aerosolized xylitol use for 2 weeks in subjects hospitalized with a pulmonary exacerbation of CF. METHODS: In a 2-week study, 60 subjects with cystic fibrosis and FEV1 > 30% predicted were enrolled to receive aerosolized 7% hypertonic saline (4 ml) or 15% xylitol (5 ml) twice a day for 14 days. Outcomes assessed included change from baseline in FEV1% predicted, change in sputum microbial density, revised CF quality of life questionnaire including the respiratory symptom score, time to next hospitalization for a pulmonary exacerbation, and frequency of adverse events. RESULTS: 59 subjects completed the study (one subject in the saline group withdrew before any study product administration). No significant differences were noted between the 2 arms in mean changes in lung function, sputum microbial density for Pseudomonas aeruginosa and Staphylococcus aureus, body weight, quality of life, and frequency of adverse events. CONCLUSIONS: Aerosolized hypertonic xylitol was well-tolerated among subjects hospitalized for CF pulmonary exacerbation. Future studies examining efficacy for long term use in patients with CF lung disease would be worthwhile. The clinical trial registration number for this study is NCT00928135.

Altered Treg and cytokine responses in RSV-infected infants.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in children under 1 y of age in the USA. The host immune response is believed to contribute to RSV-induced disease. We hypothesize that severe RSV infection in infants is mediated by insufficient regulation of the host immune response of regulatory T cells (Tregs) resulting in immunopathology. METHODS: Blood and nasal aspirates from 23 RSV-infected and 17 control infants under 1 y of age were collected. Treg frequencies were determined by flow cytometry from peripheral blood mononuclear cells. Analysis of 24 cytokines was measured by multiplex assay on nasal aspirates. RESULTS: We demonstrate that the frequency of activated Tregs is significantly reduced in the peripheral blood of RSV-infected infants compared with age-matched controls. Surprisingly, T helper (Th)17 related cytokines including interleukin (IL)-1ß, IL-17A, and IL-23 were associated with a reduction in clinical symptoms of respiratory distress. In addition, the amount of IL-33 protein in nasal washes, a cytokine important in maintaining Treg homeostasis in mucosal tissues, was decreased in RSV-infected children. CONCLUSION: These results suggest that decreased Treg numbers and an inability to properly control the host inflammatory response results in severe RSV infection.

Noninvasive positive pressure ventilation in subjects with stable COPD: a randomized trial.

BACKGROUND: The use of domiciliary noninvasive positive pressure ventilation (NPPV) in stable chronic obstructive pulmonary disease (COPD) with chronic hypercapnic respiratory failure has yielded variable effects on survival, quality of life, and dyspnea. We hypothesized that use of NPPV in stable COPD and partial pressure of carbon dioxide (PaCO2) <52 mmHg might result in improvement in quality of life and dyspnea. METHODS: Thirty patients with stable COPD (forced expiratory volume in the first second <50% predicted and PaCO2 <52 mmHg) were prospectively randomized to receive domiciliary NPPV (bilevel positive airway pressure, 15/5 cm H2O) or usual therapy for 6 months. Measurements were made at baseline, 6 weeks, 3 months, and 6 months. Primary outcomes were quality of life as assessed by the Chronic Respiratory Disease Questionnaire (CRQ), and dyspnea as measured by the Transitional Dyspnea Index (TDI). RESULTS: Fifteen subjects in the NPPV arm and 12 controls completed all the study visits. At 6 weeks and 3 months, the NPPV arm showed significant improvement in TDI total score. However, this effect persisted only in the TDI-Task at 6 months (P=0.03). NPPV use was associated with a small improvement in the CRQ-Mastery domain (0.6 versus -0.1, P=0.04). The arterial partial pressure of oxygen (PaO2) in the control arm worsened over the period of the study, whereas it remained stable in the NPPV arm (change -7.2 mmHg versus +2.1 mmHg, respectively, P=0.02). CONCLUSION: NPPV resulted in a small improvement in quality of life indices in stable COPD patients with PaCO2 <52 mmHg. Future larger studies will clarify the role of NPPV in this stable subgroup of patients with COPD.

Safety assessment of nebulized xylitol in beagle dogs.

Xylitol, a potential cystic fibrosis treatment, lowers the salt concentration of airway surface liquid and enhances innate immunity of human airways. The study objective was to evaluate the potential toxicity/recovery from a 14-consecutive day (7 days/week), facemask inhalation administration of nebulized xylitol solution in Beagle dogs. Aerosolized xylitol was generated through three Aerotech II nebulizers operating at approximately 40 psi driving pressure. Test article groups were exposed to the same concentration of aerosolized xylitol for 1, 0.5, or 0.25 h for the high, mid, and low exposures, respectively. A control group was exposed for 1 h to a nebulized normal saline solution. Animals were sacrificed the day following the last exposure or subsequently after 14 non-exposure days. Study endpoints included clinical observations, body weights, ophthalmology, and physical examinations, food consumption, clinical pathology, urinalyses, organ weights, and histopathology. Mean xylitol aerosol concentrations for all groups were approximately 3.5 mg/l. Mean total deposited doses to the pulmonary region were estimated as 21, 11, and 5 mg/kg, for the high-, mid-, and low-exposure groups, respectively. All dogs survived to the scheduled necropsy. No treatment-related findings were observed due to xylitol exposure in any end point examined. Lung findings (mild interstitial infiltration, macrophage hyperplasia, alveolitis, and bronchitis) were consistent among exposed and control groups. No exposure-related effect of xylitol in any parameter assessed was seen during or after the 14-day exposure in Beagle dogs. The No Observed Effect Level was the high-exposure level and suggests that inhaled xylitol is safe for clinical administration.

Inhaled hypertonic saline in adults hospitalised for exacerbation of cystic fibrosis lung disease: a retrospective study.

BACKGROUND: Inhaled hypertonic saline (HTS) improves quality of life and reduces pulmonary exacerbations when given long term in patients with cystic fibrosis (CF). While increasingly being offered for acute pulmonary exacerbations, little is known about the efficacy in this setting. OBJECTIVES: The authors examined the tolerability and efficacy of HTS use among adult subjects hospitalised with a CF pulmonary exacerbation and hypothesised that use of HTS would improve pulmonary function during the admission. DESIGN: Pilot retrospective non-randomised study. SETTING: Single tertiary care centre. PARTICIPANTS: 45 subjects admitted to the inpatient service for acute CF pulmonary exacerbation in 2006-2007. A subset of 18 subjects who were also admitted in 2005 when HTS was not available was included in the comparative study. PRIMARY OUTCOME: Change in forced expiratory volume in one second from admission to discharge. SECONDARY OUTCOMES: Change in weight from admission to discharge and time to next exacerbation. RESULTS: Mean age was 32.5 years, and mean length of stay was 11.5 days. HTS was offered to 33 subjects and was well tolerated for a total use of 336 days out of 364 days of hospital stay. Baseline demographics, lung function and sputum culture results were comparable in first and second visits. Use of HTS was not associated with an improvement in forced expiratory volume in one second (p=0.1), weight gain (p=0.24) or in the time to next admission (p=0.08). CONCLUSIONS: These pilot data suggest that HTS is well tolerated during CF pulmonary exacerbation but offers no clear outcome benefits. It is possible that HTS may not have much advantage above and beyond intensive rehabilitation and intravenous antibiotics and may add to hospital costs and treatment burden.

Enhancement of respiratory mucosal antiviral defenses by the oxidation of iodide.

Recent reports postulate that the dual oxidase (DUOX) proteins function as part of a multicomponent oxidative pathway used by the respiratory mucosa to kill bacteria. The other components include epithelial ion transporters, which mediate the secretion of the oxidizable anion thiocyanate (SCN(-)) into airway surface liquid, and lactoperoxidase (LPO), which catalyzes the H(2)O(2)-dependent oxidation of the pseudohalide SCN(-) to yield the antimicrobial molecule hypothiocyanite (OSCN(-)). We hypothesized that this oxidative host defense system is also active against respiratory viruses. We evaluated the activity of oxidized LPO substrates against encapsidated and enveloped viruses. When tested for antiviral properties, the LPO-dependent production of OSCN(-) did not inactivate adenovirus or respiratory syncytial virus (RSV). However, substituting SCN(-) with the alternative LPO substrate iodide (I(-)) resulted in a marked reduction of both adenovirus transduction and RSV titer. Importantly, well-differentiated primary airway epithelia generated sufficient H(2)O(2) to inactivate adenovirus or RSV when LPO and I(-) were supplied. The administration of a single dose of 130 mg of oral potassium iodide to human subjects increased serum I(-) concentrations, and resulted in the accumulation of I(-) in upper airway secretions. These results suggest that the LPO/I(-)/H(2)O(2) system can contribute to airway antiviral defenses. Furthermore, the delivery of I(-) to the airway mucosa may augment innate antiviral immunity.

Concentration of the antibacterial precursor thiocyanate in cystic fibrosis airway secretions.

A recently discovered enzyme system produces antibacterial hypothiocyanite (OSCN(-)) in the airway lumen by oxidizing the secreted precursor thiocyanate (SCN(-)). Airway epithelial cultures have been shown to secrete SCN(-) in a CFTR-dependent manner. Thus, reduced SCN(-) availability in the airway might contribute to the pathogenesis of cystic fibrosis (CF), a disease caused by mutations in the CFTR gene and characterized by an airway host defense defect. We tested this hypothesis by analyzing the SCN(-) concentration in the nasal airway surface liquid (ASL) of CF patients and non-CF subjects and in the tracheobronchial ASL of CFTR-ΔF508 homozygous pigs and control littermates. In the nasal ASL, the SCN(-) concentration was ~30-fold higher than in serum independent of the CFTR mutation status of the human subject. In the tracheobronchial ASL of CF pigs, the SCN(-) concentration was somewhat reduced. Among human subjects, SCN(-) concentrations in the ASL varied from person to person independent of CFTR expression, and CF patients with high SCN(-) levels had better lung function than those with low SCN(-) levels. Thus, although CFTR can contribute to SCN(-) transport, it is not indispensable for the high SCN(-) concentration in ASL. The correlation between lung function and SCN(-) concentration in CF patients may reflect a beneficial role for SCN(-).

Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia.

Pneumonia remains the leading cause of death from infection in the US, yet fundamentally new conceptual models underlying its pathogenesis have not emerged. We show that humans and mice with bacterial pneumonia have markedly elevated amounts of cardiolipin, a rare, mitochondrial-specific phospholipid, in lung fluid and find that it potently disrupts surfactant function. Intratracheal cardiolipin administration in mice recapitulates the clinical phenotype of pneumonia, including impaired lung mechanics, modulation of cell survival and cytokine networks and lung consolidation. We have identified and characterized the activity of a unique cardiolipin transporter, the P-type ATPase transmembrane lipid pump Atp8b1, a mutant version of which is associated with severe pneumonia in humans and mice. Atp8b1 bound and internalized cardiolipin from extracellular fluid via a basic residue-enriched motif. Administration of a peptide encompassing the cardiolipin binding motif or Atp8b1 gene transfer in mice lessened bacteria-induced lung injury and improved survival. The results unveil a new paradigm whereby Atp8b1 is a cardiolipin importer whose capacity to remove cardiolipin from lung fluid is exceeded during inflammation or when Atp8b1 is defective. This discovery opens the door for new therapeutic strategies directed at modulating the abundance or molecular interactions of cardiolipin in pneumonia.

Patterns and density of early tracheal colonization in intensive care unit patients.

OBJECTIVE: The study aimed to describe the patterns and density of early tracheal colonization among intubated patients and to correlate colonization status with levels of antimicrobial peptides and inflammatory cytokines. DESIGN: The was a prospective cohort study. SETTING: The study was conducted in medical and cardiovascular intensive care units of a tertiary referral hospital. PATIENTS: Seventy-four adult patients admitted between March 2003 and May 2006 were recruited for the study. INTERVENTIONS: Tracheal aspirates were collected daily for the first 4 days of intubation using standardized, sterile technique and sent for quantitative culture and cytokines, lactoferrin and lysozyme measurements. MEASUREMENTS AND MAIN RESULTS: The mean acute physiology and chronic health evaluation (APACHE II) score in this cohort was 24 +/- 7. Proportion of subjects colonized by any microorganism increased over the first 4 days of intubation (47%, 60%, 70%, 70%, P = .08), but density of colonization for bacteria or yeast did not change significantly. No known risk factors predicted tracheal colonization on day 1 of intubation. Several patterns of colonization were observed (persistent, transient, new colonization, and clearance of initial colonization).The most common organisms cultured were Candida albicans and coagulase-negative Staphylococcus. Levels of cytokines, lactoferrin, or lysozyme did not change over time and were not correlated with tracheal colonization status. Four subjects (6%) had ventilator-associated pneumonia. CONCLUSIONS: The density of tracheal colonization did not change significantly over the first 4 days of intubation in medical intensive care unit patients. There was no correlation between tracheal colonization and the levels of antimicrobial peptides or cytokines. Several different patterns of colonization may have to be considered while planning interventions to reduce airway colonization.

Fluid therapy in resuscitated sepsis: less is more.

Fluid infusion may be lifesaving in patients with severe sepsis, especially in the earliest phases of treatment. Following initial resuscitation, however, fluid boluses often fail to augment perfusion and may be harmful. In this review, we seek to compare and contrast the impact of fluids in early and later sepsis; show that much fluid therapy is clinically ineffective in patients with severe sepsis; explore the detrimental aspects of excessive volume infusion; examine how clinicians assess the intravascular volume state; appraise the potential for dynamic indexes to predict fluid responsiveness; and recommend a clinical approach.

Safety assessment of inhaled xylitol in subjects with cystic fibrosis.

BACKGROUND: Xylitol is a 5-carbon sugar that can lower the airway surface salt concentration, thus enhancing innate immunity. We tested the safety and tolerability of aerosolized iso-osmotic xylitol in subjects with cystic fibrosis. METHODS: In this pilot study, 6 subjects with cystic fibrosis and an FEV1>60% predicted underwent a baseline spirometry followed by exposures to aerosolized saline (10 ml) and 5% xylitol (10 ml). Serum osmolarity and electrolytes were measured at baseline and after xylitol exposure. Spirometry, oxygen saturation and respiratory symptom questionnaire using visual analog scale were tested at baseline and after each exposure. Sputum for cytokine analysis was collected after saline and xylitol nebulizations. RESULTS: There was no change in FEV1 after xylitol exposure compared with baseline or normal saline exposure (p=0.19). Laboratory values and respiratory symptoms were not affected by xylitol inhalation. The mean IL-8 level in the sputum was similar with saline and xylitol exposures (3.5+/-0.5 vs. 3.5+/-0.6 ng/ml). CONCLUSIONS: A single dose inhalation of aerosolized iso-osmotic xylitol was well tolerated by subjects with cystic fibrosis. Future studies of long term safety are required.

Bronchoscopic assessment of airway retention time of aerosolized xylitol.

BACKGROUND: Human airway surface liquid (ASL) has abundant antimicrobial peptides whose potency increases as the salt concentration decreases. Xylitol is a 5-carbon sugar that has the ability to lower ASL salt concentration, potentially enhancing innate immunity. Xylitol was detected for 8 hours in the ASL after application in airway epithelium in vitro. We tested the airway retention time of aerosolized iso-osmotic xylitol in healthy volunteers. METHODS: After a screening spirometry, volunteers received 10 ml of nebulized 5% xylitol. Bronchoscopy was done at 20 minutes (n = 6), 90 minutes (n = 6), and 3 hours (n = 5) after nebulization and ASL was collected using microsampling probes, followed by bronchoalveolar lavage (BAL). Xylitol concentration was measured by nuclear magnetic resonance spectroscopy and corrected for dilution using urea concentration. RESULTS: All subjects tolerated nebulization and bronchoscopy well. Mean ASL volume recovered from the probes was 49 +/- 23 microl. The mean ASL xylitol concentration at 20, 90, and 180 minutes was 1.6 +/- 1.9 microg/microl, 0.6 +/- 0.6 microg/microl, and 0.1 +/- 0.1 microg/microl, respectively. Corresponding BAL concentration corrected for dilution was consistently lower at all time points. The terminal half-life of aerosolized xylitol obtained by the probes was 45 minutes with a mean residence time of 65 minutes in ASL. Corresponding BAL values were 36 and 50 minutes, respectively. CONCLUSION: After a single dose nebulization, xylitol was detected in ASL for 3 hours, which was shorter than our in vitro measurement. The microsampling probe performed superior to BAL when sampling bronchial ASL.

Hospital volume-outcome relationships among medical admissions to ICUs.

BACKGROUND: Positive relationships between hospital volume and outcomes have been demonstrated for several surgeries and medical conditions. However, little is known about the volume-outcome relationship in patients admitted to medical ICUs. OBJECTIVE: To determine the relationship between hospital volume and risk-adjusted in-hospital mortality for patients admitted to ICUs with respiratory, neurologic, and GI disorders. DESIGN: Retrospective cohort study. SETTING: Twenty-nine hospitals in a single metropolitan area. PATIENTS: Adult ICU admissions from 1991 through 1997. METHODS: Using Cox proportional hazards models, we compared in-hospital mortality between tertiles of hospital volume (high, medium, and low) for respiratory (n = 16,949), neurologic (n = 13,805), and GI (n = 12,881) diseases after adjusting for age, gender, admission severity of illness, admitting diagnosis, and source. Severity of illness was measured using the APACHE (acute physiology and chronic health evaluation) III methodology. RESULTS: Among respiratory and neurologic ICU admissions, hazard ratios were similar (p > or = 0.05) in patients in low-, medium-, and high-volume hospitals. However, among GI diagnoses, risk of mortality was lower in high-volume hospitals, relative to low-volume hospitals (hazard ratio, 0.68; 95% confidence interval [CI], 0.54 to 0.85; p < 0.001), and was somewhat lower in medium-volume hospitals (hazard ratio, 0.83; 95% CI, 0.68 to 1.01; p = 0.06). Among subgroups based on severity of illness, high-volume hospitals had lower mortality, relative to low-volume hospitals, among sicker patients (APACHE III score > 57) in the respiratory cohort (hazard ratio, 0.77; 95% CI, 0.59 to 0.99) and the GI cohort (hazard ratio, 0.67; 95% CI, 0.53 to 0.85). CONCLUSIONS: Associations between ICU volume and risk-adjusted mortality were significant for patients with GI diagnoses and for sicker patients with respiratory diagnoses. However, associations were not significant for patients with neurologic diagnoses. The lack of a consistent volume-outcome relationship may reflect unmeasured patient complexity in higher-volume hospitals, relative standardization of care across ICUs, or lack of efficacy of some accepted ICU processes of care.

Safety assessment of inhaled xylitol in mice and healthy volunteers.

BACKGROUND: Xylitol is a 5-carbon sugar that can lower the airway surface salt concentration, thus enhancing innate immunity. We tested the safety and tolerability of aerosolized iso-osmotic xylitol in mice and human volunteers. METHODS: This was a prospective cohort study of C57Bl/6 mice in an animal laboratory and healthy human volunteers at the clinical research center of a university hospital. Mice underwent a baseline methacholine challenge, exposure to either aerosolized saline or xylitol (5% solution) for 150 minutes and then a follow-up methacholine challenge. The saline and xylitol exposures were repeated after eosinophilic airway inflammation was induced by sensitization and inhalational challenge to ovalbumin. Normal human volunteers underwent exposures to aerosolized saline (10 ml) and xylitol, with spirometry performed at baseline and after inhalation of 1, 5, and 10 ml. Serum osmolarity and electrolytes were measured at baseline and after the last exposure. A respiratory symptom questionnaire was administered at baseline, after the last exposure, and five days after exposure. In another group of normal volunteers, bronchoalveolar lavage (BAL) was done 20 minutes and 3 hours after aerosolized xylitol exposure for levels of inflammatory markers. RESULTS: In naive mice, methacholine responsiveness was unchanged after exposures to xylitol compared to inhaled saline (p = 0.49). There was no significant increase in Penh in antigen-challenged mice after xylitol exposure (p = 0.38). There was no change in airway cellular response after xylitol exposure in naive and antigen-challenged mice. In normal volunteers, there was no change in FEV1 after xylitol exposures compared with baseline as well as normal saline exposure (p = 0.19). Safety laboratory values were also unchanged. The only adverse effect reported was stuffy nose by half of the subjects during the 10 ml xylitol exposure, which promptly resolved after exposure completion. BAL cytokine levels were below the detection limits after xylitol exposure in normal volunteers. CONCLUSIONS: Inhalation of aerosolized iso-osmotic xylitol was well-tolerated by naive and atopic mice, and by healthy human volunteers.

Prognostic factors for mortality following interhospital transfers to the medical intensive care unit of a tertiary referral center.

OBJECTIVE: To describe characteristics of patients transferred from outside hospitals to a tertiary medical intensive care unit and to identify patient-level and system-level prognostic factors. DESIGN: Retrospective cohort study. SETTING: Tertiary university hospital. PATIENTS: We studied 3,347 patients who were transferred to the medical intensive care unit from outside hospitals from January 1990 through September 1999. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data collected included patient demographics, insurance type, discharge diagnoses, length of stay, mortality, admitting service, and distance traveled. The Charlson Comorbidity Score was used to adjust for comorbidity and the diagnostic related group risk level for risk of adverse outcome. Multivariate logistic models of early mortality (<72 hrs) and overall hospital mortality rate were developed. The most common major diagnostic categories included neurologic (10%), respiratory (10%), digestive diseases (10%), and drug overdose (10%). Most patients (70%) were transferred from >60 miles away. Mean medical intensive care unit length of stay was 5.3 days vs. 3.9 days for nontransfer patients. Transfer patients accounted for 49% of medical intensive care unit admits and 56% of intensive care unit patient-days. The overall mortality rate for transfer patients to the medical intensive care unit was 25% (95% confidence interval, 23-26), significantly higher than the 21% (95% confidence interval, 19-22) mortality rate among those admitted directly. Independent prognostic factors for early death (<72 hrs) included male gender, summer season, admitting service, diagnostic related group level, Charlson Comorbidity Score, insurance type, and major diagnostic category. Independent prognostic factors for overall hospital mortality rate included length of stay, medical complication, distance traveled, insurance type, and major diagnostic category. CONCLUSIONS: Interhospital transfers to the medical intensive care unit are patients at high risk for mortality and other adverse outcomes. System-level and patient-level characteristics influence both early and overall hospital mortality rates. These variables should be considered when risk stratifying medical intensive care unit patients and in studying outcomes of care.

Antibiotic resistance: a survey of physician perceptions.

BACKGROUND: Antibiotic resistance is caused partly by excessive antibiotic prescribing, yet little is known about prescribers' views on this problem. METHODS: We surveyed 490 internal medicine physicians at 4 Chicago-area hospitals to assess their attitudes about the importance of antibiotic resistance, knowledge of its prevalence, self-reported experience with antibiotic resistance, beliefs about its causes, and attitudes about interventions designed to address the problem. RESULTS: The response rate was 87% (424 of 490 physicians). Antibiotic resistance was perceived as a very important national problem by 87% of the respondents, but only 55% rated the problem as very important at their own hospitals. Nearly all physicians (97%) believed that widespread and inappropriate antibiotic use were important causes of resistance. Yet, only 60% favored restricting use of broad-spectrum antibiotics, although this percentage varied by hospital and physician group. CONCLUSIONS: Although most physicians view antibiotic resistance as a serious national problem, perceptions about its local importance, its causes, and possible solutions vary more widely. Disparities in physician knowledge, beliefs, and attitudes may compromise efforts to improve antibiotic prescribing and infection control practices.

Azithromycin for acute bronchitis: a randomised, double-blind, controlled trial.

BACKGROUND: The value of azithromycin for treatment of acute bronchitis is unknown, even though this drug is commonly prescribed. We have investigated this question in a randomised, double-blind, controlled trial. METHODS: Adults diagnosed with acute bronchitis, without evidence of underlying lung disease, were randomly assigned azithromycin (n=112) or vitamin C (n=108) for 5 days (total dose for each 1.5 g). All individuals were also given liquid dextromethorphan and albuterol inhaler with a spacer. The primary outcome was improvement in health-related quality of life at 7 days; an important difference was defined as 0.5 or greater. Analysis was by intention to treat. FINDINGS: The study was stopped by the data-monitoring and safety committee when 220 patients had been recruited. On day 7, the adjusted difference in health-related quality of life was small and not significant (difference 0.03 [95% CI -0.20 to 0.26], p=0.8). 86 (89%) of 97 patients in the azithromycin group and 82 (89%) of 92 in the vitamin C group had returned to their usual activities by day 7 (difference 0.5% [-10% to 9%], p>0.9). There were no differences in the frequency of adverse effects; three patients in the vitamin C group discontinued the study medicine because of perceived adverse effects, compared with none in the azithromycin group. Most patients (81%) reported benefit from the albuterol inhaler. INTERPRETATION: Azithromycin is no better than low-dose vitamin C for acute bronchitis. Further studies are needed to identify the best treatment for this disorder.