Michael J. Dowzicky

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)

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.

Antimicrobial Susceptibility Among Gram-Negative Isolates Collected From Intensive Care Units in North America, Europe, the Asia-Pacific Rim, Latin America, the Middle East, and Africa Between 2004 and 2009 as Part of the Tigecycline Evaluation and Surveillance Trial

BACKGROUND The Tigecycline Evaluation and Surveillance Trial is an antimicrobial susceptibility surveillance program that collects gram-positive and gram-negative organisms globally. OBJECTIVE This analysis reports on antimicrobial susceptibility among 23,918 gram-negative isolates collected from intensive care units globally between 2004 and 2009. METHODS MICs and susceptibility were determined according to the guidelines of the Clinical and Laboratory Standards Institute (US Food and Drug Administration breakpoints were applied against tigecycline). RESULTS Gram-negative isolates were collected from 6 geographical regions: North America, 8099 isolates; Europe, 9244; Asia-Pacific Rim, 1573; Latin America, 3996; the Middle East, 635; and Africa, 371. North America reported the lowest rates of extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae and Escherichia coli both overall (12.8% and 4.7%, respectively) and in each year of collection. High rates of ESBL production were reported among K pneumoniae from Latin America (45.5%) and Africa (54.9%) and for E coli from the Middle East (32.4%). Imipenem and tigecycline maintained >90% susceptibility against K pneumoniae, E coli, Klebsiella oxytoca, Enterobacter cloacae, and Serratia marcescens for all regions. Susceptibility to meropenem was >90% against all K oxytoca and S marcescens. Large regional variations in susceptibility among Acinetobacter baumannii were reported, with the largest variations reported for amikacin (75.2% in North America, 21.8% in the Middle East) and meropenem (60.4% in North America, 15.9% in Africa). MIC(90) values for tigecycline against A baumannii were low (1-2 mg/L) for all regions. Against P aeruginosa, susceptibility to amikacin (97.5% in North America, 67.5% in Latin America) and meropenem (79.1% in North America, 51.4% in Africa) had the largest variations. CONCLUSIONS Antimicrobial resistance among gram-negative intensive care unit isolates was highly variable between geographic regions. The carbapenems were active in vitro against Enterobacteriaceae, A baumannii and P aeruginosa, and tigecycline continued to be active in vitro against members of the Enterobacteriaceae and A baumannii collected from intensive care units in North America, Europe, the Asia-Pacific Rim, Latin America, the Middle East, and Africa.

Rising incidence of Staphylococcus aureus with reduced susceptibility to vancomycin and susceptibility to antibiotics: a global analysis 2004–2009

During 2004-2009, 20004 isolates of Staphylococcus aureus were collected from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.). Of these isolates, 8249 (41.2%) were meticillin-resistant S. aureus (MRSA) and 11755 (58.8%) were meticillin-susceptible S. aureus (MSSA). A total of 4.0%, 5.3% and 3.0% of all S. aureus, MRSA and MSSA isolates, respectively, exhibited vancomycin minimum inhibitory concentrations (MICs) ≥ 2 μg/mL. Whilst no vancomycin-resistant S. aureus were encountered in this study and the majority of these isolates remained susceptible to vancomycin at the Clinical and Laboratory Standards (CLSI) breakpoint of 2 μg/mL, the total number of isolates with MICs creeping up to 2 μg/mL and above increased in all S. aureus from 4.0% in 2004 to 7.7% in 2009 (P < 0.001). Moreover, in MRSA this phenotype increased from 5.6% in 2004 to 11.1% in 2009 (P < 0.001). The increase was also notable for MSSA, which rose from 2.6% in 2004 to 5.6% in 2009 (P < 0.001). Of the 12 antibiotics tested, linezolid, minocycline, tigecycline and vancomycin were the most active agents by susceptibility against all S. aureus, all MRSA and all MSSA isolates. Against MRSA isolates with vancomycin MICs ≥ 2 μg/mL, susceptibility to vancomycin decreased from 100% in 2004 to 95.77% in 2009 (P > 0.05). Similarly, in MSSA isolates susceptibility to vancomycin decreased from 100% in 2004 to 91.07% in 2009 (P > 0.05). These data suggest that although the number of isolates of S. aureus with reduced susceptibility to vancomycin has increased significantly from 2004 to 2009, this upward creep of MICs has not yet impacted significantly on the overall susceptibility of vancomycin against either MRSA or MSSA.

Update on antimicrobial susceptibility rates among gram-negative and gram-positive organisms in the United States: Results from the Tigecycline Evaluation and Surveillance Trial (TEST) 2005 to 2007

BACKGROUND The Tigecycline Evaluation and Surveillance Trial (TTEST) is a global surveillance study initiated in 2004.Its goal is to assess the in vitro activity of the glycylcycline, tigecycline, and comparator antimicrobials. OBJECTIVE The aim of this study was to measure the in vitro activity of a panel of antimicrobial agents against gram-negative and gram-positive organisms collected in the United States in 2005, 2006, and 2007. METHODS Isolates were collected from 172 centers across the United States.In vitro activity was assessed using Clinical and Laboratory Standards Institute (CLSI) guidelines and CLSI or US Food and Drug Administration interpretive criteria. RESULTS Overall, data on 20,897 gram-negative and 8949 gram-positive isolates were collected. For the majority of organisms, percentage susceptibilities were unchanged over the 3 years of collection. One exception was Acinetobacter baumannii; rates of susceptibility to the majority of agents in the panel decreased by approximately 10% over the 3 years. Rates of resistant phenotypes were relatively unchanged with mean percentages over the 3 years of: 8.9% (337/3787) for extended beta-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae; 2.1% (17/801) for ESBL-producing Klebsiella oxytoca; 2.3% (111/4861) for ESBL-pproducing Escherichia coli; 56.2% (2564/4560) for methicillin-resistant Staphylococcus aureus; 5.1% (97/1903) for vancomycin-resistant Enterococcus faecalis; and 67.2% (487/725) for vancomycin-resistant Enterococcus faecium. The minimum inhibitory concentration required to inhibit the growth of 90% of organisms (MIC(90)) for tigecycline was stable over the 3 years and was < or = 22 mg/L against non-ESBL-producing K pneumoniae, K oxytoca, E coli, Enterobacter aerogenes, Enterobacter cloacae, Serratia marcescens, and A baumannii. Against methicillin susceptible and -resistant S aureus, E faecalis, E faecium, and Streptococcus agalactiae tigecycline MIC(90)s were < or = 0.25 mg/L. CONCLUSIONS This report of 3 years of data from the TEST study suggests stable susceptibility rates among gram-negative and gram-positive organisms, with the exception of decreased susceptibility rates for A baumannii. Tigecycline continued to have good activity against Enterobacteriaceae, A baumannii, S aureus, E faecalis, E faecium, and S agalactiae.

In Vitro Activity of Tigecycline against Gram-Positive and Gram-Negative Pathogens as Evaluated by Broth Microdilution and Etest

ABSTRACT The current surveillance establishes the activity profile of tigecycline against recent clinical U.S. isolates of target pathogens. Findings from a distributed surveillance that utilized Etest yielded a tigecycline activity profile that varied from that observed in a separate centralized broth microdilution (BMD) surveillance (D. C. Draghi et al., Poster D-0701, 46th Intersci. Conf. Antimicrob. Agents Chemother., San Francisco, CA). Differences were noted among Acinetobacter spp. and Serratia marcescens and, to a lesser extent, with Streptococcus pyogenes. To address whether these differences were due to discordance in testing methodology or to variations among the analyzed populations, isolates from the current surveillance were concurrently tested by BMD and Etest. In all, 1,800 Staphylococcus aureus, 259 S. pyogenes, 226 Streptococcus pneumoniae, 93 Enterococcus faecalis, 1,356 Enterobacteriaceae, and 227 Acinetobacter baumannii strains were evaluated. Tigecycline had potent activity by BMD, with >99.6% susceptibility (%S) observed for all pathogens with interpretive criteria, excluding Enterobacter cloacae (98.3% S) and E. faecalis (86.0% S), and MIC90s ranged from 0.03 μg/ml (S. pyogenes/S. pneumoniae) to 1 μg/ml (Enterobacteriaceae/A. baumannii). Similar profiles were observed by Etest, with the exception of A. baumannii, although for most evaluated pathogens Etest MICs trended one doubling-dilution higher than BMD MICs. Major or very major errors were infrequent, and a high degree of essential agreement was observed, excluding A. baumannii, S. marcescens, and S. pneumoniae, for which ≥4-fold differences in MICs were observed for 29, 27.1, and 34% of the isolates, respectively. Further analysis regarding the suitability of the tigecycline Etest for testing S. marcescens, Acinetobacter spp., and S. pneumoniae is warranted.

Antimicrobial susceptibility of tigecycline and comparators against bacterial isolates collected as part of the TEST study in Europe (2004―2007)

Tigecycline is a broad-spectrum antimicrobial agent that has been approved for the treatment of skin and soft-tissue infections as well as intra-abdominal infections. The Tigecycline Evaluation and Surveillance Trial (TEST) is a global, longitudinal surveillance study established in 2004 to monitor the in vitro activity of tigecycline and comparator agents against key Gram-negative and Gram-positive pathogens. This report examines data obtained for 24748 isolates collected across 24 European countries between 2004 and 2007. Tigecycline, meropenem and imipenem were the most active antimicrobial agents against most Gram-negative isolates including multidrug-resistant Acinetobacter baumannii (15.7% of the A. baumannii isolates in this study), extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (8.5% of E. coli) and ESBL-producing Klebsiella pneumoniae (13.6% of K. pneumoniae). Only amikacin was active against >90% of Pseudomonas aeruginosa isolates (92.8% susceptible). Tigecycline, linezolid and vancomycin were the most active agents against Gram-positive agents across Europe between 2004 and 2007, with tigecycline displaying the lowest MIC(90) values (minimum inhibitory concentration for 90% of the organisms) against meticillin-resistant Staphylococcus aureus (26.5% of the collected S. aureus isolates), vancomycin-resistant Enterococcus faecium (15.7% of the E. faecium strains) and penicillin-resistant Streptococcus pneumoniae (9.3% of the S. pneumoniae strains). Longitudinal analysis showed no increase in tigecycline MIC values over the 4-year study period, whilst increased resistance was noted for several comparator agents.

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 ☆

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.

Antimicrobial susceptibility among gram-negative isolates collected in the USA between 2005 and 2011 as part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.)

BackgroundThe Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) was designed to monitor in vitro antimicrobial susceptibility to tigecycline and comparator agents. We present susceptibility data on Gram-negative organisms collected between 2005 and 2011 from nine United States census regions.MethodsT.E.S.T. was conducted using standardized CLSI methodologies or FDA-approved breakpoints.ResultsTigecycline was highly active (MIC90 ≤ 2 mg/L) against Enterobacteriaceae irrespective of species or region of collection (N = 25011). The isolates were also highly susceptible to the carbapenems when all regional data are combined, except for ESBL-producing Klebsiella pneumoniae (MIC90 16 mg/L) and Acinetobacter baumannii (MIC90 ≥ 32 mg/L). In addition, 883 (30%) of 2900 A. baumannii isolates were classified as multidrug-resistant (MDR): these MDR organisms were most susceptible to tigecycline (MIC90 2 mg/L) and minocycline (MIC90 8 mg/L) when all regional data are considered together. Susceptibility patterns also varied widely among the regionsConclusionsThe findings highlight the importance of monitoring antimicrobial susceptibility patterns and implementing effective methods to curb increased resistance and also confirm that additional studies to determine the efficacy of tigecycline in vivo, especially for treating infections with MDR organisms, are warranted.

Comparative in vitro activity of tigecycline and other antimicrobials against Gram-negative and Gram-positive organisms collected from the Asia-Pacific Rim as part of the Tigecycline Evaluation and Surveillance Trial (TEST).

As part of the Tigecycline Evaluation and Surveillance Trial (TEST), Gram-negative and Gram-positive organisms were collected from 31 medical centres in nine countries in the Asia-Pacific Rim between 2004 and 2007. Overall, 34.2% of Acinetobacter spp. were multidrug-resistant, and 17.0% of Klebsiella pneumoniae and 10.6% of Escherichia coli produced extended-spectrum beta-lactamases. A total of 39.5% of Staphylococcus aureus were meticillin-resistant and 21.7% of Enterococcus faecium were vancomycin-resistant. Tigecycline MIC(90) values (minimum inhibitory concentration for 90% of the organisms) were <or=2mg/L against Acinetobacter spp., K. pneumoniae, E. coli, Enterobacter spp. and Serratia marcescens and <or=0.25mg/L against S. aureus, E. faecalis and Enterococcus faecium. Antimicrobial resistance is widespread in the Asia-Pacific Rim. Tigecycline has excellent in vitro activity against a broad spectrum of bacteria, including resistant strains.

Rates of antimicrobial resistance in latin america (2004-2007) and in vitro activity of the glycylcycline tigecycline and of other antibiotics

As a part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.), Gram-positive and Gram-negative bacterial isolates were collected from 33 centers in Latin America (centers in Argentina, Brazil, Chile, Colombia, Guatemala, Honduras, Jamaica, Mexico, Panama, Puerto Rico, and Venezuela) from January 2004 to September 2007. Argentina and Mexico were the greatest contributors of isolates to this study. Susceptibilities were determined according to Clinical Laboratory Standards Institute guidelines. Resistance levels were high for most key organisms across Latin America: 48.3% of Staphylococcus aureus isolates were methicillin-resistant while 21.4% of Acinetobacter spp. isolates were imipenem-resistant. Extended-spectrum beta-lactamase were reported in 36.7% of Klebsiella pneumoniae and 20.8% of E. coli isolates. Tigecycline was the most active agent against Gram-positive isolates. Tigecycline was also highly active against all Gram-negative organisms, with the exception of Pseuodomonas aeruginosa, against which piperacillin-tazobactam was the most active agent tested (79.3% of isolates susceptible). The in vitro activity of tigecycline against both Gram-positive and Gram-negative isolates indicates that it may be an useful tool for the treatment of nosocomial infections, even those caused by organisms that are resistant to other antibacterial agents.