colistin and Cystic-Fibrosis

Respiratory tract infections with Pseudomonas aeruginosa occur in most people with cystic fibrosis (CF). Established chronic P aeruginosa infection is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate. This is an updated review.. Does giving antibiotics for P aeruginosa infection in people with CF at the time of new isolation improve clinical outcomes (e.g. mortality, quality of life and morbidity), eradicate P aeruginosa infection, and delay the onset of chronic infection, but without adverse effects, compared to usual treatment or an alternative antibiotic regimen? We also assessed cost-effectiveness.. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and conference proceedings. Latest search: 24 March 2022. We searched ongoing trials registries. Latest search: 6 April 2022.. We included randomised controlled trials (RCTs) of people with CF, in whom P aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous (IV) antibiotics with placebo, usual treatment or other antibiotic combinations. We excluded non-randomised trials and cross-over trials.. Two authors independently selected trials, assessed risk of bias and extracted data. We assessed the certainty of the evidence using GRADE.. We included 11 trials (1449 participants) lasting between 28 days and 27 months; some had few participants and most had relatively short follow-up periods. Antibiotics in this review are: oral - ciprofloxacin and azithromycin; inhaled - tobramycin nebuliser solution for inhalation (TNS), aztreonam lysine (AZLI) and colistin; IV - ceftazidime and tobramycin. There was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment. Two trials were supported by the manufacturers of the antibiotic used. TNS versus placebo TNS may improve eradication; fewer participants were still positive for P aeruginosa at one month (odds ratio (OR) 0.06, 95% confidence interval (CI) 0.02 to 0.18; 3 trials, 89 participants; low-certainty evidence) and two months (OR 0.15, 95% CI 0.03 to 0.65; 2 trials, 38 participants). We are uncertain whether the odds of a positive culture decrease at 12 months (OR 0.02, 95% CI 0.00 to 0.67; 1 trial, 12 participants). TNS (28 days) versus TNS (56 days) One trial (88 participants) comparing 28 days to 56 days TNS treatment found duration of treatment may make little or no difference in time to next isolation (hazard ratio (HR) 0.81, 95% CI 0.37 to 1.76; low-certainty evidence). Cycled TNS versus culture-based TNS One trial (304 children, one to 12 years old) compared cycled TNS to culture-based therapy and also ciprofloxacin to placebo. We found moderate-certainty evidence of an effect favouring cycled TNS therapy (OR 0.51, 95% CI 0.31 to 0.82), although the trial publication reported age-adjusted OR and no difference between groups. Ciprofloxacin versus placebo added to cycled and culture-based TNS therapy One trial (296 participants) examined the effect of adding ciprofloxacin versus placebo to cycled and culture-based TNS therapy. There is probably no difference between ciprofloxacin and placebo in eradicating P aeruginosa (OR 0.89, 95% CI 0.55 to 1.44; moderate-certainty evidence). Ciprofloxacin and colistin versus TNS We are uncertain whether there is any difference between groups in eradication of P aeruginosa at up to six months (OR 0.43, 95% CI 0.15 to 1.23; 1 trial, 58 participants) or up to 24 months (OR 0.76, 95% CI 0.24 to 2.42; 1 trial, 47 participants); there was a low rate of short-term eradication in both groups. Ciprofloxacin plus colistin versus ciprofloxacin plus TNS One trial (223 participants) found there may be no difference in positive respiratory cul. We found that nebulised antibiotics, alone or with oral antibiotics, were better than no treatment for early infection with P aeruginosa. Eradication may be sustained in the short term. There is insufficient evidence to determine whether these antibiotic strategies decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials comparing two active treatments have failed to show differences in rates of eradication of P aeruginosa. One large trial showed that intravenous ceftazidime with tobramycin is not superior to oral ciprofloxacin when inhaled antibiotics are also used. There is still insufficient evidence to state which antibiotic strategy should be used for the eradication of early P aeruginosa infection in CF, but there is now evidence that intravenous therapy is not superior to oral antibiotics.

Topics: Anti-Bacterial Agents; Azithromycin; Ceftazidime; Child; Child, Preschool; Ciprofloxacin; Colistin; Cystic Fibrosis; Humans; Infant; Monobactams; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

Pseudomonas aeruginosa is an opportunistic pathogen that infects the lungs of people with cystic fibrosis (CF) and is the most common cause of chronic respiratory infections with high morbidity and mortality in CF patients. This study aimed to evaluate the pattern of antibiotic resistance of P. aeruginosa strains from patients with CF using a systematic review and meta-analysis.. A comprehensive and systematic search was performed for relevant articles until August 2021 in the following database: PubMed, Scopus, Embase, and Web of Science. Finally, 122 articles with appropriate criteria were included in the meta-analysis. To estimate weighted pooled proportions Freeman-Tukey double arcsine transformation was performed using Metaprop command in Stata software version 17.1.. 122 studies evaluated the pattern of P. aeruginosa antibiotic resistance from different antibiotic classes in patients with CF. Cefotaxime had the highest resistance rate of 67% (95% CI 53_80%), while colistin had the lowest 5% (95% CI 2-8%).. High resistance to most of the studied antibiotics was observed. The high antibiotic resistance observed is worrying and it indicates the need to monitor using of antibiotics. In addition, colistin is the most appropriate treatment choice, but more randomized controlled trial studies are recommended.

Topics: Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Resistance, Microbial; Humans; Persistent Infection; Prevalence; Pseudomonas aeruginosa; Pseudomonas Infections

Biofilm is an adaptive bacterial strategy whereby microorganisms become encased in a complex glycoproteic matrix. The low concentration of oxygen and nutrients in this environment leads to heterogeneous phenotypic changes in the bacteria, with antimicrobial tolerance being of paramount importance. As with other antibiotics, the activity of colistin is impaired by biofilm-embedded bacteria. Therefore, the recommendation for administering high doses in combination with a second drug, indicated for planktonic infections, remains valid in this setting. Notably, colistin has activity against metabolically inactive biofilm-embedded cells located in the inner layers of the biofilm structure. This is opposite and complementary to the activity of other antimicrobials that are able to kill metabolically active cells in the outer layers of the biofilm. Several experimental models have shown a higher activity of colistin when used in combination with other agents, and have reported that this can avoid the emergence of colistin-resistant subpopulations. Most experience of colistin in biofilm-associated infections comes from patients with cystic fibrosis, where the use of nebulized colistin allows high concentrations to reach the site of the infection. However, limited clinical experience is available in other scenarios, such as osteoarticular infections or device-related central nervous system infections caused by multi-drug resistant microorganisms. In the latter scenario, the use of intraventricular or intrathecal colistin also permits high local concentrations and good clinical results. Overall, the efficacy of intravenous colistin seems to be poor, but its association with a second antimicrobial significantly increases the response rate. Given its activity against inner bioflm-embedded cells, its possible role in combination with other antibiotics, beyond last-line therapy situations, should be further explored.

Topics: Anti-Bacterial Agents; Biofilms; Bone Diseases, Infectious; Central Nervous System Infections; Colistin; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests

Respiratory tract infection with Pseudomonas aeruginosa occurs in most people with cystic fibrosis. Once chronic infection is established, Pseudomonas aeruginosa is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate.This is an update of a Cochrane review first published in 2003, and previously updated in 2006, 2009 and 2014.. To determine whether antibiotic treatment of early Pseudomonas aeruginosa infection in children and adults with cystic fibrosis eradicates the organism, delays the onset of chronic infection, and results in clinical improvement. To evaluate whether there is evidence that a particular antibiotic strategy is superior to or more cost-effective than other strategies and to compare the adverse effects of different antibiotic strategies (including respiratory infection with other micro-organisms).. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 10 October 2016.. We included randomised controlled trials of people with cystic fibrosis, in whom Pseudomonas aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous antibiotics with placebo, usual treatment or other combinations of inhaled, oral or intravenous antibiotics. We excluded non-randomised trials, cross-over trials, and those utilising historical controls.. Both authors independently selected trials, assessed risk of bias and extracted data.. The search identified 60 trials; seven trials (744 participants) with a duration between 28 days and 27 months were eligible for inclusion. Three of the trials are over 10 years old and their results may be less applicable today given the changes in standard treatment. Some of the trials had low numbers of participants and most had relatively short follow-up periods; however, there was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment given the interventions and comparators used. Two trials were supported by the manufacturers of the antibiotic used.Evidence from two trials (38 participants) at the two-month time-point showed treatment of early Pseudomonas aeruginosa infection with inhaled tobramycin results in microbiological eradication of the organism from respiratory secretions more often than placebo, odds ratio 0.15 (95% confidence interval (CI) 0.03 to 0.65) and data from one of these trials, with longer follow up, suggested that this effect may persist for up to 12 months.One randomised controlled trial (26 participants) compared oral ciprofloxacin and nebulised colistin versus usual treatment. Results after two years suggested treatment of early infection results in microbiological eradication of Pseudomonas aeruginosa more often than no anti-pseudomonal treatment, odds ratio 0.12 (95% CI 0.02 to 0.79).One trial comparing 28 days to 56 days treatment with nebulised tobramycin solution for inhalation in 88 participants showed that both treatments were effective and well-tolerated, with no notable additional improvement with longer over shorter duration of therapy. However, this trial was not powered to detect non-inferiority or equivalence .A trial of oral ciprofloxacin with inhaled colistin versus nebulised tobramycin solution for inhalation alone (223 participants) failed to show a difference between the two strategies, although it was underpowered to show this. A further trial of inhaled colistin with oral ciprofloxacin versus nebulised tobramycin solution for inhalation with oral ciprofloxacin also showed no superiority of the former, with increased isolation of Stenotrophomonas maltophilia in both groups.A recent, large trial in 306 children aged between one and 12 years compared cycled nebulised tobramycin solution for inhalation to culture-based therapy and also ciprofloxacin to placebo. The primary analysis showed no difference in time to pulmonary exacerbation. We found that nebulised antibiotics, alone or in combination with oral antibiotics, were better than no treatment for early infection with Pseudomonas aeruginosa. Eradication may be sustained for up to two years. There is insufficient evidence to determine whether antibiotic strategies for the eradication of early Pseudomonas aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials comparing two active treatments have failed to show differences in rates of eradication of Pseudomonas aeruginosa. There have been no published randomised controlled trials that investigate the efficacy of intravenous antibiotics to eradicate Pseudomonas aeruginosa in cystic fibrosis. Overall, there is still insufficient evidence from this review to state which antibiotic strategy should be used for the eradication of early Pseudomonas aeruginosa infection in cystic fibrosis.

Topics: Administration, Inhalation; Administration, Oral; Adult; Anti-Bacterial Agents; Child; Ciprofloxacin; Colistin; Cystic Fibrosis; Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Randomized Controlled Trials as Topic; Respiratory System; Tobramycin

Historically, the polymyxin antibacterial colistin has been administered as intravenous or nebulized colistimethate sodium in patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa infection. More recently, colistimethate sodium has been formulated as a dry powder (Colobreathe(®)) to be administered via a hand-held Turbospin(®) inhaler. Compared with nebulized colistimethate sodium, the colistimethate sodium dry powder for inhalation (DPI) formulation reduces treatment time and improves patient convenience. Colistimethate sodium DPI is approved in the EU for the treatment of chronic P. aeruginosa infections in patients with CF aged ≥6 years. In a phase III clinical trial in this patient population, it was determined that the change in percent predicted forced expiratory volume in 1 s with colistimethate sodium DPI 1.6625 MIU (125 mg) twice daily was noninferior to that with nebulized tobramycin 300 mg/5 mL twice daily. Moreover, patients found colistimethate sodium DPI easier to use than nebulized tobramycin. Colistimethate sodium DPI was generally well tolerated, with a similar adverse event profile to that of nebulized tobramycin, except for a numerically higher incidence of cough and abnormal taste. Most adverse events diminished after 28 days in patients receiving colistimethate sodium DPI, with an occurrence similar to that in nebulized tobramycin recipients. In conclusion, colistimethate sodium DPI administered via the Turbospin® inhaler is a useful option for the treatment of chronic P. aeruginosa infection in patients with CF aged ≥6 years.

Topics: Chronic Disease; Colistin; Cystic Fibrosis; Drug Resistance, Bacterial; Dry Powder Inhalers; Humans; Lung; Pseudomonas aeruginosa; Pseudomonas Infections

Inhaled medications play an important role in the daily treatment of patients with cystic fibrosis (CF). The classic route of administration was nebulisation via jet nebulisers. Respiratory delivery of fluid particles should loosen the viscid respiratory secretions, making airway clearance via cough or physiotherapy more efficient. Until recently, only jet nebulisers allowed to administer high doses of aerosolised antipseudomonal antibiotics. Powder inhalers for the treatment of cystic fibrosis have recently been made available. The newly developed powders and inhalers differ considerably from conventional dry powder inhalers used for the treatment of chronic obstructive airway disease. The present article will review two inhaled antibiotics, i. e. tobramycin and colistin, and the hyperosmotic agent mannitol, which increases the hydration of the airways. Topics are particle engineering, efficacy and tolerability results from clinical trials, as well as functional and practical aspects related to these new drugs.

Topics: Administration, Inhalation; Aerosols; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Diuretics, Osmotic; Drug Compounding; Dry Powder Inhalers; Humans; Mannitol; Powders; Pseudomonas Infections; Tobramycin

Inhaled antibiotics have been used to treat chronic airway infections since the 1940s. The earliest experience with inhaled antibiotics involved aerosolizing antibiotics designed for parenteral administration. These formulations caused significant bronchial irritation due to added preservatives and nonphysiologic chemical composition. A major therapeutic advance took place in 1997, when tobramycin designed for inhalation was approved by the U.S. Food and Drug Administration (FDA) for use in patients with cystic fibrosis (CF) with chronic Pseudomonas aeruginosa infection. Attracted by the clinical benefits observed in CF and the availability of dry powder antibiotic formulations, there has been a growing interest in the use of inhaled antibiotics in other lower respiratory tract infections, such as non-CF bronchiectasis, ventilator-associated pneumonia, chronic obstructive pulmonary disease, mycobacterial disease, and in the post-lung transplant setting over the past decade. Antibiotics currently marketed for inhalation include nebulized and dry powder forms of tobramycin and colistin and nebulized aztreonam. Although both the U.S. Food and Drug Administration and European Medicines Agency have approved their use in CF, they have not been approved in other disease areas due to lack of supportive clinical trial evidence. Injectable formulations of gentamicin, tobramycin, amikacin, ceftazidime, and amphotericin are currently nebulized "off-label" to manage non-CF bronchiectasis, drug-resistant nontuberculous mycobacterial infections, ventilator-associated pneumonia, and post-transplant airway infections. Future inhaled antibiotic trials must focus on disease areas outside of CF with sample sizes large enough to evaluate clinically important endpoints such as exacerbations. Extrapolating from CF, the impact of eradicating organisms such as P. aeruginosa in non-CF bronchiectasis should also be evaluated.

Topics: Administration, Inhalation; Amikacin; Amphotericin B; Anti-Bacterial Agents; Aztreonam; Ceftazidime; Colistin; Cystic Fibrosis; Gentamicins; Humans; Nebulizers and Vaporizers; Respiratory Tract Infections; Tobramycin

Inhaled antibiotic therapy, targeting Pseudomonas aeruginosa, is a fundamental component of cystic fibrosis (CF) management. Tobramycin inhalation solution (TIS) was approved in the United States (US) in 1998. Subsequent research efforts focused on developing products with a reduced treatment time burden. Aztreonam for inhalation solution (AZLI), administered via a more efficient nebulizer than TIS, was approved in the US in 2010. Dry powder for inhalation (DPI) formulations provide alternatives to nebulized therapy: tobramycin powder for inhalation (also known as TIP™) was approved in the US in 2013, and colistimethate sodium DPI received European approval in 2012. Other aerosolized antibiotics and regimens combining inhaled antibiotics are in development. Inhaled antibiotic rotation (e.g., TIS alternating with AZLI) is an important concept being actively tested in CF.

Topics: Administration, Inhalation; Amikacin; Anti-Bacterial Agents; Aztreonam; Colistin; Cystic Fibrosis; Equipment Design; Humans; Levofloxacin; Nebulizers and Vaporizers; Pseudomonas aeruginosa; Pseudomonas Infections; Randomized Controlled Trials as Topic; Tobramycin

Newer 'innovative' formulations of antibiotics for Pseudomonas aeruginosa lung infection in patients with cystic fibrosis include colistimethate sodium and tobramycin in the form of dry powders for inhalation (DPIs). Whilst these DPIs are anticipated to improve patient adherence because of increased convenience and ease of administration, questions remain concerning whether they are as clinically effective, safe and cost-effective as nebulized antibiotics.. This review describes the recent findings of a health technology assessment of the clinical effectiveness and cost-effectiveness of colistimethate sodium and tobramycin DPIs with regard to how innovative treatments may be judged to be incrementally better than existing treatments. The original assessment was undertaken to inform the National Institute for Health and Care Excellence's Technology Appraisal Programme to inform national clinical guidance on the use of these new treatments in the National Health Service.. Three trials were included in the systematic review. Issues surrounding the clinical effectiveness and cost-effectiveness of colistimethate sodium DPI and tobramycin DPI are discussed in light of the considerable uncertainties associated with the available evidence.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Colistin; Cost-Benefit Analysis; Cystic Fibrosis; Dry Powder Inhalers; Humans; Medication Adherence; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin; Treatment Outcome

Colistin (polymyxin E) binds to the cell wall of gram-negative bacteria, leading to osmotic destruction of the cell. Since its introduction in 1959, colistin has been little used parenterally due to a high incidence of reversible nephrotoxicity and, to a lesser extent, neurotoxicity. Colistin use remained limited to combating Pseudomonas aeruginosa in cystic fibrosis patients. In addition, oral colistin is part of the recently introduced regime of selective digestive tract decontamination in ICU patients. Intravenous administration of colistin is now increasingly prescribed for the control of multi-resistant microorganisms. Colistin monotherapy, however, rapidly selects resistant subpopulations. Therefore, only combination therapy is advised. The prodrug colistimethate sodium is less toxic and is hydrolyzed in vivo to active colistin; colistin is renally cleared. Clinical practice remains hampered by lack of uniformity and standardization of names, dosage units, dosing recommendations and methods of concentration and susceptibility testing.

Topics: Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Gastrointestinal Tract; Humans; Practice Guidelines as Topic; Pseudomonas aeruginosa; Pseudomonas Infections

Dry powder inhalers (DPIs) delivering antibiotics for the suppressive treatment of Pseudomonas aeruginosa in cystic fibrosis patients were developed recently and are now increasingly replacing time-consuming nebuliser therapy. Noninferiority studies have shown that the efficacy of inhaled tobramycin delivered by DPI was similar to that of wet nebulisation. However, there are many differences between inhaled antibiotic therapy delivered by DPI and by nebuliser. The question is whether and to what extent inhalation technique and other patient-related factors affect the efficacy of antibiotics delivered by DPI compared with nebulisers. Health professionals should be aware of the differences between dry and wet aerosols, and of patient-related factors that can influence efficacy, in order to personalise treatment, to give appropriate instructions to patients and to better understand the response to the treatment after switching. In this review, key issues of aerosol therapy are discussed in relation to inhaled antibiotic therapy with the aim of optimising the use of both nebulised and DPI antibiotics by patients. An example of these issues is the relationship between airway generation, structural lung changes and local concentrations of the inhaled antibiotics. The pros and cons of dry and wet modes of delivery for inhaled antibiotics are discussed.

Topics: Administration, Inhalation; Aerosols; Anti-Bacterial Agents; Aztreonam; Colistin; Cystic Fibrosis; Disease Progression; Dry Powder Inhalers; Humans; Nebulizers and Vaporizers; Pseudomonas aeruginosa; Tobramycin

Respiratory tract infection with Pseudomonas aeruginosa occurs in most people with cystic fibrosis. Once chronic infection is established, Pseudomonas aeruginosa is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate.This is an update of a Cochrane review first published in 2003, and previously updated in 2006 and 2009.. To determine whether antibiotic treatment of early Pseudomonas aeruginosa infection in children and adults with cystic fibrosis eradicates the organism, delays the onset of chronic infection, and results in clinical improvement. To evaluate whether there is evidence that a particular antibiotic strategy is superior to or more cost-effective than other strategies and to compare the adverse effects of different antibiotic strategies (including respiratory infection with other micro-organisms).. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 08 September 2014.. We included randomised controlled trials of people with cystic fibrosis, in whom Pseudomonas aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous antibiotics with placebo, usual treatment or other combinations of inhaled, oral or intravenous antibiotics. We excluded non-randomised trials, cross-over trials, and those utilising historical controls.. Both authors independently selected trials, assessed risk of bias and extracted data.. The search identified 49 trials; seven trials (744 participants) with a duration between 28 days and 27 months were eligible for inclusion. Three of the trials are over 10 years old and their results may be less applicable today given the changes in standard treatment. Some of the trials had low numbers of participants and most had relatively short follow-up periods; however, there was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment given the interventions and comparators used. Two trials were supported by the manufacturers of the antibiotic used.Evidence from two trials (38 participants) at the two-month time-point showed treatment of early Pseudomonas aeruginosa infection with inhaled tobramycin results in microbiological eradication of the organism from respiratory secretions more often than placebo, odds ratio 0.15 (95% confidence interval 0.03 to 0.65) and data from one of these trials, with longer follow up, suggested that this effect may persist for up to 12 months.One randomised controlled trial (26 participants) compared oral ciprofloxacin and nebulised colistin versus usual treatment. Results after two years suggested treatment of early infection results in microbiological eradication of Pseudomonas aeruginosa more often than no anti-pseudomonal treatment, odds ratio 0.12 (95% confidence interval 0.02 to 0.79).One trial comparing 28 days to 56 days treatment with nebulised tobramycin solution for inhalation in 88 participants showed that both treatments were effective and well-tolerated, with no notable additional improvement with longer over shorter duration of therapy. However, this trial was not powered to detect non-inferiority or equivalence .A trial of oral ciprofloxacin with inhaled colistin versus nebulised tobramycin solution for inhalation alone (223 participants) failed to show a difference between the two strategies, although it was underpowered to show this. A further trial of inhaled colistin with oral ciprofloxacin versus nebulised tobramycin solution for inhalation with oral ciprofloxacin also showed no superiority of the former, with increased isolation of Stenotrophomonas maltophilia in both groups.A recent, large trial in 306 children aged between one and 12 years compared cycled nebulised tobramycin solution for inhalation to culture-based therapy and also ciprofloxacin to placebo. The primary analysis showed no difference in time to pulmonary e. We found that nebulised antibiotics, alone or in combination with oral antibiotics, were better than no treatment for early infection with Pseudomonas aeruginosa. Eradication may be sustained for up to two years. There is insufficient evidence to determine whether antibiotic strategies for the eradication of early Pseudomonas aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials of two active treatments have failed to show differences in rates of eradication of Pseudomonas aeruginosa. There have been no published randomised controlled trials that investigate the efficacy of intravenous antibiotics to eradicate Pseudomonas aeruginosa in cystic fibrosis. Overall, there is still insufficient evidence from this review to state which antibiotic strategy should be used for the eradication of early Pseudomonas aeruginosa infection in cystic fibrosis.

Topics: Administration, Inhalation; Administration, Oral; Adult; Anti-Bacterial Agents; Child; Ciprofloxacin; Colistin; Cystic Fibrosis; Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Randomized Controlled Trials as Topic; Tobramycin

Inhaled antibiotics are probably the safest and most effective therapy for Pseudomonas aeruginosa chronic lung infection in cystic fibrosis (CF) patients.. To summarise the available evidence, a systematic review of the three currently available inhaled antibiotics (aztreonam lysine (AZLI), colistin (COL) and tobramycin (TOB)) was performed. The three AZLI placebo-controlled studies showed that the improvements in FEV1 and mean sputum P. aeruginosa density were statistically significant better than with placebo. The two COL placebo-controlled studies involved few patients but showed that COL was better than placebo in terms of maintenance of some pulmonary function parameters. The tobramycin inhalation solution (TIS) and tobramycin inhalation powder studies showed that the efficacy of both formulations was similar but significantly better than placebo. In the comparative studies, TIS showed more efficacy than COL solution, colistin inhalation powder showed non-inferiority to TIS and AZLI was superior to TIS.. Placebo-controlled and comparative clinical trials have shown that clinical evidence of inhaled antibiotics is very different. The choice of treatment for each individual CF patient must be based on the features of the drug (clinical evidence on efficacy and safety), the inhalation system and the patient characteristics. Development of new inhaled antibiotics will allow new end points of efficacy and therapy regimens to be assessed.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Aztreonam; Chronic Disease; Colistin; Cystic Fibrosis; Humans; Lung Diseases; Pseudomonas aeruginosa; Pseudomonas Infections; Randomized Controlled Trials as Topic; Tobramycin

Nebuliser systems are used to deliver medications to control the symptoms and the progression of lung disease in people with cystic fibrosis. Many types of nebuliser systems are available for use with various medications; however, there has been no previous systematic review which has evaluated these systems.. To evaluate effectiveness, safety, burden of treatment and adherence to nebulised therapy using different nebuliser systems for people with cystic fibrosis.. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching of relevant journals and abstract books of conference proceedings. We searched the reference lists of each study for additional publications and approached the manufacturers of both nebuliser systems and nebulised medications for published and unpublished data. Date of the most recent search: 15 Oct 2012.. Randomised controlled trials or quasi-randomised controlled trials comparing nebuliser systems including conventional nebulisers, vibrating mesh technology systems, adaptive aerosol delivery systems and ultrasonic nebuliser systems.. Two authors independently assessed studies for inclusion. They also independently extracted data and assessed the risk of bias. A third author assessed studies where agreement could not be reached.. The search identified 40 studies with 20 of these (1936 participants) included in the review. These studies compared the delivery of tobramycin, colistin, dornase alfa, hypertonic sodium chloride and other solutions through the different nebuliser systems. This review demonstrates variability in the delivery of medication depending on the nebuliser system used. Conventional nebuliser systems providing higher flows, higher respirable fractions and smaller particles decrease treatment time, increase deposition and may be preferred by people with CF, as compared to conventional nebuliser systems providing lower flows, lower respirable fractions and larger particles. Nebulisers using adaptive aerosol delivery or vibrating mesh technology reduce treatment time to a far greater extent. Deposition (as a percentage of priming dose) is greater than conventional with adaptive aerosol delivery. Vibrating mesh technology systems may give greater deposition than conventional when measuring sputum levels, but lower deposition when measuring serum levels or using gamma scintigraphy. The available data indicate that these newer systems are safe when used with an appropriate priming dose, which may be different to the priming dose used for conventional systems. There is an indication that adherence is maintained or improved with systems which use these newer technologies, but also that some nebuliser systems using vibrating mesh technology may be subject to increased failures.. Clinicians should be aware of the variability in the performance of different nebuliser systems. Technologies such as adaptive aerosol delivery and vibrating mesh technology have advantages over conventional systems in terms of treatment time, deposition as a percentage of priming dose, patient preference and adherence. There is a need for long-term randomised controlled trials of these technologies to determine patient-focused outcomes (such as quality of life and burden of care), safe and effective dosing levels of medications and clinical outcomes (such as hospitalisations and need for antibiotics) and an economic evaluation of their use.

Topics: Aerosols; Albuterol; Anti-Bacterial Agents; Bronchodilator Agents; Carbenicillin; Colistin; Cromolyn Sodium; Cystic Fibrosis; Deoxyribonuclease I; Drug Delivery Systems; Humans; Medication Adherence; Nebulizers and Vaporizers; Randomized Controlled Trials as Topic; Recombinant Proteins; Saline Solution, Hypertonic; Tobramycin

Cystic fibrosis (CF) is an inherited condition characterised by the abnormal transport of chloride ions across transporting epithelia. This leads to the production of thick sticky mucus in the lungs, pancreas, liver, intestine and reproductive tract, and an increase in the salt content in sweat. Among other problems, people with CF experience recurrent respiratory infections and have difficulties digesting food. CF affects over 9000 individuals in the UK. CF shortens life expectancy and adversely affects quality of life. In 2010, CF was recorded as the cause of 103 deaths in England and Wales.. To evaluate the clinical effectiveness and cost-effectiveness of colistimethate sodium dry powder for inhalation (DPI) (Colobreathe(®), Forest Laboratories) and tobramycin DPI (TOBI Podhaler(®), Novartis Pharmaceuticals) for the treatment of Pseudomonas aeruginosa lung infection in CF.. Electronic databases were searched in February and March 2011 [MEDLINE, MEDLINE In-Process & Other Non-Indexed citations, EMBASE, The Cochrane Library databases, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, Conference Proceedings Citation Index (CPCI) and Bioscience Information Service (BIOSIS) Previews]. Relevant databases were searched for ongoing and unpublished studies, and bibliographies of relevant systematic reviews and the manufacturers' submissions were also hand-searched.. A systematic review of the clinical effectiveness and cost-effectiveness of colistimethate sodium DPI and tobramycin DPI for the treatment of chronic P. aeruginosa lung infection in CF was conducted. Existing economic evidence within the literature was reviewed and a de novo health economic model was also developed.. Three randomised controlled trials (RCTs) were included in the clinical effectiveness review. Both colistimethate sodium DPI and tobramycin DPI were reported to be non-inferior to nebulised tobramycin for the outcome forced expiratory volume in first second percentage predicted (FEV1%). It was not possible to draw any firm conclusions as to the relative efficacy of colistimethate sodium DPI compared with tobramycin DPI. The economic analysis suggests that colistimethate sodium DPI produces fewer quality-adjusted life-years (QALYs) than nebulised tobramycin. Given the incremental discounted lifetime cost of tobramycin DPI compared with nebulised tobramycin, it highly unlikely that tobramycin DPI has an incremental cost-effectiveness ratio that is better than £30,000 per QALY gained.. The uncertainty surrounding the short-term evidence base inevitably results in uncertainty surrounding the long-term clinical effectiveness and cost-effectiveness of colistimethate sodium DPI.. Both DPI formulations have been shown to be non-inferior to nebulised tobramycin as measured by FEV1%. The results of these trials should be interpreted with caution owing to the means by which the results were analysed, the length of follow-up, and concerns about the ability of FEV1% to accurately represent changes in lung health. Although the increase in QALYs is expected to be lower with colistimethate sodium DPI than with nebulised tobramycin, a price for this intervention had not been agreed at the time of the assessment. Depending on the price of colistimethate sodium DPI, this results either in a situation whereby colistimethate sodium DPI is dominated by nebulised tobramycin or in one whereby the incremental cost-effectiveness of nebulised tobramycin compared with colistimethate sodium DPI is in the range of £24,000-277,000 per QALY gained. The economic analysis also suggests that, given its price, it is unlikely that tobramycin DPI has a cost-effectiveness ratio of < £30,000 per QALY gained when compared with nebulised tobramycin. A RCT to assess the longer-term (≥ 12 months) efficacy of colistimethate sodium DPI and tobramycin DPI in comparison with nebulised treatments would be beneficial. Such a study should include the direct assessment of HRQoL using a relevant preference-based instrument. Future studies should ensure that the European Medicines Agency guidelines are adhered to. In addition, high-quality research concerning the relationship between forced expiratory volume in first second % (FEV1%) predicted or other measures of lung function and survival/health-related quality of life (HRQoL) would be useful.. PROSPERO CRD42011001350.. The National Institute for Health Research Health Technology Assessment programme.

Topics: Administration, Inhalation; Child; Colistin; Cost-Benefit Analysis; Cystic Fibrosis; Disease Progression; Humans; Outcome Assessment, Health Care; Pseudomonas aeruginosa; Pseudomonas Infections; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Therapeutic Equivalency; Tobramycin; United Kingdom

This systematic review evaluated evidence for two dry powder formulations, colistimethate sodium and tobramycin, for the treatment of chronic Pseudomonas aeruginosa in cystic fibrosis, as part of the UK national recommendation process for new technologies. Electronic bibliographic databases were searched in May 2012 (MEDLINE, MEDLINE in-Process, EMBASE, Cochrane Library databases, CINAHL, Web of Science, Conference Proceedings Citation Index and BIOSIS Previews). Relevant outcomes included rate and extent of microbial response (e.g. sputum density of P. aeruginosa), lung function (e.g. forced expiratory volume in 1 s (FEV1)), frequency, severity of acute exacerbations and adverse events. Three trials were included, and both dry powder formulations were reported to be non-inferior in the short term to nebulised tobramycin for FEV1. However, long-term follow-up data were missing and the effect on exacerbation rates was not always reported. Whilst short-term results showed that both dry powder drugs were non-inferior to nebulised tobramycin, there was no long-term follow-up and no phase 3 trials compared nebulised and dry powder colistimethate sodium. The use of FEV1 as the primary end-point may not accurately represent changes in lung health. This review illustrates the difficulty in assessing new technologies where the evidence base is poor.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Disease Progression; Dry Powder Inhalers; Evidence-Based Medicine; Forced Expiratory Volume; Humans; Lung; Powders; Pseudomonas aeruginosa; Pseudomonas Infections; Research Design; Time Factors; Tobramycin; Treatment Outcome

Lower respiratory tract infections, due to Pseudomonas aeruginosa or Acinetobacter baumannii, are frequently encountered in patients with cystic fibrosis (CF) or in patients developing nosocomial pneumonias. Both of these conditions bear a high mortality risk and aggressive antibiotic therapy is necessary. Inhaled antibiotics might represent an effective therapeutic approach for these diseases as it has demonstrated good bactericidal efficacy and safety in both preclinical and clinical studies. This colistin formulation might be useful particularly in patients with respiratory tract infections due to multidrug-resistant Gram-negative bacteria. Its main advantages are a better safety profile with a minimal or absent risk of nephrotoxicity.. This paper discusses the available systemic formulations of colistin, with pharmacokinetic and safety profiles, followed by an overview of inhaled antibiotics in lower respiratory tract infections.. Inhaled colistin should be used selectively as monotherapy in chronic infections with P. aeruginosa in CF patients, whereas in patients with hospital/ventilator-acquired pneumonia (HAP/VAP), it should be used in a combined regimen with systemic antibiotics.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Administration, Inhalation; Animals; Anti-Bacterial Agents; Bronchiectasis; Colistin; Cross Infection; Cystic Fibrosis; Drug Synergism; Drug Therapy, Combination; Humans; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections

Various inhaled antibiotics are currently used for treating chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients, however their relative efficacies are unclear. We compared the efficacy of the inhaled antibiotics tobramycin (TIP, TIS-T, TIS-B), colistimethate sodium (colistin) and aztreonam lysine for inhalation (AZLI) based on data from randomised controlled trials.. In the base case, efficacies of antibiotics were compared using a network meta-analysis of seven trials including change from baseline in forced expiratory volume in 1 second (FEV(1)) % predicted, P. aeruginosa sputum density and acute exacerbations.. The tobramycin preparations, AZLI and colistin, showed comparable improvements in efficacy in terms of FEV1% predicted at 4 weeks; the difference in % change from baseline (95%CrI) for TIP was compared to TIS-T (-0.55, -3.5;2.4), TIS-B (-0.64, -7.1;5.7), AZLI (3.64, -1.0;8.3) and colistin (5.77, -1.2;12.8).. We conclude that all studied antibiotics have comparable efficacies for the treatment of chronic P. aeruginosa lung infection in CF.

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Bacterial Agents; Aztreonam; Bacterial Load; Bayes Theorem; Biological Availability; Chronic Disease; Colistin; Cystic Fibrosis; Disease Progression; Female; Forced Expiratory Volume; Humans; Information Services; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Randomized Controlled Trials as Topic; Respiratory Tract Infections; Tobramycin; Treatment Outcome

Therapy of chronic respiratory diseases often involves inhalation therapy with nebulizers. Patients often attempt to shorten the time consuming administration procedure by mixing drug solutions/suspensions for simultaneous inhalation. This article considers the issue of physico-chemical compatibility of admixtures of drug solutions/suspensions in nebulizers. A search of databases, prescribing information and primary literature was conducted to locate literature concerning the physico-chemical compatibility of inhalation solutions/suspensions. This was supplemented by telephone interviews. Admixtures of albuterol with ipratropium and/or cromolyn, of albuterol and budesonide, or tobramycin, or colistin are physico-chemically compatible. Physico-chemical compatibility has been demonstrated for admixtures of cromolyn with albuterol and/or ipratropium and for admixtures of cromolyn and budesonide. Admixtures of budesonide with ipratropium and/or fenoterol, and admixtures of budesonide and albuterol, or cromolyn are physico-chemically compatible. Both cromolyn and colistin are incompatible with benzalkonium chloride. Admixtures should be prepared from inhalation solutions/suspensions formulated without preservatives. Besides studies of the physico-chemical compatibility, the aerodynamic behaviour of physico-chemical mixtures needs to be studied before a final recommendation of simultaneous nebulization of compatible admixtures can be made.

Topics: Acetylcysteine; Administration, Inhalation; Albuterol; Anti-Asthmatic Agents; Anti-Bacterial Agents; Asthma; Bronchodilator Agents; Budesonide; Colistin; Cromolyn Sodium; Cystic Fibrosis; Deoxyribonuclease I; Drug Therapy, Combination; Expectorants; Humans; Ipratropium; Nebulizers and Vaporizers; Respiratory Therapy; Tobramycin

Chronic pulmonary infection with Pseudomonas aeruginosa is responsible for most of the morbidity and mortality in cystic fibrosis (CF). Once established as a biofilm, chronic P. aeruginosa infection caused by the mucoid phenotype cannot be eradicated. However, a period of intermittent colonization with P. aeruginosa precedes the establishment of the chronic infection. This window of opportunity can be utilized to eradicate P. aeruginosa from the respiratory tract of CF patients by means of oral ciprofloxacin in combination with nebulized colistin for 3 weeks or, even better, for 3 months or by means of inhaled tobramycin as monotherapy for 4 weeks or longer. This early, aggressive eradication therapy has now been used for 15 years without giving rise to resistance to the antibiotics and without serious side effects. The therapeutic results have been very successful and have completely changed the epidemiology in the Danish Cystic Fibrosis Center and a few other centers which have used this strategy for several years. The chronic P. aeruginosa lung infection is not seen in CF infants and children anymore due to the aggressive therapy, and no other bacteria have replaced P. aeruginosa in these young patients. The aggressive therapy has been shown to very cost-effective, and a European Consensus report recommends this approach.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Chronic Disease; Ciprofloxacin; Colistin; Cystic Fibrosis; Denmark; Humans; Incidence; Pseudomonas Infections

Pseudomonas aeruginosa colonisation has a negative effect on pulmonary function in cystic fibrosis patients. The organism can only be eradicated in the early stage of colonisation, while reduction of bacterial density is desirable during chronic colonisation or exacerbations. Monthly, or at least 3-monthly, microbiological culture is advisable for patients without previous evidence of P. aeruginosa colonisation. Cultures should be performed at least every 2-3 months in patients with well-established colonisation, and always during exacerbations or hospitalisations. Treatment of patients following the first isolation of P. aeruginosa, but with no clinical signs of colonisation, should be with oral ciprofloxacin (15-20 mg/kg twice-daily for 3-4 weeks) plus inhaled tobramycin or colistin (intravenous treatment with or without inhaled treatment can be used as an alternative), while patients with acute infection should be treated for 14-21 days with high doses of two intravenous antimicrobial agents, with or without an inhaled treatment during or at the end of the intravenous treatment. Maintenance treatment after development of chronic P. aeruginosa infection/colonisation (pathogenic colonisation) in stable patients (aged>6 years) should be with inhaled tobramycin (300 mg twice-daily) in 28-day cycles (on-off) or, as an alternative, colistin (1-3 million units twice-daily). Colistin is also a possible choice for patients aged<6 years. Treatment can be completed with oral ciprofloxacin (3-4 weeks every 3-4 months) for patients with mild pulmonary symptoms, or intravenously (every 3-4 months) for those with severe symptoms or isolates with ciprofloxacin resistance. Moderate and serious exacerbations can be treated with intravenous ceftazidime (50-70 mg/kg three-times-daily) or cefepime (50 mg/kg three-times-daily) plus tobramycin (5-10 mg/kg every 24 h) or amikacin (20-30 mg/kg every 24 h) for 2-3 weeks. Oral ciprofloxacin is recommended for patients with mild pulmonary disease. If multiresistant P. aeruginosa is isolated, antimicrobial agents that retain activity are recommended and epidemiological control measures should be established.

Topics: Amikacin; Anti-Bacterial Agents; Anti-Infective Agents; Bronchopneumonia; Cefepime; Ceftazidime; Cephalosporins; Ciprofloxacin; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Humans; Inhalation; Injections, Intravenous; Lung Diseases; Pneumonia, Bacterial; Practice Guidelines as Topic; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

Topics: Animals; Colistin; Cystic Fibrosis; Humans

Topics: Adolescent; Adrenergic beta-Agonists; Adult; Advance Care Planning; Anti-Bacterial Agents; Anti-Inflammatory Agents; Bone Density; Bronchodilator Agents; Career Choice; Child; Colistin; Cystic Fibrosis; Diabetes Complications; Diabetes Mellitus; Education; Employment; Energy Intake; Exercise; Expectorants; Family Planning Services; Gastrointestinal Diseases; Humans; Insurance, Disability; Liver Diseases; Nutritional Support; Oxygen Inhalation Therapy; Palliative Care; Patient Care Team; Physical Fitness; Respiration, Artificial; United States

Aerosol delivery of antibiotics offers the potential to achieve high antibiotic concentrations at the site of infection while reducing the risk of systemic untoward effects because of minimal resorption into the bloodstream. We reviewed knowledge acquired in this field over the two latter decades. While the earliest data were obtained with gentamycin, the most conclusive evidence presently regards aminoglycosides and colistin. Aerosol delivery of tobramycin was recently improved with the development of a new formulation for inhalation. Coupled with an adequate nebulization system, intermittent treatment with tobramycin for inhalation has been evaluated in randomized placebo-controlled studies. These studies have demonstrated a significant improvement of respiratory function.

Topics: Administration, Inhalation; Adolescent; Aerosols; Anti-Bacterial Agents; Carbenicillin; Child; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Gentamicins; Humans; Nebulizers and Vaporizers; Penicillins; Placebos; Polymyxins; Pseudomonas Infections; Randomized Controlled Trials as Topic; Time Factors; Tobramycin

Colistin is a cationic polypeptide antibiotic from the polymyxin family that was first introduced in 1962 but abandoned in the early 1970s because of initial reports of severe toxicities. However, a recent increase in the prevalence of multidrug resistant (MDR) Pseudomonas aeruginosa and the lack of novel agents in development calls for a need to re-examine the role of colistin therapy in patients with cystic fibrosis. Current data supports the use of intravenous colistimethate for the treatment of acute pulmonary exacerbations involving MDR P. aeruginosa and inhaled therapy for initial colonization. The frequency of nephrotoxicity and severity of neurotoxicity seem to be substantially less than previously believed. In addition, recent pharmacokinetic and pharmacodynamic data suggests new intravenous dosing regimens may enhance efficacy while minimizing toxicities; such regimens deserve further evaluation. Pre- and post-treatment spirometry is recommended at initiation of inhaled colistin therapy to identify sensitized individuals. Judicious use of colistin where the benefits have been clearly documented will retain this as a useful agent in the management of P. aeruginosa infections in patients with cystic fibrosis.

Topics: Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Resistance, Microbial; Humans; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Administration, Inhalation; Anti-Bacterial Agents; Chronic Disease; Colistin; Community Health Centers; Cystic Fibrosis; Drug Resistance, Microbial; Humans; Injections, Intravenous; Prognosis; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Amphotericin B; Anti-Bacterial Agents; Anti-Ulcer Agents; Cimetidine; Colistin; Cystic Fibrosis; Humans; Receptors, Drug; Virus Diseases

Treating chronic Pseudomonas infection of the bronchial tree is a very important part of the treatment strategy in patients with cystic fibrosis. There are only a few antibiotics which are effective against pseudomonas. Many of them soon lead to bacterial resistance (e.g. fluoro-quinolones). Inhaling antibiotics produces high sputum concentrations and low systemic toxicity. Tolerance is good and resistance rare. Several clinical studies, some of them doubleblind placebo controlled, have shown a positive effect of inhaled antibiotics on symptoms, on frequency of necessary i.v. therapies and also on pulmonary function. Most commonly aminoglycosides (tobramycin) and colistin, which is not yet registered in Switzerland, are used. The main indication is chronic therapy of Pseudomonas infection.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Bronchitis; Colistin; Cystic Fibrosis; Humans; Microbial Sensitivity Tests; Pseudomonas Infections; Tobramycin

This review mainly summarizes selected aspects of the present knowledge of drug elimination kinetics independent of developmental changes, with special attention given to clinical situations. The effects of different disease states, drug interactions, changes in urinary pH, induction of microsomal enzymes, competition for renal excretory mechanisms, possible enterohepatic recirculation, binding of drugs to tissues, effects of a drug on another drug's metabolizing organ, and dose-dependent elimination, on increase or decrease of drug elimination rates in children, have been presented. Based on the available data it seems that one may postulate the following conclusions: (1) that the distribution factors as well as changes in drug elimination capacities seem to play a role, perhaps with differing relative importance, during each of the maturational periods; (2) that the physicochemical properties of a drug and its dosage, as well as changes in the volume of distribution in children, in the course of certain disease states may have a significant effect on kinetics of drug disposition in the body; (3) that systemic clearance, a model independent parameter, rather than elimination half-life, a hybrid pharmacokinetic parameter, more accurately reflects elimination of some drugs from the body; (4) that each drug and every clinical situation may require the evaluation of the direct effect on pharmacokinetic processes, since general principles may not always apply; (5) that drug disposition studies should also be performed, if possible, on patients under actual clinical situations and receiving the usual therapeutic regime, and (6) that the half-life of colistin is independent of postnatal age which should serve as a warning not to generalize about drug excretion in the young infant.

Topics: Adult; Anti-Bacterial Agents; Brain Injuries; Child; Child, Preschool; Colistin; Cystic Fibrosis; Digoxin; Dose-Response Relationship, Drug; Drug Interactions; Female; Half-Life; Heart Failure; Humans; Hydrogen-Ion Concentration; Hypothermia, Induced; Infant; Infant, Newborn; Kidney; Kinetics; Liver; Nephrotic Syndrome; Nutrition Disorders; Pharmaceutical Preparations; Phenobarbital; Reye Syndrome; Serum Albumin; Urine

Topics: Animals; Antibodies, Bacterial; Antineoplastic Agents; Arthritis, Infectious; Bone Diseases; Burns; Carbenicillin; Carrier State; Colistin; Cross Infection; Cystic Fibrosis; Disease Models, Animal; Drug Therapy, Combination; Gentamicins; Humans; Immunologic Deficiency Syndromes; Leukemia; Lung Diseases; Pneumonia; Polymyxins; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Therapy; Skin Diseases, Infectious; Surgical Wound Infection; Transplantation, Homologous

This study assessed the ease of use of tobramycin inhalation powder (TIP) administered via T-326 inhaler versus tobramycin inhalation solution (TIS) and colistimethate sodium (COLI), both administered via nebulizers, for the treatment of chronic pulmonary Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF).. A real-world, open-label, crossover, interventional phase IV study was conducted in CF patients aged ⩾6 years with forced expiratory volume in 1 second (FEV. A total of 60 patients [mean (standard deviation) age, 27.6 (8.4) years] were allocated to three treatment arms [TIS/TIP ( n = 14); COLI/TIP ( n = 28); TIP/TIP ( n = 18)] in Cycle 1. The mean total administration time, which included device setup and cleaning, in Cycle 1 versus Cycle 2 for TIS/TIP, COLI/TIP, and TIP/TIP arms were 37.0 versus 5.0 min, 16.4 versus 3.8 min, and 4.2 versus 3.4 min, respectively. The difference in mean total administration time was significantly shorter in Cycle 2 than in Cycle 1 for TIS/TIP ( p = 0.0112) and COLI/TIP ( p = 0.0016) arms. Overall, 12 patients were found to have contaminated devices across the two treatment cycles. In the TIP/TIP arm, no contamination of the T-326 inhaler was observed in either cycle. Treatment satisfaction, assessed by the Treatment Satisfaction Questionnaire for Medication and ACCEPT® questionnaire, was better overall for TIP compared with TIS and COLI. There were no unexpected adverse events and most were mild or moderate in intensity.. The T-326 inhaler used to deliver TIP was easy to use, required shorter total administration time, and was much less frequently contaminated than the nebulizers. The safety findings observed for TIP were generally consistent with its established safety profile.

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Bacterial Agents; Child; Colistin; Cross-Over Studies; Cystic Fibrosis; Equipment Contamination; Equipment Design; Europe; Female; Forced Expiratory Volume; Humans; Lung; Male; Nebulizers and Vaporizers; Patient Satisfaction; Powders; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Time Factors; Tobramycin; Treatment Outcome; Young Adult

The purpose of this study was to define the pulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and formed colistin following intravenous (i.v.) and inhaled administration in cystic fibrosis (CF) patients. Six CF subjects were administered nebulized CMS doses of 2 and 4 million IU and an i.v. CMS infusion of 150 mg of colistin base activity. Blood plasma, sputum, and urine samples were collected for 12 to 24 h postdose. To assess the tolerability of the drug, lung function tests, blood serum creatinine concentrations, and adverse effect reports were recorded. All doses were well tolerated in the subjects. The pharmacokinetic parameters for CMS following i.v. delivery were consistent with previously reported values. Sputum concentrations of formed colistin were maintained at <1.0 mg/liter for 12 h postdose. Nebulization of CMS resulted in relatively high sputum concentrations of CMS and formed colistin compared to those resulting from i.v. administration. The systemic availability of CMS was low following nebulization of 2 and 4 million IU (7.93% ± 4.26% and 5.37% ± 1.36%, respectively), and the plasma colistin concentrations were below the limit of quantification. Less than 2 to 3% of the nebulized CMS dose was recovered in the urine samples in 24 h. The therapeutic availability and drug targeting index for CMS and colistin following inhalation compared to i.v. delivery were significantly greater than 1. Inhalation of CMS is an effective means of targeting CMS and formed colistin for delivery to the lungs, as high lung exposure and minimal systemic exposure were achieved in CF subjects.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Female; Humans; Lung; Male; Middle Aged; Sputum

To compare the efficacy, safety and treatment satisfaction with inhaled colistin versus tobramycin in the cure of chronic Pseudomonas colonization in cystic fibrosis patients.. A quasi-experimental open paired data trial in which patients with cystic fibrosis and chronic colonization by Pseudomonas aeruginosa were included. Patients performed 2 periods of 6 consecutive months of nebulized antibiotics: inhaled tobramycin at a dose of 300 mg/12 h (Pari LC Plus(®)) and colistimethate (I-neb(®)) at a dose of 1 MIU twice a day. Visits were made monthly and at the beginning and the end of each period; we evaluated the body mass index, lung function, number of exacerbations and sputum microbiology. Patient satisfaction was assessed with 2 questionnaires of satisfaction on the treatment and the inhalation devices.. A group of 25 patients (8 men and 6 under 14 years) with a mean age of 21.4 (7.2) years and 59.8 (21.1) % of forced expiratory volume in one second (FEV1) were included. During the second period, clinical benefits were obtained in terms of lung function with an FEV1 gain of 5% at 6 months of treatment and reducing the number of exacerbations (1.84 [1.2] vs 0.8 [0.8]; P=.001). The questionnaire score was higher in period 2.. Colistimethate sodium administered through the misting system I-neb(®) provides clinical benefits in terms of exacerbations and improvement of lung function and patient satisfaction for the nebulized antibiotic treatment.

Topics: Administration, Inhalation; Body Mass Index; Child; Child, Preschool; Colistin; Cross-Over Studies; Cystic Fibrosis; Drug Resistance, Bacterial; Female; Forced Expiratory Volume; Humans; Lung; Male; Nebulizers and Vaporizers; Patient Satisfaction; Pseudomonas aeruginosa; Sputum; Surveys and Questionnaires; Tobramycin; Treatment Outcome

In patients with cystic fibrosis (CF), treatment of new Pseudomonas aeruginosa (Pa) infection postpones the occurrence of chronic infection, but the best eradication regimen is unknown .. Compare 2 Pa eradication regimens in children with new Pa infection.. Children with CF (0-18 years) and a new isolation of Pa from sputum, cough swab or BAL were randomized to treatment with tobramycin inhalation solution for 28 days (TIS) or inhaled sodiumcolistimethate (2×2millU/day) plus oral ciprofloxacin (30 mg/kg/day) for 3 months (CC). Airway cultures were taken for 6 consecutive months, then every 3 months. The primary outcome was Pa eradication at the end of treatment. Secondary outcome parameters were: time to Pa relapse from end of treatment, total and Pa specific IgG, FEV(1), BMI and Pa status at 2year follow-up.. 58 patients with new Pa isolation were randomized. Their median age was 9 years (IQR 4.7-13.1) and their median FEV(1) 98% predicted (IQR 87-107). Eighteen treatments concerned the first Pa isolation 'ever' (TIS: 8; CC: 10). For the remaining, median time since previous Pa was 19 months (IQR 9-41). Eradication at end of treatment was similar for both treatments: 26/29 CC and 23/29 in TOBI treated patients (p=0.47). Median time to recurrence of Pa was 9 months (95% CI 0.0-19.0) for CC and 5 months (95% CI 1.7-8.3) for TIS (p=0.608). After 1 year, the 2 groups did not differ in change in total and Pa specific IgG, FEV(1) and BMI. After 2 years, 10% of patients had chronic Pa infection.. In children with CF and new Pa infection, inhalation of TIS (28 days) or CC (3 months) resulted in similar eradication success at the end of treatment (80 and 90% respectively) and similar clinical evolution during the first 2 years of follow-up.

Topics: Administration, Inhalation; Adolescent; Anti-Bacterial Agents; Anti-Infective Agents; Child; Child, Preschool; Ciprofloxacin; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Infant; Male; Prospective Studies; Pseudomonas Infections; Sputum; Tobramycin; Treatment Outcome

To assess efficacy and safety of a new dry powder formulation of inhaled colistimethate sodium in patients with cystic fibrosis (CF) aged ≥6 years with chronic Pseudomonas aeruginosa lung infection.. A prospective, centrally randomised, phase III, open-label study in patients with stable CF aged ≥6 years with chronic P aeruginosa lung infection. Patients were randomised to Colobreathe dry powder for inhalation (CDPI, one capsule containing colistimethate sodium 1 662 500 IU, twice daily) or three 28-day cycles with twice-daily 300 mg/5 ml tobramycin inhaler solution (TIS). Study duration was 24 weeks.. 380 patients were randomised. After logarithmic transformation of data due to a non-normal distribution, adjusted mean difference between treatment groups (CDPI vs TIS) in change in forced expiratory volume in 1 s (FEV1% predicted) at week 24 was -0.98% (95% CI -2.74% to 0.86%) in the intention-to-treat population (n=373) and -0.56% (95% CI -2.71% to 1.70%) in the per protocol population (n=261). The proportion of colistin-resistant isolates in both groups was ≤1.1%. The number of adverse events was similar in both groups. Significantly more patients receiving CDPI rated their device as 'very easy or easy to use' (90.7% vs 53.9% respectively; p<0.001).. CDPI demonstrated efficacy by virtue of non-inferiority to TIS in lung function after 24 weeks of treatment. There was no emergence of resistance of P aeruginosa to colistin. Overall, CDPI was well tolerated. TRIAL REG NO: EudraCT 2004-003675-36.

Topics: Administration, Inhalation; Adult; Anti-Bacterial Agents; Clinical Trials, Phase III as Topic; Colistin; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Male; Powders; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin; Treatment Outcome; Young Adult

Pseudomonas aeruginosa chronic pulmonary infection is an unfavourable event in cystic fibrosis. Bacterial clearance is possible with an early antibiotic treatment upon pathogen isolation. Currently, no best practice exists for early treatment. The efficacy of two different regimens against initial P. aeruginosa infection was assessed.. In a randomised, open-label, parallel-group study involving 13 centres, the superiority of inhaled tobramycin/oral ciprofloxacin compared with inhaled colistin/oral ciprofloxacin (reference treatment) over 28 days was evaluated. Patients were eligible if they were older than 1 year with first or new P. aeruginosa isolation. Treatments were assigned equally by centralised balanced randomisation, stratified by age and forced expiratory volume in 1 s values. The participants and those giving the intervention were not masked to arm assignments. The primary endpoint was P. aeruginosa eradication, defined as three successive negative cultures in 6 months. Analysis was by intention to treat. This trial was registered with EudraCT, number 2008-006502-42.. 105 patients were assigned to inhaled colistin/oral ciprofloxacin (arm A) and 118 to inhaled tobramycin/oral ciprofloxacin (arm B). All patients were analysed. P. aeruginosa was eradicated in 66 (62.8%) patients in arm A and in 77 (65.2%) in arm B (OR 0.90, 95% CI 0.52 to 1.55, p=0.81). Following treatment, an increase in Stenotrophomonas maltophilia was noted (OR 3.97, 95% CI 2.27 to 6.94, p=0.001) with no differences between the two arms (OR 0.89, 95% CI 0.44 to 1.78, p=0.88).. No superiority of treatment under study was demonstrated in comparison to the reference treatment. Early eradication treatment was associated with an increase in S maltophilia.

Topics: Administration, Inhalation; Administration, Oral; Anti-Bacterial Agents; Chi-Square Distribution; Child; Child, Preschool; Ciprofloxacin; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Infant; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Stenotrophomonas maltophilia; Tobramycin; Treatment Outcome

Antibiotic combination therapy might be more efficient than single antibiotics to combat Pseudomonas aeruginosa biofilms in the airways of patients with cystic fibrosis. We tested the ability of colistin sulphate-tobramycin combinations and single antibiotics to kill P. aeruginosa biofilms.. P. aeruginosa biofilms were generated in vitro and in rat lungs. In a pilot study, 5 patients with cystic fibrosis inhaled colistin and then tobramycin for 4 weeks. The changes in P. aeruginosa counts and lung function were assessed before and after therapy.. Antibiotic combination therapy significantly reduced the number of P. aeruginosa cells in P. aeruginosa biofilm models in vitro. When rats were challenged with 1 x 10(7) cfu of P. aeruginosa, which was embedded in alginate beads, mortality rates, lung pathologic findings, and bacterial colony-forming unit counts were significantly lower after 7 days in animals receiving antibiotic combination than in animals receiving single antibiotics. In patients with cystic fibrosis, inhaled colistin-tobramycin was well tolerated and resulted in a mean decrease of 2.52 + /- 2.5 log(10) cfu of P. aeruginosa per milliliter of sputum (P = .027). Measurements of forced expiratory volume in 1 s, obtained both before and after the study, did not differ significantly.. Colistin-tobramycin combinations are more efficient than respective single antibiotics for killing P. aeruginosa in biofilms in vitro, and they significantly reduced P. aeruginosa cell counts in a rat lung infection model and in patients with cystic fibrosis.

Topics: Administration, Inhalation; Adult; Animals; Anti-Bacterial Agents; Biofilms; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Female; Humans; Lung; Male; Microbial Sensitivity Tests; Pilot Projects; Pseudomonas aeruginosa; Pseudomonas Infections; Rats; Rats, Inbred Lew; Tobramycin; Treatment Outcome

Dry powder inhalation (DPI) may be an alternative to nebulisation of drugs in the treatment of chest infections in cystic fibrosis (CF) patients. In a pilot study the feasibility of a colistin dry powder inhaler (prototype Twincer) by a single dose in CF-patients was assessed and compared to nebulised colistin.. Ten CF-patients, chronically infected with P. aeruginosa, participated in a randomised cross over study. On two visits to the outpatient clinic, patients inhaled colistin sulphomethate as 25 mg dry powder (Twincer) or as 158 mg nebulised solution (Ventstream nebuliser, PortaNeb compressor). Pulmonary function tests were performed before, 5 and 30 min after inhalation. Serum samples were drawn prior to each dose and at 15, 45 min, 1.5; 2.5; 3.5 and 5.5 h after inhalation.. The DPI was well tolerated by the patients: no significant reduction in FEV1 was observed. Relative bioavailability of DPI to nebulisation was approx. 140% based on actual dose and approx. 270% based on drug dose label claim.. The colistin DPI (Twincer inhaler) is well tolerated and appreciated by CF-patients. Optimisation with respect to particle size and internal resistance of the inhaler is necessary to attain equivalent pulmonary deposition to liquid nebulisation.

Topics: Administration, Inhalation; Adult; Anti-Bacterial Agents; Colistin; Cross-Over Studies; Cystic Fibrosis; Dose-Response Relationship, Drug; Feasibility Studies; Female; Follow-Up Studies; Forced Expiratory Flow Rates; Forced Expiratory Volume; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pilot Projects; Powders; Surveys and Questionnaires; Treatment Outcome

Inhaled colistin is commonly used in patients with cystic fibrosis (CF), but only limited data are available to define its pharmacokinetic profile.. We performed a multicentre study in 30 CF patients to assess sputum, serum and urine concentrations after a single dose of 2 million units of colistin administered by inhalation. In a subgroup of patients we also compared the efficacy of two different nebulizers for administration of inhaled colistin.. Serum concentrations of colistin reached their maximum 1.5 h after inhalation and decreased thereafter. Serum concentrations were well below those previously reported for systemic application in all patients. A mean 4.3+/-1.3% of the inhaled dose was detected in urine. Elimination characteristics did not differ significantly from those previously reported for systemic application. A positive correlation was found between forced expiratory volume in 1 s (FEV1) in per cent predicted and both AUC and maximal colistin concentrations in serum (Cmax). Maximum sputum concentrations were at least 10 times higher than the MIC breakpoint for Pseudomonas aeruginosa proposed by the British Society for Antimicrobial Chemotherapy. Although sputum drug concentrations decreased after a peak at 1 h, the mean colistin concentrations were still above 4 mg/L after 12 h. No differences were seen in polymyxin E sputum concentrations, for CF patients between the two nebulizer systems.. The low systemic and high local concentrations of colistin support the use of inhaled colistin in CF patients infected with P. aeruginosa.

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Bacterial Agents; Chemical Phenomena; Chemistry, Physical; Colistin; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Sputum

A previous study of tobramycin nebuliser solution (TNS) compared with colistin [C] in cystic fibrosis (CF) patients, chronically infected with pseudomonas, showed benefit for the TNS treated patients over one treatment cycle only. The current report is of an extension of that study. An open randomised cross-over study of TNS compared with C was conducted on 21 patients who had previously been on the 1 cycle study. They continued for a further 5 months and then crossed over to the alternate treatment. There was an advantage for TNS over C in FEV(1) % predicted change over time. The C slope was -0.88% per month and the TNS slope 0.35% per month (p=0.0002). This suggests advantages of TNS over C in a study with a small number of patients. Larger studies are required.

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Bacterial Agents; Antibiotic Prophylaxis; Chronic Disease; Colistin; Cross-Over Studies; Cystic Fibrosis; Female; Follow-Up Studies; Humans; Male; Pseudomonas Infections; Tobramycin

Inhaled colistin is used for the treatment of Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients despite reports of chest tightness and bronchospasm. The main objective of the study was to assess whether bronchospasm occurred in pediatric CF patients with or without clinical evidence of airway hyperreactivity.. A prospective placebo-controlled clinical trial with crossover design was devised using challenge tests with 75 mg colistin in 4 mL saline solution and a placebo solution of the same osmolarity using a breath-enhanced nebulizer for administration. Subjects were recruited as follows: high risk (HR) for bronchospasm due to a personal history of recurrent wheezing, a family history of asthma and/or atopy, or bronchial lability, as demonstrated in pulmonary function tests; or low risk (LR) without these characteristics.. The mean FEV(1) (expressed as the mean [+/- SD] fall from baseline) of the HR group (n = 12) fell 12 +/- 9% after placebo was administered, and fell 17 +/- 10% after colistin was administered. For the LR group (n = 8), the mean FEV(1) fell 9 +/- 4% following placebo administration and 13 +/- 8% following colistin administration. There was a greater number of subjects in the HR group compared to the LR group, which had a mean fall in FEV(1) of >/= 15% (p < 0.01) after inhaling colistin. The differences between placebo and colistin therapy in the LR group were not significant.. The results demonstrated that colistin can cause bronchospasm, particularly in those patients with coexisting CF and asthma.

Topics: Administration, Inhalation; Adolescent; Asthma; Bronchial Spasm; Bronchitis; Bronchoconstriction; Child; Colistin; Comorbidity; Cross-Over Studies; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Male; Nebulizers and Vaporizers; Prospective Studies; Pseudomonas Infections; Risk Factors; Spirometry

Colistin, an antibiotic almost abandoned for intravenous administration for many years due to its reported toxicity, has been recently reintroduced in clinical practice due to the emergence of multidrug-resistant gram-negative bacteria and the lack of development of new antibiotics to combat them. To assess the safety and effectiveness of intravenous colistin, in combination with other antimicrobial agents, in the treatment of serious infections in patients without cystic fibrosis, a retrospective cohort study in a 450-bed tertiary-care hospital in Athens, Greece, was performed. Patients who were hospitalized from 1 October 2000 to 31 January 2004 and received intravenous colistin for more than 72 h were further analyzed. The primary outcome measure was the in-hospital mortality; secondary end points were the clinical outcome of the infections and the occurrence of colistin toxicity. Fifty patients received intravenous colistin with a median (mean) daily dose of 3 (4.5) million IU for 16.5 (21.3) days for the management of 54 episodes of infections due to multidrug-resistant gram-negative bacteria. The predominant infections were pneumonia (33.3%), bacteremia (27.8%), urinary tract infection (11.1%), and intra-abdominal infection (11.1%). The responsible pathogens were Acinetobacter baumannii (51.9%), Pseudomonas aeruginosa (42.6%), and Klebsiella pneumoniae (3.7%) strains (no pathogen was isolated from one case). In-hospital mortality was 24% (12/50 patients). Clinical response (cure or improvement) of the infection was observed in 66.7% of episodes (36/54). In the studied group, serum creatinine levels were decreased, at the end of colistin treatment, by an average of 0.2 +/- 1.3 mg/dl compared to baseline levels. Deterioration of renal function during colistin therapy was observed in 4/50 patients (8%). Coadministration of other antimicrobial agents with spectrum against gram-negative microorganisms and the absence of a control group constitute the major limitations of this study. The use of intravenous colistin for the treatment of infections due to multidrug-resistant gram-negative bacteria appears to be safe and effective.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Kidney Function Tests; Male; Microbial Sensitivity Tests; Middle Aged; Treatment Outcome

Pulmonary administration of colistin is one of the antimicrobial treatments used in Cystic Fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. Dry powder inhalation of colistin may be an attractive alternative to nebulization of colistin. However, nebulized colistin can cause bronchoconstriction in CF patients. Therefore, in the progress of developing a dry powder formula, the choice of the inhaler and its contents should be guided by optimal efficacy and the least possible side effects. To investigate the side effects, a study was initiated to compare the tolerability of colistin sulphate to colistin sulphomethate per nebulization in CF-patients.. Nine CF-patients chronically infected with P. aeruginosa participated in a double blind, randomized cross over study. On two visits to the outpatient clinic, patients were submitted to either nebulized colistin sulphate or colistin sulphomethate solution. Lung function tests were performed immediately before and 15 and 30 min after nebulization.. Nebulization of colistin sulphate caused a significant larger mean decrease in lung function compared to nebulized colistin sulphomethate. A significant decrease in mean changes (SD) in FEV1 at 30 min and FVC at 15 and 30 min after nebulization compared to baseline of -7.3% (8.6%), -5.7% (7.3%) and -8.4% (7.5%) respectively was seen after colistin sulphate nebulization compared to colistin sulphomethate (P < 0.05). Seven patients were not able to complete the nebulization of colistin sulphate because of throat irritation and severe cough.. Based on these results it was concluded that inhalation with nebulized colistin sulphate is not suitable for treatment of CF patients chronically infected with P. aeruginosa. Colistin sulphomethate is the drug of choice for pulmonary administration of colistin.

Topics: Administration, Inhalation; Adult; Colistin; Cross-Over Studies; Cystic Fibrosis; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Nebulizers and Vaporizers; Pilot Projects; Probability; Respiratory Function Tests; Risk Assessment; Severity of Illness Index; Treatment Outcome

To examine the effectiveness of delivery of nebulised colistin by the HaloLite nebuliser compared to the Pari LC Plus in patients with cystic fibrosis.. Randomised crossover trial of 15 patients aged >6 years. Inhalation of one mega unit of colistin in 3 ml diluent, labelled with technetium-99m DTPA, was used to assess lung deposition. The Pari was nebulised to dryness and one button press of the HaloLite was completed. Following a seven day washout period, patients inhaled colistin twice daily for seven days through the first device. Sputum specimens were analysed for colistin levels and pseudomonas load. This procedure was repeated with the alternative device.. Lung uptake of radiolabelled colistin was significantly higher with the Pari. However, lung uptake calculated as a percentage of the amount of drug used was significantly higher for the HaloLite. Time to nebulise was significantly shorter with the HaloLite. Sputum levels of colistin were higher following use of the Pari; this was close to significance.. The manufacturer's recommended dosages for nebulising antibiotics with a HaloLite result in a lower delivery than patients receive when using a Pari nebuliser. The concept of adaptive aerosol delivery has several theoretical advantages but the recommended doses for the HaloLite need to be modified in order to improve effectiveness.

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Bacterial Agents; Child; Colistin; Cross-Over Studies; Cystic Fibrosis; Humans; Lung; Nebulizers and Vaporizers; Opportunistic Infections; Pseudomonas Infections; Radiopharmaceuticals; Sputum; Technetium Tc 99m Pentetate

Chronic infection with Pseudomonas aeruginosa is associated with progressive deterioration in lung function in cystic fibrosis (CF) patients. The purpose of this trial was to assess the efficacy and safety of tobramycin nebuliser solution (TNS) and nebulised colistin in CF patients chronically infected with P. aeruginosa. One-hundred and fifteen patients, aged > or = 6 yrs, were randomised to receive either TNS or colistin, twice daily for 4 weeks. The primary end point was an evaluation of the relative change in lung function from baseline, as measured by forced expiratory volume in one second % predicted. Secondary end points included changes in sputum P. aeruginosa density, tobramycin/colistin minimum inhibitory concentrations and safety assessments. TNS produced a mean 6.7% improvement in lung function (p=0.006), whilst there was no significant improvement in the colistin-treated patients (mean change 0.37%). Both nebulised antibiotic regimens produced a significant decrease in the sputum P. aeruginosa density, and there was no development of highly resistant strains over the course of the study. The safety profile for both nebulised antibiotics was good. Tobramycin nebuliser solution significantly improved lung function of patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa, but colistin did not, in this study of 1-month's duration. Both treatments reduced the bacterial load.

Topics: Administration, Inhalation; Adolescent; Adult; Aerosols; Anti-Bacterial Agents; Child; Chronic Disease; Colistin; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

The optimal treatment for the eradication of initial P. aeruginosa infection in CF is still unclear. Recently long-term inhaled tobramycin has been proposed. Here we report the results with brief inhaled and/or systemic anti-pseudomonal treatments. Initial P. aeruginosa colonization was successfully eradicated as demonstrated by negative repetitive throat cultures or sputa and serum antipseudomonal antibodies in 15 of 17 patients for at least two years. Randomized, controlled trials are urgently needed to define the optimal protocol for the eradication of P. aeruginosa. Pseudomonas aeruginosa, infection, treatment, antibodies; inhaled tobramycin

Topics: Administration, Inhalation; Administration, Oral; Adolescent; Adult; Case-Control Studies; Ceftazidime; Child; Child, Preschool; Ciprofloxacin; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Humans; Infant; Injections, Intravenous; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin; Treatment Outcome

The clinical course of cystic fibrosis (CF) is characterised by chronic bronchial infection with Pseudomonas aeruginosa. Therapy with inhaled aminoglycosides was introduced to decrease the rate of infectious exacerbations and to delay pulmonary progression. However, development of resistance to aminoglycosides is frequent. Few investigations are available into the resistance profile under treatment with colistin. Antibiotic resistance to colistin was analysed in 44 adult CF patients treated with inhaled colistin. Resistance to aminoglycosides was observed in 86% of cases (38/44) before therapy and decreased to 43% (19/44) under treatment with colistin. Five patients (11%) developed polymyxin resistance. After cessation of therapy pseudomonas became sensitive to polymyxin within a few months and enabled colistin to be reintroduced. In addition, we performed a pilot study analysing the effect of inhaled colistin on the growth of pseudomonas. The number of Pseudomonas aeruginosa decreased from 16.7 million (CFU) bacteria per ml sputum to 2.9 million under therapy with colistin. There was a more than tenfold increase in bacterial counts after inhaled colistin was stopped. Genotyping revealed no change in the type of pseudomonas strains.. Development of resistance to polymyxin is not rare under long-term treatment with inhaled colistin and requires temporary interruption of therapy. Sputum cultures should therefore be tested regularly for polymyxin resistance in patients treated with inhaled colistin.

Topics: Administration, Inhalation; Adult; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Resistance, Microbial; Female; Humans; Lung Diseases; Male; Pilot Projects; Polymyxins; Pseudomonas aeruginosa; Pseudomonas Infections; Sputum

To assess the safety and tolerability of bolus intravenous doses of colistin during acute respiratory exacerbations in adults with cystic fibrosis and chronic Pseudomonas aeruginosa infection.. Twelve patients with acute exacerbations of cystic fibrosis were enrolled in a Phase I open-label study. On day 1, patients received three doses of colistin 2 mega-units (160 mg), reconstituted in 50 mL of NaCl 0.9%, by infusion over 30 minutes three times daily. On days 2, 3, and 4, the same dose of colistin was administered by bolus injection three times a day over five minutes after reconstitution in 20, 15, and 10 mL of NaCl 0.9%, respectively. The injection was given by a nurse or physician using a hand-held syringe. If the latter dose was tolerated, it was continued for the remaining eight days of the study. If any dose was not tolerated, treatment reverted to the previously tolerated concentration, which was continued throughout the remainder of the study.. No serious adverse events occurred during the course of the trial. Patients without total indwelling venous access systems experienced mild to moderate injection pain. There were no clinically significant changes in renal function.. This study indicates that the administration of bolus intravenous colistin as 2 mega-units (160 mg) in 10 mL of NaCl 0.9% three times a day is safe. It is well-tolerated by patients with total indwelling venous access systems.

Topics: Adult; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections

Nearly all strains of Pseudomonas aeruginosa are sensitive to colomycin sulphomethate, but studies in the 1970s using large doses demonstrated significant renal and neurotoxic side-effects and it is not now commonly used. In this study colomycin (2 megaunits i.v. t.d.s.) has been used extensively in adult cystic fibrosis (CF) patients and its use reviewed to determine its efficacy and safety profile. Fifty-two CF patients (28 male, 24 female; mean age 26 yrs, range 17-39 yrs) received 135 courses (mean two courses each, range 1-7, median length 14 days) of i.v. colomycin (2,414 patient days in total). It was used in combination with one other i.v. antibiotic in 114 courses (85%) and with two others in 18 (13%). In all cases there was significant improvement in spirometry (pretreatment forced expiratory volume in one second (FEV1) % predicted mean 44.4, range 10-101; post-treatment mean 51.3, range 14-108; p<0.0001). No patient had any neurotoxicity but one developed a skin rash and myositis. There was no change in renal function (urea mean pretreatment 4.1 mmol x L(-1) (sD 1.4), mean post-treatment 43 (2.2), p=NS; creatinine mean pretreatment 77.9 mmol x L(-1) (15.3), mean post-treatment 803 (21.6), p=NS). In the authors' experience intravenous colomycin sulphomethate in moderate doses is an effective and safe antipseudomonal antibiotic which is easy to administer. Other clinicians should consider its use in patients with cystic fibrosis.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Female; Humans; Injections, Intravenous; Kidney Function Tests; Male; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Sputum; Treatment Outcome

Chronic pulmonary infection with Pseudomonas aeruginosa (PA) develops in most patients with cystic fibrosis (CF) and is associated with a poor prognosis. Much effort has been directed toward treating the chronic infection, but it is almost impossible to eradicate it once established; therefore, prevention is preferable. Since 1989 CF patients at the Danish CF Center in Copenhagen have been treated with an intensive three-step-protocol consisting of colistin inhalations and oral ciprofloxacin at the time of initial PA colonization. This study compares 48 patients treated according to this intensive protocol with 43 historic controls. The study was carried out over 44 months and included 218 patient-years. Only 16% of the treated patients developed chronic PA infection after 3 1/2 years compared with 72% of the control patients (Kaplan Meier estimate, P < 0.005, log rank test). This indicates that aggressive treatment prevented or delayed chronic PA infection in 78% of the patients for 3 1/2 years. Furthermore, aggressive treatment maintained or increased pulmonary function (forced vital capacity and forced expiratory volume in 1 second in percent of predicted values) during the year after inclusion compared with the control group, in which pulmonary function declined (P < 0.01, Mann-Whitney test). Although some of the treated patients eventually developed chronic PA infection, these patients had significantly better pulmonary function at the onset of chronic PA infection compared with control patients (P < 0.001, Mann-Whitney test). When the different steps in the intensive three-step-protocol were analyzed, there was a trend suggesting that 3 months of high-dose treatment with colistin inhalation and oral ciprofloxacin produced the best results in terms of postponement or prevention of chronic PA infection (P < 0.05).

Topics: Adolescent; Adult; Anti-Bacterial Agents; Anti-Infective Agents; Carrier State; Child; Child, Preschool; Chronic Disease; Ciprofloxacin; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Infant; Lung Diseases; Male; Proportional Hazards Models; Pseudomonas aeruginosa; Pseudomonas Infections; Statistics, Nonparametric; Vital Capacity

Inhalation of hypertonic nebulised colistin causes chest tightness and is a reason for discontinuing the treatment. This study examines the relationship of chest tightness and change in lung function in response to the inhalation of a range of tonicities of nebulised colistin and their influence on patients' preference.. Twenty seven adult patients with cystic fibrosis and a mean forced expiratory volume in one second (FEV1) of 54% predicted (range 24-98) were studied. They inhaled a nebulised solution of hypertonic, isotonic, and hypotonic colistin over three consecutive days in random order in a double blind fashion. Measurements of chest tightness, using a visual analogue scale (VAS), and FEV1 were recorded before and 0, 15, 30, 60, and 90 minutes following inhalation. The solution preferred by each patient was determined at the end of the three days.. All tonicities caused a significant fall in FEV1 % predicted and an increase in chest tightness, with no differences between the solutions. However, the mean (SE) time to the maximum fall in FEV1 % predicted was significantly different between the solutions (hypertonic 7.8 (2.1) min, isotonic 19.2 (5.5) min, and hypotonic 34.2 (5.9) min) with a mean difference (95% CI) between hypotonic and hypertonic solutions of 28.04 (14.6 to 41.5) min, between isotonic and hypertonic solutions of 12.0 (-0.1 to 24.1) min, and between hypotonic and isotonic solutions of 15.6 (1.8 to 29.4) min. Positive correlations existed for the maximum fall in FEV1 % predicted between the hypertonic and isotonic solutions (r = 0.62, p < 0.001) and between the hypotonic and isotonic solutions (r = 0.64, p < 0.001). There was no correlation between the objective and subjective measurements for any solution. The patients' preference varied.. All tonicities of colistin caused equal symptoms of chest tightness and reduction in pulmonary function. It is recommended that the patient is challenged with nebulised colistin before prescription of the drug and that the challenge is preceded by an inhaled bronchodilator. Most of the patients preferred the isotonic or hypotonic solutions. The isotonic solution reflects a fall in FEV1 representative of all the solutions. The fall in FEV1 to the hypotonic solution occurred over a longer period and may be better tolerated by some patients.

Topics: Administration, Inhalation; Adolescent; Adult; Analysis of Variance; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Hypertonic Solutions; Isotonic Solutions; Lung; Male; Statistics, Nonparametric; Time Factors

Patients with cystic fibrosis have received more intravenous antibiotic courses as median survival has steadily increased. A number of centres have adopted a policy of regular (three monthly) rather than on demand intravenous antipseudomonal antibiotics. More widespread bacterial antibiotic resistance has resulted from this increased antibiotic use. Most Pseudomonas aeruginosa strains remain fully sensitive to colistin but its use has been resisted owing to concerns about neurotoxicity and nephrotoxicity. A study was carried out to assess the safety and efficacy of intravenous colistin in the treatment of acute respiratory exacerbations in adult patients with cystic fibrosis.. Patients with chronic Pseudomonas aeruginosa colonisation who presented with protocol defined respiratory tract exacerbations were randomised to receive treatment for 12 days with either colistin (2 MU tds intravenously) alone or with a second anti-pseudomonal antibiotic. Comparisons of the absolute values of respiratory function tests on days 1, 5, and 12 and of overnight oxygen saturation on days 1 and 12 were the primary outcome measures. Patient's weight, clinical and chest radiographic scores, and peripheral blood markers of inflammation were also documented. The effect of each treatment regimen individually was assessed by the change in clinical measurements from baseline values. Adverse renal effects were monitored by measurement of serum levels of urea and electrolytes, creatinine clearance, and ward urine testing. Neurotoxicity was monitored by direct questioning for symptoms.. Fifty three patients, 18 of whom entered the study twice, were enrolled. The mean forced expiratory volume in one second (FEV1) increased significantly in both groups, mean forced vital capacity (FVC) only with dual therapy. Both groups showed a non-significant increase in overnight oxygen saturation. All patients showed clinical improvement. Thirty seven adverse neurological events (two severe) were reported in 33 patients in the monotherapy group and 37 (none severe) in 36 patients in the dual therapy group. One patient withdrew because of severe weakness and dizziness. All other adverse neurological events were well tolerated and resolved during or shortly after treatment. Significant changes were seen in mean serum urea levels in both groups, but in only four patients to a level above the normal range, and in creatinine clearance in the dual therapy group. At 24 month follow up no long term adverse consequences from intravenous colistin were found in patients who completed the study.. Intravenous colistin is an effective treatment for Pseudomonas aeruginosa associated pulmonary exacerbations in patients with cystic fibrosis. Assessment of the individual effect of each treatment regimen suggests a greater efficacy when colistin is combined with a second antibiotic to which the pseudomonas shows in vitro sensitivity. Changes in renal function should be monitored.

Topics: Acute Disease; Adult; Analysis of Variance; Anti-Bacterial Agents; Colistin; Creatinine; Cystic Fibrosis; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Kidney; Male; Pseudomonas Infections; Statistics, Nonparametric; Urea

The objective of this study was to quantify the deposition in the lung of a Colistine aerosol generated using a pneumatic nebuliser (Pari LL(R) equipped with a Pari Master, Pari, Germany) and to compare this with the results obtained with an ultrasonic nebuliser (DP100, DP Medical, France) in four subjects suffering from cystic fibrosis being colonised with Pseudomonas aeruginosa. To quantify the pulmonary deposition of the aerosols we have used an indirect isotopic method which consists in assimilating the kinetics of the molecules studied with a serum albumin tagged with Technetium 99m (Tc99mm) and added to a preparation of Colistine. We have previously verified that the addition of a radioactive tracer does not change the normal distribution or dynamics of the medication within the aerosol and the radioactive counter linked to the tracer reflects the mass of the medicament. The pulmonary deposition was expressed as a percentage of the nebuliser dose. A regional analysis of the deposition (central, peripheral, superior and inferior) was carried out and in central deposition compared to the periphery (C/P) and superior compared to inferior (S/I) were calculated. With the DP100 nebuliser the pulmonary deposition of the aerosol was very reproducible from one patient to another, varying only between 9.5 to 14 percent of the nebuliser dose. With the Pari LL the fraction deposited varied more from one patient to another from 5.6 to 27% of the nebuliser dose. In three of four patients, the pulmonary deposition was superior or equal to that obtained with the ultrasonic nebuliser. The patients whose pulmonary deposition was inferior, using the pneumatic nebuliser, was the youngest in the group and co-ordinately poorly the triggering of the nebuliser with the beginning of inspiration. With the two nebulisers, the pulmonary deposition of Colisitine was very heterogeneous throughout the pulmonary parenchyma. The mean of the ratio C/P and S/I obtained in all four patients was identical (1.35 an 0.86 respectively), indicating a deposition of the aerosol which was predominantly central and inferior but was distributed equally in the peripheral parts of the lung. Pneumatic nebulisers offer a reliable alternative notably for domiciliary treatment for Colistine aerosols in patients suffering from cystic fibrosis. In younger patients who have not yet acquired good motor co-ordination, nebulisers which function continuously or are triggered by inspiration seem to be the pr

Topics: Administration, Inhalation; Adolescent; Adult; Aerosols; Anti-Bacterial Agents; Child; Colistin; Cystic Fibrosis; Equipment Design; Female; Humans; Lung Diseases; Male; Nebulizers and Vaporizers; Pseudomonas Infections; Tissue Distribution

Topics: Adolescent; Aerosols; Bronchial Diseases; Child; Child, Preschool; Chronic Disease; Ciprofloxacin; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Sputum; Time Factors

To assess whether chronic pulmonary colonisation with Pseudomonas aeruginosa in cystic fibrosis is preventable, 26 patients who had never received anti-pseudomonas chemotherapy were randomly allocated to groups receiving either no anti-pseudomonas chemotherapy or oral ciprofloxacin and aerosol inhalations of colistin twice daily for 3 weeks, whenever Ps aeruginosa was isolated from routine sputum cultures. During the 27 months of the trial, infection with Ps aeruginosa became chronic in significantly fewer treated than untreated subjects (2 [14%] vs 7 [58%]; p less than 0.05) and there were significantly fewer Ps aeruginosa isolates in routine sputum cultures in the treated group (49/214 [23%] vs 64/158 [41%]; p = 0.0006). Thus, chronic colonisation with Ps aeruginosa can be prevented in cystic fibrosis by early institution of anti-pseudomonas chemotherapy.

Topics: Child; Child, Preschool; Chronic Disease; Ciprofloxacin; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Female; Humans; Infant; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Sputum

Forty patients with cystic fibrosis and chronic broncho-pulmonary Pseudomonas aeruginosa infection entered a prospective double-blind placebo-controlled study of colistin inhalation. Active treatment consisted of inhalation of colistin one million units twice daily for three months and was compared to placebo inhalations of isotonic saline. Significantly more patients in the colistin inhalation group completed the study as compared to the placebo group (18 versus 11). Colistin treatment was superior to placebo treatment in terms of a significantly better clinical symptom score, maintenance of pulmonary function and inflammatory parameters. We recommend colistin inhalation therapy for cystic fibrosis patients with chronic P. aeruginosa lung infection as a supplementary treatment to frequent courses of intravenous anti-pseudomonas chemotherapy.

Topics: Administration, Inhalation; Adolescent; Adult; Child; Chronic Disease; Clinical Trials as Topic; Colistin; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Lung Diseases; Male; Pseudomonas Infections; Vital Capacity

Several clinical guidelines recommend chronic inhaled therapy for pwCF (people with cystic fibrosis) and chronic Pseudomonas aeruginosa infection of the lungs.. To demonstrate what kind of therapy regimens are used in Germany, we retrospectively analysed chronic inhaled antibiotic therapy within the cohort of the German CF Registry in 2020. For comparison we also analysed the use of inhaled antibiotics in pwCF with intermittent Pseudomonas or without Pseudomonas infection.. A total of 1960 pwCF had chronic P. aeruginosa infection and were retrospectively evaluated. Almost 90% (n = 1751) received at least one inhaled antibiotic. The most commonly used inhaled antibiotic was colistin solution for inhalation (55.2%), followed by aztreonam solution for inhalation (32.6%) and tobramycin solution for Inhalation (30%). Almost 56% of adults and 44% of children alternated two antibiotics for inhalation. In children, alternating colistin + tobramycin was the most often used regimen. In adults, only 23% used colistin + tobramycin; there was a wide range of treatment regimens among adults using two inhaled antibiotics alternately. 2456 pwCF had no Pseudomonas infection, but almost 24% had a chronic inhaled antibiotic therapy, while 56% of 361 pwCF and intermittent chronic Pseudomonas infection had a chronic inhaled antibiotic therapy.. In all three groups the most commonly used inhaled antibiotic was colistin solution for inhalation. Almost 56% of adults and 44% of children with chronic Pseudomonas infection alternated two antibiotics for inhalation. It will be interesting to see how the introduction of the highly effective modulator elexacaftor/tezacaftor/ivacaftor will change the use of inhaled antibiotics.

Topics: Administration, Inhalation; Adult; Anti-Bacterial Agents; Child; Colistin; Cystic Fibrosis; Germany; Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Tobramycin

The

Topics: Anti-Bacterial Agents; Ceftazidime; Colistin; Cystic Fibrosis; Drug Synergism; Humans; Meropenem; Microbial Sensitivity Tests

Topics: Anti-Bacterial Agents; Aztreonam; Biofilms; Colistin; Cystic Fibrosis; Melaleuca; Microbial Sensitivity Tests; Oils, Volatile; Pseudomonas aeruginosa; Tea; Tea Tree Oil; Tobramycin; Trees

The use of inhalable nanoparticles (NPs) for cystic fibrosis (CF) has been advocated as a promising tool to improve the efficacy of antimicrobials taking advantage of their ability to penetrate airway mucus and pathogen biofilm and to release the drug in or in proximity to the enclosed bacteria. Here, inhalable calcium phosphate (CaP) NPs were functionalized with colistin (Col) which is one of the most active antimicrobials against Gram-negative bacteria. The adsorption kinetic and isotherm of Col on CaP-NPs were investigated and fitted according to different mathematical models and revealed an electrostatic interaction between positively charged amine groups of Col and negatively charged surface of CaP-NPs. The maximum Col payload was of about 50 mg g

Topics: Anti-Bacterial Agents; Biofilms; Calcium Phosphates; Colistin; Cystic Fibrosis; Humans; Nanoparticles; Pseudomonas aeruginosa

The airways of people with cystic fibrosis (CF) often harbour diverse polymicrobial communities. These airway infections can be impossible to resolve through antibiotic intervention, even though isolates of the individual species present are susceptible to the treatment when tested in vitro. In this work, we investigate how polymicrobial cultures comprised of key CF-associated pathogens respond to challenge with species-specific antimicrobial agents; colistin (targets Pseudomonas aeruginosa), fusidic acid (targets Staphylococcus aureus), and fluconazole (targets Candida albicans). We found that growth in a polymicrobial environment protects the target microorganism (sometimes by several orders of magnitude) from the effect(s) of the antimicrobial agent. This decreased antimicrobial efficacy was found to have both non-heritable (physiological) and heritable (genetic) components. Whole-genome sequencing of the colistin-resistant P. aeruginosa isolates revealed single nucleotide polymorphisms and indels in genes encoding lipopolysaccharide (LPS) biosynthesis and/or pilus biogenesis, indicating that a previously undescribed colistin resistance mechanism was in operation. This was subsequently confirmed through further genetic analyses. Our findings indicate that the polymicrobial nature of the CF airways is likely to have a significant impact on the clinical response to antimicrobial therapy.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Colistin; Cystic Fibrosis; Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Staphylococcus aureus

In a number of chronic respiratory diseases e.g. cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), the production of viscous mucin reduces pulmonary function and represents an effective barrier to diffusion of inhaled therapies e.g. antibiotics. Here, a 2-compartment Transwell model was developed to study impaired diffusion of the antibiotic colistin across an artificial sputum (AS) matrix/medium and to quantify its antimicrobial activity against Pseudomonas aeruginosa NH57388A biofilms (alone and in combination with mucolytic therapy). High-performance liquid chromatography coupled with fluorescence detection (HPLC-FLD) revealed that the presence of AS medium significantly reduced the rate of colistin diffusion (> 85% at 48 h; p < 0.05). Addition of alginate oligosaccharide (OligoG CF-5/20) significantly improved colistin diffusion by 3.7 times through mucin-rich AS medium (at 48 h; p < 0.05). Increased diffusion of colistin with OligoG CF-5/20 was shown (using confocal laser scanning microscopy and COMSTAT image analysis) to be associated with significantly increased bacterial killing (p < 0.05). These data support the use of this model to study drug and small molecule delivery across clinically-relevant diffusion barriers. The findings indicate the significant loss of colistin and reduced effectiveness that occurs with mucin binding, and support the use of mucolytics to improve antimicrobial efficacy and lower antibiotic exposure.

Topics: Alginates; Anti-Bacterial Agents; Biofilms; Colistin; Cystic Fibrosis; Humans; Mucins; Oligosaccharides; Pseudomonas aeruginosa; Pseudomonas Infections

Colistimethate sodium and tobramycin are important systemic antibiotics for treatment of cystic fibrosis (CF) pulmonary exacerbations but can induce acute kidney injury (AKI). We characterize the rate of AKI in CF patients treated with systemic colistimethate sodium compared with tobramycin.. This single-centre, retrospective cohort study included hospitalized CF patients treated with IV colistimethate sodium or tobramycin. The primary outcome was AKI defined using the RIFLE criteria. Multivariate logistic regression using a mixed model was performed to identify variables that were independently associated with AKI.. Overall, 156 patients representing 507 care encounters were included. The OR of AKI was not increased with IV colistimethate sodium relative to IV tobramycin after adjusting for other potential predictor variables (aOR 1.00; 95% CI 0.16-6.03). The frequency of AKI was 9.5% across all encounters, 6.9% with IV colistimethate sodium and 9.9% with IV tobramycin, with RIFLE category R (risk) being the most common stage, accounting for 4.2% of encounters with IV colistimethate sodium and 9.2% with IV tobramycin. The concomitant use of another nephrotoxin (aOR 2.51; 95% CI 1.27-4.95) or the combination of vancomycin and piperacillin/tazobactam (aOR 5.95; 95% CI 2.05-17.3) were both associated with increased odds of AKI.. Systemic treatment with colistimethate sodium or tobramycin in the CF patient population is associated with a similar rate of nephrotoxicity. However, clinicians should be mindful of the increased risk for AKI in patients treated with either IV colistimethate sodium or IV tobramycin when used concurrently with other nephrotoxic agents, particularly the combination of vancomycin and piperacillin/tazobactam.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Humans; Piperacillin, Tazobactam Drug Combination; Retrospective Studies; Tobramycin; Vancomycin

The Pseudomonas aeruginosa bacterium is a common pathogen of cystic fibrosis (CF) patients due to its ability to evolve resistance to antibiotics during treatments. While P. aeruginosa resistance evolution is well-characterized in monocultures, it is less well-understood in polymicrobial CF infections. Here, we investigated how exposure to ciprofloxacin, colistin, or tobramycin antibiotics, administered at sub-minimum inhibitory concentration (MIC) doses, both alone and in combination, shaped the tolerance evolution of P. aeruginosa (PAO1 lab and clinical CF LESB58 strains) in the absence and presence of a commonly co-occurring species, Stenotrophomonas maltophilia. The increases in antibiotic tolerances were primarily driven by the presence of that antibiotic in the treatment. We observed a reciprocal cross-tolerance between ciprofloxacin and tobramycin, and, when combined, the selected antibiotics increased the MICs for all of the antibiotics. Though the presence of S. maltophilia did not affect the tolerance or the MIC evolution, it drove P. aeruginosa into extinction more frequently in the presence of tobramycin due to its relatively greater innate tobramycin tolerance. In contrast, P. aeruginosa dominated and drove S. maltophilia extinct in most other treatments. Together, our findings suggest that besides driving high-level antibiotic tolerance evolution, sub-MIC antibiotic exposure can alter competitive bacterial interactions, leading to target pathogen extinctions in multispecies communities.

Topics: Anti-Bacterial Agents; Ciprofloxacin; Colistin; Cystic Fibrosis; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Stenotrophomonas maltophilia; Tobramycin

Adherence to treatment by adolescents and adults with cystic fibrosis (CF) is often poor.. To assess the impact of a focused clinical intervention on adherence in individual patients, including help in problem-solving key barriers to adherence. To implement a patient-centered problem-solving intervention using CF My Way tools. To identify and overcome a selected barrier to adherence.. Medication possession ratios (MPRs), number of airway clearance sessions, forced expiratory volume (FEV1), body mass index (BMI), and health-related quality of life (HRQoL) were measured before and after the intervention.. Sixteen patients with CF, aged 23.4 ± 6.7 years, participated. MPR increased for colistimethate sodium and tobramycin inhalations from a median of 21 (range 0-100) to 56 (range 0-100), P = 0.04 and 20 (range 0-100) to 33.3 (range 25-100), P = 0.03, respectively. BMI standard deviation score rose from -0.37 to -0.21, P = 0.05. No significant improvements were found in FEV1, airway clearance, or HRQoL scores.. The CF My Way problem-solving intervention increased adherence to medical treatments by removing barriers directly related to the needs and goals of young adults with CF.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Body Mass Index; Colistin; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Male; Medication Adherence; Patient-Centered Care; Problem Solving; Quality of Life; Tobramycin; Young Adult

As part of the risk management plan in Europe, a long-term observational study was conducted to monitor the safety of colistimethate sodium dry powder for inhalation (CMS-DPI) compared to other inhaled antibiotics.. A cohort of CMS-DPI patients and a matched cohort were identified from the UK Cystic Fibrosis Registry (UKCFR) from 2014-2018. The primary outcome was a composite endpoint, defined as adverse events (AEs) or new cystic fibrosis (CF) complications. Other outcomes included pulmonary exacerbations and treatment discontinuations.. Of 1466 and 3503 patients in the CMS-DPI and comparator cohorts, respectively, 82.7% and 79.4% had AEs. Among the most common new CF complications were osteopenia, CF-related diabetes, and increased liver enzymes. The adjusted event rate ratio (ERR) for the primary outcome was 1.25 (95% confidence interval [CI]: 1.18-1.33, p<0.001). After excluding new CF complications, there was no difference between cohorts (ERR=1.04, 95% CI: 0.79-1.38, p=0.785). Pulmonary exacerbations were common in CMS-DPI and comparator cohorts (78.0% and 79.9% of patients, respectively), with adjusted ERR of 1.02 (95% CI: 0.95-1.10, p=0.523). Rates of discontinuation were similar in the CMS-DPI and Tobramycin inhalation powder comparator cohorts (37.8% and 39.8% of patients, respectively).. There was no difference in the rate of adverse events between CMS-DPI and comparator cohorts. The safety profile of CMS-DPI is similar to those of other inhaled antibiotics, supporting its long-term safety in people with CF. The UKCFR has developed a successful model for partnership with industry to conduct long-term studies aimed at assessing drug safety.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Anti-Bacterial Agents; Child; Colistin; Cystic Fibrosis; Female; Humans; Male; Middle Aged; Pseudomonas Infections; Registries; Respiratory Tract Infections; Symptom Flare Up; United Kingdom

The effective prescription of antibiotics for the bacterial biofilms present within the lungs of individuals with cystic fibrosis (CF) is limited by a poor correlation between antibiotic susceptibility testing (AST) results using standard diagnostic methods (e.g., broth microdilution, disk diffusion, or Etest) and clinical outcomes after antibiotic treatment. Attempts to improve AST by the use of off-the-shelf biofilm growth platforms show little improvement in results. The limited ability of in vitro biofilm systems to mimic the physicochemical environment of the CF lung and, therefore bacterial physiology and biofilm architecture, also acts as a brake on the discovery of novel therapies for CF infection. Here, we present a protocol to perform AST of CF pathogens grown as mature, in vivo-like biofilms in an ex vivo CF lung model comprised of pig bronchiolar tissue and synthetic CF sputum (ex vivo pig lung, EVPL). Several in vitro assays exist for biofilm susceptibility testing, using either standard laboratory medium or various formulations of synthetic CF sputum in microtiter plates. Both growth medium and biofilm substrate (polystyrene plate vs. bronchiolar tissue) are likely to affect biofilm antibiotic tolerance. We show enhanced tolerance of clinical Pseudomonas aeruginosa and Staphylococcus aureus isolates in the ex vivo model; the effects of antibiotic treatment of biofilms is not correlated with the minimum inhibitory concentration (MIC) in standard microdilution assays or a sensitive/resistant classification in disk diffusion assays. The ex vivo platform could be used for bespoke biofilm AST of patient samples and as an enhanced testing platform for potential antibiofilm agents during pharmaceutical research and development. Improving the prescription or acceleration of antibiofilm drug discovery through the use of more in vivo-like testing platforms could drastically improve health outcomes for individuals with CF, as well as reduce the costs of clinical treatment and discovery research.

Topics: Animals; Anti-Bacterial Agents; Biofilms; Colistin; Colony Count, Microbial; Cystic Fibrosis; Dissection; Floxacillin; Humans; Linezolid; Lung; Microbial Sensitivity Tests; Microbial Viability; Pseudomonas aeruginosa; Sputum; Staphylococcus aureus; Swine

Current cystic fibrosis (CF) treatment strategies are primarily focused on oral/inhaled anti-inflammatories and antibiotics, resulting in a considerable treatment burden for CF patients. Therefore, combination treatments consisting of anti-inflammatories with antibiotics could reduce the CF treatment burden. However, there is an imperative need to understand the potential drug-drug interactions of these combination treatments to determine their efficacy. Thus, this study aimed to determine the interactions of the anti-inflammatory agent Ibuprofen with each of the CF-approved inhaled antibiotics (Tobramycin, Colistin and its prodrug colistimethate sodium/Tadim) and anti-bacterial and anti-inflammatory efficacy. Chemical interactions of the Ibuprofen:antibiotic combinations were elucidated using High-Resolution Mass-Spectrometry (HRMS) and

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Cell Survival; Colistin; Cystic Fibrosis; Drug Combinations; Humans; Ibuprofen; Inflammation; Interleukin-8; Lipopolysaccharides; Pseudomonas aeruginosa; Tobramycin

Topics: Biofilms; Colistin; Cystic Fibrosis; Humans; Infections; Pseudomonas aeruginosa

Colistin, administered as the prodrug colistin methanesulphonate (CMS), is an antibiotic frequently administered as aerosol in cystic fibrosis (CF) patient. Our aim was to assess the plasma PK of colistin in CF patients treated with CMS administered intravenously or as aerosol and to compare these results with those previously reported in healthy volunteers.. Six CF patients were included, CMS and colistin concentrations were measured in plasma, urine and sputum. Either after single intravenous administration of 2 Million International Unit (MIU) or after repeated nebulizations of 2 MIU of CMS. PK of CMS and colistin were assessed by a mixed effect modeling approach.. Renal clearance of CMS was lower in CF patients compared to that previously reported in healthy volunteers (64.3 mL/min (RSE = 15%) vs. 103 mL/min (RSE = 8%)). However, apparent clearance of colistin was higher in CF patients compared to healthy volunteers (124 mL/min (RSE = 13%) vs. 48.7 mL/min (RSE = 15%)), resulting in reduced systemic exposure to colistin (dose normalized AUC (2 MIU) of 7.4 h.mg/L/MIU vs. 11.2 h.mg/L/MIU). After repeated nebulizations, colistin concentrations were very low in plasma (<0.21 mg/L).. Although our study suggests a lower median dose normalized colistin plasma concentrations in CF patients compared with healthy controls, this difference was not significant and a larger study is needed to substantiate this.

Topics: Administration, Inhalation; Administration, Intravenous; Adult; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Mesylates; Metabolic Clearance Rate; Prodrugs; Renal Elimination; Sputum

Pseudomonas aeruginosa cross-infections are related to increased morbidity and mortality in cystic fibrosis (CF).. The aim of the study was to evaluate the incidence of cross-infections with P. aeruginosa in children with CF.. CF patients from whom at least one P. aeruginosa strain had been isolated were included in the study. The strain genotyping was performed using pulse-field gel electrophoresis. The history of contacts between patients was established based on questionnaires.. The study group consisted of 75 patients (aged 1.0-19.2 years) and the material included 170 P. aeruginosa strains. Cross-infections occurred in a group of 26 patients. In this group, the risk of the predicted occurrence of forced expiratory volume in 1 second ≤ 70% was five times greater and the risk of longer cumulative hospitalization time for intravenous antibiotic therapy (>14 days/year) was almost five times greater. In the clonal groups of strains, the multidrug-resistance rate was significantly higher than in other groups. In 2011, all tested strains were susceptible to colistin, whereas in 2012, three strains from the largest clonal group showed high levels of resistance to colistin.. Cross-infections with P. aeruginosa occurred in our group of patients and were associated with poor clinical outcomes. Antimicrobial resistance rate in the strains isolated from such infections was significantly higher, and this included three strains resistant to colistin.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Cross Infection; Cystic Fibrosis; Drug Resistance, Microbial; Female; Forced Expiratory Volume; Genotype; Humans; Incidence; Infant; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Treatment Outcome; Young Adult

We present four case reports that describe neurotoxicity experienced in adult patients with cystic fibrosis (CF) receiving intravenous polymyxin B. Paresthesia was observed after the first dose of polymyxin B in all patients. These symptoms resolved after discontinuation of polymyxin B and switching treatment to colistin. All four patients completed therapy with colistin without experiencing additional adverse reactions. This report contributes to the small body of literature currently available on the use of polymyxin B in the CF population.

Topics: Adult; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Female; Humans; Male; Middle Aged; Paresthesia; Polymyxin B; Young Adult

Achromobacter xylosoxidans is an emerging pathogen in cystic fibrosis (CF). Relatively little is known about its clinical impact and optimal management. In the present study, the in vitro bactericidal activities of meropenem, either alone or in combination with colistin, levofloxacin, or chloramphenicol, were assessed using A. xylosoxidans strains isolated from CF patients. The synergistic interactions of these combinations were also investigated.. Minimal inhibitory concentrations (MICs) were determined by microbroth dilution. Bactericidal and synergistic effects of the tested antibiotic combinations were assessed by using the time-kill curve technique.. Based on the time-kill curves, we found that meropenem-colistin combinations have bactericidal and synergistic activities for 24 h against A. xylosoxidans strains, both at 1 × MIC and 4 × MIC. Although synergistic interactions were seen with meropenem-levofloxacin combinations, no bactericidal interactions were observed. Additionally, the meropenem-chloramphenicol combinations were found to be neither bactericidal nor synergistic. No antagonism was observed with any combination tested.. This study's findings could have important implications for empirical or combination antimicrobial therapy with tested antibiotics.

Topics: Achromobacter denitrificans; Anti-Bacterial Agents; Chloramphenicol; Colistin; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Humans; Levofloxacin; Meropenem

Cystic fibrosis (CF) patients, with Pseudomonas aeruginosa infection, often require repeated aminoglycoside courses for the management of acute pulmonary exacerbations (APEs). Acute kidney injury (AKI) due to aminoglycosides has been reported; little data exist regarding long-term nephrotoxicity with repeated exposure. The objective of this study was to describe the incidence of acute and chronic nephrotoxicity due to cumulative intravenous (IV) aminoglycoside exposure. This is a retrospective, observational study of pediatric and adult CF patients admitted to an academic medical center between January 1, 2006 and October 1, 2018 for APE management. Patients were eligible for inclusion if they received at least five courses of an IV aminoglycoside for at least 7 days each. Cumulative weight-based aminoglycoside dose was reported in milligrams per kilogram. For each admission, baseline and highest serum creatinine were collected to assess the incidence of AKI. The baseline and final estimated glomerular filtration rate (eGFR) were calculated to assess long-term effects on renal function. Sixty-six patients, representing greater than 700 courses, were included in the final analysis. The median cumulative weight-based aminoglycoside dose was 1183 mg/kg of tobramycin or tobramycin equivalent. Twenty percent of courses resulted in AKI; 86% were Stage 1. A repeated measure multivariate model showed colistin, piperacillin/tazobactam, vancomycin, and age were significant AKI risk factors. There was no correlation between cumulative aminoglycoside dose and change in eGFR. AKI from IV aminoglycoside exposure occurred in 20% of courses. Cumulative exposure to IV aminoglycosides in APE management was not correlated with long-term renal dysfunction.

Topics: Acute Kidney Injury; Adolescent; Adult; Age Factors; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Cystic Fibrosis; Female; Humans; Incidence; Infant; Male; Middle Aged; Piperacillin, Tazobactam Drug Combination; Pseudomonas Infections; Retrospective Studies; Risk Factors; Tobramycin; Vancomycin; Young Adult

Colistin is considered as one of the last-resort antibiotics and reliable antimicrobial susceptibility testing is therefore crucial. The reference standard for AST according to EUCAST and CLSI is broth microdilution (BMD). However, BMD is labor intensive to perform. Commercial antimicrobial susceptibility tests derived from BMD method are available. We investigated the performance of four different commercial tests: Sensititre™, SensiTest™ Colistin, Micronaut MIC Strip Colistin and UMIC Colistin using 70 clinical isolates (half of them was deemed by VITEK2 as resistant), including isolates from cystic fibrosis patients and mcr-1 bearing isolates. We used two reference standards: BMD and composite MIC as determined by all four tests. Sensititre™ had essential agreement (EA, defined as minimum inhibitory concentration within ± 1 dilution) of 87% and 89% compared to BMD and composite reference standard, respectively. For SensiTest™, the EA's were 93% and 90%. For UMIC, 87% and 90%, and for Micronaut, 83% and 84%. All four tests demonstrated categorical agreement (CA) above 90%. CA for SensiTest™ and Micronaut was both 96%, UMIC 94%, and Sensititre™ 93%. All tests were reproducible as tested in two quality control isolates. In conclusion, in clinical isolates from a large referral center, the four commercial tests for determination of colistin minimum inhibitory concentrations showed acceptable performance.

Topics: Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Reproducibility of Results; Sensitivity and Specificity

Nebulization of antimicrobial drugs such as tobramycin and colistin is a cornerstone in the treatment of patients with cystic fibrosis (CF) infected with Pseudomonas aeruginosa. However, nebulization has a high treatment burden. The Twincer™ is a dry powder inhaler specifically developed for the inhalation of antibiotics such as colistin. The aim of this study was to compare patient outcomes and experience with colistin dry powder by the Twincer with nebulization of colistin or tobramycin in adult CF patients in a real-life setting.. This was a retrospective study from 01-01-2015 until 01-07-2018. Effectiveness was evaluated by comparing FEV1 decline and exacerbation rate during a mean of 4.1 years of nebulization therapy prior to the initiation of the Twincer against the same values during a mean of 1.7 years of treatment with the Twincer.. Twenty-one patients were evaluated, of whom twelve could be included in the effectiveness analysis, with a total of twenty patient years. Of all patients 71.4% preferred therapy with the Twincer over nebulization. Twincer use resulted in high treatment adherence with an average adherence rate of 92.5%. There was no significant difference in annual decline in FEV1%pred prior to and after start changing from nebulization to the use of the Twincer powder inhaler (median decline -1.56 [-5.57-5.31] and 1.35 [-8.45-6.36]) respectively, p = 0.45 (linear mixed effect model)). No significant difference was found in the number of intravenous or combined total intravenous and oral antibiotic courses during Twincer therapy compared to when using nebulization (1.68 and 2.49 courses during Twincer therapy versus 1.51 and 2.94 courses during nebulization, p = 0.88 and p = 0.63).. Colistin dry powder inhalation with the Twincer is a more patient friendly alternative to nebulization, and we did not observe significant differences in the clinical outcome, regarding lung function and exacerbation rates.

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Female; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pseudomonas Infections

Topics: Animals; Anti-Bacterial Agents; Biofilms; Colistin; Culture Media; Cystic Fibrosis; Drug Resistance, Bacterial; Humans; Lung; Microbial Sensitivity Tests; Models, Biological; Pseudomonas aeruginosa; Sputum; Swine

Topics: Administration, Inhalation; Adult; Anti-Bacterial Agents; Bronchiectasis; Colistin; Cost-Benefit Analysis; Cystic Fibrosis; Humans; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Desensitization, Immunologic; Drug Hypersensitivity; Humans; Male; Middle Aged; Skin Tests

We describe a case of one patient with cystic fibrosis who developed a pan-resistant Burkholderia cepacia complex rapidly progressive bacteraemic pneunonia, following bilateral lung transplantation. The patient was treated with a targeted combination antibiotic therapy (meropenem plus ceftazidime/avibactam plus high doses of nebulized colistimethate sodium). Evolution of the disease was complicated by multiple organ system dysfunction. Finally, clinical improvement and microbiological cure was achieved.

Topics: Adult; Anti-Bacterial Agents; Bacteremia; Burkholderia cepacia complex; Burkholderia Infections; Colistin; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Humans; Lung Transplantation; Male; Pneumonia, Bacterial; Treatment Outcome; X-Rays

Pseudomonas aeruginosa isolates from Cystic fibrosis (CF) patients are growing slowly, and frequently rendering automated susceptibility testing unsuitable. Colistin is an important antibiotic for treatment of P. aeruginosa infections. Broth microdilution is the only EUCAST endorsed antimicrobial susceptibility test for colistin. The VIZION™ device aids in reading broth microdilution plates and allows safe data transfer to laboratory information systems. In this study, reproducibility between visual MIC readout and readout, employing the VIZION™ device was assessed in susceptibility testing of colistin and beta-lactam antibiotics in P. aeruginosa isolates from CF patients.. Fifty-six unique P. aeruginosa isolates were derived from respiratory secretions of CF patients. Susceptibility testing was performed using commercially available microdilution plates. MIC readout by VIZION™ was compared to visual readout aided by a mirror (reference test).. Pseudomonas aeruginosa isolates displayed significantly slower growth rates compared to quality control isolates. Colistin exact MIC agreement between VIZION™ and visual readout after 24 and 48 h incubation, respectively, was 82% and 95%, essential MIC agreement was 98% and 100%, categorical agreement was 98% and 98% and reliability (weighted kappa) was 0.95 (95% CI = 0.91-0.99) and 0.99 (95% CI = 0.97-1.00). For all five antibiotics, the total number of errors (using VIZION™, in comparison with visual readout) decreased from 15 (5%) to 10 (4%) after 24 and 48 h incubation, respectively.. VIZION™ readout reproducibly determines MIC values in comparison with visual readout after 24 h of incubation. Reproducibility between the VIZION™ and visual readout increases after prolonged incubation of 48 h.

Topics: Anti-Bacterial Agents; beta-Lactams; Colistin; Cystic Fibrosis; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Reproducibility of Results

Topics: Administration, Inhalation; Administration, Intravenous; Adult; Anti-Bacterial Agents; Azithromycin; Colistin; Cystic Fibrosis; Disease Progression; Female; Forced Expiratory Volume; Humans; Logistic Models; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Tobramycin; Young Adult

Topics: Biofilms; Colistin; Cystic Fibrosis; Humans; Pseudomonas aeruginosa; Pseudomonas Infections

Colistimethate sodium (CMS) for treatment of lung infections in cystic fibrosis patient was transformed into a dry powder for inhalation by spray drying. Design of Experiment was applied for understanding the role of the spray-drying process parameters on the critical quality attributes of the CMS spray-dried (SD) powders and agglomerates thereof. Eleven experimental SD microparticle powders were constructed under different process conditions according to a central composite design. The SD microparticles were then agglomerated in soft pellets. Eleven physico-chemical characteristics of SD CMS microparticle powders or agglomerates thereof were selected as critical quality attributes. The yield of SD process was higher than 75%. The emitted fraction of agglomerates from RS01 inhaler was 75-84%, and the fine particle fraction (particles <5 µm) was between 58% and 62%. The quality attributes of CMS SD powders and respective agglomerates that were significantly influenced by spray-drying process parameters were residual solvent and drug content of the SD microparticles as well as bulk density and respirable dose of the agglomerates. These attributes were also affected by the combination of the process variables. The air aspiration rate was found as the most positively influential on drug and solvent content and respirable dose. The residual solvent content significantly influenced the powder bulk properties and aerodynamic behavior of the agglomerates, i.e. quality attributes that govern drug metering in the device and the particles lungs deposition. Agglomerates of CMS SD microparticles, in combination with RS01 DPI, showed satisfactory results in terms of dose emitted and fine particle fraction.

Topics: Administration, Inhalation; Aerosols; Colistin; Cystic Fibrosis; Drug Compounding; Dry Powder Inhalers; Humans; Infections; Lung; Particle Size; Powders; Solvents

Topics: Achromobacter; Anti-Bacterial Agents; Bacterial Proteins; Colistin; Cystic Fibrosis; Denmark; Drug Resistance, Bacterial; Humans; Pseudomonas aeruginosa

Pulmonary exacerbations in patients with cystic fibrosis (CF) caused by chronic Gram-negative bacterial infections are associated with reduced survival. These pathogens are usually treated with repeated courses of systemic antimicrobial agents. However, there is associated emergence of multidrug-resistant (MDR) pathogens. Ceftolozane/tazobactam (C/T) is a novel cephalosporin/β-lactamase inhibitor combination that has been demonstrated to have good activity against MDR Pseudomonas aeruginosa.. In this study, C/T was compared with other commonly used intravenous antimicrobial agents against 193 non-fermenting Gram-negative bacteria isolated from CF sputum specimens, including P. aeruginosa, Achromobacter xylosoxidans, Stenotrophomonas maltophilia and Burkholderia cenocepacia. Minimum inhibitory concentrations (MICs) to C/T were determined by standard Etest assay and were interpreted according to current European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines.. C/T had good in vitro antimicrobial activity against CF clinical isolates of P. aeruginosa in comparison with other antimicrobial agents, with the exception of colistin. C/T also had activity against S. maltophilia but was not active against B. cenocepacia or A. xylosoxidans.. C/T showed excellent in vitro activity against P. aeruginosa CF clinical isolates. This antimicrobial agent is a potential therapeutic option when presented with challenging MDR P. aeruginosa and S. maltophilia exacerbations. Further clinical experience and trials in CF are required to determine the place of C/T in clinical practice.

Topics: Achromobacter denitrificans; Adult; beta-Lactamase Inhibitors; Burkholderia cenocepacia; Cephalosporins; Colistin; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Pseudomonas aeruginosa; Sputum; Stenotrophomonas maltophilia; Tazobactam

The emergence of colistin-resistant

Topics: Anti-Bacterial Agents; Biofilms; Colistin; Cystic Fibrosis; Drug Carriers; Humans; Lipids; Microbial Sensitivity Tests; Nanostructures; Pseudomonas aeruginosa; Spatio-Temporal Analysis

Antimicrobial peptides (AMPs) represent a promising therapeutic alternative for the treatment of antibiotic-resistant bacterial infections. The present study investigates the antimicrobial activity of new, rationally-designed derivatives of a short α-helical peptide, RR. From the peptides designed, RR4 and its D-enantiomer, D-RR4, emerged as the most potent analogues with a more than 32-fold improvement in antimicrobial activity observed against multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii. Remarkably, D-RR4 demonstrated potent activity against colistin-resistant strains of P. aeruginosa (isolated from cystic fibrosis patients) indicating a potential therapeutic advantage of this peptide over several AMPs. In contrast to many natural AMPs, D-RR4 retained its activity under challenging physiological conditions (high salts, serum, and acidic pH). Furthermore, D-RR4 was more capable of disrupting P. aeruginosa and A. baumannii biofilms when compared to conventional antibiotics. Of note, D-RR4 was able to bind to lipopolysaccharide to reduce the endotoxin-induced proinflammatory cytokine response in macrophages. Finally, D-RR4 protected Caenorhabditis elegans from lethal infections of P. aeruginosa and A. baumannii and enhanced the activity of colistin in vivo against colistin-resistant P. aeruginosa.

Topics: Acinetobacter baumannii; Animals; Antimicrobial Cationic Peptides; Biofilms; Caenorhabditis elegans; Colistin; Cystic Fibrosis; Drug Design; Drug Resistance, Multiple, Bacterial; Drug Stability; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Cystic fibrosis is an autosomal recessive disorder characterized by chronic progressive multisystem involvement. AH1N1 virus infections caused classic influenza symptoms in the majority of cystic fibrosis patients while others experienced severe outcomes.. We report a case of late incidental cystic fibrosis diagnosis in a young Caucasian man suffering from respiratory failure following infection due to AH1N1 influenza virus. The patient was admitted to our department with fever, cough, and dyspnea at rest unresponsive to antibiotics CONCLUSIONS: Late diagnosis of cystic fibrosis in uncommon. This report highlights the importance of early cystic fibrosis diagnosis to minimize risk of occurrence of potential life-threatening complications.

Topics: Anti-Bacterial Agents; Ceftazidime; Colistin; Cystic Fibrosis; Delayed Diagnosis; Drainage, Postural; Genetic Testing; Humans; Incidental Findings; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Meropenem; Pneumonia; Referral and Consultation; Sweat; Thienamycins; Tomography, X-Ray Computed; Young Adult

Various fungi have the ability to colonize surfaces and to form biofilms. Fungal biofilm-associated infections are frequently refractory to targeted treatment because of resistance to antifungal drugs. One fungus that frequently colonises the respiratory tract of cystic fibrosis (CF) patients is the opportunistic black yeast-like fungus Exophiala dermatitidis. We investigated the biofilm-forming ability of E. dermatitidis and its susceptibility to various antiinfective agents and natural compounds. We tested 58 E. dermatitidis isolates with a biofilm assay based on crystal violet staining. In addition, we used three isolates to examine the antibiofilm activity of voriconazole, micafungin, colistin, farnesol, and the plant derivatives 1,2,3,4,6-penta-O-galloyl-b-D-glucopyranose (PGG) and epigallocatechin-3-gallate (EGCG) with an XTT reduction assay. We analysed the effect of the agents on cell to surface adhesion, biofilm formation, and the mature biofilm. The biofilms were also investigated by confocal laser scan microscopy. We found that E. dermatitidis builds biofilm in a strain-specific manner. Invasive E. dermatitidis isolates form most biomass in biofilm. The antiinfective agents and the natural compounds exhibited poor antibiofilm activity. The greatest impact of the compounds was detected when they were added prior cell adhesion. These findings suggest that prevention may be more effective than treatment of biofilm-associated E. dermatitidis infections.

Topics: Antifungal Agents; Bacterial Adhesion; beta-Glucans; Biofilms; Catechin; Colistin; Cystic Fibrosis; Echinocandins; Exophiala; Farnesol; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mycoses; Voriconazole

Tolerance towards antibiotics of Pseudomonas aeruginosa biofilms is recognized as a major cause of therapeutic failure of chronic lung infection in cystic fibrosis (CF) patients. This lung infection is characterized by antibiotic-tolerant biofilms in mucus with zones of O2 depletion mainly due to polymorphonuclear leukocytic activity. In contrast to the main types of bactericidal antibiotics, it has not been possible to establish an association between the bactericidal effects of colistin and the production of detectable levels of OH ˙ on several strains of planktonic P. aeruginosa. Therefore, we propose that production of OH ˙ may not contribute significantly to the bactericidal activity of colistin on P. aeruginosa biofilm. Thus, we investigated the effect of colistin treatment on biofilm of wild-type PAO1, a catalase-deficient mutant (ΔkatA) and a colistin-resistant CF isolate cultured in microtiter plates in normoxic- or anoxic atmosphere with 1 mM nitrate. The killing of bacteria during colistin treatment was measured by CFU counts, and the OH⋅ formation was measured by 3(')-(p-hydroxylphenyl fluorescein) fluorescein (HPF) fluorescence. Validation of the assay was done by hydrogen peroxide treatment. OH⋅ formation was undetectable in aerobic PAO1 biofilms during 3 h of colistin treatment. Interestingly, we demonstrate increased susceptibility of P. aeruginosa biofilms towards colistin during anaerobic conditions. In fact, the maximum enhancement of killing by anaerobic conditions exceeded 2 logs using 4 mg L(-1) of colistin compared to killing at aerobic conditions.

Topics: Aerobiosis; Anaerobiosis; Anti-Bacterial Agents; Biofilms; Colistin; Colony Count, Microbial; Cystic Fibrosis; Fluoresceins; Fluorometry; Humans; Hydroxyl Radical; Microbial Viability; Pseudomonas aeruginosa; Pseudomonas Infections

MICs and biofilm inhibitory concentrations (BICs) were measured for 68 cystic fibrosis (CF) Achromobacter isolates for amikacin, aztreonam, colistin, levofloxacin, and tobramycin. With the exception of colistin and levofloxacin, the remaining antibiotics had MIC90s, BICs at which 50% of the isolates were susceptible (BIC50s), and BICs at which 90% of the isolates were susceptible (BIC90s) equal to or above the highest concentrations tested. In a biofilm model, tobramycin was able to significantly increase killing of bacterial cells compared to controls, for intermediate-resistant strains only, at concentrations of 1,000 and 2,000 μg/ml.

Topics: Achromobacter; Amikacin; Anti-Bacterial Agents; Aztreonam; Biofilms; Colistin; Cystic Fibrosis; Gram-Negative Bacterial Infections; Humans; Levofloxacin; Microbial Sensitivity Tests; Plankton; Tobramycin

Pseudomonas aeruginosa frequently infects the respiratory tract of cystic fibrosis (CF) patients. Multidrug-resistant phenotypes and high capacity to form stable biofilms are common. Recent studies have described the emergence of colistin-resistant isolates in CF patients treated with long-term inhaled colistin. The use of nanoparticles containing antimicrobials can contribute to overcome drug resistance mechanisms. The aim of this study was to explore antimicrobial activity of nanoencapsulated colistin (SLN-NLC) versus free colistin against P. aeruginosa clinical isolates from CF patients and to investigate their efficacy in biofilm eradication. Susceptibility of planktonic bacteria to antimicrobials was examined by using the broth microdilution method and growth curve assay. Minimal biofilm eradication concentration (MBEC) and biofilm prevention concentration (BPC) were determined to assess antimicrobial susceptibility of sessile bacteria. We used atomic force microscopy (AFM) to visualize treated and untreated biofilms and to determine surface roughness and other relevant parameters. Colistin nanoparticles had the same antimicrobial activity as free drug against planktonic bacteria. However, nanoencapsulated colistin was much more efficient in the eradication of biofilms than free colistin. Thus, these formulations have to be considered as a good alternative therapeutic option to treat P. aeruginosa infections.

Topics: Adult; Anti-Bacterial Agents; Biofilms; Child; Colistin; Cystic Fibrosis; Drug Delivery Systems; Drug Monitoring; Drug Resistance, Bacterial; Female; Humans; Male; Middle Aged; Nanoparticles; Outcome Assessment, Health Care; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory System; Respiratory Tract Infections; Spain

In this work different nebulisers were investigated in order to assess their efficiency in combination with colistimethate sodium (CMS) inhalation products. Four nebulisers, namely I-neb(®), Aeroneb(®) Go, eFlow(®)rapid and PARI LC(®) Sprint were studied in terms of delivered dose (DD), drug delivery rate (DDR) and respirable dose (RD) of CMS. The goal was to provide scientific data to physicians for prescribing the most appropriate nebuliser for the CMS specific user. All the apparatuses nebulised ColiFin 1MIU/3 ml solution (80 mg of CMS) with delivered doses between 31% and 41% of the loaded amount. Aeroneb Go showed the longest nebulisation time (more than 20 min). When ColiFin 2 MIU/4 ml was nebulised with eFlow rapid or PARI LC Sprint, the CMS respirable dose was 45.3mg and 39.2mg, in times of 5.6 and 10.8 min, respectively. I-neb, having a medication cup capacity limited to 0.4 ml, loaded with Promixin 0.4 MIU/0.4 ml (32 mg of CMS), provided in a time of 9 min a RD of 21.5mg, a value slightly higher than those obtained by nebulising ColiFin 1 MIU/3 ml with the other nebulisers (range 15.9-17.6 mg). The results illustrate that the clinical outcome depends on the comparative analysis of nebulisation efficiency (respirable dose) and convenience (time), not disregarding the ratios between the amount loaded, delivered and deposited at lung level.

Topics: Anti-Bacterial Agents; Bacterial Infections; Colistin; Cystic Fibrosis; Humans; Lung Diseases; Nebulizers and Vaporizers; Solutions

In cystic fibrosis (CF), chronic microbial lung infections are difficult to treat and cause morbidity and increased mortality.. In a multicentre, open-label, exploratory, non-interventional study, inhaled tobramycin (300 mg twice daily) and colistin (1 million I.U. twice daily) were sequentially combined with the aim to investigate the effect on 41 CF patients with chronic P. aeruginosa infections for six months (mean age 24 ± 10.8y).. Six patients had adverse events that were assessed as being related to treatment. Mucus production and coughing both decreased in 39%, whereas FEV1 absolute and relative to baseline increased by 4.9% and 9.1%, respectively (p = 0.004) in 29 patients, who were definitely treated sequentially. Efficacy of the therapy was rated 'excellent' or 'good' by the physicians in 80.5% of the patients.. The results indicate that treatment with inhaled antibiotics, sequentially combined, was very well tolerated by most patients and may have a beneficial effect, even if transitory on lung function and respiratory symptoms.

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Bacterial Agents; Chronic Disease; Colistin; Cystic Fibrosis; Drug Administration Schedule; Drug Combinations; Female; Forced Expiratory Volume; Humans; Male; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin; Treatment Outcome

In the last decades, the encapsulation of antibiotics into nanoparticulate carriers has gained increasing attention for the treatment of infectious diseases. Sodium colistimethate-loaded solid lipid nanoparticles (Colist-SLNs) and nanostructured lipid carriers (Colist-NLCs) were designed aiming to treat the pulmonary infection associated to cystic fibrosis patients. The nanoparticles were freeze-dried using trehalose as cryoprotectant. The stability of both nanoparticles was analysed over one year according to the International Conference of Harmonisation (ICH) guidelines by determining the minimum inhibitory concentration (MIC) against clinically isolated Pseudomonas aeruginosa strains and by studying their physico-chemical characteristics. The results showed that Colist-SLNs lost their antimicrobial activity at the third month; on the contrary, the antibacterial activity of Colist-NLCs was maintained throughout the study within an adequate range (MIC ≤16 μg/mL). In addition, Colist-NLCs exhibited suitable physico-chemical properties at 5 °C and 25 °C/60% relative humidity over one year. Altogether, Colist-NLCs proved to have better stability than Colist-SLNs.

Topics: Colistin; Cystic Fibrosis; Drug Stability; Humans; Lipids; Nanoparticles; Pseudomonas aeruginosa; Pseudomonas Infections

Colistin is an antimicrobial peptide that has become the only remaining alternative for the treatment of multidrug-resistant Gram-negative bacterial infections, but little is known of how clinical levels of colistin resistance evolve. We use in vitro experimental evolution and whole-genome sequencing of colistin-resistant Pseudomonas aeruginosa isolates from cystic fibrosis patients to reconstruct the molecular evolutionary pathways open for high-level colistin resistance. We show that the evolution of resistance is a complex, multistep process that requires mutation in at least five independent loci that synergistically create the phenotype. Strong intergenic epistasis limits the number of possible evolutionary pathways to resistance. Mutations in transcriptional regulators are essential for resistance evolution and function as nodes that potentiate further evolution towards higher resistance by functionalizing and increasing the effect of the other mutations. These results add to our understanding of clinical antimicrobial peptide resistance and the prediction of resistance evolution.

Topics: Alleles; Antimicrobial Cationic Peptides; Colistin; Cystic Fibrosis; DNA Mutational Analysis; Drug Resistance, Bacterial; Epistasis, Genetic; Escherichia coli; Evolution, Molecular; Genome, Fungal; Mutation; Peptides; Phenotype; Polymorphism, Single Nucleotide; Pseudomonas aeruginosa

In 2010, aztreonam for inhalation solution joined aminoglycosides and colistimethate as a new cystic fibrosis (CF) chronic inhaled antimicrobial therapy. We studied how the introduction of this new inhaled antibiotic class changed the management of US CF patients.. The use of inhaled aminoglycosides, colistimethate, and aztreonam among patients followed in the CF Foundation Patient Registry was analyzed by age group, lung disease stage, and microbiologic status both annually, and at individual visits between 2009 and 2012.. The overall prevalence of inhaled antibiotic use did not change during the period, but the prevalence of annual and any visit treatment with >1 inhaled antibiotic class more than doubled. Adults, those with advanced lung disease, and those with >1 Pseudomonas aeruginosa respiratory culture were more likely to receive >1 antibiotic class.. Inhaled antibiotic management of US CF patients has dramatically changed in association with the introduction of a third inhaled antibiotic class.

Topics: Administration, Inhalation; Adolescent; Adult; Aerosols; Anti-Bacterial Agents; Aztreonam; Child; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Prevalence; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Tobramycin; Treatment Outcome; Young Adult

For the first time, we report the whole-genome sequence analysis of Chryseobacterium oranimense G311, a multidrug-resistant bacterium, from a cystic fibrosis patient in France, including resistance to colistin. Whole-genome sequencing of C. oranimense G311 was performed using Ion Torrent PGM, and RAST, the EMBL-EBI server, and the Antibiotic Resistance Gene-ANNOTation (ARG-ANNOT) database were used for annotation of all genes, including antibiotic resistance (AR) genes. General features of the C. oranimense G311 draft genome were compared to the other available genomes of Chryseobacterium gleum and Chryseobacterium sp. strain CF314. C. oranimense G311 was found to be resistant to all β-lactams, including imipenem, and to colistin. The genome size of C. oranimense G311 is 4,457,049 bp in length, with 37.70% GC content. We found 27 AR genes in the genome, including β-lactamase genes which showed little similarity to the known β-lactamase genes and could likely be novel. We found the type I polyketide synthase operon followed by a zeaxanthin glycosyltransferase gene in the genome, which could impart the yellow pigmentation of the isolate. We located the O-antigen biosynthesis cluster, and we also discovered a novel capsular polysaccharide biosynthesis cluster. We also found known mutations in the orthologs of the pmrA (E8D), pmrB (L208F and P360Q), and lpxA (G68D) genes. We speculate that the presence of the capsular cluster and mutations in these genes could explain the resistance of this bacterium to colistin. We demonstrate that whole-genome sequencing was successfully applied to decipher the resistome of a multidrug resistance bacterium associated with cystic fibrosis patients.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Bacterial Typing Techniques; Base Composition; beta-Lactamases; Chryseobacterium; Colistin; Cystic Fibrosis; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Flavobacteriaceae Infections; France; Humans; Imipenem; Mutation; Phylogeny; Sequence Analysis, DNA

The spread of Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae continues to increase, and the possible development of KPC-producing K. pneumoniae infections in cystic fibrosis (CF) patients is a matter of concern. Here, we describe the establishment of a chronic lung infection due to a colistin-resistant KPC-producing K. pneumoniae isolate in an Italian CF patient.

Topics: Anti-Bacterial Agents; Chronic Disease; Colistin; Cystic Fibrosis; Drug Resistance, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Underage Drinking

Pseudomonas and Burkholderia pose a significant health threat to people with chronic respiratory conditions; the resistance inherent in these bacteria indicates that new antimicrobial strategies are required. Susceptibility of 56 strains of P. aeruginosa and 55 strains of Burkholderia to manuka honey, tobramycin and colistin using microbroth dilution and E strip was determined. MICs of antibiotics with honey were determined to search for synergistic combinations against two representative strains of each genus. All strains exhibited susceptibility to honey ≤10 % (w/v); mean susceptibility of Burkholderia (4.6 % w/v) was lower than P. aeruginosa (7.3 % w/v). Synergistic or additive combinations were found with all four strains tested. Combinations of manuka honey with antibiotics can be used to lower the MIC need to successfully inhibit both P. aeruginosa and B. cepacia. The use of honey as a combination agent may be possible for the management of P. aeruginosa and B. cepacia.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Burkholderia; Burkholderia Infections; Colistin; Cystic Fibrosis; Honey; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

Topics: Adolescent; Adult; Analysis of Variance; Anti-Bacterial Agents; Chi-Square Distribution; Ciprofloxacin; Cohort Studies; Colistin; Confidence Intervals; Culture Media, Conditioned; Cystic Fibrosis; Female; Follow-Up Studies; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Risk Assessment; Severity of Illness Index; Treatment Outcome; Young Adult

Case description The use of i.v. colistin reappeared recently for the treatment of multidrug-resistant Gram negative organisms in the intensive care and cystic fibrosis (CF) setting. According to the latest pharmacokinetic data, a loading dose and high antibiotic doses are given. Two cases of adverse events (paraesthesias, bad taste) were observed immediately after the start of infusion of a high dose of i.v. colistin in adult CF patients at the Ghent University Hospital. Conclusion Recommendations for optimal administration of i.v. colistin in adult CF patients are scarce. This article highlights the importance of mode of administration to avoid toxicity and relates it to recent pharmacokinetic/-dynamic literature.

Topics: Adult; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Female; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Male; Paresthesia

The impact of physicochemical conditions observed in cystic fibrosis (CF) lung on colistin activity against both planktonic and biofilm P. aeruginosa cells was evaluated. MIC, minimum bactericidal concentration (MBC), and minimum biofilm eradication concentration (MBEC) values were assessed against 12 CF strains both under "CF-like" (anaerobiosis, pH6.4) and "standard" (aerobiosis, pH7.4) conditions. The activity of colistin was significantly higher under "CF-like" conditions compared to "standard" ones, both against planktonic (MIC90: 1 and 4 μg/mL, respectively) and biofilm (MBEC90: 512 and 1.024 μg/mL, respectively) cells, as confirmed by scanning electron microscopy. Improved activity was not related to biofilm matrix amount. It may be necessary to adequately "rethink" the protocols used for in vitro assessment of colistin activity, by considering physicochemical and microbiological features in the CF lung at the site of infection. This could provide a more favorable therapeutic index, rationale for administration of lower doses, probably resulting in reduced toxicity and emergence of resistant clones.

Topics: Anaerobiosis; Anti-Bacterial Agents; Biofilms; Colistin; Culture Media; Cystic Fibrosis; Humans; Hydrogen-Ion Concentration; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Patients suffering from cystic fibrosis (CF) are commonly affected by chronic Pseudomonas aeruginosa biofilm infections. This is the main cause for the high disease severity. In this study, we demonstrate that P. aeruginosa is able to efficiently colonize murine solid tumors after intravenous injection and to form biofilms in this tissue. Biofilm formation was evident by electron microscopy. Such structures could not be observed with transposon mutants, which were defective in biofilm formation. Comparative transcriptional profiling of P. aeruginosa indicated physiological similarity of the bacteria in the murine tumor model and the CF lung. The efficacy of currently available antibiotics for treatment of P. aeruginosa-infected CF lungs, such as ciprofloxacin, colistin, and tobramycin, could be tested in the tumor model. We found that clinically recommended doses of these antibiotics were unable to eliminate wild-type P. aeruginosa PA14 while being effective against biofilm-defective mutants. However, colistin-tobramycin combination therapy significantly reduced the number of P. aeruginosa PA14 cells in tumors at lower concentrations. Hence, we present a versatile experimental system that is providing a platform to test approved and newly developed antibiofilm compounds.

Topics: Animals; Anti-Infective Agents; Biofilms; Cell Line, Tumor; Colistin; Cystic Fibrosis; Disease Models, Animal; Female; Lung Diseases; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

Pseudomonas aeruginosa plays an important role in chronic lung infections among patients with cystic fibrosis (CF) through its ability to form antibiotic-resistant biofilms. In P. aeruginosa, biofilm development and the production of several virulence factors are mainly regulated by the rhl and las quorum-sensing (QS) systems, which are controlled by two N-acyl-homoserine lactone signal molecules. In a previous study, we discovered an original QS inhibitor, N-(2-pyrimidyl)butanamide, called C11, based on the structure of C4-homoserine lactone, and found that it is able to significantly inhibit P. aeruginosa biofilm formation. However, recent data indicate that P. aeruginosa grows under anaerobic conditions and forms biofilms in the lungs of CF patients that are denser and more robust than those formed under aerobic conditions. Our confocal microscopy observations of P. aeruginosa biofilms developed under aerobic and anaerobic conditions confirmed that the biofilms formed under these two conditions have radically different architectures. C11 showed significant dose-dependent antibiofilm activity on biofilms grown under both aerobic and anaerobic conditions, with a greater inhibitory effect being seen under conditions of anaerobiosis. Gene expression analyses performed by quantitative reverse transcriptase PCR showed that C11 led to the significant downregulation of rhl QS regulatory genes but also to the downregulation of both las QS regulatory genes and QS system-regulated virulence genes, rhlA and lasB. Furthermore, the activity of C11 in combination with antibiotics against P. aeruginosa biofilms was tested, and synergistic antibiofilm activity between C11 and ciprofloxacin, tobramycin, and colistin was obtained under both aerobic and anaerobic conditions. This study demonstrates that C11 may increase the efficacy of treatments for P. aeruginosa infections by increasing the susceptibility of biofilms to antibiotics and by attenuating the pathogenicity of the bacterium.

Topics: Amides; Anti-Bacterial Agents; Bacterial Adhesion; Biofilms; Ciprofloxacin; Colistin; Cystic Fibrosis; Drug Synergism; Drug Therapy, Combination; Humans; Lung; Microscopy, Confocal; Pseudomonas aeruginosa; Pseudomonas Infections; Pyrimidines; Quorum Sensing; Respiratory Tract Infections; Tobramycin

Cystic fibrosis (CF) affects over 9,000 people in the UK and limits life expectancy. CF patients are susceptible to lung infections, most commonly Pseudomonas aeruginosa. Once infection is established, patients require lifetime treatment using nebulised antibiotics. Newer dry powder formulations of antibiotics may reduce treatment burden and improve compliance.. Our objective was to evaluate the cost effectiveness of (i) colistimethate sodium dry powder for inhalation (DPI) and (ii) tobramycin DPI versus nebulised tobramycin for the treatment of chronic P. aeruginosa lung infection in patients with CF from the perspective of the National Health Service (NHS) and Personal Social Services (PSS).. We developed a state transition model based on transitions between three strata of lung function measured in terms of forced expiratory volume in 1 second (FEV1) % predicted. Additional health states representing post-lung transplantation and dead are also modelled. The model structure was informed by systematic reviews of evidence concerning the plausibility of potential relationships between intermediate endpoints and final outcomes. The model assumes that treatment impacts on FEV1 trajectory, which manifest as changes in health-related quality of life. No survival benefit is assumed due to the absence of robust quantifiable evidence. Model parameters were informed by patient-level and aggregate data from two randomised controlled trials together with the best available evidence from the literature. Resource use and costs associated with drug acquisition, the management of exacerbations and reduced nebuliser maintenance were drawn from reference sources and expert opinion. Costs were valued at 2011/2012 prices. Costs and health outcomes were discounted at a rate of 3.5 %. Simple and probabilistic sensitivity analyses were undertaken, including additional analyses of Patient Access Scheme (PAS) price discounts offered by the manufacturers of both DPI products.. Colistimethate sodium DPI is expected to produce fewer quality-adjusted life-years (QALYs) than nebulised tobramycin. Based on its list price, colistimethate sodium DPI is expected to be dominated by nebulised tobramycin. When the PAS is incorporated, the incremental cost-effectiveness ratio (ICER) for colistimethate sodium DPI versus nebulised tobramycin is expected to be approximately £288,600 saved per QALY lost. Based on its current list price, the ICER for tobramycin DPI versus nebulised tobramycin is expected to be approximately £124,000 per QALY gained. When the proposed PAS is included, tobramycin DPI is expected to dominate nebulised tobramycin.. Under their list prices, neither DPI product is likely to represent good value for money for the NHS given current cost-effectiveness thresholds. The PAS discounts have a significant impact upon the economic attractiveness of both DPI products compared against nebulised tobramycin. The clinical effectiveness and cost effectiveness of the DPIs against other nebulised antibiotics, such as aztreonam and inhaled colistimethate sodium, remains unclear.

Topics: Adult; Anti-Bacterial Agents; Colistin; Cost-Benefit Analysis; Cystic Fibrosis; Decision Support Techniques; Dry Powder Inhalers; Humans; Models, Economic; Pneumonia, Bacterial; Probability; Pseudomonas aeruginosa; Pseudomonas Infections; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Survival Analysis; Tobramycin; Young Adult

In cystic fibrosis (CF) patients the paranasal sinuses can constitute a niche for bacteria, which can migrate to the lungs. Nasal administration of antibiotics may be effective, but safety of this treatment has to be established first. The objective of this study was to investigate the systemic absorption of nasally administered tobramycin, colistin (administered as colistin sulfomethate sodium; CMS) and a combination of both drugs using systemic absorption as surrogate for safety. In addition, tolerability of the nasal irrigations was examined.. Ten adult CF patients performed three different nasal irrigations: 300 mg of tobramycin; 160 mg of CMS; and 300 mg of tobramycin combined with 160 mg of CMS. Serum concentrations of tobramycin and colistin A and B (the main components of colistin) were analysed. Tolerability was measured using a visual analogue scale. Dutch Trial Register: NTR 4008.. Following the tobramycin and the combined irrigation, only two patients had detectable tobramycin serum levels, with the highest being 0.054 mg/L. Serum levels of colistin A and B were not detectable. All three nasal irrigation solutions were well tolerated with a higher tolerability for CMS compared with tobramycin.. Nasal irrigations with tobramycin, CMS and a combination of tobramycin and CMS resulted in safe serum levels and were well tolerated.

Topics: Absorption, Physiological; Administration, Intranasal; Adult; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Female; Humans; Male; Nasal Mucosa; Tobramycin; Young Adult

Lung impairment is the most life-threatening factor for cystic fibrosis patients. Indeed, Pseudomonas aeruginosa is the main pathogen in the pulmonary infection of these patients. In this work, we developed sodium colistimethate loaded lipid nanoparticles, namely, solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), as a strategy to enhance the antimicrobial therapy against P. aeruginosa in cystic fibrosis patients. The nanoparticles obtained displayed a 200-400 nm size, high drug entrapment (79-94%) and a sustained drug release profile. Moreover, both SLN and NLC presented antimicrobial activity against clinically isolated P. aeruginosa. The integrity of the nanoparticles was not affected by nebulization through a mesh vibrating nebulizer. Moreover, lipid nanoparticles appeared to be less toxic than free sodium colistimethate in cell culture. Finally, an in vivo distribution experiment showed that nanoparticles spread homogenously through the lung and there was no migration of lipid nanoparticles to other organs, such as liver, spleen or kidneys.

Topics: Administration, Inhalation; Animals; Anti-Bacterial Agents; Cell Line; Cell Survival; Colistin; Cystic Fibrosis; Drug Carriers; Drug Delivery Systems; Drug Liberation; Humans; Lipids; Mice; Microbial Sensitivity Tests; Nanoparticles; Particle Size; Pseudomonas aeruginosa; Pseudomonas Infections; Surface Properties; Tissue Distribution

Most patients with cystic fibrosis (CF) have chronic rhinosinusitis; their sinuses are often colonized with bacteria that can initiate and maintain deleterious pulmonary infections. Theoretically, eradication of the sinus bacteria should reduce the frequency of lung infections and thereby reduce pulmonary morbidity. This article addressed whether bacteria in CF sinuses are eligible for eradication by sinus surgery and postoperative treatment.. A prospective study including 58 CF patients, who had extensive sinus surgery and growth of Pseudomonas aeruginosa, Achromobacter xylosoxidans, and/or Burkholderia multivorans in their sinuses, was initiated. All patients followed a systematic postoperative treatment program of nasal irrigations with saline and colistimethate sodium and systematic endoscopic cleansing. All patients had follow-up examinations including sinus cultures; each side of the nose was cultured separately.. At the 6-month follow-up visit, 49 patients were cultured; 66 of 98 maxillary-ethmoidal complexes (67%) showed no growth of pathogenic bacteria. Some patients were not free from CF pathogenic bacteria at all cultures; however, 20 (41%) patients had no bilateral regrowth (p < 0.01) and 4 patients had no unilateral regrowth at any time during 6 months of follow-up. The eradication of CF pathogens was accomplished in patients from all three lung infection groups: intermittently colonized, chronically infected, and lung transplanted. The patient with the longest follow-up had no bacterial growth for 3 years.. Extensive sinus surgery combined with intensive follow-up can eradicate pathogenic bacteria from CF sinuses.

Topics: Achromobacter denitrificans; Adolescent; Adult; Burkholderia; Burkholderia Infections; Child; Chronic Disease; Colistin; Cystic Fibrosis; Female; Follow-Up Studies; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Nasal Lavage; Paranasal Sinuses; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Rhinitis; Sinusitis; Treatment Outcome; Young Adult

The emergence of multidrug-resistant (MDR) bacteria in cystic fibrosis (CF) patients has led to the use of colistin drug and the emergence of colistin-resistant Gram-negative bacteria. The aim of this study was to compare the disk diffusion and Etest methods for colistin susceptibility testing on MDR bacteria associated with CF from Marseille, France. Forty-nine MDR clinical isolates (27 Stenotrophomonas maltophilia, 22 Achromobacter xylosoxidans) were used in this study. Disk diffusion and Etest assays were used to assess the reliability of these two techniques. For S. maltophilia, 25 out of 27 isolates had low minimum inhibitory concentrations (MICs, 0.125-0.75 mg/L), whereas two isolates displayed high MICs (32 mg/L). Similarly, 19 out of 22 A. xylosoxidans isolates had low MICs (0.75-3.0 mg/L), whereas three isolates had high MICs (32-256 mg/L). The diameters of zone inhibition with a 50-μg colistin disk displayed a good correlation with the MICs obtained by the Etest. Susceptible and resistant strains were eventually separated using a disk diffusion assay at a cut-off of ≤ 12 mm for a 50-μg disk. Colistin displayed excellent activity against S. maltophilia and A. xylosoxidans and the disk diffusion assay could be confidently used to determine the susceptibility to colistin for MDR Gram-negative bacteria in the context of CF.

Topics: Achromobacter denitrificans; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; France; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Stenotrophomonas maltophilia

Topics: Administration, Inhalation; Adult; Anti-Bacterial Agents; Bronchoalveolar Lavage Fluid; Colistin; Cystic Fibrosis; Humans; Lung Transplantation; Respiratory Tract Infections; Retrospective Studies; Treatment Outcome; Young Adult

Topics: Administration, Inhalation; Anti-Bacterial Agents; Clinical Trials as Topic; Colistin; Cystic Fibrosis; Drug Monitoring; Drug Therapy, Combination; Dry Powder Inhalers; Humans; Practice Guidelines as Topic; Pseudomonas Infections; Respiratory Function Tests; Respiratory Tract Infections; State Medicine; Tobramycin; United Kingdom

Patients with cystic fibrosis (CF) often experience acute pulmonary exacerbations (APE) and may be treated with a wide variety of intravenous antibiotics. The aim of this review is to provide an evidence-based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing the intravenous (IV) polymixin antibiotic colistimethate sodium (CMS) in the treatment of APE and to identify areas where further study is warranted. Currently, there is not an international standard on the labeling of CMS products. As a result, this has lead to confusion in the interpretation of the literature with respect to efficacy, tolerance, and optimal dosing strategy. The dosing ranges of IV CMS from the literature are 5.3-12.9 mg/kg/day, maximum 480 mg per day for 60 kg patient (Colomycin® injection-European product) and 8-21.3 mg/kg/day, maximum 800 mg per day for 60 kg patient (Coly-Mycin M® parenteral-US product).The literature supports a CMS dose of 8 mg/kg/day divided every 8 hr (maximum 480 mg/day) for the treatment of APE secondary to Pseudomonas aeruginosa. The maximum recommended CMS dose of 480 mg/day is less than is recommended by the FDA-approved and CFF dosing guidelines but in agreement with UK CF Trust Antibiotic Working Group recommendations. There is debate over the frequency of CMS administration (once daily vs. thrice-daily) and its impact on resistance and clinical efficacy. Further study is needed to determine the tolerability and efficacy of extended-interval dosing of CMS in the treatment of APE.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Disease Progression; Female; Humans; Male; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Young Adult

Because published reports indicate that the antibiotic colistin (COL) has antifungal properties, this study investigated the antifungal in vitro activity of COL as single agent and in combination with the antifungal compounds voriconazole (VRC), caspofungin (CAS) and amphotericin B (AMB) against Scedosporium/Pseudallescheria spp., Exophiala dermatitidis and Geosmithia argillacea. In total, susceptibility was determined for 77 Scedosporium/Pseudallescheria spp., 82 E. dermatitidis and 17 G. argillacea isolates. The minimal inhibitory concentrations (MICs) of COL and the antifungals as single compound and in combination were determined with MIC test strips. Drug interactions were detected by crossing the MIC test strips at a 90º angle. The fractional inhibitory concentration index was used to categorise the drugs' interaction. The MIC50 value of COL was 12 μg ml(-1) for S. prolificans, 16 μg ml(-1) for P. apiosperma, 16 μg ml(-1) for P. boydii, 12 μg ml(-1) for E. dermatiditis and 6 μg ml(-1) for G. argillacea. VRC was the most active drug in combination without any antagonism with the exception of few P. boydii isolates. COL as single agent and in most combinations with antifungals exhibits in vitro antifungal activity against filamentous ascomycetes occurring in cystic fibrosis patients and may offer a novel therapeutic option, especially for multidrug-resistant S. prolificans.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Colistin; Cystic Fibrosis; Drug Evaluation, Preclinical; Drug Synergism; Echinocandins; Exophiala; Humans; Lipopeptides; Microbial Sensitivity Tests; Mitosporic Fungi; Mycoses; Pyrimidines; Scedosporium; Triazoles; Voriconazole

Topics: Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Dry Powder Inhalers; Equipment Design; Humans; Nebulizers and Vaporizers; Pseudomonas Infections

Pseudomonas aeruginosa can develop resistance to polymyxin and other cationic antimicrobial peptides. Previous work has shown that mutations in the PmrAB and PhoPQ regulatory systems can confer low to moderate levels of colistin (polymyxin E) resistance in laboratory strains and clinical isolates of this organism (MICs of 8 to 64 mg/liter). To explore the role of PmrAB in high-level clinical polymyxin resistance, P. aeruginosa isolates from chronically colistin-treated cystic fibrosis patients, most with colistin MICs of >512 mg/liter, were analyzed. These cystic fibrosis isolates contained probable gain-of-function pmrB alleles that conferred polymyxin resistance to strains with a wild-type or pmrAB deletion background. Double mutant pmrB alleles that contained mutations in both the periplasmic and dimerization-phosphotransferase domains markedly augmented polymyxin resistance. Expression of mutant pmrB alleles induced transcription from the promoter of the arnB operon and stimulated addition of 4-amino-l-arabinose to lipid A, consistent with the known role of this lipid A modification in polymyxin resistance. For some highly polymyxin-resistant clinical isolates, repeated passage without antibiotic selection pressure resulted in loss of resistance, suggesting that secondary suppressors occur at a relatively high frequency and account for the instability of this phenotype. These results indicate that pmrB gain-of-function mutations can contribute to high-level polymyxin resistance in clinical strains of P. aeruginosa.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Colistin; Cystic Fibrosis; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Polymyxins; Pseudomonas aeruginosa; Transcription Factors

Topics: Amikacin; Anti-Bacterial Agents; Bacterial Load; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Cystic fibrosis (CF) patients have numerous infectious exacerbations requiring prolonged antibiotic treatments, some of which are nephrotoxic. Inhaled antibiotics can reach detectable serum levels. We studied the impact of chronic nephrotoxic antibiotic exposure on kidney function in CF population. We collected data retrospectively for 113 adult CF patients followed for 8.5 years. Fifty-seven (50.4%) were males and 56 (49.5%) females (mean age 31.7 years [SD 9.9]), of which 31% had diabetes and 9.7% had hypertension. Over 8.5 years follow up, there were no significant changes in blood urea nitrogen (BUN; P = 0.92) or creatinine (P = 0.2) in the whole group. 22% of patients had ≥1 episodes of acute kidney injury (AKI). The presence of AKI was associated with increased BUN (P = 0.002) and creatinine (P = 0.056) at the end of follow up. Use of intravenous colistin, gentamicin, tobramycin, or vancomycin did not correlate with increased BUN (P = 0.64; P = 0.49; P = 0.51; P = 0.47) or creatinine (P = 0.43; P = 0.49; P = 0.17; P = 0.2) after 8.5 years. Elevated tobramycin peak and trough levels did not correlate with increased BUN or creatinine. Inhaled colistin and gentamicin correlated with increased BUN (P = 0.009; P = 0.02) but not creatinine (P = 0.45; P = 0.46). Inhaled tobramycin did not correlate with increased BUN (P = 0.17) or creatinine (P = 0.58). Only inhaled colistin correlated with AKI episodes (P = 0.03). Chronic inhaled colistin and gentamicin are associated with an increase in BUN but not creatinine at the end of follow up. Inhaled colistin was associated with episodes of AKI. Well-managed intravenous use of nephrotoxic antibiotics in CF population is associated with no major long-term renal toxicity.

Topics: Administration, Inhalation; Adult; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Female; Gentamicins; Humans; Infusions, Intravenous; Kidney; Male; Retrospective Studies; Time; Tobramycin

Topics: Adolescent; Ceftazidime; Colistin; Cystic Fibrosis; Desensitization, Immunologic; Humans; Injections, Intravenous; Male; Pseudomonas Infections

To compare clinical and microbiologic outcomes in adults without cystic fibrosis who had Pseudomonas aeruginosa bronchial colonization and were receiving inhaled colistin or colistin plus tobramycin with those who were receiving inhaled tobramycin as outpatient treatment.. Prospective, observational cohort study.. Referral pneumology service at a tertiary university care hospital.. Eighty-one Caucasian adults without cystic fibrosis who received 97 courses of inhaled colistin alone, colistin plus tobramycin, or inhaled tobramycin alone as outpatient treatment of P. aeruginosa bronchial colonization between January 2004 and December 2008.. The frequency and duration of hospitalizations for respiratory exacerbations were the primary outcomes compared among treatment groups. Secondary outcomes were emergence of bacterial resistance, antibiotic use during admission, emergence of other opportunistic microorganisms, achievement of sustained P. aeruginosa eradication in the airways, and mortality, as well as safety and changes in respiratory function. No significant differences between colistin and tobramycin were found in the mean number of hospital admissions, duration of hospitalizations, duration of antibiotic treatment, adverse events, mortality, or emergence of other opportunistic microorganisms. Emergence of resistance to colistin was lower than resistance to tobramycin (hazard ratio 0.09, 95% confidence interval [CI] 0.03-0.32). Patients treated with both inhaled antibiotics had fewer days of hospitalization and fewer days of antibiotic use than those treated with tobramycin alone (relative risk [RR] 0.33, 95% CI 0.10-1.12, and RR 0.27, 95% CI 0.08-0.93, respectively).. Results with colistin were similar to those with tobramycin for inhaled treatment of P. aeruginosa colonization in this population; however, combined use of colistin and tobramycin appeared to be associated with fewer days of hospitalization and shorter duration of antibiotic treatment. Prospective, double-blind, placebo-controlled trials of outpatient nebulized antibiotics, especially colistin plus tobramycin, should be performed to ascertain the efficacy of this therapy for treatment of P. aeruginosa colonization in patients without cystic fibrosis.

Topics: Administration, Inhalation; Ambulatory Care; Anti-Bacterial Agents; Bronchitis, Chronic; Colistin; Cystic Fibrosis; Data Interpretation, Statistical; Drug Therapy, Combination; Female; Hospitalization; Humans; Male; Middle Aged; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin; Treatment Outcome

Acquisition of Pseudomonas aeruginosa (Psa) and infection with mucoid strains is associated with repeated pulmonary exacerbations which often require intravenous and long-term nebulised antibiotic treatments, repeated hospitalizations and leads to a more precipitous decline in lung function. Anti-Psa antibiotic therapy early in the course of Psa infection in patients with cystic fibrosis (CF) may result in eradication of Psa and prevention or delay of colonization with the organism. From January 1995 to December 2009 our paediatric CF clinic has followed an early eradication protocol for the first appearance of Psa. In this paper we report on the economic effects after 15 years as reflected in hospitalization and antibiotic usage and cost.. The Psa-eradication protocol includes 2 weeks of IV piperacillin and tobramycin, followed by oral ciprofloxacin for 3 weeks, and nebulised colistimethate for 6 months. The same protocol is used for newly diagnosed CF patients who grow Psa on their first visit or who grow a mucoid strain, multiresistant strain of Psa or whose Psa co-cultured with Burkholderia cepacia complex, and for patients in whom Psa recurs after initial clearance.. 195 Psa eradication courses were completed from 1995 to 2009 with an overall Psa clearance rate of 90%. Patients that only cultured a Psa classic (non-mucoid) strain had a clearance rate was 96.5%. The percentage of children chronically infected with Psa has declined from 44% in 1994 to 15% in 2009.Total days spent in hospital for all reasons declined by 43%; chronic Psa hospital days declined by 75%; IV and nebulised anti-Psa antibiotic costs reduced by 44%.. Results indicate that application of a Pseudomonas eradication protocol as described in this report has economic and resource utilization benefits in addition to clinical benefits.

Topics: Administration, Oral; Adolescent; Anti-Bacterial Agents; Anti-Infective Agents; Burkholderia cepacia complex; Child; Child, Preschool; Ciprofloxacin; Cohort Studies; Colistin; Cystic Fibrosis; Disease-Free Survival; Drug Administration Schedule; Drug Therapy, Combination; Health Care Costs; Health Resources; Humans; Infant; Injections, Intravenous; Nebulizers and Vaporizers; Piperacillin; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin; Treatment Outcome

Combination therapy may be required for multidrug-resistant (MDR) Pseudomonas aeruginosa. The aim of this study was to systematically investigate bacterial killing and emergence of colistin resistance with colistin and doripenem combinations against MDR P. aeruginosa. Studies were conducted in a one-compartment in vitro pharmacokinetic/pharmacodynamic model for 96 h at two inocula (~10(6) and ~10(8) CFU/ml) against a colistin-heteroresistant reference strain (ATCC 27853) and a colistin-resistant MDR clinical isolate (19147 n/m). Four combinations utilizing clinically achievable concentrations were investigated. Microbiological response was examined by log changes and population analysis profiles. Colistin (constant concentrations of 0.5 or 2 mg/liter) plus doripenem (peaks of 2.5 or 25 mg/liter every 8 h; half-life, 1.5 h) substantially increased bacterial killing against both strains at the low inoculum, while combinations containing colistin at 2 mg/liter increased activity against ATCC 27853 at the high inoculum; only colistin at 0.5 mg/liter plus doripenem at 2.5 mg/liter failed to improve activity against 19147 n/m at the high inoculum. Combinations were additive or synergistic against ATCC 27853 in 16 and 11 of 20 cases (4 combinations across 5 sample points) at the 10(6)- and 10(8)-CFU/ml inocula, respectively; the corresponding values for 19147 n/m were 16 and 9. Combinations containing doripenem at 25 mg/liter resulted in eradication of 19147 n/m at the low inoculum and substantial reductions in regrowth (including to below the limit of detection at ∼50 h) at the high inoculum. Emergence of colistin-resistant subpopulations of ATCC 27853 was substantially reduced and delayed with combination therapy. This investigation provides important information for optimization of colistin-doripenem combinations.

Topics: Anti-Bacterial Agents; Carbapenems; Colistin; Colony Count, Microbial; Cystic Fibrosis; Doripenem; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Half-Life; Humans; Models, Biological; Pseudomonas aeruginosa; Pseudomonas Infections

Pseudomonas aeruginosa can develop resistance to polymyxin and other cationic antimicrobial peptides. Previous work has shown that mutations in the PmrAB and PhoPQ regulatory systems can confer low to moderate levels of polymyxin resistance (MICs of 8 to 64 mg/liter) in laboratory and clinical strains of this organism. To explore the role of PhoPQ in high-level clinical polymyxin resistance, P. aeruginosa strains with colistin MICs > 512 mg/liter that had been isolated from cystic fibrosis patients treated with inhaled colistin (polymyxin E) were analyzed. Probable loss-of-function phoQ alleles found in these cystic fibrosis strains conferred resistance to polymyxin. Partial and complete suppressor mutations in phoP were identified in some cystic fibrosis strains with resistance-conferring phoQ mutations, suggesting that additional loci can be involved in polymyxin resistance in P. aeruginosa. Disruption of chromosomal phoQ in the presence of an intact phoP allele stimulated 4-amino-l-arabinose addition to lipid A and induced transcription from the promoter of the pmrH (arnB) operon, consistent with the known role of this lipid A modification in polymyxin resistance. These results indicate that phoQ loss-of-function mutations can contribute to high-level polymyxin resistance in clinical strains of P. aeruginosa.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Colistin; Cystic Fibrosis; Drug Resistance, Bacterial; Female; Humans; Lipid A; Male; Microbial Sensitivity Tests; Mutation; Polymyxins; Pseudomonas aeruginosa; Pseudomonas Infections

The rise in the rates of antibiotic resistance among Pseudomonas aeruginosa strains from cystic fibrosis (CF) patients is concerning and underscores the need for the development of novel compounds. Among them CSA-13, a cationic steroid molecule, mimics the activity of naturally occurring antimicrobial peptides.. MICs and MBCs were determined using the microbroth dilution technique. Combinations were assessed using the checkerboard technique. The bactericidal activity of CSA-13 in combination with colistin was measured using the time-kill curve method for two strains.. The MIC(90) values of CSA-13, colistin, tobramycin, and ciprofloxacin were 2, 1, 1, and 2 mg/l, respectively. The MBCs were equal to or two-fold greater than those of the MICs. With a fractional inhibitory concentration index of ≤0.5 as borderline, synergistic interactions were mostly seen with the CSA-13-colistin combination (54%). No antagonism was observed. The results of the time-kill curve analysis demonstrated rapid bactericidal activity of CSA-13 and synergism with colistin; in one strain early synergy was achieved.. CSA-13 appears to be a good candidate in the treatment of P. aeruginosa strains in CF patients. Future studies should be performed to correlate the safety, efficacy, and pharmacokinetic parameters of this molecule.

Topics: Ciprofloxacin; Colistin; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Steroids; Tobramycin

Antibiotic susceptibility methods that are commonly used to test bacterial isolates from patients with cystic fibrosis are of uncertain reliability for the polymyxins. To assess the reliability of four standard testing methods, this pilot study used a challenge set that included polymyxin-resistant isolates of Pseudomonas aeruginosa and Stenotrophomonas maltophilia.. Twenty-five P. aeruginosa and 12 S. maltophilia isolates were tested for susceptibility to colistin (polymyxin E). Repeatability (concordance of replicates performed concurrently), reproducibility (concordance of replicates performed over time) and comparability (concordance of different methods) of agar dilution, broth microdilution, Etest and disc diffusion were assessed through the use of descriptive statistics and scatterplot analyses.. All four methods displayed excellent repeatability (overall concordance rate of 99%). However, analysis of reproducibility revealed substantially lower rates of concordance (74% for agar dilution, 84% for broth microdilution and Etest, and 91% for disc diffusion). In addition, comparability to agar dilution of the three other methods was generally poor, with overall rates of very major error ranging from 12% for broth microdilution to 18% for Etest and disc diffusion.. Compared with agar dilution, other susceptibility testing methods give high rates of apparent false polymyxin susceptibility for cystic fibrosis isolates of P. aeruginosa and S. maltophilia. Prospective study of the correlation between in vitro susceptibility and clinical response is needed to clarify whether these discrepancies reflect oversensitivity of the agar dilution method or insensitivity of the other methods.

Topics: Anti-Bacterial Agents; Colistin; Cystic Fibrosis; False Positive Reactions; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Reproducibility of Results; Sensitivity and Specificity; Stenotrophomonas maltophilia

Pseudomonas aeruginosa (PsA) is the most common pathogen to cause chronic lung infection in children with cystic fibrosis (CF), and is associated with an increase in both morbidity and mortality. Whilst the non-mucoid strain can be eradicated, it is believed that mucoid PsA is difficult, if not impossible, to eradicate. We hypothesized that with modern and aggressive antibiotic regimes, mucoid PsA can be eradicated in children with CF. We investigated this hypothesis through a retrospective review of respiratory tract cultures of children with CF at The Royal Brompton Hospital, London. Children aged under 16 with a confirmed diagnosis of CF and mucoid PsA on respiratory tract culture during a defined 9-year period were eligible for inclusion. Respiratory tract culture results were followed up for each patient to establish whether children remained infected with mucoid PsA and specifically to identify clearance of infection. Factors which may have been associated with persistence or clearance were also sought. One hundred sixteen children had the minimum dataset, and of these patients 67 (58%) cleared mucoid PsA for more than 1 year. Of the 67 patients who cleared mucoid PsA for more than 1 year, 38 (57%) patients remained clear of mucoid PsA at the last available culture (median 30, range 2-106 clear cultures, and median 55, 12-103 months clear). We conclude that isolation of mucoid PsA does not necessarily equate to lifelong infection. We suggest that trials of eradication of mucoid PsA at first isolation are required.

Topics: Adolescent; Anti-Bacterial Agents; Child; Colistin; Cystic Fibrosis; Female; Gentamicins; Humans; Longitudinal Studies; Male; Nebulizers and Vaporizers; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies

Topics: Aged; Anti-Bacterial Agents; Bronchiectasis; Colistin; Cystic Fibrosis; Drug Evaluation; Female; Humans; Male; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies

Inhaled antibiotics are commonly used in the treatment of cystic fibrosis lung disease. A previous study suggested neutrophil elastase activation by colistin in vitro. Here, we investigated direct effects of the commonly used antibiotics colistin and tobramycin on neutrophil elastase activity.. Neutrophil elastase was measured spectrophotometrically. The antibiotics colistin and tobramycin were added in different concentrations with or without the addition of albumin.. Generally, neutrophil elastase activity was lower in the absence of albumin compared to its presence. Both antibiotics, colistin and tobramycin, had inhibitory effects on neutrophil elastase activity except for high concentrations of colistin when albumin was absent.. Our results suggest inhibitory effects of colistin and tobramycin in vitro. There was a clear dependency of neutrophil elastase measurements on the presence of albumin. Clinical studies are needed to investigate potential direct effects of inhaled antibiotics on neutrophil elastase activity in cystic fibrosis airways.

Topics: Administration, Inhalation; Albumins; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Humans; Leukocyte Elastase; Microbial Sensitivity Tests; Pseudomonas; Pseudomonas Infections; Tobramycin

Data regarding the role of inhaled colistin in critically ill pediatric patients without cystic fibrosis are scarce. Three children (one female), admitted to the intensive care unit (ICU) of a tertiary-care pediatric hospital in Athens, Greece, during 2004-2009 received inhaled colistin as monotherapy for tracheobronchitis (two children), and as adjunctive therapy for necrotizing pneumonia (one child). Colistin susceptible Acinetobacter baumannii and Pseudomonas aeruginosa were isolated from the cases' bronchial secretions specimens. All three children received inhaled colistin at a dosage of 75 mg diluted in 3 ml of normal saline twice daily (1,875,000 IU of colistin daily), for a duration of 25, 32, and 15 days, respectively. All three children recovered from the infections. Also, a gradual reduction, and finally total elimination of the microbial load in bronchial secretions was observed during inhaled colistin treatment in the reported cases. All three cases were discharged from the ICU. No bronchoconstriction or any other type of toxicity of colistin was observed. In conclusion, inhaled colistin was effective and safe for the treatment of two children with tracheobronchitis, and one child with necrotizing pneumonia. Further studies are needed to clarify further the role of inhaled colistin in pediatric critically ill patients without cystic fibrosis.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Administration, Inhalation; Albuterol; Anti-Bacterial Agents; Bronchitis; Bronchodilator Agents; Case-Control Studies; Child; Child, Preschool; Colistin; Critical Care; Critical Illness; Cystic Fibrosis; Female; Hospitals, Pediatric; Humans; Infant; Ipratropium; Male; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Tracheitis; Treatment Outcome

Tobramycin and colistin represent 2 standard antimicrobial agents in the treatment of cystic fibrosis (CF) patients who are chronically colonized with Pseudomonas aeruginosa. In this study, we determined the rate of resistance to tobramycin and colistin in 1844 isolates of P. aeruginosa obtained from 22 CF patients under alternate therapy with inhaled tobramycin and colistin. Resistance to tobramycin was observed in 27.5% of isolates. In contrast, all isolates were susceptible to colistin. Molecular typing of selected isolates suggested that only 1 clone occurred over time in each patient. To conclude, resistance to tobramycin in P. aeruginosa isolates from CF patients under antimicrobial therapy may occur while colistin resistance remains uncommon.

Topics: Adult; Anti-Bacterial Agents; Bacterial Typing Techniques; Chronic Disease; Cluster Analysis; Colistin; Cystic Fibrosis; DNA Fingerprinting; Drug Resistance, Bacterial; Female; Genotype; Humans; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

The increasing frequency of infections caused by multidrug-resistant (MDR) Gram-negative bacteria has led to the reappraisal of colistimethate use.. We present a case series of critically ill pediatric patients without cystic fibrosis who received intravenous colistimethate treatment. All available relevant medical records were reviewed.. Seven children without cystic fibrosis (mean age 7.7 years; 2 female), admitted to the intensive care unit of a tertiary-care pediatric hospital in Athens, Greece, were identified to have received intravenous colistimethate during October 2004 to May 2008. MDR Acinetobacter baumannii, Pseudomonas aeruginosa, and/or Klebsiella pneumoniae were isolated from blood and/or bronchial secretions specimens in 6 of 7 reported patients. All isolates were susceptible to colistin. All 7 patients received intravenous colistimethate in a dosage of 5 mg/kg daily (divided in 3 equal doses, administered every 8 hours). Five children received colistimethate for 10 days and the remaining 2 for 2 and 23 days, respectively. The infections caused by MDR Gram-negative bacteria were improved in 6 children with microbiologically documented infections. Five of the 7 children were discharged from the ICU. The remaining 2 children died (1 of them had received colistimethate for 2 days); their death was not attributed to MDR Gram-negative infection. No nephrotoxicity or other type of toxicity of colistimethate was noted in this case-series.. Although the small number of included cases precludes any firm conclusions, our study suggests that colistimethate may have a role for the treatment of infections caused by MDR Gram-negative bacteria in critically ill pediatric patients.

Topics: Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Critical Illness; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infant; Infant, Newborn; Injections, Intravenous; Male

Several guidelines on infection control and treatment of infection exist for cystic fibrosis (CF) caregivers, although the extent of implementation is variable.. Adherence to European Consensus Guidelines for CF was studied by sending surveys to named healthcare professionals in 487 European CF centres/units. Qualitative data analysis was performed.. A total of 177/547 (32%) surveys were returned. Infection control policies were implemented by most (77%) respondents. Separation of patients with Burkholderia cepacia was more common in adults (95%) than children (9%), and was implemented by 53% of respondents for Pseudomonas aeruginosa. Nebulised colistin plus oral ciprofloxacin was the most common (43%) therapy for P. aeruginosa infection. First infections of P. aeruginosa were usually treated with inhaled tobramycin; 41% of repondents did not intervene until lung function deteriorated. Most exacerbations were treated for less than the recommended period.. European Consensus Guidelines are widely adhered to. Areas for improvement include: initiating therapy for exacerbations early, separating infected patients and optimising duration of antibiotic therapy.

Topics: Administration, Inhalation; Adult; Anti-Bacterial Agents; Bacterial Infections; Burkholderia cepacia; Burkholderia Infections; Child; Child, Preschool; Ciprofloxacin; Colistin; Cystic Fibrosis; Europe; Guideline Adherence; Humans; Infection Control; Practice Guidelines as Topic; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Surveys and Questionnaires; Tobramycin; Young Adult

The aim of cystic fibrosis (CF) care is to improve both the life expectancy and quality of life of patients. However, rising costs and limited resources of health services must be taken into account. There are many different antibiotic strategies for therapy of Pseudomonas aeruginosa infection in CF patients. In this 5-year retrospective study we found that the cost of treatment of initial infection is considerably lower than the cost of treating chronic P. aeruginosa infections. The percentage distribution of costs of antibiotic treatment in relationship to the administration route was considerably different between outpatients and inpatients. We observed an increase in antibiotic costs with the age of the patient and the decrease in FEV(1)values. The implementation of early eradication treatment, in addition to decreasing the prevalence of patients chronically infected by P. aeruginosa, might also bring about a notable decrease in costs.

Topics: Adult; Anti-Bacterial Agents; Ceftazidime; Child, Preschool; Chronic Disease; Ciprofloxacin; Clavulanic Acids; Colistin; Cost of Illness; Cystic Fibrosis; Humans; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Thienamycins; Ticarcillin; Tobramycin

Adaptive aerosol delivery (AAD) nebuliser devices can reduce treatment times whilst enabling adherence to be monitored using inbuilt data logs. Using one such device, we have monitored nebulised antibiotic adherence in children with Cystic Fibrosis (CF).. In CF children infected with Pseudomonas aeruginosa, downloaded data from an AAD device was used to calculate morning, evening and overall monthly adherence to antibiotic therapy over a year.. Overall monthly adherence to nebulised antibiotic therapy in 28 children was maintained between 60 and 70% over the year. Considerable variation in adherence, both between and within patients, was evident (Mean [SD] coefficient of variation, 37[44]%). Evening adherence (75[37]%) was better than morning adherence (58[34]%: p=0.012). Treatment regimens were changed in 8/28 patients based on adherence data.. Routine adherence monitoring can be implemented in an outpatient setting. Using this type of information it is possible to identify which aspects of treatment can be improved and to work together with families to individualize treatments.

Topics: Administration, Inhalation; Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Cystic Fibrosis; Drug Monitoring; Humans; Medication Adherence; Nebulizers and Vaporizers; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies

Respiratory infections with multidrug-resistant (MDR) bacteria are life-threatening in patients with cystic fibrosis (CF). Squalamine and aminosterol derivatives (ASDs) have previously demonstrated interesting antibacterial activity against bacterial reference strains. This study investigated for the first time their activity against MDR clinical isolates recovered from the sputa of CF patients.. Antibacterial activity of squalamine and two ASDs (1 and 2) was evaluated against 135 MDR gram-negative and gram-positive bacteria using the broth microdilution method for MIC determination.. For gram-negative bacteria, MICs ranged from 2 to 128 mg/L. Resistance to colistin and mucoidity were significantly associated with higher MICs of squalamine and ASDs 1 and 2. Tested compounds were active against various gram-positive bacteria with MIC values varying from 0.5 to 8 mg/L, with the exception of two capsulated isolates of Streptococcus pneumoniae demonstrating MICs of 32 mg/L.. In this study, we present new findings concerning the antibacterial potential of ASDs against MDR bacteria. Colistin-resistant, mucoid and capsulated bacteria were found to exhibit decreased susceptibility to ASDs indicating that these compounds might share some mechanistic aspects with polymyxins towards gram-negative bacteria. However, ASDs were remarkably active against gram-positive species suggesting different mechanisms of action towards gram-positive and gram-negative bacteria. As tested ASDs exhibited elevated MICs in some cases, we believe that these compounds may be developed to be locally administrated as aerosols rather than via systemic administration routes. Further work is warranted to evaluate their in vivo efficacy in aerosol formulations using a lung-infected animal model.

Topics: Anti-Bacterial Agents; Cholestanols; Colistin; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Microbial Sensitivity Tests

Antibiotic inhalation has become widely accepted as a standard treatment for cystic fibrosis (CF) airway infection. We assessed the prevalence and context of inhaled antibiotic use in the North American CF population. Our working hypothesis was that a shift from acute to chronic use of inhaled antibiotics has coincided with increased prevalence of use among CF patients.. Descriptive statistics were collected for 30,833 patients enrolled in the Epidemiologic Study of CF (ESCF) during 1996 through 2005. A multivariate analysis was performed on data from a subgroup of 18,021 patients enrolled in ESCF during 2003 through 2005.. The prevalence of inhaled antibiotic use in the North American CF population increased during 1996 through 2005 due to increased chronic use, while acute use to treat pulmonary exacerbations decreased. In 2005, 50% of CF patients used inhaled tobramycin and 9% used inhaled colistin chronically; most of the latter used both agents concurrently. Airway obstruction severity and airway infection status were predictors of inhaled antibiotic use.. Increased chronic use and decreased acute use of inhaled antibiotics presumably reflect a shift toward more proactive management of airway infections in the North American CF population. The effects of these usage patterns on long-term clinical outcomes and emergence of antibiotic-resistant Pseudomonas aeruginosa strains warrant further study.

Topics: Administration, Inhalation; Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Cystic Fibrosis; Drug Utilization; Female; Humans; Male; Respiratory Tract Infections; Tobramycin

Since 1989, CF-patients intermittently colonized with Pseudomonas aeruginosa have been treated with inhaled colistin and oral ciprofloxacin in the Copenhagen CF-centre. The study evaluates 15 years results of this treatment.. All isolates of P. aeruginosa from CF-patients intermittently colonized with P. aeruginosa from 1989 to 2003 were identified All anti-P. aeruginosa treatments were evaluated for antibiotics used, treatment duration, pseudomonas-free interval and development of chronic infection. All P. aeruginosa isolates were assessed for resistance and for non-mucoid or mucoid phenotype.. 146 CF-patients were included in the study (1106 patient-years). 99 patients had first ever isolate during the study period. Median observation time 7 years (0.1-14.9). 12 patients developed chronic infection. A Kaplan Meyer plot showed protection from chronic infection in up to 80% of patients for up to 15 years. 613 colistin/ciprofloxacin treatments were given. There was no difference in pseudomonas-free interval comparing 3 weeks (5 months) and 3 months (10.4 months) of colistin and ciprofloxacin, but a significant difference compared to no treatment (1.9 months). Patients developing chronic infection had significantly shorter pseudomonas-free interval after treatment of first ever isolate compared to patients remaining intermittently colonized (p<0.003). Treatment failure (P. aeruginosa-positive culture immediately after ended treatment of first ever isolate) was a strong risk factor for development of chronic infection after 3-4 years, OR 5.8. 1093 pseudomonas-isolates were evaluated (86.6% non-mucoid). No colistin-resistance was found. Ciprofloxacin-resistance was found in 4% of isolates.. Treatment of intermittent P. aeruginosa colonization in CF-patients using colistin and ciprofloxacin can protect up to 80% of patients from development of chronic infection for up to 15 years. A positive culture immediately after treatment of first ever isolate is a strong risk factor for development of chronic infection. We found no colistin-resistance and minimal ciprofloxacin-resistance.

Topics: Administration, Inhalation; Administration, Oral; Adolescent; Adult; Anti-Bacterial Agents; Child; Child, Preschool; Chronic Disease; Ciprofloxacin; Cohort Studies; Colistin; Cystic Fibrosis; Disease-Free Survival; Female; Humans; Infant; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Retrospective Studies; Treatment Outcome; Young Adult

The in vitro activities of various antibiotics, either alone or in combination with colistin methanesulfonate, were assessed using Pseudomonas aeruginosa strains isolated from cystic fibrosis patients.. Except for colistin methanesulfonate, minimum inhibitory concentrations were determined by microbroth dilution technique as described by the Clinical and Laboratory Standards Institute (CLSI); for colistin methanesulfonate, a modified method of the CLSI was used. Minimum bactericidal concentrations were determined as described by the CLSI. The in vitro activities of antibiotics in combination were determined by microbroth checkerboard technique, and results were interpreted by fractional inhibitory concentration index.. According to MIC values, 100, 98, 96 and 84% of the isolates were found susceptible to amikacin, colistin methanesulfonate, meropenem and ceftazidime, respectively. The minimum bactericidal concentrations were generally equal to or twice as high as those of the minimum inhibitory concentrations. With a fractional inhibitory concentration index of < or =0.5 as borderline, synergistic interactions were more frequent with combinations where amikacin was involved than with those with colistin methanesulfonate. No antagonism was observed.. The findings of this study may play a useful role in selecting the appropriate combinations when a single agent is inadequate to treat cystic fibrosis patients with P. aeruginosa infections.

Topics: Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Colistin resistant Pseudomonas aeruginosa have rarely been reported in cystic fibrosis (CF) patients.. We performed a 17-year prospective study on colistin susceptibility and compared our findings with clinical variables.. The first outbreak started in 1995 and lasted 5 years. It involved 27 CF patients who had inhaled colistin twice daily for a median of 10 years. Colistin resistant isolates persisted in individual patients for a median of 75 days after colistin was withdrawn. A second outbreak started in 2004. It involved 40 patients, 17 of whom were the same as in the first outbreak. Most resistant isolates belonged to two major clones that had similar genotypes in the two outbreaks. The P. aeruginosa isolates were all non-mucoid and they appeared in a group of chronically infected patients that had been admitted to the same ward for antibiotic treatment and had been followed at the same week-days in the outpatient clinic. Patients were individually isolated to avoid cross-infection and colistin inhalation was avoided in the CF outpatient clinic and in the ward after both outbreaks. Since 2004, no further spread has been observed.. It is important that the colistin resistant clones do not spread to non-infected patients since colistin is an important antibiotic for eradication of initial and intermittent P. aeruginosa colonisation.

Topics: Administration, Inhalation; Adolescent; Adult; Child; Colistin; Cystic Fibrosis; Denmark; Disease Outbreaks; Drug Resistance, Bacterial; Female; Humans; Male; Microbial Sensitivity Tests; Patient Isolation; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Function Tests

Patients with cystic fibrosis (CF) are at high risk from the nephrotoxic effects of intravenous antibiotics due to repeated and prolonged courses of therapy. Routine methods of monitoring renal injury are insensitive. N-acetyl-b-d-glucosaminidase (NAG) is a lysosomal enzyme present in the renal proximal tubular cells, with increased excretion an indicator of renal tubular dysfunction.. Urinary NAG, creatinine, serum creatinine, electrolytes and BUN were measured on days 1, 14 and at the first out-patient visit following treatment with tobramycin or colistin. Urinary NAG levels were corrected for urinary creatinine and expressed as a NAG ratio. Patients who received>1 course of intravenous antibiotics during the study period were included in a separate analysis of the cumulative effect of treatment.. 88 patients (44 female, 31 with CFRD) completed a single course of intravenous antibiotics. 71 patients had urinary NAG levels at follow-up. The median time to follow-up was 50 days. Serum electrolytes, creatinine and BUN were normal throughout. A 3.5-fold increase in urinary NAG excretion was observed between day 1 and 14 and 46% of patients had an elevated NAG level at follow-up. A highly significant difference in NAG excretion was observed on day 14 for tobramycin vs. colistin (median 2.24 vs. 0.98, p<0.001). A significant difference in NAG excretion was seen in patients with CFRD at all measured time points. Patients with CFRD had a significantly worse clinical status and had received more days of intravenous antibiotics over the previous 6 years. In 20 (80%) of 25 patients who received>1 course of treatment during the study period, baseline NAG levels were significantly higher in subsequent courses (p<0.001). There was a significant correlation between previous exposure to colistin and baseline NAG levels (r=0.389, p<0.001).. Both tobramycin and colistin cause acute renal tubular injury with a significant rise in urinary NAG excretion. Patients with CFRD seem to be at greatest risk of renal tubular damage. Cumulative damage is evident with repeated dosing. Previous exposure to nephrotoxic antibiotics, especially colistin, is associated with elevated baseline NAG levels. We recommend that colistin is reserved for patients with resistant Pseudomonas aeruginosa or those who are intolerant to tobramycin. Serial longitudinal NAG measurements may be useful in patients with CF, especially those with CFRD, to identify patients at risk of developing renal disease.

Topics: Acetylglucosaminidase; Adolescent; Adult; Anti-Bacterial Agents; Colistin; Creatinine; Cystic Fibrosis; Diabetes Mellitus; Female; Humans; Kidney Tubules; Kidney Tubules, Proximal; Male; Prospective Studies; Tobramycin

Topics: Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Humans

Topics: Administration, Inhalation; Adult; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Compounding; Fatal Outcome; Female; Humans; Nebulizers and Vaporizers; Prodrugs; Pseudomonas Infections; Respiratory Distress Syndrome

Topics: Administration, Inhalation; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Humans

Increased use of colistin therapy for infections caused by Pseudomonas aeruginosa has indicated a need for a more robust microbiological assay technique. This report describes a quick and simple microbiological assay for quantifying levels of colistin sulphomethate in serum and urine samples from cystic fibrosis patients. The technique uses no specialised or costly equipment and is suitable for use in all routine diagnostic microbiology laboratories.

Topics: Biological Assay; Colistin; Culture Media; Cystic Fibrosis; Drug Stability; Escherichia coli; Humans; Sensitivity and Specificity; Temperature

We report a case of cystic fibrosis in a 19-year-old woman who suffered from frequent exacerbations of lower respiratory infection due to multidrug-resistant Pseudomonas aeruginosa and who was successfully treated with parenteral colistin. Multidrug-resistant Pseudomonas aeruginosa isolated from sputum had become resistant to all parenteral antibiotics commercially available in Japan. She did not show clinical improvement despite treatment with several different combinations of available antibiotics. We therefore obtained parenteral colistin from a pharmacy outside Japan. She responded well to parenteral colistin without apparent side effects such as serious nephrotoxicity or neurotoxicity. Colistin is therefore an important alternative antibiotic for treating multidrug-resistant Pseudomonas aeruginosa and its use should be considered in severe infection. We hope that parenteral colistin will become available in Japan in the near future.

Topics: Adult; Anti-Bacterial Agents; Bronchitis, Chronic; Colistin; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Female; Humans; Injections, Intravenous; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

We studied the effects of increasingly intensive treatment regimens on anti-pseudomonal antibody response and survival in five successive cohorts of a total of 157 Danish cystic fibrosis patients after they had acquired chronic P. aeruginosa lung infection. The time periods were 1971-1975 (N = 21), 1976-1980 (N = 64), 1981-1986 (N = 27), 1987-1993 (N = 26), and 1994-2000 (N = 19). During this 30-year period, we introduced elective 2-week courses of chemotherapy every third month in all chronically infected patients, early aggressive treatment with inhalation of colistin and oral ciprofloxacin for 3 months whenever P. aeruginosa was cultured in sputum from noncolonized patients, and inhalation of recombinant human dornase alfa. There was a significant correlation between the calendar year when chronic P. aeruginosa infection was acquired and the subsequent increase in the level of precipitins (P < 0.00001). The median number of precipitins increased by 5 per year in the oldest calendar year cohort, and 1 per year in the youngest. The median age of onset of chronic P. aeruginosa increased from 9.3 years from 1981-1986 to 13.8 years from 1987-2000. Survival after acquisition of chronic P. aeruginosa lung infection improved with time (P = 0.008). Our study shows that CF patients who are treated intensively have lower antibody responses and longer survival after acquisition of chronic P. aeruginosa lung infection.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bacterial; Child; Ciprofloxacin; Cohort Studies; Colistin; Cystic Fibrosis; Deoxyribonuclease I; Humans; Immunoelectrophoresis, Two-Dimensional; Linear Models; Pseudomonas Infections; Survival Analysis; Time Factors

With their potent activity against Gram-negative bacteria, the polymyxins are important alternative antibiotics for cystic fibrosis (CF) patients. A retrospective evaluation of polymyxin activity against 6001 Pseudomonas aeruginosa, 150 Achromobacter xylosoxidans and 506 Stenotrophomonas maltophilia CF isolates was initiated. In addition, we looked at how polymyxin susceptibility testing was affected by the testing method (agar dilution versus microdilution), the agent (polymyxin E versus polymyxin B), incubation time (24 h versus 48 h) and by different interpretative criteria (German DIN, French FSM, British BSAC).. Polymyxin B exhibited reasonable activity against P. aeruginosa (MIC(90)< or =2 mg/L), whereas it was less active against A. xylosoxidans (MIC(90)< or =16 mg/L) and S. maltophilia (MIC(90)< or =16 mg/L). During 2000-2002, polymyxin B resistance in P. aeruginosa, S. maltophilia and A. xylosoxidans was found to be 6.7%, 17.0% and 29.9% (corresponding to 12.4%, 20.7% and 35.4% of infected patients), respectively. When the agar dilution method was used, polymyxin E exhibited higher MICs than polymyxin B. The microdilution method produced lower polymyxin MICs than the agar dilution method. Therefore, the microdilution MICs after prolonged incubation (48 h) and the agar dilution MICs of polymyxin B correlated best (AUC of 0.93, r(2) of 0.44 and s of 0.83).. Polymyxin resistance among common CF pathogens is not rare, thus underlining the necessity of accurate susceptibility testing. When compared with the agar dilution method, it was found that the microdilution method is a valid, rapid and cost effective alternative for the determination of polymyxin activity. The performance of the microdilution method was most reliable after prolonged incubation (48 h) at a susceptibility breakpoint of < or =4 mg/L according to the BSAC guidelines (specificity 91%, sensitivity 89%, 1.5% very major errors).

Topics: Achromobacter denitrificans; Adolescent; Adult; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Cystic Fibrosis; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Polymyxins; Pseudomonas aeruginosa; Quality Control; Stenotrophomonas maltophilia

Respiratory infection with Pseudomonas aeruginosa is very common in patients with cystic fibrosis (CF) but antimicrobial resistance rates of CF isolates across the UK are largely unknown.. The susceptibility of 417 CF patient isolates of P aeruginosa from 17 hospitals to six commonly prescribed antibiotics were examined. Isolates were tested by an agar break point dilution method and E-tests according to British Society of Antimicrobial Chemotherapy guidelines. Genotyping of isolates was performed by XbaI DNA macrorestriction and pulsed field gel electrophoresis.. 38% of isolates were susceptible to all of the agents tested; almost half were resistant to gentamicin compared with ceftazidime (39%), piperacillin (32%), ciprofloxacin (30%), tobramycin (10%), and colistin (3%). Approximately 40% were resistant to two or more compounds with ceftazidime in combination with gentamicin, piperacillin or ciprofloxacin being the most common cross resistances. Resistance rates were generally similar to those reported recently from the USA and Germany. A selection of resistant isolates proved to be predominantly genotypically distinct by XbaI DNA macrorestriction but six pairs from three centres had similar genotypes.. The level of resistance to front line antipseudomonal agents, with the exception of colistin, is disturbingly high. The prudent use of antimicrobial drugs and closer monitoring of accumulation of resistant strain populations should be actively considered.

Topics: Adult; Anti-Bacterial Agents; Ceftazidime; Ciprofloxacin; Colistin; Cystic Fibrosis; Drug Resistance, Bacterial; Gentamicins; Humans; Piperacillin; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

To define the steady-state pharmacokinetics of colistin methanesulphonate and colistin in patients with cystic fibrosis (CF) following intravenous administration of the former.. The study was conducted in 12 patients with CF following intravenous administration of colistin methanesulphonate (1.63-3.11 mg/kg) every 8 h for at least 2 days. On the day of study, four blood samples were collected from each patient at 60, 120, 240 and 360 min after the end of the infusion. Concentrations of colistin methanesulphonate and colistin in plasma were measured separately by HPLC.. At steady-state, colistin methanesulphonate had a mean (+/- S.D.) total body clearance, volume of distribution and half-life of 2.01 +/- 0.46 mL/min per kg, 340 +/- 95 mL/kg and 124 +/- 52 min, respectively. Colistin had a significantly longer mean half-life of 251 +/- 79 min (P<0.001). With the regimen used, colistin methanesulphonate was well tolerated. This is the first report on the pharmacokinetics of colistin methanesulphonate in CF patients determined using concentrations of colistin methanesulphonate and colistin in plasma.. Based on the in vitro pharmacodynamics against Pseudomonas aeruginosa previously published by our group and these pharmacokinetic findings, dose escalating trials may be warranted to maximize efficacy.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Chromatography, High Pressure Liquid; Colistin; Cystic Fibrosis; Drug Stability; Female; Half-Life; Humans; Infusions, Intravenous; Male; Middle Aged

Nonantimicrobial effects of antibiotics may contribute to their activity in the treatment of infective airway disease. The aim of this study was to identify antibiotics used for the treatment of infection in cystic fibrosis that may alter the activity of human neutrophil elastase (HNE) and Pseudomonas aeruginosa elastase (PE). The effect of antibiotics on the activity of purified HNE and PE, and HNE in sputum was assessed using colourimetric and fluorescent substrate assays by kinetic measurements, and by examining the interaction of HNE with inhibitors. Ceftazidime, tobramycin, and gentamycin slightly inhibited purified HNE activity whereas erythromycin and colistin significantly stimulated purified HNE and PE (395 and 557%, respectively). However, only colistin increased HNE activity in sputum (+102%) and was therefore studied in more detail. This increase in activity was not due an interference with the specific inhibition of HNE by alpha1-antitrypsin but colistin was found to reverse the inhibitory effects of small molecular weight molecules like heparin. Colistin increases the activity of human neutrophil elastase and Pseudomonas aeruginosa elastase, two proteases that contribute to the pathogenesis of cystic fibrosis airway disease.

Topics: Adolescent; Adult; alpha 1-Antitrypsin; Amino Acid Chloromethyl Ketones; Anti-Bacterial Agents; Anticoagulants; Bacterial Proteins; Ceftazidime; Child; Colistin; Cystic Fibrosis; Enzyme Activation; Erythromycin; Female; Gentamicins; Heparin; Humans; In Vitro Techniques; Leukocyte Elastase; Male; Metalloendopeptidases; Respiratory Tract Infections; Serine Proteinase Inhibitors; Sputum; Tobramycin

We report on an outbreak of colistin-resistant Pseudomonas aeruginosa (CRPA) that occurred in a United Kingdom pediatric cystic fibrosis (CF) unit and involved six children over a period of 5 years. All CRPA-positive children had received aerosolized colistin therapy before first isolation of resistant organisms (mean duration, 3.1 years). Four of the 6 had also received courses of intravenous colistin in the year before the first isolation of CRPA. No impact of CRPA acquisition on respiratory function, clinical condition, or radiological parameters could be demonstrated. Four of the 6 children carried isolates of CRPA indistinguishable on genotyping. Two of these 4 children were sisters. The other 2 were on the same ward together at time of first isolation, and subsequently shared overlapping admissions with one of the sisters. While there is no conclusive evidence for the route of transmission, the frequency of overlapping in-patient admissions between 3 of these patients is suggestive of patient-to-patient transfer in the nosocomial setting.CF clinicians should be aware that colistin resistance can occur in P. aeruginosa, and some of these strains are capable of spread within CF units.

Topics: Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Cross Infection; Cystic Fibrosis; Disease Outbreaks; Drug Resistance, Microbial; Female; Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Time Factors

The major cause of morbidity and mortality in patients with cystic fibrosis (CF) is respiratory disease (Penketh et al., Thorax 1987; 42: 526-532). Recent studies in the USA have shown that intermittent administration of inhaled tobramycin is beneficial to patients with CF who are chronically infected with Pseudomonas aeruginosa (Ramsey et al., N Engl J Med 1999; 340: 23-30; Ramsey et al., Proceedings of the 12th Annual North American Cystic Fibrosis Conference, 1998, Montreal, Canada; Ramsey et al., Abstract from 23rd European Cystic Fibrosis Conference, 1999, the Hague, Netherlands). In Europe, the use of nebulised colistin in patients chronically infected with P. aeruginosa is widespread. A recently published study compared the efficacy and safety of tobramycin nebuliser solution (TNS) and nebulised colistin in CF patients . One hundred and fifteen patients were randomised to receive either TNS or colistin in a multi-centre open-labelled study that assessed change from baseline in FEV(1) and sputum P. aeruginosa density. TNS produced a mean 6.7% improvement in lung function (P=0.006), whilst there was no significant improvement in the colistin-treated patients. The TNS-treated patients had a significantly greater improvement in lung function than those treated with colistin (P=0.008). The safety profile of both treatments was good. We conclude that patients treated with TNS for 1 month experience improved lung function compared with patients treated with colistin.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Europe; Humans; Lung Diseases; Nebulizers and Vaporizers; Pseudomonas Infections; Randomized Controlled Trials as Topic; Respiratory Function Tests; Tobramycin; Treatment Outcome

The infection of the airways of cystic fibrosis patients by Pseudomonas aeruginosa is a complex, multistaged process that is associated with a deterioration of lung function. The complexity of the formation of biofilms and their interaction with the immune system means that treatment with antibiotics has been an uncertain science. Tobramycin nebuliser solution (TNS) is a novel formulation of the antibiotic tobramycin developed specifically for inhalation. A recent large trial comparing TNS with inhaled colistin provided an opportunity to define further the effect of antibiotic treatment on microbial infection. In the TNS group, the percentage of patients with a tobramycin minimal inhibitory concentration (MIC) > or = 4 mg l(-1) increased from 38 to 49%, and the percentage of patients with a colistin MIC > or = 4 mg l(-1) remained at 55%. In the colistin group, the percentage of patients with a colistin MIC > or = 4 mg l(-1) remained at 34%, whereas the percentage of patients with a tobramycin MIC > or = 4 mg l(-1) decreased from 27 to 16%. Furthermore, clinical and bacterial response to TNS and colistin was independent of the MIC at baseline. Neither antimicrobial therapy was associated with infection by Burkholderia cepacia or other inherently resistant pathogens. We conclude that conventional measures of antimicrobial resistance may underestimate the effectiveness of tobramycin and colistin when delivered at the high concentrations achieved with the TNS formulation.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Biofilms; Colistin; Cystic Fibrosis; Europe; Humans; Lung Diseases; Microbial Sensitivity Tests; Nebulizers and Vaporizers; Pseudomonas Infections; Randomized Controlled Trials as Topic; Tobramycin

Three hundred and eighty-five mucoid and non-mucoid strains of Pseudomonas aeruginosa isolated from 192 sputa from 57 adult cystic fibrosis patients were studied. Susceptibility testing using an agar dilution technique was performed for ceftazidime, ciprofloxacin, fosfomycin, meropenem and piperacillin, and the aerosolized agents colistin and tobramycin. Meropenem, ceftazidime and piperacillin were the most potent agents (susceptibility 86.2%, 84.2% and 84%, respectively). Tobramycin and colistin susceptibility rates were lower, but in light of higher intrabronchial concentrations of these drugs a greater percentage of strains might still be clinically susceptible. Only 46.2% and 41.8% of isolates were susceptible to ciprofloxacin and fosfomycin, respectively.

Topics: Aerosols; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Evaluation, Preclinical; Germany; Humans; Injections, Intravenous; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Tobramycin

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Child; Ciprofloxacin; Clinical Trials as Topic; Colistin; Cystic Fibrosis; Humans; Pseudomonas Infections; Tobramycin

The aim of this study was to investigate the pulmonary administration of antibiotics as dry powder to patients with cystic fibrosis (CF), as an alternative for nebulization. This part of the study describes the development of a powder formulation with colistin sulfate as model substance. The aim of the new dosage form was to increase pulmonary deposition, therapeutic efficiency and, by that, compliance by the CF patients. A physical powder mixture of colistin and a size fraction of lactose (106-150 microm) was prepared and the mixture was optimized with respect to colistin content (83.3%) for use in a special test inhaler. A laser diffraction apparatus with special inhaler adapter was applied for analysis of the size distribution of the aerosol cloud from the inhaler. The size distributions of the aerosol clouds from the test inhaler at flow rates between 30 and 60 l/min for the optimized formulation showed nearly the same median diameter as that for the primary drug particles. But the X(100)-value was much lower, because of an effective large particle separation from the inspiratory air by an air classifier in the test inhaler. The results suggest that dry powder inhalation might be a suitable and highly efficient alternative for nebulization of antibiotic drugs in CF therapy.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Chemistry, Pharmaceutical; Colistin; Cystic Fibrosis; Nebulizers and Vaporizers; Powders

The aim of the present study was to perform a proof of principle study with a new colistin dry powder inhalation system in six healthy volunteers and five patients with cystic fibrosis. All subjects were asked to inhale 25 mg colistin sulfate dry powder. The patients were also asked to nebulize 160 mg colistin sulfomethate as a solution. Colistin serum concentrations were determined as an indirect parameter to compare both forms of administration. Pulmonary function tests were performed. Peak serum colistin concentrations ranged from 14 to 59 microg/l in volunteers after inhalation of 25 mg as dry powder. In patients, peak concentrations ranged from 18 to 64 microg/l after nebulization of 160 mg colistin sulfomethate solution and from 77 to 159 microg/l after inhalation of 25 mg colistin sulfate dry powder. Pulmonary function tests were not significantly different after inhalation of the dry powder by the volunteers nor after nebulization of the solution by the patients. In some patients a decrease in pulmonary function and moderate to severe cough was observed after inhalation of the dry powder. The new colistin inhaler provides an attractive alternative for nebulized colistin and was highly appreciated by the patients. The decrease in pulmonary function and cough in patients is a drawback, which may be overcome by dose reduction and a further improvement of the new dosage form.

Topics: Administration, Inhalation; Adult; Anti-Bacterial Agents; Area Under Curve; Chemistry, Pharmaceutical; Colistin; Cystic Fibrosis; Humans; Nebulizers and Vaporizers; Patients; Pilot Projects; Powders; Respiratory Function Tests

To develop practical ways of nebulizing colistin by determining the rate of drug output, total drug output, and particle-size distribution of two commercially available jet nebulizers, the disposable Hudson 1730 Updraft II (Hudson Respiratory Care; Temecula, CA) and the reusable Pari LC Star breath-enhanced nebulizer (Pari Respiratory Equipment; Midlothian, VA).. The nebulizers contained colistin, 75 mg, in 4 mL of isotonic solution. Particle-size distribution was measured by helium-neon laser diffraction, allowing calculation of the respirable fraction (RF), the mass of aerosol comprised of droplets < 5 microm.. The mean (95% confidence interval [CI]) total rate of output of the Updraft II was 2.6 mg/min (2.0, 3.1; n = 4) with 1.3 mg/min (1.0, 1.5) mg/min within the RF. The rate of output of the LC Star increased in a quadratic relationship to the inspiratory flow, delivering 1.8 mg/min (0.7, 2.0; n = 4) with 1.4 mg/min (1.3, 1.6) within the RF, and 6.2 mg/min (5.6, 6.8) with 5.3 mg/min (4.8, 5.7) within the RF, at 0 L/min and 20 L/min inspiratory flows, respectively. Efficiency, as the rate of expected pulmonary deposition divided by rate of total output, was then calculated. The LC Star estimated 56% (51, 61) efficiency, with pulmonary delivery of 29% (26, 32) of the charge of the nebulizer, compared to the Updraft II at 22% (22, 23) efficiency and expected pulmonary deposition of 10% (10, 10) of the dose.. Colistin can be successfully nebulized with both nebulizers tested. This study provides an estimate of in vivo efficiency and expected pulmonary deposition that may be used in future trials.

Topics: Adolescent; Aerosols; Child; Colistin; Cystic Fibrosis; Equipment Design; Female; Forced Expiratory Volume; Humans; Lung; Male; Nebulizers and Vaporizers; Particle Size

The in vitro pharmacodynamic properties of colistin and colistin methanesulfonate were investigated by studying the MICs, time-kill kinetics, and postantibiotic effect (PAE) against mucoid and nonmucoid strains of Pseudomonas aeruginosa isolated from patients with cystic fibrosis. Twenty-three clinical strains, including multiresistant strains, and one type strain were selected for MIC determination. Eleven strains were resistant; MICs for these strains were >128 mg/liter. For the susceptible strains, MICs of colistin ranged from 1 to 4 mg/liter, while the MICs of colistin methanesulfonate were significantly higher and ranged from 4 to 16 mg/liter. The time-kill kinetics were investigated with three strains at drug concentrations ranging from 0.5 to 64 times the MIC. Colistin showed extremely rapid killing, resulting in complete elimination at the highest concentrations within 5 min, while colistin methanesulfonate killed more slowly, requiring a concentration of 16 times the MIC to achieve complete killing within 24 h. Colistin exhibited a significant PAE of 2 to 3 h at 16 times the MIC against the three strains after 15 min of exposure. For colistin methanesulfonate, PAEs were shorter at the concentrations tested. Colistin methanesulfonate had lower overall bactericidal and postantibiotic activities than colistin, even when adjusted for differences in MICs. Our data suggest that doses of colistin methanesulfonate higher than the recommended 2 to 3 mg/kg of body weight every 12 h may be required for the effective treatment of P. aeruginosa infections in cystic fibrosis patients.

Topics: Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Humans; Kinetics; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Time Factors

Nebulised colistin is regularly used as antipseudomonal therapy in children with cystic fibrosis. We assessed bronchoconstriction in response to nebulised colistin in 58 children. Nebulised colistin significantly reduced FEV(1), MEF(25%), and SaO(2) for 15 minutes. In 20 children the reduction was greater than 10% from baseline FEV(1), and was still at that level in five at 30 minutes. Subjective assessment, baseline FEV(1), and serum IgE were unable to identify susceptible children. It is recommended that children receiving colistin should be carefully assessed for bronchoconstriction.

Topics: Administration, Inhalation; Adolescent; Anti-Bacterial Agents; Bronchoconstriction; Child; Child, Preschool; Colistin; Cross-Sectional Studies; Cystic Fibrosis; Forced Expiratory Volume; Humans; Prospective Studies

The safety and pharmacokinetics of colistin were determined after first dose (n = 30) and again under steady-state conditions (n = 27) in 31 patients with cystic fibrosis receiving the drug as a component of their treatment for an acute pulmonary exacerbation of their disease. Patients ranged in age from 14 to 53 years and received colistin for 6 to 35 days. Each patient was started on colistin 5 to 7 mg/kg/day administered intravenously in three equally divided doses. Elimination half-life (t1/2), mean residence time (MRT), steady-state volume of distribution (Vdss), total body clearance (Cl), and renal clearance (Clr) after first-dose administration averaged 3.4 hours, 4.4 hours, 0.09 l/kg, and 0.35 and 0.24 ml/min/kg, respectively. No differences in colistin disposition characteristics between first-dose and steady-state evaluations were observed. Sputum sampling was incomplete and confounded by previous aerosol administration but revealed colistin concentrations that markedly exceeded observed plasma concentrations. Twenty-one patients experienced one or more side effects attributed to colistin administration. The most common reactions involved reversible neurologic manifestations, including oral and perioral paresthesias (n = 16), headache (n = 5), and lower limb weakness (n = 5). All of these apparent colistin-induced neurologic adverse effects, though bothersome, were benign and reversible. Intermittent proteinuria was observed on urinalysis in 14 patients, and 1 patient developed reversible, colistin-induced nephrotoxicity. No relationship between the occurrence of any colistin-associated adverse effect and plasma colistin concentration or colistin pharmacokinetic parameter estimate was observed. These data provide no basis for routine monitoring of colistin plasma concentrations to guide dosing for patient safety and suggest slow upward dose titration to minimize the incidence and severity of associated side effects.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Child; Colistin; Cystic Fibrosis; Female; Humans; Male; Middle Aged

Chronic infection by Pseudomonas aeruginosa (PA) in patients with cystic fibrosis (CF) is preceded by a period of colonization and acute infection. Early aggressive antibiotic treatment of initial colonisation may prevent or at least delay chronic pulmonary infection. We initiated treatment with a combination of IV beta-lactam tobramycin, followed by nebulized colistin when PA was first isolated from patients with CF. Subsequent serial PA isolates obtained from these colonized CF patients were characterized by means of molecular methods to determine whether they were genetically related to the initial strain. Initial colonization was eradicated in all 19 patients. All patients reacquired PA within 3-25 months during the 3 years of follow-up. Fourteen patients acquired a new PA strain with a distinct genotypic profile, suggesting a new source of contamination. Five patients had two PA isolates with identical genotypes, suggesting either previous undetected respiratory tract colonization or a persistent environmental source of contamination.

Topics: Administration, Inhalation; Administration, Oral; Ceftazidime; Child; Child, Preschool; Chronic Disease; Colistin; Colony Count, Microbial; Cystic Fibrosis; DNA, Bacterial; Drug Therapy, Combination; Electrophoresis, Gel, Pulsed-Field; Female; Genotype; Humans; Imipenem; Infant; Male; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Risk Assessment; Tobramycin

Inhalation therapy of colistin is widespread in patients with cystic fibrosis. To date, no pharmacokinetic data of colistin after inhalation are available. To optimize the inhalation therapy, pharmacokinetic data of colistin are necessary. In this study, the authors describe a chromatographic analysis for measurement of colistin concentrations in serum. After protein precipitation, the colistin sample is treated with orthophthalaldehyde for derivatization. The sum of the peak areas of the two main components of colistin (polymyxin E1 and E2) were used for quantitation. The performance of the analytical method was assessed by determining the lower limit of quantitation, the selectivity of the method, the intra-assay variation, the reproducibility, the interassay variation, and the accuracy. The lower limit of quantitation was 28 microg/L. Ceftazidime, aztreonam, piperacilline, or tobramycin showed no interference with the colistin assay. In a pilot study, the authors found a trough value of approximately 10 microg/L and peak values of approximately 100 microg/L after inhalation of 160 mg colistin in serum samples of a representative patient. These values show that the method can be used to design further experiments. The applicability of the method was also tested on urine and sputum samples. Colistin was detectable but further validation experiments are required to confirm the usefulness of the method in these biologic matrices. To the authors' knowledge this is the first study in which serum concentrations are described after inhalation of colistin in patients with cystic fibrosis.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Chromatography, High Pressure Liquid; Colistin; Cystic Fibrosis; Drug Monitoring; Humans; Predictive Value of Tests; Reproducibility of Results; Sensitivity and Specificity; Sputum

An 8 year old girl with cystic fibrosis had severe respiratory disease associated with chronic Pseudomonas aeruginosa bronchopulmonary infection. Despite regular courses of intravenous antipseudomonal antibiotics, she continued to deteriorate over 18 months with persistent productive cough, worsening respiratory function, and increasing oxygen dependence. During her 11th admission Streptococcus milleri was isolated from sputum cultures in addition to P aeruginosa. She failed to respond to antipseudomonal antibiotics but improved dramatically with the addition of intravenous benzylpenicillin. Although S milleri is considered a normal mouth commensal and its isolation from sputum of cystic fibrosis patients is of uncertain significance, it was associated with clinically significant infection in this child. S milleri was eradicated with antibiotic treatment and clinical improvement has been maintained.

Topics: Acute Disease; Child; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Female; Floxacillin; Humans; Metronidazole; Penicillin G; Pseudomonas Infections; Sputum; Streptococcal Infections; Streptococcus

We compared the performance of selected ultrasonic and jet nebulizers when aerosolizing several antibiotic formulations to determine optimum combinations for delivery of a respirable antibiotic aerosol. Three ultrasonic devices were tested: the UltraNeb 99/100, the UltraAIR and the Aerosonic. The reusable jet nebulizers were the Dura ProNeb, Pari-LL and the Sidestream. The six disposable jet nebulizers were Marquest Acorn II, Hudson T Updraft II, Baxter MistyNeb, Pari-LC, Pari IS-2, and a disposable Sidestream. Each jet was tested with four compressors: a DeVilbiss AP-50, a Pulmo-Aide, a DuraNeb and a PariMaster. All nebulizing systems were initially tested with normal saline. From the initial data, six jet nebulizers and one ultrasonic device were tested with varying concentrations of tobramycin, gentamicin, ceftazidime, ciprofloxacin and colistin. Output was assessed by measuring volume (milliliters per minute), and amount of drug (milligrams per minute) nebulized. We then measured mean particle size of the antibiotic aerosol with seven jet nebulizers and two different compressors, Pulmo-Aide and PariMaster, and two ultrasonic devices. The rate of nebulization of saline and antibiotic solutions (milliliters per minute) was greater with the ultrasonic device(s) than all jet nebulizer systems tested. Increasing the reservoir antibiotic concentration increased the drug output (milligrams per minute) with the jet nebulizers to a maximum, followed by decreasing output. When antibiotic concentrations were increased the output decreased more precipitously with the ultrasonic devices than with the jet nebulizers. At the highest antibiotic concentrations tested, the ultrasonic devices had the lowest output. Particle size distribution was most dependent on the specific jet device, with particle size distribution less affected by a specific antibiotic or its concentration. Higher reservoir concentrations can be utilized for increasing output of respirable antibiotic aerosols by jet nebulizers. We conclude that antibiotic output is dependent upon both the nebulizing system and the reservoir concentration of antibiotic.

Topics: Aminoglycosides; Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Infections; Ceftazidime; Ciprofloxacin; Colistin; Cystic Fibrosis; Equipment Design; Humans; Hydrogen-Ion Concentration; Nebulizers and Vaporizers; Osmolar Concentration; Particle Size; Viscosity

In patients with cystic fibrosis (CF) who are awaiting lung transplant, prolonged exposure to systemic antibiotics has frequently led to airway colonization with resistant isolates of Pseudomonas. This resistance limits the arsenal of effective antimicrobials available for infections after the initiation of immunosuppression and has been considered a theoretical deterrent to lung transplantation.. Twenty CF transplant candidates with "pan-resistant" Pseudomonas received maintenance antibiotic therapy with aerosolized colistin sodium (75 mg b.i.d.), and intravenous antibiotics were eliminated. Ten other CF candidates did not use colistin sodium. Sputum cultures and antibiotic sensitivities were followed every 3-6 weeks.. All 20 candidates (100%) who used aerosolized colistin sodium became colonized with sensitive isolates of Pseudomonas in an average of 45.1+/-20.2 days. In contrast, only 3 of 10 CF transplant candidates (30%) who did not use colistin sodium later became colonized with sensitive isolates. The mean time to spontaneous emergence of sensitive organisms was 144.6+/-48.0 days in candidates who did not use colistin sodium and was significantly longer than in the candidates who used colistin sodium (P=0.007). The occurrence of redeveloping sensitive isolates of Pseudomonas was significantly greater in the candidates who used colistin sodium (P<0.05). Of the candidates who used colistin sodium, six have been transplanted at our institution. In five of these six recipients (83.3%) bacterial cultures taken from the explanted lungs continued to demonstrate sensitive organisms.. Aerosolized colistin sodium may be a useful therapy to promote emergence of sensitive microbes in CF candidates with pan-resistant isolates of Pseudomonas.

Topics: Aerosols; Colistin; Cystic Fibrosis; Follow-Up Studies; Graft Rejection; Humans; Lung Transplantation; Microbial Sensitivity Tests; Pseudomonas; Sputum

This study had, as its aim, to test twelve nebulizers (6 jet, 6 ultrasonic) which are used in the treatment of cystic fibrosis. Devices were connected to a respirator in order to mimic the ventilation of a child and of an adult suffering from cystis fibrosis. Three medications: tobramycine, colistine and amiloride were nebulised. The volume of the recommended solution varied between 1.5 and 13 ml according to the manufacturer. During a session of ten minutes the ultrasonic nebulizer delivered an inhaled volume which was significantly greater than the jet (2.72 +/- 0.98 ml vs 1.22 +/- 0.59 ml, p < 0.0001) for the three drugs. Regarding granulometry, the fraction of particles between 0.5 and 5 microns, was higher with ultrasonic than with pneumatic nebulizer for tobramycine (67.1 +/- 10.7 vs 55.5 +/- 11.5%, p < 0.001) and amiloride (66.4 +/- 9.2% vs 58.1 +/- 15%, p < 0.05%). The variation of concentration due to nebulisation were independent of the type of apparatus but influenced by the drug since concentration was increased for tobramycine (+10.5 +/- 18.6%) and amiloride (+13.4 +/- 8/9%). In summary the effective fraction resulting from the inhalable fraction, from granulometry and from changes in concentration was significantly greater for ultrasonic than for jet nebrulizer (17.3 +/- 6.7% vs 9.7 +/- 9.6%, p < 0.001). This study underlines the great variability of the performance of aerosols generators and therefore the need for an accurate evaluation of nebulizer performances in order to prescribe the best nebulizer/drug association in clinical practice.

Topics: Administration, Inhalation; Adult; Aerosols; Amiloride; Anti-Bacterial Agents; Child; Colistin; Cystic Fibrosis; Diuretics; Equipment Design; Ergonomics; Humans; Materials Testing; Nebulizers and Vaporizers; Particle Size; Tobramycin

Inhalation of aerosols contaminated with gram-negative bacteria generated from home-use nebulizers used by cystic fibrosis (CF) patients may be a primary route for bacterial colonization of the lung. Burkholderia cepacia was isolated from 3 of [corrected] 35 home-use nebulizers, and Stenotrophomonas maltophilia was isolated from 4 of 35 home-use nebulizers. Sputum cultures for two patients whose nebulizers were contaminated with B. cepacia did not yield the organism. However, DNA macrorestriction analysis by pulsed-field gel electrophoresis confirmed that one of two strains of B. cepacia recovered from the nebulizer of a third patient was also present in the sputum of that patient. Although Pseudomonas aeruginosa was isolated from 34 patients, none of the nebulizers were positive for the organism. Sixty-nine percent of nebulizers were contaminated, and up to 16 different environmental colistin-resistant, gram-negative species were identified. The heaviest contamination was found beneath the chamber atomizer. A questionnaire survey showed that the majority of patients (28 of 34) were receiving nebulized colistin and/or gentamicin. Patients who followed recommended instructions for good nebulizer hygienic practice and paid particular attention to drying had minimal or no contamination of their nebulizers.

Topics: Adult; Anti-Bacterial Agents; Burkholderia cepacia; Colistin; Cystic Fibrosis; Drug Resistance, Microbial; Gram-Negative Bacteria; Humans; Nebulizers and Vaporizers

This study was conducted by the AFLM order to determine the performance characteristics of 12 commercially available nebulizers (6 ultrasonic and 6 jet) used in the treatment of cystic fibrosis (CF). The nebulizers were connected to a circuit which simulated the ventilation of a CF child and CF adult, and were tested using three drug solutions: tobramycin (T), colistin (C), and amiloride (A). Nebulizer performance was evaluated according to the volume of drug solution delivered in 10 min during the simulated inspiratory phase (VI), drug granulometry (G%), drug concentration modification in the nebulizer reservoir (delta C), and percentage of efficiently aerosolized drug EA%). The ultrasonic devices delivered a significantly higher VI than the jet nebulizers (p < 0.0001) for all three study drug. Ventilation rate did not influence VI. Regarding granulometry, higher percentages of T and A were found to be contained in droplets ranging from 0.5 to 5.0 micron following ultrasonic nebulization. Drug concentration modifications were independent of the nebulizer used but were influenced by drug type; overconcentrations of T and A were observed (delta C = +10.5 +/- 18.6 and +13.4 +/- 8.9%, respectively). On average, the ultrasonic devices achieved a higher EA% than the jet nebulizers (17.3 +/- 6.7 and 9.7 +/- 9.6%, respectively). This study highlights the significant variability in performance of different nebulizer types and empahsizes the importance of accurately testing nebulizers prior to clinical use so that the most efficacious nebulizer/drug combinations may be prescribed.

Topics: Administration, Inhalation; Aerosols; Amiloride; Colistin; Cystic Fibrosis; Humans; Nebulizers and Vaporizers; Tobramycin

The objective of this study was to assess the performance of a new pneumatic nebuliser NL9 Atomisor. The performance was assessed in terms of particle distribution, fraction nebulised, fraction inhaled and percentage of particles of a diameter of between 1 and 4 microns for the nebulisation of physiological serum, colistin, tobramycin and amiloride. The solutions were nebulised in the approved formula for their reconstitution as used in the clinic after the addition of sodium pertechnetate. The validity of this indirect isotopic method has been shown before. The nebuliser was coupled, during the nebulisation, to a pump respirator with six settings. The fraction nebulised was defined as the percentage of the volume of the solution which had left the aerosol generator at the end of the nebulisation. The fraction inhaled was defined as a percentage of the volume of the solution which was gathered at the end of the nebulisation on a filter placed in the inspiratory circuit of the aerosol generator. The study of the distribution of aerosol particle sizes was carried out using a cascade impactor at ten stages. Each of these parameters was determined in triplicate for the four solutions studied. The nebulised fraction consisted of between 33.5 and 58.6% (mean 49.7 +/- 8.1%). The inhaled fraction consisted of between 14 and 30.4% (mean 24.5 +/- 5.5) and the duration of nebulisation was between 10 and 20 minutes. The MMAD was between 1.6 microns with tobramycin 3.5 microns with physiological serum.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aerosols; Amiloride; Colistin; Cystic Fibrosis; Evaluation Studies as Topic; Humans; Nebulizers and Vaporizers; Particle Size; Sodium Pertechnetate Tc 99m; Surface Tension; Tobramycin

Topics: Adolescent; Adult; Bronchial Provocation Tests; Bronchoconstriction; Bronchodilator Agents; Colistin; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Male; Nebulizers and Vaporizers; Pseudomonas Infections; Time Factors

Pulmonary exacerbations of cystic fibrosis associated with strains of Pseudomonas aeruginosa that are resistant to multiple antibiotics are becoming increasingly common. The search for treatment alternatives continues and may include the reexamination of older antibiotics. Colistin sulfate is a polypeptide antibiotic with good activity against P. aeruginosa. Although its use was largely discontinued in the early 1970s because of reports of frequent renal and neurologic toxicity, intravenous colistin is often prescribed at our institution for patients with P. aeruginosa resistant to multiple-drug therapy. We prospectively monitored 19 patients during 21 courses of colistin therapy to identify the character and incidence of this agent's toxicity. Only one case of renal toxicity occurred. Six cases of neurotoxicity occurred, which were characterized by perioral paresthesia, ataxia, or both. The rate of intolerable renal adverse effects secondary to colistin therapy was appreciably lower among these patients than that reported previously for other patients. It appears that intravenous colistin can be considered for cystic fibrosis patients with strains of P. aeruginosa that are resistant to more commonly used antibiotics.

Topics: Adolescent; Adult; Ataxia; Child; Child, Preschool; Colistin; Cystic Fibrosis; Drug Monitoring; Female; Humans; Injections, Intravenous; Male; Paresthesia; Prospective Studies; Proteinuria; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Adolescent; Child; Child, Preschool; Colistin; Cystic Fibrosis; Female; Humans; Infant; Male; Pseudomonas Infections; Respiratory Tract Infections

The bacteriological effect of chemotherapy against Pseudomonas aeruginosa (Ps.ae.) in lungs of patients with cystic fibrosis is reviewed. During a 5-year period 49 children and adults were treated with 190 courses of different antibiotics. The mucoid strains of Ps.ae. disappeared in 72.0% of the courses in which a combination of tobramycin and carbenicillin was employed. Tobramycin given alone had only bacteriological effect in 26.6% of the courses. Colimycin alone or in combination with carbenicillin had no effect. In 18 patients who received subsequent courses of tobramycin and combination of tobramycin and carbenicillin a significant difference in favour of the combination therapy was found, also in cases with many precipitins against Ps.ae. in serum. In 74.5% of the initially successful courses the patients were recolonized with Ps.ae. within 1 month. No nephrotoxic or ototoxic side effects were demonstrated in spite of the high doses of tobramycin (10 mg/kg/24 h) emmployed and the repeated courses.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Carbenicillin; Child; Child, Preschool; Chronic Disease; Colistin; Cystic Fibrosis; Drug Evaluation; Drug Therapy, Combination; Female; Gentamicins; Humans; Infant; Male; Pneumonia; Precipitins; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

Of 97 well-defined strains of Pseudomonas, isolated from sputum of patients with cystic fibrosis (CF), the minimum inhibitory concentration (MIC) of several antibiotics was determined with a broth dilution method. The majority of the strains were resistant to ampicillin and cephalothin, moderately susceptible to carbenicillin (70% to 100 microgram/ml) and highly susceptible to piperacillin (100% to 25 microgram/ml, 88% to 6.25 microgram and 60% to 3.12 microgram/ml). If the pharmacological properties of piperacillin are comparable with those of carbenicillin, it can be expected that the sputum level of this drug will be adequate to treat Pseudomonas pulmonary infections. At the lowest concentration tested (0.78 microgram/ml) 3% of the strains were susceptible to kanamycin, 85,5% to amikacin, 95% to gentamicin, 98% of tobramycin, and 80% to colimycin. With regard to clinically attainable concentrations, 98.9% of the strains were susceptible to gentamicin and tobramycin 97.9% to amikacin, 96.9% to colimycin, 88.6% to piperacillin, 38% to carbenicillin, 25.7% to kanamycin, 12.3% to ampicillin, and 1% to cephalothin.

Topics: Amikacin; Aminoglycosides; Ampicillin; Carbenicillin; Cephalothin; Child; Colistin; Cystic Fibrosis; Gentamicins; Humans; Kanamycin; Microbial Sensitivity Tests; Penicillin Resistance; Penicillins; Pseudomonas; Sputum; Tobramycin

Topics: Administration, Oral; Adolescent; Adult; Anti-Bacterial Agents; Child; Colistin; Cystic Fibrosis; Gentamicins; Humans; Infusions, Parenteral; Outpatient Clinics, Hospital; Pseudomonas aeruginosa; Respiratory Function Tests; Respiratory Tract Infections; Staphylococcus

Topics: Adolescent; Alanine Transaminase; Ampicillin; Aspartate Aminotransferases; Blood Cell Count; Child; Child, Preschool; Clinical Enzyme Tests; Colistin; Cystic Fibrosis; Drug Synergism; Gentamicins; Humans; Oxacillin; Penicillins; Polymyxins; Pseudomonas aeruginosa; Pseudomonas Infections; Sputum; Tetracycline