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Michael J Dowzicky - One of the best experts on this subject based on the ideXlab platform.
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global assessment of the activity of Tigecycline against multidrug resistant gram negative pathogens between 2004 and 2014 as part of the Tigecycline evaluation and surveillance trial
mSphere, 2017Co-Authors: Anna Giammanco, Cinzia Cala, Teresa Fasciana, Michael J DowzickyAbstract:ABSTRACT Multidrug-resistant (MDR) Gram-negative organisms are a burden on the global health care system. The Tigecycline Evaluation and Surveillance Trial (TEST) is an ongoing global study designed to monitor the in vitro activities of Tigecycline and a panel of marketed antimicrobials against a range of clinically significant pathogens. In this study, in vitro data are presented for MDR Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter aerogenes, and Enterobacter cloacae isolates collected from 2004 to 2014. In total, 13% (21,967/170,759) of isolates displayed multidrug resistance globally, with the highest rates recorded among A. baumannii (overall rate, 44% [8,294/18,741], increasing from 23% [309/1,323] in 2004 to 63% [447/712] in 2014). Other multidrug resistance rates ranged from 2.5% for K. oxytoca (203/8,000) to 12% for P. aeruginosa and K. pneumoniae (3,951/32,786 and 3,895/32,888, respectively), and rates among these pathogens remained stable during the study period. Against MDR E. coli, Klebsiella spp., and E. aerogenes, the lowest rates of resistance were to Tigecycline (0.2%, 6%, and 12%, respectively), and the lowest MIC90 value against A. baumannii was observed for Tigecycline (2 mg/liter; MIC range, ≤0.008 to ≥32 mg/liter). The only significant change in resistance to Tigecycline during the study period was for MDR E. coli (P IMPORTANCE Multidrug resistance among bacterial pathogens is an ongoing global problem and renders antimicrobial agents ineffective at treating bacterial infections. In the health care setting, infections caused by multidrug-resistant (MDR) Gram-negative bacteria can cause increased mortality, longer hospital stays, and higher treatments costs. The aim of the Tigecycline Evaluation and Surveillance Trial (TEST) is to assess the in vitro antimicrobial activities of Tigecycline and other contemporary agents against clinically relevant pathogens. This paper presents antimicrobial activity data from the TEST study between 2004 and 2014 and examines global rates of MDR Gram-negative isolates, including Acinetobacter baumannii, Pseudomonas aeruginosa, and members of the Enterobacteriaceae, during this time. Our results show that Tigecycline retained in vitro activity against many MDR Gram-negative pathogens over the study period, while rates of MDR A. baumannii increased globally. Using these findings, we hope to highlight the current status of multidrug resistance in medical facilities worldwide.
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Antimicrobial susceptibility among Gram-positive and Gram-negative organisms collected from the Latin American region between 2004 and 2015 as part of the Tigecycline Evaluation and Surveillance Trial
BMC, 2017Co-Authors: Silvio Vega, Michael J DowzickyAbstract:Abstract Background The in vitro activity of Tigecycline and comparator agents was evaluated against Gram-positive and Gram-negative isolates collected in Latin American centers between 2004 and 2015 as part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) global surveillance study. Methods Minimum inhibitory concentrations (MICs) were determined using the broth microdilution methodology according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Antimicrobial susceptibility was determined using CLSI breakpoints, except for Tigecycline for which the US Food and Drugs Administration breakpoints were used. Results A total of 48.3% (2202/4563) of Staphylococcus aureus isolates were methicillin-resistant S. aureus (MRSA). All MRSA isolates were susceptible to linezolid and vancomycin, and 99.9% (2199/2202) were susceptible to Tigecycline. Among Streptococcus pneumoniae isolates, 13.8% (198/1436) were penicillin-resistant; all were susceptible to linezolid and vancomycin, and 98.0% (194/198) were susceptible to Tigecycline. Susceptibility was >99.0% for linezolid and Tigecycline against Enterococcus faecium and Enterococcus faecalis isolates. A total of 40.8% (235/576) E. faecium and 1.6% (33/2004) E. faecalis isolates were vancomycin-resistant. Among the Enterobacteriaceae, 36.3% (1465/4032) of Klebsiella pneumoniae isolates, 16.4% (67/409) of Klebsiella oxytoca isolates and 25.4% (1246/4912) of Escherichia coli isolates were extended-spectrum β-lactamase (ESBL) producers. Of the ESBL-producing K. pneumoniae and E. coli isolates, susceptibility was highest to Tigecycline [93.4% (1369/1465) and 99.8% (1244/1246), respectively] and meropenem [86.9% (1103/1270) and 97.0% (1070/1103), respectively]. A total of 26.7% (966/3613) of Pseudomonas aeruginosa isolates were multidrug-resistant (MDR). Among all P. aeruginosa isolates, susceptibility was highest to amikacin [72.8% (2632/3613)]. A total of 70.3% (1654/2354) of Acinetobacter baumannii isolates were MDR, and susceptibility was highest to minocycline [88.3% (2079/2354) for all isolates, 86.2% (1426/1654) for MDR isolates]. Tigecycline had the lowest MIC90 (2 mg/L) among A. baumannii isolates, including MDR isolates. Conclusions This study of isolates from Latin America shows that linezolid, vancomycin and Tigecycline continue to be active in vitro against important Gram-positive organisms such as MRSA, and that susceptibility rates to meropenem and Tigecycline against members of the Enterobacteriaceae, including ESBL-producers, were high. However, we report that Latin America has high rates of MRSA, MDR A. baumannii and ESBL-producing Enterobacteriaceae which require continued monitoring
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global in vitro activity of Tigecycline and comparator agents Tigecycline evaluation and surveillance trial 2004 2013
Annals of Clinical Microbiology and Antimicrobials, 2015Co-Authors: Daryl J Hoban, S Bouchillon, Ralf Rene Reinert, Michael J DowzickyAbstract:The Tigecycline Evaluation and Surveillance Trial (TEST) is a global antimicrobial susceptibility surveillance study which has been ongoing since 2004. This report examines the in vitro activity of Tigecycline and comparators against clinically important pathogens collected globally between 2004 and 2013. Antimicrobial susceptibility was determined using guidelines published by the Clinical and Laboratory Standards Institute. The Cochran Armitage Trend Test was used to identify statistically significant changes in susceptibility between 2004 and 2013. Among the Enterobacteriaceae susceptibility was highest to the carbapenems [imipenem 97.1% (24,655/25,381), meropenem 97.0% (90,714/93,518)], Tigecycline (97.0%, 115,361/118,899) and amikacin (96.9%, 115,200/118,899). Against Acinetobacter baumannii the highest rates of susceptibility were for minocycline (84.5%, 14,178/16,778) and imipenem (80.0%, 3,037/3,795). The MIC90 for Tigecycline was 2 mg/L. 40% (6,743/16,778) of A. baumannii isolates were multidrug-resistant. Enterococci were highly susceptible to Tigecycline and linezolid (>99%); vancomycin resistance was observed among 2% of Enterococcus faecalis (325/14,615) and 35% of Enterococcus faecium (2,136/6,167) globally. 40% (14,647/36,448) of Staphylococcus aureus were methicillin-resistant while 15% (2,152/14,562) of Streptococcus pneumoniae were penicillin-resistant. Against S. aureus and S. pneumoniae susceptibility to linezolid, vancomycin, and Tigecycline was ≥99.9%. Globally, 81% (331/410) of statistically significant susceptibility changes during the study period were decreases in susceptibility. Amikacin, the carbapenems, and Tigecycline were active against most gram-negative pathogens while linezolid, Tigecycline, and vancomycin retained activity against most gram-positive pathogens collected in TEST during 2004–2013.
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in vitro activity of Tigecycline and comparators against gram positive and gram negative isolates collected from the middle east and africa between 2004 and 2011
International Journal of Antimicrobial Agents, 2014Co-Authors: Souha S Kanj, Andrew Whitelaw, Michael J DowzickyAbstract:Abstract The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) was established in 2004 to monitor longitudinal changes in bacterial susceptibility to numerous antimicrobial agents, specifically Tigecycline. In this study, susceptibility among Gram-positive and Gram-negative isolates between 2004 and 2011 from the Middle East and Africa was examined. Antimicrobial susceptibilities were determined using Clinical and Laboratory Standards Institute (CLSI) interpretive criteria, and minimum inhibitory concentrations (MICs) were determined by broth microdilution methods. US Food and Drug Administration (FDA)-approved breakpoints were used for Tigecycline. In total, 2967 Gram-positive and 6322 Gram-negative isolates were examined from 33 participating centres. All Staphylococcus aureus isolates, including meticillin-resistant S. aureus , were susceptible to Tigecycline, linezolid and vancomycin. Vancomycin, linezolid, Tigecycline and levofloxacin were highly active (>97.6% susceptibility) against Streptococcus pneumoniae , including penicillin-non-susceptible strains. All Enterococcus faecium isolates were susceptible to Tigecycline and linezolid, including 32 vancomycin-resistant isolates. Extended-spectrum β-lactamases were produced by 16.6% of Escherichia coli and 32.9% of Klebsiella pneumoniae . More than 95% of E. coli and Enterobacter spp. were susceptible to amikacin, Tigecycline, imipenem and meropenem. The most active agents against Pseudomonas aeruginosa and Acinetobacter baumannii were amikacin (88.0% susceptible) and minocycline (64.2% susceptible), respectively; the MIC 90 (MIC required to inhibit 90% of the isolates) of Tigecycline against A. baumannii was low at 2 mg/L. Tigecycline and carbapenem agents were highly active against most Gram-negative pathogens. Tigecycline, linezolid and vancomycin showed good activity against most Gram-positive pathogens from the Middle East and Africa.
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in vitro activity of Tigecycline and comparator agents against a global collection of gram negative and gram positive organisms Tigecycline evaluation and surveillance trial 2004 to 2007
Diagnostic Microbiology and Infectious Disease, 2009Co-Authors: Mark W Garrison, Reinier Mutters, Michael J DowzickyAbstract:The Tigecycline Evaluation and Surveillance Trial began in 2004 to monitor the in vitro activity of Tigecycline and comparator agents against a global collection of Gram-negative and Gram-positive pathogens. Against Gram negatives (n = 63 699), Tigecycline MIC(90)'s ranged from 0.25 to 2 mg/L for Escherichia coli, Haemophilus influenzae, Acinetobacter baumannii, Klebsiella oxytoca, Enterobacter cloacae, Klebsiella pneumoniae, and Serratia marcescens (but was > or =32 for Pseudomonas aeruginosa). Against Gram-positive organisms (n = 32 218), Tigecycline MIC(90)'s were between 0.06 and 0.25 mg/L for Streptococcus pneumoniae, Enterococcus faecium, Streptococcus agalactiae, Staphylococcus aureus, and Enterococcus faecalis. The in vitro activity of Tigecycline was maintained against resistant phenotypes, including multidrug-resistant A. baumannii (9.2% of isolates), extended-spectrum beta-lactamase-producing E. coli (7.0%) and K. pneumoniae (14.0%), beta-lactamase-producing H. influenzae (22.2%), methicillin-resistant S. aureus (44.5%), vancomycin-resistant E. faecium (45.9%) and E. faecalis (2.8%), and penicillin-resistant S. pneumoniae (13.8%). Tigecycline represents a welcome addition to the armamentarium against difficult to treat organisms.
Patricia A Bradford - One of the best experts on this subject based on the ideXlab platform.
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rama a transcriptional regulator and acrab an rnd type efflux pump are associated with decreased susceptibility to Tigecycline in enterobacter cloacae
Microbial Drug Resistance, 2007Co-Authors: David Keeney, Alexey Ruzin, Patricia A BradfordAbstract:Tigecycline, a novel broad-spectrum glycylcycline antibiotic, is active against many gram-positive and gram-negative bacterial pathogens including most strains of Enterobacter cloacae. Recently, however, a few clinical strains of E. cloacae with decreased susceptibility to Tigecycline were isolated. In this study, two Tigecycline-susceptible mutants of E. cloacae, GC7696 and GC7697, were obtained by transposon mutagenesis of a Tigecycline-resistant clinical isolate G946. Transposon insertions were mapped to either the acrA or acrB genes. Restoration of the original resistant phenotype occurred when GC7696 and GC7697 were transcomplemented with a plasmid harboring the intact acrAB region amplified from G946. Northern blot analysis of G946 and several other E. cloacae clinical strains that exhibited decreased susceptibility to Tigecycline, revealed increased levels of the acrAB transcript. In addition, overexpression of acrAB correlated with increased expression of the ramA gene, whereas the expression of a...
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in vitro activity of Tigecycline against isolates from patients enrolled in phase 3 clinical trials of treatment for complicated skin and skin structure infections and complicated intra abdominal infections
Clinical Infectious Diseases, 2005Co-Authors: Patricia A Bradford, Tasha Weaver D Sands, Peter J. PetersenAbstract:The in vitro activity of Tigecycline was evaluated against 4913 baseline pathogens isolated from 1986 patients enrolled in 4 pivotal phase 3 clinical trials. The trials, which were conducted in 38 countries worldwide, involved patients with complicated skin and skin-structure infections or complicated intra-abdominal infections. Tigecycline was active against the most prevalent pathogens for each infection type, including gram-positive and gram-negative strains of both aerobic and anaerobic bacteria (MICs, ≤2 μg/mL for most pathogens). The spectrum of activity of Tigecycline included important pathogens, such as Staphylococcus aureus (including methicillin-resistant S. aureus), Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, and Bacteroides fragilis. A few genera, such as Pseudomonas aeruginosa and members of the tribe Proteeae, were generally less susceptible to Tigecycline than were other gram-negative pathogens. The susceptibility of the pathogens to Tigecycline was similar for isolates obtained from patients enrolled in the studies of complicated skin and skin-structure infection or of complicated intra-abdominal infection. For most pathogens, the susceptibility to Tigecycline was similar across all geographic regions. The excellent expanded broad-spectrum activity of Tigecycline demonstrated in vitro against clinical isolates confirmed its potential utility for pathogens associated with complicated skin and skin-structure infections or complicated intra-abdominal infections.
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Tigecycline mic testing by broth dilution requires use of fresh medium or addition of the biocatalytic oxygen reducing reagent oxyrase to standardize the test method
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Patricia A Bradford, Peter Petersen, Mairead Young, Hal C Jones, Mark Tischler, John OconnellAbstract:Tigecycline is a broad-spectrum glycylcycline antibiotic with activity against not only susceptible gram-positive and gram-negative pathogens but also strains that are resistant to many other antibiotics. In the process of determining quality control (QC) limits for the American Type Culture Collection reference strains for Tigecycline, a number of inconsistencies in MICs were encountered which appeared to be related to the age of the Mueller-Hinton broth (MHB) medium used in the MIC testing. The objective of this study was to determine the cause of the discrepant MIC results between fresh and aged MHB. The MICs of Tigecycline were determined in MHB that was either prepared fresh ( 3 log 10 difference in viable growth when Tigecycline was tested in fresh or Oxyrase-supplemented MHB compared to aged MHB. High-pressure liquid chromatography analysis revealed the accumulation of an early peak (oxidative by-product of Tigecycline) to be 3.5% in fresh media and 25.1% in aged media after 24 h and that addition of Oxyrase prevented the accumulation of this oxidized by-product. These results suggested that the activity of Tigecycline was affected by the amount of dissolved oxygen in the media. The use of fresh MHB or supplementation with Oxyrase resulted in a more standardized test method for performing MIC tests with Tigecycline.
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a novel mate family efflux pump contributes to the reduced susceptibility of laboratory derived staphylococcus aureus mutants to Tigecycline
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Fionnuala Mcaleese, Peter J. Petersen, Alexey Ruzin, Ellen Murphy, Steven J Projan, Paul M Dunman, Patricia A BradfordAbstract:Tigecycline, an expanded-broad-spectrum glycylcycline antibiotic is not affected by the classical tetracycline resistance determinants found in Staphylococcus aureus. The in vitro selection of mutants with reduced susceptibility to Tigecycline was evaluated for two methicillin-resistant S. aureus strains by serial passage in increasing concentrations of Tigecycline. Both strains showed a stepwise elevation in Tigecycline MIC over a period of 16 days, resulting in an increase in Tigecycline MIC of 16- and 32-fold for N315 and Mu3, respectively. Transcriptional profiling revealed that both mutants exhibited over 100-fold increased expression of a gene cluster, mepRAB (multidrug export protein), encoding a MarR-like transcriptional regulator (mepR), a novel MATE family efflux pump (mepA), and a hypothetical protein of unknown function (mepB). Sequencing of the mepR gene in the mutant strains identified changes that presumably inactivated the MepR protein, which suggested that MepR functions as a repressor of mepA. Overexpression of mepA in a wild-type background caused a decrease in susceptibility to Tigecycline and other substrates for MATE-type efflux pumps, although it was not sufficient to confer high-level resistance to Tigecycline. Complementation of the mepR defect by overexpressing a wild-type mepR gene reduced mepA transcription and lowered the Tigecycline MIC in the mutants. Transcription of tet(M) also increased by over 40-fold in the Mu3 mutant. This was attributed to a deletion in the promoter region of the gene that removed a stem-loop responsible for transcriptional attenuation. However, overexpression of the tet(M) transcript in a Tigecycline-susceptible strain was not enough to significantly increase the MIC of Tigecycline. These results suggest that the overexpression of mepA but not tet(M) may contribute to decreased susceptibility of Tigecycline in S. aureus.
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influence of transcriptional activator rama on expression of multidrug efflux pump acrab and Tigecycline susceptibility in klebsiella pneumoniae
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Alexey Ruzin, David Keeney, Melissa A Visalli, Patricia A BradfordAbstract:Tigecycline is an expanded broad-spectrum antibacterial agent that is active against many clinically relevant species of bacterial pathogens, including Klebsiella pneumoniae. The majority of K. pneumoniae isolates are fully susceptible to Tigecycline; however, a few strains that have decreased susceptibility have been isolated. One isolate, G340 (for which the Tigecycline MIC is 4 g/ml and which displays a multidrug resistance [MDR] phenotype), was selected for analysis of the mechanism for this decreased susceptibility by use of transposon mutagenesis with IS903kan. A Tigecycline-susceptible mutant of G340, GC7535, was obtained (Tigecycline MIC, 0.25 g/ml). Analysis of the transposon insertion mapped it to ramA, a gene that was previously identified to be involved in MDR in K. pneumoniae. For GC7535, the disruption of ramA led to a 16-fold decrease in the MIC of Tigecycline and also a suppression of MDR. Trans-complementation with plasmid-borne ramA restored the original parental phenotype of decreased susceptibility to Tigecycline. Northern blot analysis revealed a constitutive overexpression of ramA that correlated with an increased expression of the AcrAB transporter in G340 compared to that in Tigecycline-susceptible strains. Laboratory mutants of K. pneumoniae with decreased susceptibility to Tigecycline could be selected at a frequency of approximately 4 10 8 . These results suggest that ramA is associated with decreased Tigecycline susceptibility in K. pneumoniae due to its role in the expression of the AcrAB multidrug efflux pump. Tigecycline is an expanded broad-spectrum antibiotic representing a new class called the glycylcyclines. The glycylcyclines are semisynthetic derivatives of minocycline and have activity against many bacterial pathogens (2, 14, 15). It has been noted that a few species of gram-negative bacteria, including Pseudomonas aeruginosa, Proteus spp., Providencia spp., and Morganella morganii, are intrinsically less susceptible to Tigecycline. Previous studies revealed the involvement of multidrug efflux systems such as MexXY and AcrAB in the decreased Tigecycline susceptibility of P. aeruginosa and Proteus mirabilis, respectively (3, 22). These pumps belong to the resistance-nodulation-division (RND) family that combines bacterial transporters with a tripartite architecture and broad substrate specificity (9, 12). Due to the broad substrate specificity of RND pumps, their overexpression usually results in the multidrug resistance (MDR) phenotype. Klebsiella pneumoniae causes infections of wounds, the urinary tract, and the respiratory system. This bacterial species is generally susceptible to Tigecycline; however, a few clinical strains with decreased Tigecycline susceptibility have been isolated. In this study, one such an isolate, G340, was investigated to determine the mechanism of decreased Tigecycline susceptibility in K. pneumoniae. (These results were reported, in part, previously [M. A.
Daryl J Hoban - One of the best experts on this subject based on the ideXlab platform.
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global in vitro activity of Tigecycline and comparator agents Tigecycline evaluation and surveillance trial 2004 2013
Annals of Clinical Microbiology and Antimicrobials, 2015Co-Authors: Daryl J Hoban, S Bouchillon, Ralf Rene Reinert, Michael J DowzickyAbstract:The Tigecycline Evaluation and Surveillance Trial (TEST) is a global antimicrobial susceptibility surveillance study which has been ongoing since 2004. This report examines the in vitro activity of Tigecycline and comparators against clinically important pathogens collected globally between 2004 and 2013. Antimicrobial susceptibility was determined using guidelines published by the Clinical and Laboratory Standards Institute. The Cochran Armitage Trend Test was used to identify statistically significant changes in susceptibility between 2004 and 2013. Among the Enterobacteriaceae susceptibility was highest to the carbapenems [imipenem 97.1% (24,655/25,381), meropenem 97.0% (90,714/93,518)], Tigecycline (97.0%, 115,361/118,899) and amikacin (96.9%, 115,200/118,899). Against Acinetobacter baumannii the highest rates of susceptibility were for minocycline (84.5%, 14,178/16,778) and imipenem (80.0%, 3,037/3,795). The MIC90 for Tigecycline was 2 mg/L. 40% (6,743/16,778) of A. baumannii isolates were multidrug-resistant. Enterococci were highly susceptible to Tigecycline and linezolid (>99%); vancomycin resistance was observed among 2% of Enterococcus faecalis (325/14,615) and 35% of Enterococcus faecium (2,136/6,167) globally. 40% (14,647/36,448) of Staphylococcus aureus were methicillin-resistant while 15% (2,152/14,562) of Streptococcus pneumoniae were penicillin-resistant. Against S. aureus and S. pneumoniae susceptibility to linezolid, vancomycin, and Tigecycline was ≥99.9%. Globally, 81% (331/410) of statistically significant susceptibility changes during the study period were decreases in susceptibility. Amikacin, the carbapenems, and Tigecycline were active against most gram-negative pathogens while linezolid, Tigecycline, and vancomycin retained activity against most gram-positive pathogens collected in TEST during 2004–2013.
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in vitro activity of Tigecycline against 6792 gram negative and gram positive clinical isolates from the global Tigecycline evaluation and surveillance trial test program 2004
Diagnostic Microbiology and Infectious Disease, 2005Co-Authors: Daryl J Hoban, S Bouchillon, B Johnson, J Johnson, Michael J DowzickyAbstract:Tigecycline, a new glycylcycline antibiotic, has shown promising in vitro activity against many common pathogens, including multidrugresistant strains. To determine the activity of Tigecycline against a broad range of pathogens from diverse populations and geographic areas, the Tigecycline Evaluation and Surveillance Trial (TEST Program) commenced in 2003. This study evaluated the activity of Tigecycline and commonly used antimicrobials against 6792 clinical isolates from 40 study centers in 11 countries. Tigecycline was the most active agent tested against Gram-positive facultative species including multidrug-resistant strains. MIC90 results (Ag/mL) for Tigecycline against Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus agalactiae, and Streptococcus pneumoniae were 0.12, 0.12, 0.25, and 0.25 Ag/mL, respectively. Tigecycline was active against Enterobacteriaceae with an MIC90 of 1 Ag/mL. Haemophilus influenzae was very susceptible to Tigecycline with an MIC90 of only 0.25 Ag/mL. Pseudomonas aeruginosa was the least susceptible organism tested against Tigecycline. Tigecycline appears to be a promising new glycylcycline agent for the treatment of many types of
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in vitro activity of Tigecycline against 6792 gram negative and gram positive clinical isolates from the global Tigecycline evaluation and surveillance trial test program 2004
Diagnostic Microbiology and Infectious Disease, 2005Co-Authors: Daryl J Hoban, S Bouchillon, B Johnson, J Johnson, Michael J DowzickyAbstract:Tigecycline, a new glycylcycline antibiotic, has shown promising in vitro activity against many common pathogens, including multidrug-resistant strains. To determine the activity of Tigecycline against a broad range of pathogens from diverse populations and geographic areas, the Tigecycline Evaluation and Surveillance Trial (TEST Program) commenced in 2003. This study evaluated the activity of Tigecycline and commonly used antimicrobials against 6792 clinical isolates from 40 study centers in 11 countries. Tigecycline was the most active agent tested against Gram-positive facultative species including multidrug-resistant strains. MIC90 results (microg/mL) for Tigecycline against Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus agalactiae, and Streptococcus pneumoniae were 0.12, 0.12, 0.25, and 0.25 microg/mL, respectively. Tigecycline was active against Enterobacteriaceae with an MIC90 of 1 microg/mL. Haemophilus influenzae was very susceptible to Tigecycline with an MIC90 of only 0.25 microg/mL. Pseudomonas aeruginosa was the least susceptible organism tested against Tigecycline. Tigecycline appears to be a promising new glycylcycline agent for the treatment of many types of pathogens with varying resistance phenotypes.
Gilbert M Rose - One of the best experts on this subject based on the ideXlab platform.
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the efficacy and safety of Tigecycline in the treatment of skin and skin structure infections results of 2 double blind phase 3 comparison studies with vancomycin aztreonam
Clinical Infectious Diseases, 2005Co-Authors: Evelyn J Ellisgrosse, Nathalie Dartois, Timothy Babinchak, Gilbert M RoseAbstract:Two phase 3, double-blind studies in hospitalized adults with complicated skin and skin-structure infections (cSSSI) determined the safety and efficacy of Tigecycline versus that of vancomycin-aztreonam. Patients received Tigecycline (100 mg, followed by 50 mg intravenously twice daily) or vancomycin (1 g intravenously twice daily) plus aztreonam (2 g intravenously twice daily) for up to 14 days. Populations were as follows: 1116 patients (566 treated with Tigecycline, and 550 treated with vancomycin-aztreonam) constituted the modified intent-to-treat (mITT) population, 1057 patients (538 treated with Tigecycline, and 519 treated with vancomycin-aztreonam) constituted the clinical mITT (c-mITT) population, and 833 patients (422 treated with Tigecycline, and 411 treated with vancomycin-aztreonam) constituted the clinically evaluable population. Clinical responses to Tigecycline and vancomycin-aztreonam at test-of-cure were similar: c-mITT, 79.7% (95% confidence interval [CI], 76.1%-83.1%) versus 81.9% (95% CI, 78.3%-85.1%) (P = .4183); and clinically evaluable, 86.5% (95% CI, 82.9%-89.6%) versus 88.6% (95% CI, 85.1%-91.5%) (P = .4233). Adverse events were similar, with increased nausea and vomiting in the Tigecycline group and increased rash and elevated hepatic aminotransferase levels in the vancomycin-aztreonam group. Tigecycline monotherapy is as safe and efficacious as the vancomycin-aztreonam combination in treating patients with cSSSI.
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the efficacy and safety of Tigecycline for the treatment of complicated intra abdominal infections analysis of pooled clinical trial data
Clinical Infectious Diseases, 2005Co-Authors: Timothy Babinchak, Nathalie Dartois, Evelyn J Ellisgrosse, Gilbert M Rose, Evan LohAbstract:This pooled analysis includes 2 phase 3, double-blind trials designed to evaluate the safety and efficacy of Tigecycline, versus that of imipenem-cilastatin, in 1642 adults with complicated intra-abdominal infections. Patients were randomized to receive either Tigecycline (initial dose of 100 mg, followed by 50 mg intravenously every 12 h) or imipenem-cilastatin (500/500 mg intravenously every 6 h) for 5‐14 days. The primary end point was the clinical response at the test-of-cure visit (12‐42 days after therapy) in the co-primary end point microbiologically evaluable and microbiological modified intent-to-treat populations. For the microbiologically evaluable group, clinical cure rates were 86.1% (441/512) for Tigecycline, versus 86.2% (442/513) for imipenemcilastatin (95% confidence interval for the difference, 4.5% to 4.4%; for noninferiority). Clinical P ! .0001 cure rates in the microbiological modified intent-to-treat population were 80.2% (506/631) for Tigecycline, versus 81.5% (514/631) for imipenem-cilastatin (95% confidence interval for the difference, 5.8% to 3.2%; for noninferiority). Nausea (24.4% Tigecycline, 19.0% imipenem-cilastatin [ ]), vomiting P ! .0001 P p .01 (19.2% Tigecycline, 14.3% imipenem-cilastatin [ ]), and diarrhea (13.8% Tigecycline, 13.2% imipenem
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efficacy and safety of Tigecycline monotherapy compared with vancomycin plus aztreonam in patients with complicated skin and skin structure infections results from a phase 3 randomized double blind trial
International Journal of Infectious Diseases, 2005Co-Authors: Sarvajna Sacchidanand, Evan Loh, Evelyn Ellisgrosse, Robert L Penn, John M Embil, Maria E Campos, Daniel Curcio, Gilbert M RoseAbstract:Summary Objectives: To compare the effect of Tigecycline monotherapy, a first-in-class, expanded broad spectrum glycylcycline, with the combination of vancomycin and aztreonam (V + A) in the treatment of complicated skin and skin structure infections (cSSSI). Methods: A phase 3, double-blind study conducted in 8 countries enrolled adults with cSSSI who required intravenous (IV) antibiotic therapy for ≥5 days. Patients were randomly assigned (1:1) to receive either Tigecycline or V + A for up to 14 days. Primary endpoint was the clinical cure rate at the test-of-cure visit. Secondary endpoints included microbiologic efficacy and in vitro susceptibility to Tigecycline of bacteria that cause cSSSI. Safety was assessed by physical examination, laboratory analyses, and adverse event reporting. Results: A total of 596 patients were screened for enrollment, 573 were analyzed for safety, 537 were included in the clinical modified intent-to-treat (c-mITT) population, 397 were clinically evaluable (CE), and 228 were microbiologically evaluable (ME). At test-of-cure, cure rates were similar between Tigecycline and V + A groups in the CE population (82.9% versus 82.3%, respectively) and in the c-mITT population (75.5% versus 76.9%, respectively). Microbiologic eradication rates (subject level) at test-of-cure in the ME population were also similar between Tigecycline and V + A. Frequency of adverse events was similar between groups, although patients receiving Tigecycline had higher incidence of nausea, vomiting, dyspepsia, and anorexia, while increased ALT/SGPT, pruritis, and rash occurred significantly more often in V + A-treated patients. Conclusions: This study demonstrates that the efficacy of Tigecycline monotherapy for the treatment of patients with cSSSI is statistically noninferior to the combination of V + A.
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efficacy and safety of Tigecycline monotherapy compared with vancomycin plus aztreonam in patients with complicated skin and skin structure infections results from a phase 3 randomized double blind trial
International Journal of Infectious Diseases, 2005Co-Authors: Sarvajna Sacchidanand, Evelyn Ellisgrosse, Robert L Penn, John M Embil, Maria E Campos, Daniel Curcio, Gilbert M RoseAbstract:Summary Objectives: To compare the effect of Tigecycline monotherapy, a first-in-class, expanded broad spectrum glycylcycline, with the combination of vancomycin and aztreonam (V + A) in the treatment of complicated skin and skin structure infections (cSSSI). Methods: A phase 3, double-blind study conducted in 8 countries enrolled adults with cSSSI who required intravenous (IV) antibiotic therapy for ≥5 days. Patients were randomly assigned (1:1) to receive either Tigecycline or V + A for up to 14 days. Primary endpoint was the clinical cure rate at the test-of-cure visit. Secondary endpoints included microbiologic efficacy and in vitro susceptibility to Tigecycline of bacteria that cause cSSSI. Safety was assessed by physical examination, laboratory analyses, and adverse event reporting. Results: A total of 596 patients were screened for enrollment, 573 were analyzed for safety, 537 were included in the clinical modified intent-to-treat (c-mITT) population, 397 were clinically evaluable (CE), and 228 were microbiologically evaluable (ME). At test-of-cure, cure rates were similar between Tigecycline and V + A groups in the CE population (82.9% versus 82.3%, respectively) and in the c-mITT population (75.5% versus 76.9%, respectively). Microbiologic eradication rates (subject level) at test-of-cure in the ME population were also similar between Tigecycline and V + A. Frequency of adverse events was similar between groups, although patients receiving Tigecycline had higher incidence of nausea, vomiting, dyspepsia, and anorexia, while increased ALT/SGPT, pruritis, and rash occurred significantly more often in V + A-treated patients. Conclusions: This study demonstrates that the efficacy of Tigecycline monotherapy for the treatment of patients with cSSSI is statistically noninferior to the combination of V + A.
Joan M Korthbradley - One of the best experts on this subject based on the ideXlab platform.
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randomized phase 2 trial to evaluate the clinical efficacy of two high dosage Tigecycline regimens versus imipenem cilastatin for treatment of hospital acquired pneumonia
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Julio A Ramirez, Joan M Korthbradley, Nathalie Dartois, Hassan Gandjini, Paul C. McgovernAbstract:ABSTRACT In a previous phase 3 study, the cure rates that occurred in patients with hospital-acquired pneumonia treated with Tigecycline at the approved dose were lower than those seen with patients treated with imipenem and cilastatin (imipenem/cilastatin). We hypothesized that a higher dose of Tigecycline is necessary in patients with hospital-acquired pneumonia. This phase 2 study compared the safety and efficacy of two higher doses of Tigecycline with imipenem/cilastatin in subjects with hospital-acquired pneumonia. Subjects with hospital-acquired pneumonia were randomized to receive one of two doses of Tigecycline (150 mg followed by 75 mg every 12 h or 200 mg followed by 100 mg every 12 h) or 1 g of imipenem/cilastatin every 8 h. Empirical adjunctive therapy was administered for initial coverage of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa infection, depending on the randomization regimen. Clinical response, defined as cure, failure of treatment, or indeterminate outcome, was assessed 10 to 21 days after the last day of therapy. In the clinically evaluable population, clinical cure with Tigecycline 100 mg (17/20, 85.0%) was numerically higher than with Tigecycline 75 mg (16/23, 69.6%) and imipenem/cilastatin (18/24, 75.0%). No new safety signals with the high-dose Tigecycline were identified. A numerically higher clinical response was observed with the 100-mg dose of Tigecycline. This supports our hypothesis that a higher area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) may be necessary to achieve clinical cure in patients with hospital-acquired pneumonia. Further studies are necessary. (The ClinicalTrials.gov identifier for this clinical trial is NCT00707239.)
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Tigecycline population pharmacokinetics in patients with community or hospital acquired pneumonia
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Christopher M Rubino, Gary Dukart, Angel Cooper, Joan M Korthbradley, Alan Forrest, Sujata M Bhavnani, Paul G AmbroseAbstract:Tigecycline is a new-generation of tetracycline (glycylcyclines) and is active in vitro against bacteria that possess any of the classical genes that confer tetracycline resistance through ribosomal protection or efflux pumps. Herein, Tigecycline disposition in patients with community- or hospital-acquired pneumonia was described using a population pharmacokinetic model. Additionally, the influence of covariates, such as body surface area, severity of illness, and clinical laboratory measures, on Tigecycline disposition was evaluated. An intravenous loading dose of 100 mg was followed by 50 mg of Tigecycline every 12 h. The final population pharmacokinetic model was a two-compartment model with linear elimination and with a relationship between Tigecycline clearance and body surface area and creatinine clearance. The model was parameterized using total clearance (CL), the volume of the central compartment, distributional clearance from the central to the peripheral compartment, and volumes of distribution at steady state. Relationships between body surface area and creatinine clearance were identified as significant predictors of interindividual variability on CL. This model will serve as the basis for estimating Tigecycline exposure for pharmacokinetic-pharmacodynamic analyses for efficacy and safety among patients with community- or hospital-acquired pneumonia.
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comparison of Tigecycline with imipenem cilastatin for the treatment of hospital acquired pneumonia
Diagnostic Microbiology and Infectious Disease, 2010Co-Authors: Antonio T Freire, Gary Dukart, Vasyl Melnyk, Oleksiy Datsenko, Oleksandr Dzyublik, Felix Glumcher, Robert Maroko, Angel C Cooper, Yinching Chuang, Joan M KorthbradleyAbstract:To compare efficacy and safety of a Tigecycline regimen with an imipenem/cilastatin regimen in hospital-acquired pneumonia patients, a phase 3, multicenter, randomized, double-blind, study evaluated 945 patients. Coprimary end points were clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure. Cure rates were 67.9% for Tigecycline and 78.2% for imipenem (CE patients) and 62.7% and 67.6% (c-mITT patients), respectively. A statistical interaction occurred between ventilator-associated pneumonia (VAP) and non-VAP subgroups, with significantly lower cure rates in Tigecycline VAP patients compared to imipenem; in non-VAP patients, Tigecycline was noninferior to imipenem. Overall mortality did not differ between the Tigecycline (14.1%) and imipenem regimens (12.2%), although more deaths occurred in VAP patients treated with Tigecycline than imipenem. Overall, the Tigecycline regimen was noninferior to the imipenem/cilastatin regimen for the c-mITT but not the CE population; this difference appears to have been driven by results in VAP patients.
