Association of sputum microbiome with clinical outcome of initial antibiotic treatment in hospitalized patients with acute exacerbations of COPD.

Identification of risk factors for antibiotic treatment failure is urgently needed in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Here we investigated the relationship between sputum microbiome and clinical outcome of choice of initial antibiotics during hospitalization of AECOPD patients. Sputum samples of 41 AECOPD patients and 26 healthy controls were collected from Guangzhou Medical University, China. Samples were processed for 16S rRNA gene-based microbiome profiling. Thirty patients recovered with initial antibiotic treatment (antibiotic success or AS), while 11 patients showed poor outcome (antibiotic failure or AF). Substantial differences in microbiome were observed in AF versus AS patients and healthy controls. There was significantly decreased alpha diversity and increased relative abundances of Pseudomonas, Achromobacter, Stenotrophomonas and Ralstonia in AF patients. Conversely, Prevotella, Peptostreptococcus, Leptotrichia and Selenomonas were depleted. The prevalence of Selenomonas was markedly reduced in AF versus AS patients (9.1 % versus 60.0 %, P = 0.004). The AF patients with similar microbiome profiles in general responded well to the same new antibiotics in the adjusted therapy, indicating sputum microbiome may help guide the adjustment of antibiotics. Random forest analysis identified five microbiome operational taxonomic units together with C-reactive protein, procalcitonin and blood neutrophil count showing best predictability for antibiotic treatment outcome (area under curve 0.885). Functional inference revealed an enrichment of microbial genes in xenobiotic metabolism and antimicrobial resistance in AF patients, whereas genes in DNA repair and amino acid metabolism were depleted. Sputum microbiome may determine the clinical outcome of initial antibiotic treatment and be considered in the risk management of antibiotics in AECOPD.

Preclinical Evaluation of the Antimicrobial-Immunomodulatory Dual Action of Xenohormetic Molecules against Haemophilus influenzae Respiratory Infection.

Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammation and impaired airway immunity, providing an opportunistic platform for nontypeable Haemophilus influenzae (NTHi) infection. In this context, therapies targeting not only overactive inflammation without significant adverse effects, but also infection are of interest. Increasing evidence suggests that polyphenols, plant secondary metabolites with anti-inflammatory and antimicrobial properties, may be protective. Here, a Cistus salviifolius plant extract containing quercetin, myricetin, and punicalagin was shown to reduce NTHi viability. Analysis of these polyphenols revealed that quercetin has a bactericidal effect on NTHi, does not display synergies, and that bacteria do not seem to develop resistance. Moreover, quercetin lowered NTHi airway epithelial invasion through a mechanism likely involving inhibition of Akt phosphorylation, and reduced the expression of bacterially-induced proinflammatory markers il-8, cxcl-1, il-6, pde4b, and tnfα. We further tested quercetin's effect on NTHi murine pulmonary infection, showing a moderate reduction in bacterial counts and significantly reduced expression of proinflammatory genes, compared to untreated mice. Quercetin administration during NTHi infection on a zebrafish septicemia infection model system showed a bacterial clearing effect without signs of host toxicity. In conclusion, this study highlights the therapeutic potential of the xenohormetic molecule quercetin against NTHi infection.

Systemic inflammation and the effects of short-term antibiotic treatment for PPM positive patients with stable COPD.

Objective: To evaluate patients with stable COPD for the presence of potentially pathogenic microorganisms (PPM), systemic inflammation and the effects of short-term antibiotic therapy in PPM positive patients. Methods: From January 2016 to June 2017, we enrolled 96 stable COPD patients. Bacterial cultures from sputum collections were quantitated, along with markers for systemic inflammation including serum C-reactive protein (CRP), interleukin-8 (IL-8) and plasma fibrinogen (FIB) in all patients. All enrolled patients were followed for 12 months. Forty patients were identified as PPM positive and were randomly divided into an antibiotic group and a control group. The antibiotic group was treated with moxifloxacin orally for 6 days. Lung function and markers for systemic inflammation were repeatedly measured at 30 days and 6 months in PPM positive subjects. Results: Binary logistic regression analysis showed that risk factors for PPM positive are bronchiectasis (OR 4.18, 95% CI 1.20-14.59; P=0.025), COPD assessment test (CAT) ≥20 (OR 17.55, 95% CI 2.82-109.18; P=0.002), spontaneous sputum (OR 15.09, 95% CI 1.36-168.02; P=0.027) and sputum purulence (OR 38.43, 95% CI 5.39-274.21; P=0.000). CRP and IL-8 were higher in PPM positive group than those in PPM negative group (P=0.001, P=0.007, respectively), but there were no differences of FIB between the two groups (P=0.086). Compared to the PPM negative group, the rate of acute exacerbation of COPD was higher (P=0.029) and time to next acute exacerbation was shorter (P=0.030) in PPM positive group. There were no differences in lung function and systemic inflammatory markers either in the control group or the antibiotic group at different time points of follow-up. Conclusion: PPM exists in stable COPD patients and can cause systemic inflammation and is associated with acute exacerbation of COPD. Short-term antibiotic therapy had no effect on systemic inflammation nor on acute exacerbation of COPD.China Clinical Trials Registry: ChiCTR-IOR-15006769.

[Intestinal microbiota, nutrients and probiotics viewed from the «gut-lung¼ axis].

Disturbance of the bronchopulmonary system are among the most common and socially significant diseases, so, the prevention and treatment of these disorders are the priority tasks of practical health care. Being based on the accumulated literature data on the interaction of the intestinal microflora and respiratory tract, the role of symbiotic bacteria of the intestinal biotope has been discussed in the respiratory diseases' pathogenesis. The aim of the work was to analyze the results of experimental and clinical studies confirming the effect of intestinal microflora on the development and progression of respiratory diseases. The analysis of the available data on the risk reducing of occurrence, duration and severity of symptoms of bronchial asthma when taking probiotics, both in childhood and in the adult population, has been carried out. The effectiveness of the probiotic microorganisms' intake for the treatment of chronic obstructive pulmonary disease, pneumonia, viral infection, cystic fibrosis, and lung cancer has been analyzed. The main possible molecular mechanisms of the symbiotic bacteria prevention of the bronchopulmonary diseases development have been discussed in the article. Conclusion. The probiotics usage in the complex treatment of bronchopulmonary diseases demonstrates encouraging results. Its potential may be useful in the treatment of various lung diseases. However, a number of questions have been related to the individual selection of specific strains, the dosage and duration of use to achieve sustained remission for a patient.

Potential Micronutrients and Phytochemicals against the Pathogenesis of Chronic Obstructive Pulmonary Disease and Lung Cancer.

Lung cancer and chronic obstructive pulmonary disease have shared etiology, including key etiological changes (e.g., DNA damage and epigenetics change) and lung function impairment. Focusing on those shared targets may help in the prevention of both. Certain micronutrients (vitamins and minerals) and phytochemicals (carotenoids and phenols) have potent antioxidant or methyl-donating properties and thus have received considerable interest. We reviewed recent papers probing into the potential of nutrients with respect to lung function preservation and prevention of lung cancer risk, and suggest several hypothetical intervention patterns. Intakes of vitamins (i.e., A, C, D, E, B12), carotenoids, flavonoids, curcumins, resveratrol, magnesium, and omega-3 fatty acids all show protective effects against lung function loss, some mainly by improving average lung function and others through reducing decline rate. Dietary interventions early in life may help lung function reserve over the lifespan. Protective nutrient interventions among smokers are likely to mitigate the effects of cigarettes on lung health. We also discuss their underlying mechanisms and some possible causes for the inconsistent results in observational studies and supplementation trials. The role of the lung microbiome on lung health and its potential utility in identifying protective nutrients are discussed as well. More prospective cohorts and well-designed clinical trials are needed to promote the transition of individualized nutrient interventions into health policy.

Pulmonary Practice Pearls for Primary Care Physicians 13-part eNewsletter series.

The aim of this supplement is to provide an introduction to recent advances in the understanding of the impact of microorganisms on the normal and diseased lung for patients with asthma and COPD.

Systems pharmacology-based approach for dissecting the active ingredients and potential targets of the Chinese herbal Bufei Jianpi formula for the treatment of COPD.

BACKGROUND: The Chinese herbal Bufei Jianpi formula (BJF) provides an effective treatment option for chronic obstructive pulmonary disease (COPD). However, the systems-level mechanism underlying the clinical effects of BJF on COPD remains unknown. METHODS: In this study, a systems pharmacology model based on absorption filtering, network targeting, and systems analyses was applied specifically to clarify the active compounds and therapeutic mechanisms of BJF. Then, a rat model of cigarette smoke- and bacterial infection-induced COPD was used to investigate the therapeutic mechanisms of BJF on COPD and its comorbidity. RESULTS: The pharmacological system successfully identified 145 bioactive ingredients from BJF and revealed 175 potential targets. There was a significant target overlap between the herbal constituents of BJF. These results suggested that each herb of BJF connected with similar multitargets, indicating potential synergistic effects among them. The integrated target-disease network showed that BJF probably was efficient for the treatment of not only respiratory tract diseases but also other diseases, such as nervous system and cardiovascular diseases. The possible mechanisms of action of BJF were related to activation of inflammatory response, immune responses, and matrix metalloproteinases, among others. Furthermore, we demonstrated that BJF treatment could effectively prevent COPD and its comorbidities, such as ventricular hypertrophy, by inhibition of inflammatory cytokine production, matrix metalloproteinases expression, and other cytokine production in vivo. CONCLUSION: This study using the systems pharmacology method, in combination with in vivo experiments, helped us successfully dissect the molecular mechanism of BJF for the treatment of COPD and predict the potential targets of the multicomponent BJF, which provides a new approach to illustrate the synergetic mechanism of the complex prescription and discover more effective drugs against COPD.

Effects of different antibiotic classes on airway bacteria in stable COPD using culture and molecular techniques: a randomised controlled trial.

BACKGROUND: Long-term antibiotic therapy is used to prevent exacerbations of COPD but there is uncertainty over whether this reduces airway bacteria. The optimum antibiotic choice remains unknown. We conducted an exploratory trial in stable patients with COPD comparing three antibiotic regimens against placebo. METHODS: This was a single-centre, single-blind, randomised placebo-controlled trial. Patients aged ≥45 years with COPD, FEV1<80% predicted and chronic productive cough were randomised to receive either moxifloxacin 400 mg daily for 5 days every 4 weeks, doxycycline 100 mg/day, azithromycin 250 mg 3 times a week or one placebo tablet daily for 13 weeks. The primary outcome was the change in total cultured bacterial load in sputum from baseline; secondary outcomes included bacterial load by 16S quantitative PCR (qPCR), sputum inflammation and antibiotic resistance. RESULTS: 99 patients were randomised; 86 completed follow-up, were able to expectorate sputum and were analysed. After adjustment, there was a non-significant reduction in bacterial load of 0.42 log10 cfu/mL (95% CI -0.08 to 0.91, p=0.10) with moxifloxacin, 0.11 (-0.33 to 0.55, p=0.62) with doxycycline and 0.08 (-0.38 to 0.54, p=0.73) with azithromycin from placebo, respectively. There were also no significant changes in bacterial load measured by 16S qPCR or in airway inflammation. More treatment-related adverse events occurred with moxifloxacin. Of note, mean inhibitory concentrations of cultured isolates increased by at least three times over placebo in all treatment arms. CONCLUSIONS: Total airway bacterial load did not decrease significantly after 3 months of antibiotic therapy. Large increases in antibiotic resistance were seen in all treatment groups and this has important implications for future studies. TRIAL REGISTRATION NUMBER: clinicaltrials.gov (NCT01398072).

Prognostic factors for clinical failure of exacerbations in elderly outpatients with moderate-to-severe COPD.

BACKGROUND: Acute exacerbations represent a significant burden for patients with moderate-to-severe chronic obstructive pulmonary disease. Each exacerbation episode is frequently associated with a lengthy recovery and impaired quality of life. Prognostic factors for outpatients that may predict poor outcome after treatment with antibiotics recommended in the guidelines, are not fully understood. We aimed to identify pretherapy factors predictive of clinical failure in elderly (≥60 years old) outpatients with acute Anthonisen type 1 exacerbations. TRIAL REGISTRATION: NCT00656747. METHODS: Based on the moxifloxacin in AECOPDs (acute exacerbations of chronic obstructive pulmonary disease) trial (MAESTRAL) database, this study evaluated pretherapy demographic, clinical, sputum bacteriological factors using multivariate logistic regression analysis, with internal validation by bootstrap replicates, to investigate their possible association with clinical failure at end of therapy (EOT) and 8 weeks posttherapy. RESULTS: The analyses found that the independent factors predicting clinical failure at EOT were more frequent exacerbations, increased respiratory rate and lower body temperature at exacerbation, treatment with long-acting anticholinergic drugs, and in vitro bacterial resistance to study drug. The independent factors predicting poor outcome at 8 weeks posttherapy included wheezing at preexacerbation, mild or moderate (vs extreme) sleep disturbances, lower body temperature at exacerbation, forced expiratory volume in 1 second <30%, lower body mass index, concomitant systemic corticosteroids for the current exacerbation, maintenance long-acting ß2-agonist and long-acting anticholinergic treatments, and positive sputum culture at EOT. CONCLUSION: Several bacteriological, historical, treatment-related factors were identified as predictors of early (EOT) and later (8 weeks posttherapy) clinical failure in this older outpatient population with moderate-to-severe chronic obstructive pulmonary disease. These patients should be closely monitored and sputum cultures considered before and after treatment.

Novel aspects of pathogenesis and regeneration mechanisms in COPD.

Chronic obstructive pulmonary disease (COPD), a major cause of death and morbidity worldwide, is characterized by expiratory airflow limitation that is not fully reversible, deregulated chronic inflammation, and emphysematous destruction of the lungs. Despite the fact that COPD is a steadily growing global healthcare problem, the conventional therapies remain palliative, and regenerative approaches for disease management are not available yet. We aim to provide an overview of key reviews, experimental, and clinical studies addressing lung emphysema development and repair mechanisms published in the past decade. Novel aspects discussed herein include integral revision of the literature focused on lung microflora changes in COPD, autoimmune component of the disease, and environmental risk factors other than cigarette smoke. The time span of studies on COPD, including emphysema, chronic bronchitis, and asthmatic bronchitis, covers almost 200 years, and several crucial mechanisms of COPD pathogenesis are described and studied. However, we still lack the holistic understanding of COPD development and the exact picture of the time-course and interplay of the events during stable, exacerbated, corticosteroid-treated COPD states, and transitions in-between. Several generally recognized mechanisms will be discussed shortly herein, ie, unregulated inflammation, proteolysis/antiproteolysis imbalance, and destroyed repair mechanisms, while novel topics such as deviated microbiota, air pollutants-related damage, and autoimmune process within the lung tissue will be discussed more extensively. Considerable influx of new data from the clinic, in vivo and in vitro studies stimulate to search for novel concise explanation and holistic understanding of COPD nowadays.

Molecular characterization of fluoroquinolone resistance in nontypeable Haemophilus influenzae clinical isolates.

Nontypeable Haemophilus influenzae (NTHi) is a common cause of respiratory infections in adults, who are frequently treated with fluoroquinolones. The aims of this study were to characterize the genotypes of fluoroquinolone-resistant NTHi isolates and their mechanisms of resistance. Among 7,267 H. influenzae isolates collected from adult patients from 2000 to 2013, 28 (0.39%) were ciprofloxacin resistant according to Clinical and Laboratory Standards Institute (CLSI) criteria. In addition, a nalidixic acid screening during 2010 to 2013 detected five (0.23%) isolates that were ciprofloxacin susceptible but nalidixic acid resistant. Sequencing of their quinolone resistance-determining regions and genotyping by pulse-field gel electrophoresis and multilocus sequence typing of the 25 ciprofloxacin-resistant isolates available and all 5 nalidixic acid-resistant isolates were performed. In the NTHi isolates studied, two mutations producing changes in two GyrA residues (Ser84, Asp88) and/or two ParC residues (Ser84, Glu88) were associated with increased fluoroquinolone MICs. Strains with one or two mutations (n = 15) had ciprofloxacin and levofloxacin MICs of 0.12 to 2 µg/ml, while those with three or more mutations (n = 15) had MICs of 4 to 16 µg/ml. Long persistence of fluoroquinolone-resistant strains was observed in three chronic obstructive pulmonary disease patients. High genetic diversity was observed among fluoroquinolone-resistant NTHi isolates. Although fluoroquinolones are commonly used to treat respiratory infections, the proportion of resistant NTHi isolates remains low. The nalidixic acid disk test is useful for detecting the first changes in GyrA or in GyrA plus ParC among fluoroquinolone-susceptible strains that are at a potential risk for the development of resistance under selective pressure by fluoroquinolone treatment.

The role of cefditoren in the treatment of lower community-acquired respiratory tract infections (LRTIs): from bacterial eradication to reduced lung inflammation and epithelial damage.

OBJECTIVES: Lower respiratory tract infections (LRTIs), including pneumonia and acute exacerbations of Chronic Obstructive Pulmonary Disease (COPD), are among the most common diagnoses in both outpatient and inpatient settings. Due to the burden of LRTIs healthcare providers must adopt practices focused on improving outcomes with the aim to reduce treatment failure and antibiotic resistances. Moreover, the role of acute and chronic infection in the pathogenesis of COPD has received considerable attention, since chronic infection can contribute to airways inflammation and COPD progression. This review discusses the role of cefditoren for the treatment of LRTIs, compared with the definition of "appropriate" of the WHO as "the cost-effective use of antimicrobials which maximizes clinical therapeutic effect while minimizing both drug-related toxicity and the development of antimicrobial resistance". RESULTS AND CONCLUSIONS: Cefditoren appears to meet the definition of "appropriate" for the treatment of LRTIs. In fact, this molecule shows an adequate pharmacokinetic profile without the need for any adjustment also in aged patients with mild renal impairment or mild-to-moderate hepatic dysfunction. The low drug-drug interaction potential of cefditoren can be an advantage also in poly-treated patients. The antimicrobial spectrum of cefditoren includes both Gram+ and Gram- bacteria, with high activity against Streptococcus pneumoniae, including drug-resistant strains, Haemophilus infuenzae and Moraxella chatarrhalis. Last, recent findings suggested that cefditoren can be a valid alternative to levofloxacin in outpatients with acute exacerbation of COPD; in this setting a treatment with cefditoren showed to be associated with a significant reduction of some key inflammatory markers involved in epithelial damage, including KL-6 and IL-6.

Efficacy of levofloxacin versus cefuroxime in treating acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Antibiotic treatment is one of the major pharmacologic treatments for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, the choice of antibiotic depends on the local resistance pattern. A multicenter, randomized, controlled trial was done in patients with AECOPD to compare the efficacy of levofloxacin with that of cefuroxime axetil. METHODS: Patients with AECOPD and without radiographic evidence of pneumonia were enrolled and randomized to either levofloxacin 500 mg daily or cefuroxime 250 mg twice daily in the mildmoderate exacerbation group, or 500 mg twice daily in the severe exacerbation group, for seven days. Clinical efficacy and microbiologic response were evaluated 5-7 days after the last dose. RESULTS: Treatment was clinically successful in 90.4% of patients in the levofloxacin group, and in 90.6% of patients in the cefuroxime group (95% confidence interval -9.40 to 10.91), within a noninferiority margin of 10%. The microbiologic response appeared to be higher in the levofloxacin group, but the difference was not statistically significant. The safety profile was similar in both groups. CONCLUSION: Levofloxacin is not inferior to cefuroxime with regard to clinical efficacy in treating AECOPD.

[Infectious exacerbation of chronic obstructive pulmonary disease: prospects for high-dose levofloxacin therapy].

This open comparative randomized study of efficacy, safety, and pharmacoeconomic characteristics of hilifox-750 (750 mg daily for 5 days) and amoxiclav 2X (875/125 mg twice daily for 10 days) included 60 patients with chronic obstructive pulmonary disease (COPD). Duration of the study was 6 months. Medians of age and smoking index in the group treated with hilifox-750 were 63.5 yr (59, 67) and 30 packs/yr (15, 60) respectively. The treatment reduced cough, apnea, sputum volume and pyoptysis with comparative rates of normalization of body temperature and peripheral leukocyte counts in both groups. Helifox-750 promoted decrease in coughing and apnea within the first three days of therapy. 28 (93%) and 26 (87%) patients recovered by day 4 of helifox and amoxiclav therapy (F-test p = 0.67). Both drugs showed comparable bacteriological efficacy. They were not different in terms of side effect frequency that were mild, resolved spontaneously and did not require withdrawal of therapy. Helifox had advantages over amoxiclav in that it reduced duration of antibacterial therapy to 5 days and of temporary incapacity to 12 days (vs 14); moreover, it needs to be taken only once daily.

Bacteria associated with acute exacerbations of chronic obstructive pulmonary disease requiring mechanical ventilation and antimicrobial management in Respiratory Care Unit of Central Chest Institute of Thailand.

OBJECTIVE: To investigate the role of bacterial infection, antimicrobial sensitivity and antibiotics usage in severe acute exacerbations of COPD requiring mechanical ventilation in the respiratory care unit of the central chest institute of Thailand. MATERIAL AND METHOD: All data were analyzed from medical records of 38 patients admitted in RCU of CCIT during 1 November 2008-31 August 2011 with severe acute exacerbations of COPD requiring mechanical ventilation. The tracheobronchial aspirates specimens were collected for Gram stain, quantitative culture and sensitivities testing. The sera were tested for antibodies to Chlamydophila pneumoniae and Mycoplasma pneumoniae with the immunofluorescence test. RESULTS: Bacterial pathogens were isolated by quantitative culture from 18 of 38 patients (47.3%). Gram-negative bacilli were the predominant organisms. K. pneumoniae was the predominant isolates 7 cases (18.4%) followed by H. influenzae 3 cases and P. aeruginosa 3 cases (7.9% each). A single pathogen was isolated from 12 patients (31.6%), two pathogens were isolated from 5 patients (13.2%) and three pathogens from 1 patient (2.6%). Serological samples were positive for Chlamydophila pneumoniae in 5 (13.2%) cases. 1 of these patients had coinfection with Acinetobacter baumannii. In the RCU, 33 (86.8%) patients were empirically treated with antibiotic. Ceftriaxone was the most commonly used antibiotic. CONCLUSION: 57.8% (22/38 cases) of the patients with severe exacerbations in COPD requiring mechanical ventilation caused by bacterial infection, Gram-negative bacilli were the predominant organism with a resistance to commonly used antibiotics of K. pneumoniae, P. aeruginosa, S. aureus, E. coli, A. baumannii, P. mirabilis, S. dysgalactiae and S. pneumoniae. 13.2% of the patients had serological evidence of Chlamydophila pneumoniae infection.

The use of moxifloxacin for acute exacerbations of chronic obstructive pulmonary disease and chronic bronchitis.

Chronic obstructive pulmonary disease is a common condition which causes considerable morbidity and mortality. It is a heterogenous disorder in which the majority of patients have chronic bronchitis. Bacterial infections are a major cause of acute exacerbations of both conditions which have a major impact on healthcare resources, quality of life and disease progression. Antibiotics are used to treat exacerbations involving purulent sputum production, together with increased breathlessness and/or sputum volume. Moxifloxacin is a quinolone antibiotic and is one of the treatment options. This article discusses pathophysiology of these diseases, moxifloxacin clinical studies and appropriate use of moxifloxacin.

A novel study design for antibiotic trials in acute exacerbations of COPD: MAESTRAL methodology.

Antibiotics, along with oral corticosteroids, are standard treatments for acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The ultimate aims of treatment are to minimize the impact of the current exacerbation, and by ensuring complete resolution, reduce the risk of relapse. In the absence of superiority studies of antibiotics in AECOPD, evidence of the relative efficacy of different drugs is lacking, and so it is difficult for physicians to select the most effective antibiotic. This paper describes the protocol and rationale for MAESTRAL (moxifloxacin in AECBs [acute exacerbation of chronic bronchitis] trial; www.clinicaltrials.gov: NCT00656747), one of the first antibiotic comparator trials designed to show superiority of one antibiotic over another in AECOPD. It is a prospective, multinational, multicenter, randomized, double-blind controlled study of moxifloxacin (400 mg PO [per os] once daily for 5 days) vs. amoxicillin/clavulanic acid (875/125 mg PO twice daily for 7 days) in outpatients with COPD and chronic bronchitis suffering from an exacerbation. MAESTRAL uses an innovative primary endpoint of clinical failure: the requirement for additional or alternate treatment for the exacerbation at 8 weeks after the end of antibiotic therapy, powered for superiority. Patients enrolled are those at high-risk of treatment failure, and all are experiencing an Anthonisen type I exacerbation. Patients are stratified according to oral corticosteroid use to control their effect across antibiotic treatment arms. Secondary endpoints include quality of life, symptom assessments and health care resource use.

Pharmacokinetics of ciprofloxacin and its penetration into bronchial secretions of mechanically ventilated patients with chronic obstructive pulmonary disease.

We evaluated the pharmacokinetic profile of ciprofloxacin and its penetration into bronchial secretions of critically ill patients with chronic obstructive pulmonary disease (COPD). Twenty-five mechanically ventilated patients with severe COPD who were suffering from an acute, infectious exacerbation were included in this prospective, open-label study. All subjects received a 1-hour intravenous infusion of 400 mg ciprofloxacin every 8 h. Serial blood and bronchial secretion samples were obtained at steady state, and concentrations were determined using high-performance liquid chromatography. The pharmacodynamic parameters that are associated with the efficacy of fluoroquinolones against Gram-negative pathogens were also calculated. The mean peak (maximum) concentration (C(max)) and trough (minimum) concentration in plasma were 5.37 ± 1.57 and 1 ± 0.53 mg/liter, respectively. Mean values for volume of distribution, clearance, half-life, and area under the curve from 0 to 24 h (AUC(0-24)) were 169.87 ± 84.11 liters, 26.96 ± 8.86 liters/h, 5.35 ± 2.21 h, and 47.41 ± 17.02 mg · h/liter, respectively. In bronchial secretions, a mean C(max) of 3.08 ± 1.21 mg/liter was achieved in 3.12 ± 1.01 h, and the penetration ratio was 1.16 ± 0.59. The target of AUC(0-24)/MIC of ≥125 was attained in all patients, in the majority of them (76%), and in none at MICs of 0.125, 0.25, and 1 µg/ml, respectively. Slightly better results were obtained for the ratio C(max)/MIC of ≥10. In conclusion, ciprofloxacin demonstrates excellent penetration into bronchial secretions. There is wide interindividual variability in its pharmacokinetic parameters in critically ill COPD patients and inadequate pharmacodynamic exposure against bacteria with MICs of ≥0.5 µg/ml.