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113 Inhalative meropenem–tobramycin–colistin combination improves lung function in chronic Pseudomonas aeruginosa colonization
S86
4. Microbiology
Posters
113 Inhalative meropenem–tobramycin–colistin combination improves lung function in chronic Pseudomonas aeruginosa colonization
115 Intravenous antibiotics for pulmonary exacerbations in people with cystic fibrosis − Cochrane review
G. Herrmann1 , E. Freitag1 , C. Deppisch1 , S. Heyder1 , U. Graepler-Mainka1 , J. Riethm¨uller1 . 1 University Children’s Hospital, Tuebingen, Germany
M. Hurley1,2 , A. Prayle1 , P. Flume3 . 1 University of Nottingham, Child Health, Nottingham, United Kingdom; 2 Nottingham Children’s Hospital, Paediatric Respiratory Medicine, Nottingham, United Kingdom; 3 Medical University of South Carolina, Charleston, United States
Objectives: Pseudomonas aeruginosa in the airways of CF-patients restricts the efficacy of antibiotics leading to chronic infections which have a large impact on morbidity and mortality. Antibiotic combination therapy might be more efficient than single antibiotics to combat lung infections in CF. Methods: In an observational pilot study CF patients, suffering from chronic P. aeruginosa lung infection, pre-treated either with tobramycin or colistin, were inhalatively treated for 28 days with 300 mg tobramycin in combination with colistin (1 Mio IU) and meropenem 250 mg twice daily. Lung function expressed as expiratory volume in 1 second (FEV1 ), bacterial cfu and adverse events were determined before and after treatment. Results: 15 adult CF patients (mean age 27.9±9.4 years) inhaled b-sympathomimetics prior to the triple antibiotic solution which was well tolerated by all patients. FEV1 increased significantly by 7.8±5.7% absolute and 11.6±10% relative to baseline (p = 0.001) since only one patient showed no benefit after 28 days of inhalation. P. aeruginosa decreased significantly by 1.46±1.4 log cfu/ml (p = 0.042). No adverse reactions were found. Conclusion: For the first time administered, the efficacy of an inhalative triple antibiotic solution with meropenem, tobramycin and colistin suggest, that this combination therapy seems to be safe and efficient to increase lung function and decrease chronic Pseudomonas infection in CF patients. This alternative combination of inhalative antibiotics has to be investigated in further trials.
Background: Intravenous (IV) antibiotics are used in the treatment of pulmonary exacerbations. Recently the assumption that exacerbations are due to increases in bacterial burden has been questioned. Objective: To establish if IV antibiotics for the treatment of pulmonary exacerbations in CF improve clinical outcomes. Method: We searched the Cochrane CF Trials Register, PubMed and reference lists of relevant articles. We included randomised controlled trials and first treatment cycles of cross-over trials comparing IV antibiotics (given alone or in an antibiotic combination) with placebo, inhaled or oral antibiotics for patients with CF experiencing a pulmonary exacerbation. Results: We included 41 studies involving 1736 participants. The quality of these, with few exceptions, was poor comprising mainly small, inadequately reported studies. The comparisons of IV antibiotics with placebo were such that no conclusions could be drawn. In the comparison of single versus combination antibiotics, patients receiving combinations had greater improvement in lung function but no differences between groups on other measures (except excess renal toxicity in those receiving combination regimens). When comparing specific antibiotic combinations, and in the comparisons between IV and nebulised and oral antibiotics, there were no significant differences between groups. Conclusions: The quality of evidence comparing IV antibiotics with placebo is poor. Combination antibiotics appear superior to single-agent regimens. No specific antibiotic combination can be considered to be superior, and neither is there evidence showing that the IV route is superior to the inhaled or oral routes.
114 Investigating the activity of antibiotics at aerosolized concentrations against Burkholderia cepacia complex biofilms
116 Pharmacokinetic variability of ciprofloxacin in cystic fibrosis − is CYP3A4 involved?
S. Kennedy1,2 , Y. Yau3 , E. Caraher4 , V. Waters1,2 . 1 Hospital for Sick Children, Physiology and Experimental Medicine, Toronto, Canada; 2 Hospital for Sick Children, Infectious Diseases, Toronto, Canada; 3 Hospital for Sick Children, Microbiology, Toronto, Canada; 4 Institute of Technology Tallaght, Centre of Host Microbial Interactions, Dublin, Ireland
A.N.Ø. Schultz1 , N. Høiby1 , X.C. Nielsen1 , T. Pressler2 , K. Dalhoff3 , M. Duno4 , A. Buchard5 , H.K. Johansen1 , C.S. Dalbøge1 . 1 University of Copenhagen/Rigshospitalet, Dept. of Clinical Microbiology, Copenhagen, Denmark; 2 Rigshospitalet, Cystic Fibrosis Center, Copenhagen, Denmark; 3 Bispebjerg Hospital, Dept. of Clinical Pharmacology, Copenhagen, Denmark; 4 Rigshospitalet, Dept. of Clinical Genetics, Copenhagen, Denmark; 5 University of Copenhagen, Dept. of Forensic Medicine, Copenhagen, Denmark
Objectives: Burkholderia cepacia complex (Bcc) causes chronic pulmonary infections in patients with Cystic Fibrosis (CF). Bcc isolates are drug resistant and grow as biofilms in vivo, thus protecting themselves from host defences. Currently, there is no effective antimicrobial therapy for CF patients infected with Bcc. New aerosolized antimicrobials can deliver very high intrapulmonary concentrations of drug that may be able to overcome this antimicrobial resistance. The objective of this study was to compare the activity of tobramycin at systemically achievable vs aerosolized concentrations on Bcc biofilms cultured under continuous flow in the novel microfluidic Bioflux system. Methods: Biofilms of CF Burkholderia multivorans (tagged with gfp) were generated for 24 hours and were treated with 8 and 1,000 mg/ml tobramycin for 24 hrs. Results: Analysis of each channel demonstrated that biofilm biomass decreased in comparison to the controls after treatment with tobramycin. However, while biomass was decreased, confocal Z-stack images indicated that thickness of microcolonies within treated biofilms (8 mg/ml, 33 mm; 1000 mg/ml, 41 mm) are similar to controls (48 hr, 40 mm). Conclusion: In conclusion, although tobramycin at concentrations achievable by aerosolization does not eradicate Bcc biofilms in vitro, additional work is underway to determine its effect on the viability of bacterial cells within this biofilm. Taken together, this and future work will provide a greater understanding of how Bcc biofilms can be eradicated in order to improve existing antibiotic therapies and develop novel treatments, for patients with Cystic Fibrosis.
Objectives: Ciprofloxacin (CIP), is frequently used, when treating cystic fibrose (CF) patients with intermittent P. aeruginosa lung colonization. However, approximately 20% of the patients progress to chronic infection despite early intervention. The aim of this study was to investigate the pharmacokinetics of CIP, to evaluate if CYP3A4-related metabolism is involved and to find the optimal dose needed to eradicate intermittently colonizing bacteria in the lungs of CF patients. Methods: An open-label, prospective pharmacokinetic study was preformed. Twenty-one CF-patients were each given 500 mg CIP orally. During the following 12 hr, 8 blood samples were collected. The optimal dose and interval was then calculated by Monte Carlo simulation. CYP3A4-activity was mesured using the Erythromycin Breath Test (ERMBT). Results: An 14-fold variation in AUC for CIP (median 473.5 mg/mL·min, range 138–1880), and a 30-fold variation in Cmax for CIP (median 2 mg/mL, range 0.25−7.6) were found. For CYP3A4-activity the variation was 8-fold. No correlation was found between the CYP3A4-activity and CIP-concentrations. The probability of eradicating intermittent P. aeruginosa colonization in the lungs of CF patients was found to be 17% (1 dose/day), 40% (2 doses/day) and 57% (3 doses/day), respectively when 500 mg CIP was given. It was 63% (1 dose/day), 89% (2 doses/day) and 94% (3 doses/day), respectively when 750 mg CIP was given. Conclusion: The study showed a large pharmacokinetic difference of CIP in CF patiens, not explained by CYP3A4 variation. To prevent treatment faliure in intermittently colonized patients CIP should be given at 750 mg three times daily to adult CF patients.
4. Microbiology
Posters
113 Inhalative meropenem–tobramycin–colistin combination improves lung function in chronic Pseudomonas aeruginosa colonization
115 Intravenous antibiotics for pulmonary exacerbations in people with cystic fibrosis − Cochrane review
G. Herrmann1 , E. Freitag1 , C. Deppisch1 , S. Heyder1 , U. Graepler-Mainka1 , J. Riethm¨uller1 . 1 University Children’s Hospital, Tuebingen, Germany
M. Hurley1,2 , A. Prayle1 , P. Flume3 . 1 University of Nottingham, Child Health, Nottingham, United Kingdom; 2 Nottingham Children’s Hospital, Paediatric Respiratory Medicine, Nottingham, United Kingdom; 3 Medical University of South Carolina, Charleston, United States
Objectives: Pseudomonas aeruginosa in the airways of CF-patients restricts the efficacy of antibiotics leading to chronic infections which have a large impact on morbidity and mortality. Antibiotic combination therapy might be more efficient than single antibiotics to combat lung infections in CF. Methods: In an observational pilot study CF patients, suffering from chronic P. aeruginosa lung infection, pre-treated either with tobramycin or colistin, were inhalatively treated for 28 days with 300 mg tobramycin in combination with colistin (1 Mio IU) and meropenem 250 mg twice daily. Lung function expressed as expiratory volume in 1 second (FEV1 ), bacterial cfu and adverse events were determined before and after treatment. Results: 15 adult CF patients (mean age 27.9±9.4 years) inhaled b-sympathomimetics prior to the triple antibiotic solution which was well tolerated by all patients. FEV1 increased significantly by 7.8±5.7% absolute and 11.6±10% relative to baseline (p = 0.001) since only one patient showed no benefit after 28 days of inhalation. P. aeruginosa decreased significantly by 1.46±1.4 log cfu/ml (p = 0.042). No adverse reactions were found. Conclusion: For the first time administered, the efficacy of an inhalative triple antibiotic solution with meropenem, tobramycin and colistin suggest, that this combination therapy seems to be safe and efficient to increase lung function and decrease chronic Pseudomonas infection in CF patients. This alternative combination of inhalative antibiotics has to be investigated in further trials.
Background: Intravenous (IV) antibiotics are used in the treatment of pulmonary exacerbations. Recently the assumption that exacerbations are due to increases in bacterial burden has been questioned. Objective: To establish if IV antibiotics for the treatment of pulmonary exacerbations in CF improve clinical outcomes. Method: We searched the Cochrane CF Trials Register, PubMed and reference lists of relevant articles. We included randomised controlled trials and first treatment cycles of cross-over trials comparing IV antibiotics (given alone or in an antibiotic combination) with placebo, inhaled or oral antibiotics for patients with CF experiencing a pulmonary exacerbation. Results: We included 41 studies involving 1736 participants. The quality of these, with few exceptions, was poor comprising mainly small, inadequately reported studies. The comparisons of IV antibiotics with placebo were such that no conclusions could be drawn. In the comparison of single versus combination antibiotics, patients receiving combinations had greater improvement in lung function but no differences between groups on other measures (except excess renal toxicity in those receiving combination regimens). When comparing specific antibiotic combinations, and in the comparisons between IV and nebulised and oral antibiotics, there were no significant differences between groups. Conclusions: The quality of evidence comparing IV antibiotics with placebo is poor. Combination antibiotics appear superior to single-agent regimens. No specific antibiotic combination can be considered to be superior, and neither is there evidence showing that the IV route is superior to the inhaled or oral routes.
114 Investigating the activity of antibiotics at aerosolized concentrations against Burkholderia cepacia complex biofilms
116 Pharmacokinetic variability of ciprofloxacin in cystic fibrosis − is CYP3A4 involved?
S. Kennedy1,2 , Y. Yau3 , E. Caraher4 , V. Waters1,2 . 1 Hospital for Sick Children, Physiology and Experimental Medicine, Toronto, Canada; 2 Hospital for Sick Children, Infectious Diseases, Toronto, Canada; 3 Hospital for Sick Children, Microbiology, Toronto, Canada; 4 Institute of Technology Tallaght, Centre of Host Microbial Interactions, Dublin, Ireland
A.N.Ø. Schultz1 , N. Høiby1 , X.C. Nielsen1 , T. Pressler2 , K. Dalhoff3 , M. Duno4 , A. Buchard5 , H.K. Johansen1 , C.S. Dalbøge1 . 1 University of Copenhagen/Rigshospitalet, Dept. of Clinical Microbiology, Copenhagen, Denmark; 2 Rigshospitalet, Cystic Fibrosis Center, Copenhagen, Denmark; 3 Bispebjerg Hospital, Dept. of Clinical Pharmacology, Copenhagen, Denmark; 4 Rigshospitalet, Dept. of Clinical Genetics, Copenhagen, Denmark; 5 University of Copenhagen, Dept. of Forensic Medicine, Copenhagen, Denmark
Objectives: Burkholderia cepacia complex (Bcc) causes chronic pulmonary infections in patients with Cystic Fibrosis (CF). Bcc isolates are drug resistant and grow as biofilms in vivo, thus protecting themselves from host defences. Currently, there is no effective antimicrobial therapy for CF patients infected with Bcc. New aerosolized antimicrobials can deliver very high intrapulmonary concentrations of drug that may be able to overcome this antimicrobial resistance. The objective of this study was to compare the activity of tobramycin at systemically achievable vs aerosolized concentrations on Bcc biofilms cultured under continuous flow in the novel microfluidic Bioflux system. Methods: Biofilms of CF Burkholderia multivorans (tagged with gfp) were generated for 24 hours and were treated with 8 and 1,000 mg/ml tobramycin for 24 hrs. Results: Analysis of each channel demonstrated that biofilm biomass decreased in comparison to the controls after treatment with tobramycin. However, while biomass was decreased, confocal Z-stack images indicated that thickness of microcolonies within treated biofilms (8 mg/ml, 33 mm; 1000 mg/ml, 41 mm) are similar to controls (48 hr, 40 mm). Conclusion: In conclusion, although tobramycin at concentrations achievable by aerosolization does not eradicate Bcc biofilms in vitro, additional work is underway to determine its effect on the viability of bacterial cells within this biofilm. Taken together, this and future work will provide a greater understanding of how Bcc biofilms can be eradicated in order to improve existing antibiotic therapies and develop novel treatments, for patients with Cystic Fibrosis.
Objectives: Ciprofloxacin (CIP), is frequently used, when treating cystic fibrose (CF) patients with intermittent P. aeruginosa lung colonization. However, approximately 20% of the patients progress to chronic infection despite early intervention. The aim of this study was to investigate the pharmacokinetics of CIP, to evaluate if CYP3A4-related metabolism is involved and to find the optimal dose needed to eradicate intermittently colonizing bacteria in the lungs of CF patients. Methods: An open-label, prospective pharmacokinetic study was preformed. Twenty-one CF-patients were each given 500 mg CIP orally. During the following 12 hr, 8 blood samples were collected. The optimal dose and interval was then calculated by Monte Carlo simulation. CYP3A4-activity was mesured using the Erythromycin Breath Test (ERMBT). Results: An 14-fold variation in AUC for CIP (median 473.5 mg/mL·min, range 138–1880), and a 30-fold variation in Cmax for CIP (median 2 mg/mL, range 0.25−7.6) were found. For CYP3A4-activity the variation was 8-fold. No correlation was found between the CYP3A4-activity and CIP-concentrations. The probability of eradicating intermittent P. aeruginosa colonization in the lungs of CF patients was found to be 17% (1 dose/day), 40% (2 doses/day) and 57% (3 doses/day), respectively when 500 mg CIP was given. It was 63% (1 dose/day), 89% (2 doses/day) and 94% (3 doses/day), respectively when 750 mg CIP was given. Conclusion: The study showed a large pharmacokinetic difference of CIP in CF patiens, not explained by CYP3A4 variation. To prevent treatment faliure in intermittently colonized patients CIP should be given at 750 mg three times daily to adult CF patients.