Antibacterial activities of a fosfomycin/tobramycin combination: a novel inhaled antibiotic for bronchiectasis
Objectives To compare the in vitro and in vivo activities of a 4:1 (w/w) fosfomycin/tobramycin combination (FTI) with those of fosfomycin and tobramycin alone against cystic fibrosis (CF) and non-CF bronchiectasis pathogens. Methods Clinical isolates of CF Pseudomonas aeruginosa, Staphylococcus aure...
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| creator | MacLeod, David L. Barker, Lynn M. Sutherland, Jennifer L. Moss, Suzanne C. Gurgel, Jesse L. Kenney, Thomas F. Burns, Jane L. Baker, William R. |
| description | Objectives To compare the in vitro and in vivo activities of a 4:1 (w/w) fosfomycin/tobramycin combination (FTI) with those of fosfomycin and tobramycin alone against cystic fibrosis (CF) and non-CF bronchiectasis pathogens. Methods Clinical isolates of CF Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, Stenotrophomonas maltophilia, Burkholderia cepacia complex, Escherichia coli and Klebsiellia spp. were evaluated by MIC, MBC, post-antibiotic effect (PAE), synergy, time–kill, a rat pneumonia model and spontaneous mutation frequency (SMF). Results FTI showed high activity against E. coli, H. influenzae, S. aureus and Klebsiella spp. For the S. aureus strains, 75% of which were methicillin resistant (MRSA), FTI had a lower MIC90 than tobramycin. For P. aeruginosa, FTI had a lower MIC90 than fosfomycin, but tobramycin was more active than either. Synergy studies showed no antagonism between fosfomycin and tobramycin, and 93% of the isolates demonstrated no interaction. FTI was rapidly bactericidal and exhibited concentration-dependent killing in time–kill studies. In the rat pneumonia model, FTI and tobramycin demonstrated bactericidal killing of P. aeruginosa; both were more active than fosfomycin alone. The SMF for S. aureus resistance to FTI was 2–4 log10 lower than that for tobramycin and 2–7 log10 lower than that for fosfomycin. For P. aeruginosa, the FTI SMF was 2–3 log10 lower than that for fosfomycin and 1–2 log10 lower than that for tobramycin. Conclusions FTI is a broad-spectrum antibiotic combination with high activity in vitro and in vivo. These data suggest FTI could be a potential treatment for respiratory infections caused by Gram-positive and Gram-negative aerobic bacteria. |
| doi_str_mv | 10.1093/jac/dkp282 |
| format | Article |
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Methods Clinical isolates of CF Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, Stenotrophomonas maltophilia, Burkholderia cepacia complex, Escherichia coli and Klebsiellia spp. were evaluated by MIC, MBC, post-antibiotic effect (PAE), synergy, time–kill, a rat pneumonia model and spontaneous mutation frequency (SMF). Results FTI showed high activity against E. coli, H. influenzae, S. aureus and Klebsiella spp. For the S. aureus strains, 75% of which were methicillin resistant (MRSA), FTI had a lower MIC90 than tobramycin. For P. aeruginosa, FTI had a lower MIC90 than fosfomycin, but tobramycin was more active than either. Synergy studies showed no antagonism between fosfomycin and tobramycin, and 93% of the isolates demonstrated no interaction. FTI was rapidly bactericidal and exhibited concentration-dependent killing in time–kill studies. In the rat pneumonia model, FTI and tobramycin demonstrated bactericidal killing of P. aeruginosa; both were more active than fosfomycin alone. The SMF for S. aureus resistance to FTI was 2–4 log10 lower than that for tobramycin and 2–7 log10 lower than that for fosfomycin. For P. aeruginosa, the FTI SMF was 2–3 log10 lower than that for fosfomycin and 1–2 log10 lower than that for tobramycin. Conclusions FTI is a broad-spectrum antibiotic combination with high activity in vitro and in vivo. These data suggest FTI could be a potential treatment for respiratory infections caused by Gram-positive and Gram-negative aerobic bacteria.</description><identifier>ISSN: 0305-7453</identifier><identifier>EISSN: 1460-2091</identifier><identifier>DOI: 10.1093/jac/dkp282</identifier><identifier>PMID: 19679597</identifier><identifier>CODEN: JACHDX</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Administration, Inhalation ; Animals ; Anti-Bacterial Agents - administration & dosage ; Anti-Bacterial Agents - pharmacology ; Anti-Bacterial Agents - therapeutic use ; Antibiotics ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Bacteria - drug effects ; Bacteria - isolation & purification ; Bacterial Infections - microbiology ; Biological and medical sciences ; Bronchiectasis - complications ; Burkholderia cepacia ; Colony Count, Microbial ; Comparative studies ; Cystic fibrosis ; Drug Combinations ; Drug Interactions ; Escherichia coli ; Fosfomycin - administration & dosage ; Fosfomycin - pharmacology ; Fosfomycin - therapeutic use ; Haemophilus influenzae ; Humans ; Klebsiella ; Lung - microbiology ; Male ; Medical sciences ; Microbial Sensitivity Tests ; Microbial Viability ; Original Research ; P. aeruginosa ; Pharmacology ; Pharmacology. Drug treatments ; Pneumology ; Pneumonia, Bacterial - drug therapy ; Pseudomonas aeruginosa ; Rats ; respiratory infections ; Respiratory system : syndromes and miscellaneous diseases ; Respiratory therapy ; S. aureus ; Staphylococcus aureus ; Stenotrophomonas maltophilia ; Tobramycin - administration & dosage ; Tobramycin - pharmacology ; Tobramycin - therapeutic use ; Treatment Outcome</subject><ispartof>Journal of antimicrobial chemotherapy, 2009-10, Vol.64 (4), p.829-836</ispartof><rights>The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org 2009</rights><rights>2009 INIST-CNRS</rights><rights>The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c599t-c06b111aa47c58d97ddf315895488733a5ea68f2852dbd79b18177e7ee87577e3</citedby><cites>FETCH-LOGICAL-c599t-c06b111aa47c58d97ddf315895488733a5ea68f2852dbd79b18177e7ee87577e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,1584,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21960726$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19679597$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MacLeod, David L.</creatorcontrib><creatorcontrib>Barker, Lynn M.</creatorcontrib><creatorcontrib>Sutherland, Jennifer L.</creatorcontrib><creatorcontrib>Moss, Suzanne C.</creatorcontrib><creatorcontrib>Gurgel, Jesse L.</creatorcontrib><creatorcontrib>Kenney, Thomas F.</creatorcontrib><creatorcontrib>Burns, Jane L.</creatorcontrib><creatorcontrib>Baker, William R.</creatorcontrib><title>Antibacterial activities of a fosfomycin/tobramycin combination: a novel inhaled antibiotic for bronchiectasis</title><title>Journal of antimicrobial chemotherapy</title><addtitle>J Antimicrob Chemother</addtitle><description>Objectives To compare the in vitro and in vivo activities of a 4:1 (w/w) fosfomycin/tobramycin combination (FTI) with those of fosfomycin and tobramycin alone against cystic fibrosis (CF) and non-CF bronchiectasis pathogens. Methods Clinical isolates of CF Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, Stenotrophomonas maltophilia, Burkholderia cepacia complex, Escherichia coli and Klebsiellia spp. were evaluated by MIC, MBC, post-antibiotic effect (PAE), synergy, time–kill, a rat pneumonia model and spontaneous mutation frequency (SMF). Results FTI showed high activity against E. coli, H. influenzae, S. aureus and Klebsiella spp. For the S. aureus strains, 75% of which were methicillin resistant (MRSA), FTI had a lower MIC90 than tobramycin. For P. aeruginosa, FTI had a lower MIC90 than fosfomycin, but tobramycin was more active than either. Synergy studies showed no antagonism between fosfomycin and tobramycin, and 93% of the isolates demonstrated no interaction. FTI was rapidly bactericidal and exhibited concentration-dependent killing in time–kill studies. In the rat pneumonia model, FTI and tobramycin demonstrated bactericidal killing of P. aeruginosa; both were more active than fosfomycin alone. The SMF for S. aureus resistance to FTI was 2–4 log10 lower than that for tobramycin and 2–7 log10 lower than that for fosfomycin. For P. aeruginosa, the FTI SMF was 2–3 log10 lower than that for fosfomycin and 1–2 log10 lower than that for tobramycin. Conclusions FTI is a broad-spectrum antibiotic combination with high activity in vitro and in vivo. These data suggest FTI could be a potential treatment for respiratory infections caused by Gram-positive and Gram-negative aerobic bacteria.</description><subject>Administration, Inhalation</subject><subject>Animals</subject><subject>Anti-Bacterial Agents - administration & dosage</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Anti-Bacterial Agents - therapeutic use</subject><subject>Antibiotics</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Bacteria - drug effects</subject><subject>Bacteria - isolation & purification</subject><subject>Bacterial Infections - microbiology</subject><subject>Biological and medical sciences</subject><subject>Bronchiectasis - complications</subject><subject>Burkholderia cepacia</subject><subject>Colony Count, Microbial</subject><subject>Comparative studies</subject><subject>Cystic fibrosis</subject><subject>Drug Combinations</subject><subject>Drug Interactions</subject><subject>Escherichia coli</subject><subject>Fosfomycin - administration & dosage</subject><subject>Fosfomycin - pharmacology</subject><subject>Fosfomycin - therapeutic use</subject><subject>Haemophilus influenzae</subject><subject>Humans</subject><subject>Klebsiella</subject><subject>Lung - microbiology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Microbial Sensitivity Tests</subject><subject>Microbial Viability</subject><subject>Original Research</subject><subject>P. aeruginosa</subject><subject>Pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Pneumology</subject><subject>Pneumonia, Bacterial - drug therapy</subject><subject>Pseudomonas aeruginosa</subject><subject>Rats</subject><subject>respiratory infections</subject><subject>Respiratory system : syndromes and miscellaneous diseases</subject><subject>Respiratory therapy</subject><subject>S. aureus</subject><subject>Staphylococcus aureus</subject><subject>Stenotrophomonas maltophilia</subject><subject>Tobramycin - administration & dosage</subject><subject>Tobramycin - pharmacology</subject><subject>Tobramycin - therapeutic use</subject><subject>Treatment Outcome</subject><issn>0305-7453</issn><issn>1460-2091</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90c-LEzEUB_AgilurF_8AGQQ9CGOTzOSXB2FZVldckIKKeAlvMhmb7jSpSabs_vdmbemqB095kE9eXvJF6CnBrwlWzWINZtFfbamk99CMtBzXFCtyH81wg1ktWtacoEcprTHGnHH5EJ0QxYViSsyQP_XZdWCyjQ7GqhRu57KzqQpDBdUQ0hA2N8b5RQ5dhN9lZcKmcx6yC_5NQT7s7Fg5v4LR9hXcNnQhO1NOx6qLwZuVsyZDcukxejDAmOyTwzpHX96dfz67qC8_vf9wdnpZG6ZUrg3mHSEEoBWGyV6Jvh8awqRirZSiaYBZ4HKgktG-64XqiCRCWGGtFKwUzRy93ffdTt3G9sb6HGHU2-g2EG90AKf_3vFupX-EnaaixbzhpcHLQ4MYfk42Zb1xydhxBG_DlDQltHxmSwp8_g9chyn68rhiBBdElojm6NUemRhSinY4TkKwvs1Qlwz1PsOCn_05-x09hFbAiwOAZGAcInjj0tHRArGg_M6Fafv_C-u9cynb66OEeKW5aATTF9--6698-ZEv8VLL5hepMcOE</recordid><startdate>20091001</startdate><enddate>20091001</enddate><creator>MacLeod, David L.</creator><creator>Barker, Lynn M.</creator><creator>Sutherland, Jennifer L.</creator><creator>Moss, Suzanne C.</creator><creator>Gurgel, Jesse L.</creator><creator>Kenney, Thomas F.</creator><creator>Burns, Jane L.</creator><creator>Baker, William R.</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QO</scope><scope>7T7</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20091001</creationdate><title>Antibacterial activities of a fosfomycin/tobramycin combination: a novel inhaled antibiotic for bronchiectasis</title><author>MacLeod, David L. ; Barker, Lynn M. ; Sutherland, Jennifer L. ; Moss, Suzanne C. ; Gurgel, Jesse L. ; Kenney, Thomas F. ; Burns, Jane L. ; Baker, William R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c599t-c06b111aa47c58d97ddf315895488733a5ea68f2852dbd79b18177e7ee87577e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Administration, Inhalation</topic><topic>Animals</topic><topic>Anti-Bacterial Agents - administration & dosage</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Anti-Bacterial Agents - therapeutic use</topic><topic>Antibiotics</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Bacteria - drug effects</topic><topic>Bacteria - isolation & purification</topic><topic>Bacterial Infections - microbiology</topic><topic>Biological and medical sciences</topic><topic>Bronchiectasis - complications</topic><topic>Burkholderia cepacia</topic><topic>Colony Count, Microbial</topic><topic>Comparative studies</topic><topic>Cystic fibrosis</topic><topic>Drug Combinations</topic><topic>Drug Interactions</topic><topic>Escherichia coli</topic><topic>Fosfomycin - administration & dosage</topic><topic>Fosfomycin - pharmacology</topic><topic>Fosfomycin - therapeutic use</topic><topic>Haemophilus influenzae</topic><topic>Humans</topic><topic>Klebsiella</topic><topic>Lung - microbiology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Microbial Sensitivity Tests</topic><topic>Microbial Viability</topic><topic>Original Research</topic><topic>P. aeruginosa</topic><topic>Pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Pneumology</topic><topic>Pneumonia, Bacterial - drug therapy</topic><topic>Pseudomonas aeruginosa</topic><topic>Rats</topic><topic>respiratory infections</topic><topic>Respiratory system : syndromes and miscellaneous diseases</topic><topic>Respiratory therapy</topic><topic>S. aureus</topic><topic>Staphylococcus aureus</topic><topic>Stenotrophomonas maltophilia</topic><topic>Tobramycin - administration & dosage</topic><topic>Tobramycin - pharmacology</topic><topic>Tobramycin - therapeutic use</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MacLeod, David L.</creatorcontrib><creatorcontrib>Barker, Lynn M.</creatorcontrib><creatorcontrib>Sutherland, Jennifer L.</creatorcontrib><creatorcontrib>Moss, Suzanne C.</creatorcontrib><creatorcontrib>Gurgel, Jesse L.</creatorcontrib><creatorcontrib>Kenney, Thomas F.</creatorcontrib><creatorcontrib>Burns, Jane L.</creatorcontrib><creatorcontrib>Baker, William R.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of antimicrobial chemotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MacLeod, David L.</au><au>Barker, Lynn M.</au><au>Sutherland, Jennifer L.</au><au>Moss, Suzanne C.</au><au>Gurgel, Jesse L.</au><au>Kenney, Thomas F.</au><au>Burns, Jane L.</au><au>Baker, William R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antibacterial activities of a fosfomycin/tobramycin combination: a novel inhaled antibiotic for bronchiectasis</atitle><jtitle>Journal of antimicrobial chemotherapy</jtitle><addtitle>J Antimicrob Chemother</addtitle><date>2009-10-01</date><risdate>2009</risdate><volume>64</volume><issue>4</issue><spage>829</spage><epage>836</epage><pages>829-836</pages><issn>0305-7453</issn><eissn>1460-2091</eissn><coden>JACHDX</coden><abstract>Objectives To compare the in vitro and in vivo activities of a 4:1 (w/w) fosfomycin/tobramycin combination (FTI) with those of fosfomycin and tobramycin alone against cystic fibrosis (CF) and non-CF bronchiectasis pathogens. Methods Clinical isolates of CF Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, Stenotrophomonas maltophilia, Burkholderia cepacia complex, Escherichia coli and Klebsiellia spp. were evaluated by MIC, MBC, post-antibiotic effect (PAE), synergy, time–kill, a rat pneumonia model and spontaneous mutation frequency (SMF). Results FTI showed high activity against E. coli, H. influenzae, S. aureus and Klebsiella spp. For the S. aureus strains, 75% of which were methicillin resistant (MRSA), FTI had a lower MIC90 than tobramycin. For P. aeruginosa, FTI had a lower MIC90 than fosfomycin, but tobramycin was more active than either. Synergy studies showed no antagonism between fosfomycin and tobramycin, and 93% of the isolates demonstrated no interaction. FTI was rapidly bactericidal and exhibited concentration-dependent killing in time–kill studies. In the rat pneumonia model, FTI and tobramycin demonstrated bactericidal killing of P. aeruginosa; both were more active than fosfomycin alone. The SMF for S. aureus resistance to FTI was 2–4 log10 lower than that for tobramycin and 2–7 log10 lower than that for fosfomycin. For P. aeruginosa, the FTI SMF was 2–3 log10 lower than that for fosfomycin and 1–2 log10 lower than that for tobramycin. Conclusions FTI is a broad-spectrum antibiotic combination with high activity in vitro and in vivo. These data suggest FTI could be a potential treatment for respiratory infections caused by Gram-positive and Gram-negative aerobic bacteria.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>19679597</pmid><doi>10.1093/jac/dkp282</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Administration, Inhalation Animals Anti-Bacterial Agents - administration & dosage Anti-Bacterial Agents - pharmacology Anti-Bacterial Agents - therapeutic use Antibiotics Antibiotics. Antiinfectious agents. Antiparasitic agents Bacteria - drug effects Bacteria - isolation & purification Bacterial Infections - microbiology Biological and medical sciences Bronchiectasis - complications Burkholderia cepacia Colony Count, Microbial Comparative studies Cystic fibrosis Drug Combinations Drug Interactions Escherichia coli Fosfomycin - administration & dosage Fosfomycin - pharmacology Fosfomycin - therapeutic use Haemophilus influenzae Humans Klebsiella Lung - microbiology Male Medical sciences Microbial Sensitivity Tests Microbial Viability Original Research P. aeruginosa Pharmacology Pharmacology. Drug treatments Pneumology Pneumonia, Bacterial - drug therapy Pseudomonas aeruginosa Rats respiratory infections Respiratory system : syndromes and miscellaneous diseases Respiratory therapy S. aureus Staphylococcus aureus Stenotrophomonas maltophilia Tobramycin - administration & dosage Tobramycin - pharmacology Tobramycin - therapeutic use Treatment Outcome |
| title | Antibacterial activities of a fosfomycin/tobramycin combination: a novel inhaled antibiotic for bronchiectasis |
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