Temporal trends of the in vitro activity of tigecycline and comparator antibiotics against clinical aerobic bacterial isolates collected in Germany, 2006–2014: results of the Tigecycline Evaluation and Surveillance Trial (TEST)

id000025 10.3205/id000025 urn:nbn:de:0183-id0000256 Research Article Temporal trends of the in vitro activity of tigecycline and comparator antibiotics against clinical aerobic bacterial isolates collected in Germany, 2006–2014: results of the Tigecycline Evaluation and Surveillance Trial (TEST) Kresken Kresken Michael M Prof. Dr.

Antiinfectives Intelligence GmbH, Campus Hochschule Bonn-Rhein-Sieg, Von-Liebig-Straße 20, 53359 Rheinbach, GermanyAntiinfectives Intelligence GmbH, Rheinbach, GermanyUniversity of Applied Sciences gGmbH, Cologne, Germany

michael.kresken@antiinfectives-intelligence.de author Körber-Irrgang Körber-Irrgang Barbara B

Antiinfectives Intelligence GmbH, Rheinbach, Germany

barbara.koerber-irrgang@antiinfectives-intelligence.de author Petrik Petrik Christian C

Pfizer Pharma GmbH, Berlin, Germany

Christian.Petrik@pfizer.com author Seifert Seifert Harald H

University Hospital Cologne, Institute for Medical Microbiology, Immunology and Hygiene, Cologne, Germany

harald.seifert@uni-koeln.de author Rodloff Rodloff Arne A

University Hospital Leipzig, Institute for Medical Microbiology and Epidemiology of Infectious Diseases, Leipzig, Germany

acr@medizin.uni-leipzig.de author Becker Becker Karsten K

University Hospital Münster, Institute of Medical Microbiology, Münster, Germany

kbecker@uni-muenster.de author German Medical Science GMS Publishing House

Düsseldorf

610 tigecycline antimicrobial susceptibility multidrug resistance Tigecycline Evaluation and Surveillance Trial (TEST) Germany extended-spectrum beta-lactamase methicillin-resistant Staphylococcus aureus vancomycin-resistant enterococci 20161004 engl This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). 2195-8831 4 GMS Infectious Diseases GMS Infect Dis 07 Given the rapidly changing landscape of antimicrobial resistance, continuous monitoring of antimicrobial susceptibility in clinically relevant bacterial isolates plays an important role in the management of infectious diseases. The Tigecycline Evaluation and Surveillance Trial (TEST) is an ongoing worldwide surveillance programme monitoring the in vitro activity of tigecycline and a panel of representative comparator antibiotics. We report longitudinal susceptibility data on a large set of isolates (n=36,044) from clinically significant bacterial species collected in 25 microbiological</PlainText></TextGroup> laboratories from 2006 to 2014. Trends include a strong increase of carbapenem and levofloxacin resistance in <Mark2>Acinetobacter</Mark2> spp., and smaller increasing rates of ESBL-producing <Mark2>Escherichia coli</Mark2> and vancomycin-resistant enterococci. Across the reporting period, the tigecycline minimum inhibitory concentrations (MICs) at which 50% and 90% of isolates were inhibited remained stable and susceptibility rates were consistently high (93–100%) for all bacterial species.</Pgraph></Abstract> <TextBlock linked="yes" name="Introduction"> <MainHeadline>Introduction</MainHeadline><Pgraph>As the World Health Organization recently pointed out in its global report, antimicrobial resistance threatens the effective treatment of an increasing range of infectious diseases <TextLink reference="1"></TextLink>. Patients with infections caused by multidrug-resistant (MDR) bacteria are generally at elevated risk of unfavorable clinical outcomes and death <TextLink reference="2"></TextLink>. In many settings and patient groups, standard antimicrobials are no longer considered adequate choices for empirical therapy of serious infections <TextLink reference="3"></TextLink>, <TextLink reference="4"></TextLink>. A particularly concerning development is the rapid spread of MDR Gram-negative pathogens as infecting and colonizing organisms, which is mostly due to the expansion of genetic determinants associated with extended-spectrum beta-lactamases (ESBL) or carbapenemase production <TextLink reference="5"></TextLink>.</Pgraph><Pgraph>Tigecycline (Tygacil<Superscript>®</Superscript>; Pfizer Inc.) is a glycylcycline antibiotic <TextLink reference="6"></TextLink> licensed for complicated intraabdominal infections (cIAI) and complicated skin/soft-tissue infections (cSSTI) since 2006. It exhibits activity against a broad spectrum of aerobic and anaerobic Gram-negative and Gram-positive bacteria including most MDR organsims of the critically important group of “ESCAPE” pathogens (<Mark2>Enterococcus faecium, Staphylococcus aureus, Clostridium difficile, Acinetobacter baumannii, Pseudomonas aeruginosa</Mark2>, and Enterobacteriaceae) <TextLink reference="7"></TextLink> such as Gram-negative bacteria producing ESBLs and/or carbapenemases, methicillin-resistant <Mark2>S. aureus</Mark2> (MRSA) and vancomycin-resistant enterococci (VRE) <TextLink reference="8"></TextLink>. </Pgraph><Pgraph><Mark2>P. aeruginosa</Mark2> is intrinsically resistant to tigecyline. Susceptibility to tigecycline may be reduced in bacteria of the Proteeae tribe, mostly mediated by overexpression of efflux pumps <TextLink reference="9"></TextLink>. Acquired resistance has been described in isolates of <Mark2>A. baumannii</Mark2>, several Enterobacteriaceae species and Gram-positive cocci <TextLink reference="8"></TextLink>, <TextLink reference="10"></TextLink>. </Pgraph><Pgraph>In view of the fact that the number of MDR bacterial pathogens has increased over the past 20–30 years, tigecycline plays an important role in the management of complicated bacterial infections. Longitudinal monitoring of the antimicrobial activity of tigecycline is important in assessing the continued usefulness of this agent. As pathogen distribution and resistance patterns show substantial heterogeneity across countries, as evident for Europe from the data compiled by the EARS-Net <TextLink reference="11"></TextLink>, country-specific data on the tigecycline suceptibility is necessary and has been published for several geographic areas, including Germany <TextLink reference="12"></TextLink>, <TextLink reference="13"></TextLink>, <TextLink reference="14"></TextLink>, <TextLink reference="15"></TextLink>, <TextLink reference="16"></TextLink>, <TextLink reference="17"></TextLink>, <TextLink reference="18"></TextLink>, <TextLink reference="19"></TextLink>, <TextLink reference="20"></TextLink>, <TextLink reference="21"></TextLink>.</Pgraph><Pgraph>The Tigecycline Evaluation and Surveillance Trial (TEST) monitors the in vitro activity of tigecycline and a panel of representative comparator antibiotics against clinically relevant pathogens from microbiological laboratories worldwide <TextLink reference="22"></TextLink>. This report provides susceptibility data of tigecycline and comparator agents collected as part of TEST <TextLink reference="23"></TextLink> in Germany between the market introduction of tigecycline in 2006 until 2014, thus expanding earlier German data from TEST reported by Seifert and Dowzicky for the years 2004–2007 <TextLink reference="24"></TextLink> to a more recent observation period. </Pgraph><Pgraph>The present report focussed on (i) bacterial species which are frequently associated with resistance phenotypes and infections in severely ill patients and (ii) antimicrobials frequently used in severe infection and/or representing important groups of antibiotics. A full regularly updated data set of this study is available online via the TEST surveillance website <TextLink reference="23"></TextLink>.</Pgraph></TextBlock> <TextBlock linked="yes" name="Methods"> <MainHeadline>Methods</MainHeadline><SubHeadline>Bacterial strains</SubHeadline><Pgraph>This report includes data from clinical isolates collected by 25 German microbiological laboratories in the time period from 2006 to 2014. Some laboratories, however, did not participate for the entire study period covered in this report. At the beginning of TEST, each participating laboratory had to provide a minimum of 200 isolates per year. These were 135 isolates of Gram-negative pathogens comprising <Mark2>Acinetobacter</Mark2> spp. (n=15), <Mark2>Enterobacter</Mark2> spp. (n=25), <Mark2>Escherichia</Mark2> <Mark2>coli</Mark2> (n=25), <Mark2>Haemophilus</Mark2> <Mark2>influenzae</Mark2> (n=15), <Mark2>Klebsiella</Mark2> spp. (<Mark2>K. oxytoca</Mark2> and <Mark2>K. pneumoniae</Mark2> only; n=25), <Mark2>P. aeruginosa</Mark2> (n=20), <Mark2>Serratia</Mark2> spp. (n=10) and 65 isolates of Gram-positive pathogens comprising <Mark2>Enterococcus</Mark2> spp. (<Mark2>E. faecium</Mark2> and <Mark2>E. faecalis</Mark2> only; n=15), <Mark2>S. aureus</Mark2> (n=25), <Mark2>Streptococcus agalactiae</Mark2> (n=10) and <Mark2>Streptococcus pneumoniae</Mark2> (n=15). As of 2012, clinical isolates of two additional important genera, <Mark2>Citrobacter</Mark2> spp. <TextLink reference="25"></TextLink> and <Mark2>Stenotrophomonas</Mark2> spp., were included by several laboratories.</Pgraph><Pgraph>Eligible sources of clinical isolates included all sampled body sites as well as medical devices (e.g. catheters, prostheses). Isolates derived from the urinary tract were limited to 25% of the total number. Isolates (one per patient) were collected consecutively from patients with community-acquired or healthcare-associated infections. No restrictions were applied regarding patient age, gender, medical history or previous use of antimicrobials.</Pgraph><SubHeadline>Antimicrobial susceptibility testing</SubHeadline><Pgraph>Minimum inhibitory concentrations (MICs) were determined at the participating local laboratories, but partly also at the central laboratory (International Health Management Associates, Inc. [IHMA, Schaumburg, IL, USA]) using broth microdilution as described by the Clinical and Laboratory Standards Institute (CLSI) <TextLink reference="26"></TextLink>. Test plates were Sensititre<Superscript>®</Superscript> plates (TREK Diagnostic Systems, West Sussex, England (2008–2011) or MicroScan<Superscript>®</Superscript> panels (Siemens, Sacramento, CA, USA; 2006–2007 and 2012–2014). Test media were prepared fresh on the day of use.</Pgraph><Pgraph>The panel of tested antimicrobials included amoxicillin-clavulanate (AMX/CLV), ampicillin (AMP), ceftriaxone (CXO), levofloxacin (LVX), meropenem (MEM), minocycline (MIN), piperacillin-tazobactam (PTX) and tigecycline (TGC). Gram-negative isolates were also tested for susceptibility to amikacin (AMI), cefepime (CFP) and ceftazidime (CFM), whereas Gram-positive isolates were additionally tested for susceptibility to linezolid (LZD), penicillin (PEN), and vancomycin (VAN). <Mark2>S</Mark2>. <Mark2>pneumoniae</Mark2> isolates were additionally tested for susceptibility to azithromycin (AZI), clarithromycin (CLA), erythromycin (ERY) and clindamycin (CLI) at the central laboratory. In 2006, imipenem was tested instead of meropenem against the majority of collected isolates.</Pgraph><Pgraph>Confirmation of ESBL production in <Mark2>E. coli</Mark2> and <Mark2>Klebsiella</Mark2> spp. isolates was performed according to CLSI guidelines using discs of cefotaxime (30 µg), cefotaxime-clavulanic acid (30/10 µg), ceftazidime (30 µg), and ceftazidime-clavulanic acid (30/10 µg) <TextLink reference="26"></TextLink>. Antibiotic discs were manufactured by Oxoid, Inc. (Ogdensburg, NY, USA). Mueller-Hinton agar was produced by Remel, Inc. (Lenexa, KS, USA). </Pgraph><Pgraph>All clinical isolates were sent to the central laboratory which organised the transport of the isolates and managed the study database. It also re-identified the isolates and verified the susceptibility results of 10–15% of the isolates annually.</Pgraph><Pgraph>Quality control (QC) strains included <Mark2>S. aureus</Mark2> ATCC 29213, <Mark2>S. pneumoniae</Mark2> ATCC 49619, <Mark2>E. faecalis</Mark2> ATCC 29212, <Mark2>E. coli</Mark2> ATCC 25922, <Mark2>P. aeruginosa</Mark2> ATCC 27853, <Mark2>H.</Mark2> <Mark2>influenzae</Mark2> ATCC 49247, and <Mark2>H. influenzae</Mark2> ATCC 49766. MIC data of the clinical isolates were only considered for evaluation if the MICs of the QC strains determined on the day of susceptibility testing were within the quality control ranges defined by CLSI <TextLink reference="26"></TextLink>. QC strains used for quality control of ceftazidime and cefotaxime discs were <Mark2>K. pneumoniae</Mark2> ATCC 700603 (ESBL-positive) and <Mark2>E. coli</Mark2> ATCC 25922 (ESBL-negative), as well as <TextGroup><Mark2>P. aeruginosa</Mark2></TextGroup> (ATCC 27853). All isolate data were subject to a quality assurance programme to ensure the validity of the results.</Pgraph><Pgraph>European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints (version 5.0) were applied to antimicrobial agents and organisms for interpretation <TextLink reference="27"></TextLink>. Neither EUCAST nor CLSI have set breakpoints for tigecycline against <Mark2>A. baumannii</Mark2>. Therefore, the breakpoints proposed by Jones et al. <TextLink reference="28"></TextLink> (susceptible: ≤2 µg/mL; resistant: ≥8 µg/mL) were tentatively used for the determination of resistance rates when testing this organism/antibiotic combination. </Pgraph></TextBlock> <TextBlock linked="yes" name="Results"> <MainHeadline>Results</MainHeadline><Pgraph>Between 2006 and 2014, the 25 participating laboratories collected a total of 36,044 isolates comprising 12,542 Gram-positive isolates and 23,502 Gram-negative organisms. Annual MIC<Subscript>50</Subscript> and MIC<Subscript>90</Subscript> values as well as resistance rates of tigecycline and comparators for the most clinically relevant species are shown in Table 1 <ImgLink imgNo="1" imgType="table"/>. A total of 30.1% of these isolates were collected from intensive care patients. </Pgraph><SubHeadline>Gram-negative pathogens</SubHeadline><SubHeadline2>Acinetobacter spp.</SubHeadline2><Pgraph>The percentage of meropenem-resistant strains among all <Mark2>Acinetobacter</Mark2> spp. isolates (n=893) increased from 4,2% in 2007 to 33% in 2014. Resistance to amikacin remained relatively stable at about 10% until 2012, but then increased to more than 30% in 2013/2014. A similar trend was observed for levofloxacin with resistance rates increasing from around 20% to ca. 40% in the last two years. MIC<Subscript>50</Subscript> and MIC<Subscript>90</Subscript> values of tigecycline were in the range of 0.12–0.25 µg/ml and 0.5–2 µg/ml, respectively. Applying the tentative breakpoints proposed by Jones et al. <TextLink reference="28"></TextLink>, none of the isolates tested were classified as tigecycline-resistant.</Pgraph><SubHeadline2>Escherichia coli</SubHeadline2><Pgraph>Among the 2,385 isolates, 16.7% (n=399) showed an ESBL-phenotype. The ESBL rate slightly increased during the test period, with annual rates ranging between 9.3% and 22.7% (Figure 1 <ImgLink imgNo="1" imgType="figure"/>). Resistance to ceftriaxone and levofloxacin was lowest in the first year of the study period and then varied between 15–25% and 27–42%, respectively, but a clear trend was not observed for either drug. Throughout the study, levofloxacin resistance was more common among ESBL-positive isolates (58–87%) than among ESBL-negative isolates (18–36%), as expected. Piperacillin-tazobactam resistance remained stable, with rates of <10% (data not shown) for ESBL-negative isolates and rates varying between 9% and 38% for ESBL-positive isolates. Meropenem susceptibility was high with no resistant isolates until 2012 and <1% in the last two years. Tigecycline was constantly active against <Mark2>E. coli</Mark2> during the entire study period, with MIC<Subscript>90</Subscript> values of 0.25–1 µg/ml and an overall susceptibility rate of 100%.</Pgraph><SubHeadline2>Enterobacter spp.</SubHeadline2><Pgraph>Meropenem activity against <Mark2>E. aerogenes</Mark2> (n=395) and <Mark2>E. cloacae</Mark2> (n=1,762) remained very high throughout the reporting period, with resistance rates ranging between 0% and 1.6% for both species. Low resistance rates were also observed for tigecycline (0–7% and 2–7%, respectively). Piperacillin-tazobactam was less active against either species, with resistance rates fluctuating around 20%.</Pgraph><SubHeadline2>Klebsiella spp.</SubHeadline2><Pgraph>The ESBL rates found for <Mark2>K. pneumoniae</Mark2> (n=1,481) ranged between 5.9% to 22.1%, with a mean of 15% (Figure 1 <ImgLink imgNo="1" imgType="figure"/>). Levofloxacin and piperacillin-tazobactam showed poor activity against ESBL-positive isolates, with resistance rates of 50% and 29% at the end of the study period. In contrast, meropenem remained highly active against <Mark2>K.</Mark2> <Mark2>pneumoniae</Mark2>, though resistance was observed in 2008 and between 2011 and 2013, albeit at fairly low rates. The MIC<Subscript>90</Subscript> of tigecycline remained at ≤2 µg/ml throughout the reporting period (≤6% resistant isolates overall). However, six out of 38 ESBL-producing isolates exhibited resistance to tigecycline in 2014.</Pgraph><Pgraph>As to <Mark2>K. oxytoca</Mark2>, there were 20 ESBL-positive strains among 829 isolates (2.4%). Resistance to meropenem was not detected throughout the reporting period. Tigecycline resistance rates were 0–4% even for ESBL-positive isolates (data not shown). Resistance rates for piperacillin-tazobactam and levofloxacin greatly varied during the study period, with approximately 20% and <10% resistant isolates, respectively, in the last year.</Pgraph><SubHeadline2>Pseudomonas aeruginosa</SubHeadline2><Pgraph>As expected, tigecycline showed low activity against <TextGroup><Mark2>P. aeruginosa</Mark2></TextGroup> (n=1,884). Resistance to ceftazidime was mostly >15% until 2011 and afterwards <15%. No clear trends of susceptibility rates were observed for other antimicrobials, with moderately high rates of resistant isolates recorded for levofloxacin (range 19.8–33.0%), meropenem (6.9–19.4%), and piperacillin-tazobactam (11.0–28.4%).</Pgraph><SubHeadline2>Stenotrophomonas maltophilia</SubHeadline2><Pgraph><Mark2>S. maltophilia</Mark2> isolates (n=303) were collected in the last 3 years of the reporting period. MIC<Subscript>50</Subscript> and MIC<Subscript>90</Subscript> values recorded for tigecycline were 0.25 and 0.5–1 µg/ml, respectively. Minocycline was slightly less active than tigecycline, but the MIC<Subscript>90</Subscript> values were also 0.5–1 µg/ml (data not shown). MIC<Subscript>90</Subscript> values of levofloxacin were 2–4 µg/ml. Trimethoprim-sulfamethoxazole was not tested. </Pgraph><SubHeadline>Gram-positive pathogens</SubHeadline><SubHeadline2>Enterococcus spp.</SubHeadline2><Pgraph>The proportion of vancomycin-resistant (VRE) strains among the <Mark2>E. faecium</Mark2> isolates increased from 7.4% in 2006 to 31.6% in 2014 (Figure 1 <ImgLink imgNo="1" imgType="figure"/>), but remained very low among <Mark2>E</Mark2>. <Mark2>faecalis</Mark2> isolates (data not shown). Resistance rates for levofloxacin were very high (90.7% overall) for <Mark2>E. faecium</Mark2> and about 40% for <Mark2>E. faecalis</Mark2>. Further, resistance for ampicillin was low in <Mark2>E. faecalis</Mark2>, while 92.4% of <Mark2>E. faecium</Mark2> isolates were found to be resistant. In contrast, 99–100% of the <Mark2>E. faecium</Mark2> isolates, including VRE, remained susceptible to tigecycline and linezolid throughout the reporting period.</Pgraph><SubHeadline2>Staphylococcus aureus</SubHeadline2><Pgraph>The proportion of MRSA among <Mark2>S. aureus</Mark2> isolates (n=2,351) varied over the years, with an average rate of 20.4% (range 14.3% to 50.7%) with higher and lower MRSA rates in the first an second half of the reporting period, respectively (Figure 1 <ImgLink imgNo="1" imgType="figure"/>). Resistance to levofloxacin varied between 4.9% and 17.8% among MSSA isolates and between 73.3% and 98.1% among MRSA isolates. All <Mark2>S. aureus</Mark2> isolates tested were susceptible to tigecycline, linezolid and vancomycin. </Pgraph><SubHeadline2>Streptococcus pneumoniae</SubHeadline2><Pgraph>The susceptibility pattern of <Mark2>S. pneumoniae</Mark2> remained largely unchanged during the observation period. Resistance rates for penicillin and ceftriaxone varied between 0% and 3.2% and those for levofloxacin between 0% and 2.7%, while the resistance rate for clarithromycin ranged from 8.5% to 22.5%, without a clear temporal trend. Resistance to linezolid was lacking and tigecyline showed MIC<Subscript>50</Subscript> and MIC<Subscript>90</Subscript> values of 0.015–0.03 µg/mL and 0.015–0.06 µg/mL, respectively.</Pgraph></TextBlock> <TextBlock linked="yes" name="Discussion"> <MainHeadline>Discussion</MainHeadline><Pgraph>Given the rapidly changing landscape of antimicrobial resistance, particularly in Gram-negative bacteria <TextLink reference="29"></TextLink>, long-term monitoring of the activity of available antibiotics against common and problematic pathogens involved in serious infections is of great importance in the management of infectious diseases. MRSA rates have been reported to decline in Germany in recent years <TextLink reference="11"></TextLink>, <TextLink reference="30"></TextLink>, <TextLink reference="31"></TextLink>, <TextLink reference="32"></TextLink>, while the rates of Gram-negative bacteria producing ESBLs and the rate of VRE remained either unchanged or increased over the past years <TextLink reference="11"></TextLink>, <TextLink reference="31"></TextLink>, <TextLink reference="32"></TextLink>, <TextLink reference="33"></TextLink>. Efficient hygiene measures, antibiotic stewardship programmes and rational use of the available treatment options are crucial for the maintenance of the ability to control serious bacterial diseases, particularly in critically ill patients. Given the highly heterogenerous healthcare situations in Europan countries, regional longitudinal susceptibility data are key to enable adequate early action and policy adjustments if untoward trends in resistance emerge. The present study provides data from a larger and more diverse sample of isolates than previous surveys on the comparative susceptibility of tigecycline in Germany <TextLink reference="12"></TextLink>, <TextLink reference="13"></TextLink>, <TextLink reference="14"></TextLink>, <TextLink reference="24"></TextLink>.</Pgraph><Pgraph>The moderate increase in the prevalence of ESBL-producing <Mark2>E. coli</Mark2> and the stable proportion of ESBL-producing <Mark2>K. pneumoniae</Mark2> isolates found in the present study (<TextGroup><PlainText>Figure 1 </PlainText></TextGroup><ImgLink imgNo="1" imgType="figure"/>) corresponds approximately with the ESBL rates reported by the Paul-Ehrlich-Gesellschaft für Chemotherapie (PEG) <TextLink reference="31"></TextLink>. The low ESBL rate observed in <Mark2>K. oxytoca</Mark2> is explained by the low activity of the K1 beta-lactamase against the antibiotics cefotaxime and ceftazidime <TextLink reference="34"></TextLink>, which were used for ESBL screening. </Pgraph><Pgraph>The rate of carbapenem-resistant <Mark2>Acinetobacter</Mark2> spp. showed a dramatic increase, reaching 33% in 2014, which is consistent with observations of other German surveillance studies for <Mark2>A. baumannii</Mark2> <TextLink reference="31"></TextLink>, <TextLink reference="35"></TextLink>.</Pgraph><Pgraph>Regarding Gram-positive pathogens, Gastmeier et al. <TextLink reference="29"></TextLink> reported a strong increase in the proportion of VRE among nosocomial infections in Germany for the time period of 2007 to 2012. This observation corresponds to the trend towards higher VRE rates in the second half of the present study. </Pgraph><Pgraph>MRSA rates varied considerably during the study period. The unusually high percentage of MRSA observed in 2009 is most likely due to random variation, given the low total number of isolates tested in that year. The downward trend of MRSA rates in the last three years, as also observed by other study groups in Germany, possibly reflects improved effects of infection control measures.</Pgraph><Pgraph>The clinical usefulness of tigecycline in the management of complicated infections, particularly cIAI and cSSTI, including those caused by pathogens with MDR has recently been confirmed in a large observational study programme performed in Germany <TextLink reference="36"></TextLink>, <TextLink reference="37"></TextLink>, <TextLink reference="38"></TextLink>. These observations are supported by the results of the present multicentre in vitro study comprising more than 36,000 clinical isolates obtained from patients with community-acquired or nosocomial infections in Germany, confirming that eight years after its introduction into the German market, tigecycline invariably retains its high antimicrobial activity against a broad range of important Gram-negative and Gram-positive pathogens, including ESBL-producing Enterobacteriaceae, MRSA and VRE. The good activity of tigecycline found in the present study reassured the results of a German Tigecycline Evaluation and Surveillance Trial (G-TEST) performed between 2005 and 2009 <TextLink reference="10"></TextLink>, <TextLink reference="11"></TextLink>, <TextLink reference="12"></TextLink>. Moreover, the German long-term findings for tigecycline from TEST are consistent with those published for Europe in general <TextLink reference="39"></TextLink>, and other individual European regions, particularly France <TextLink reference="15"></TextLink>, Italy <TextLink reference="16"></TextLink>, and Eastern European countries <TextLink reference="17"></TextLink>.</Pgraph><Pgraph>MIC<Subscript>50</Subscript> and MIC<Subscript>90</Subscript> values of 0.25 µg/mL and 0.5–1 µg/mL, respectively, assessed for <Mark2>S. maltophilia</Mark2> in the present study point to a potential usefulness of tigecycline in the mangement of infections caused by this opportunistic MDR pathogen of growing importance <TextLink reference="40"></TextLink>. </Pgraph><Pgraph>Tigecycline has been shown to be effective and well tolerated at higher than standard doses in critically ill patients infected with MDR bacteria <TextLink reference="41"></TextLink> and in patients with hospital-acquired pneumonia <TextLink reference="42"></TextLink>. Further studies investigating higher dosages of tigecycline in severly ill patients with difficult-to-treat infections appear warranted.</Pgraph><Pgraph>In conclusion, our findings indicate sustained activity of tigecycline against pathogens known to cause infections in severely ill patients. This is true for isolates susceptible to standard antibiotics as well as MDR bacteria like ESBL-producing Enterobacteriaceae, carbapenem-resistant <Mark2>Acinetobacter</Mark2> spp., VRE and MRSA, where choices of active drugs are generally limited or resistance rates worrisome.</Pgraph></TextBlock> <TextBlock linked="yes" name="Notes"> <MainHeadline>Notes</MainHeadline><SubHeadline>Acknowledgements</SubHeadline><Pgraph>The authors thank all investigators and staff of the participating laboratories and clinical centers for submitting bacterial isolates and the related data: University Hospital Aachen, Center for Microbiology and Infectiology Berlin, University Hospital Charité Berlin, Helios Hospital Berlin, Institute for Medical Laboratory Diagnostics Bochum, City Hospital Braunschweig, University Hospital Cologne, University Hospital Essen, University Hospital Frankfurt, University Hospital Freiburg, Medical Microbiology Laboratory Görlitz, University Hospital Halle, Regional Hospital Hannover, University Hospital Heidelberg, University Hospital Homburg/Saar, University Hospital Mannheim, University Hospital Kiel, University Hospital Leipzig, University Hospital Marburg, City Hospital Minden, Pettenkofer Institute Munich, University Hospital Münster, Antiinfectives Intelligence Rheinbach, University Hospital Tübingen, University Hospital Ulm.</Pgraph><Pgraph>Editorial support was provided by M. Fischer, Fischer BioMedical. This study was sponsored by Pfizer Inc. </Pgraph><SubHeadline>Conflicts of interest</SubHeadline><Pgraph>M.K. is a partner and CEO of Antiinfectives Intelligence GmbH, a research organisation providing services to pharmaceutical companies. </Pgraph><Pgraph>B.K.-I. is an employee of Antiinfectives Intelligence GmbH.</Pgraph><Pgraph>C.P. is an employee of Pfizer Pharma GmbH.</Pgraph><Pgraph>H.S. has received grants or research support from the Bundesministerium für Bildung und Forschung (BMBF), Germany, the German Center for Infection Research (DZIF), Basilea, Novartis and Pfizer, has been a consultant for Astellas, AstraZeneca, Basilea, Cubist, Novartis, Pfizer, Tetraphase, and The Medicines Company, and has received payments for lectures from MSD, Novartis and Pfizer.</Pgraph><Pgraph>A.R. has been a consultant for Oxoid/Thermo, MSD, Novartis, InfectoPharm, BAG, Pfizer, Bayer, Siemens, Clinigen, Gilead and bestbion, and has received speakers honoraria from Pfizer.</Pgraph><Pgraph>K.B. has received grants or research support from from the Bundesministerium für Bildung und Forschung (BMBF), Germany, the German Center for Infection Research (DZIF), the Bundesministerium für Wirtschaft (BMWi), the European Territorial Cooperation (ETC)/INTERREG, Cepheid and Pfizer as well as lecture, travel and other fees from Cepheid, Cubist Pharmaceuticals, MSD Sharp & Dohme, Novartis Pharma, Oxoid, Pfizer and Siemens Healthcare Diagnostics.</Pgraph></TextBlock> <References linked="yes"> <Reference refNo="1"> <RefAuthor>World Health Organization</RefAuthor> <RefTitle></RefTitle> <RefYear>2015</RefYear> <RefBookTitle>Antimicrobial resistance</RefBookTitle> <RefPage></RefPage> <RefTotal>World Health Organization. Antimicrobial resistance. Updated April 2015. (Fact Sheet, 194). Available from: http://www.who.int/mediacentre/factsheets/fs194/en/</RefTotal> <RefLink>http://www.who.int/mediacentre/factsheets/fs194/en/</RefLink> </Reference> <Reference refNo="2"> <RefAuthor>Tanwar J</RefAuthor> <RefAuthor>Das S</RefAuthor> <RefAuthor>Fatima Z</RefAuthor> <RefAuthor>Hameed S</RefAuthor> <RefTitle>Multidrug resistance: an emerging crisis</RefTitle> <RefYear>2014</RefYear> <RefJournal>Interdiscip Perspect Infect Dis</RefJournal> <RefPage>541340</RefPage> <RefTotal>Tanwar J, Das S, Fatima Z, Hameed S. Multidrug resistance: an emerging crisis. Interdiscip Perspect Infect Dis. 2014;2014:541340. DOI: 10.1155/2014/541340.</RefTotal> <RefLink>http://dx.doi.org/10.1155/2014/541340.</RefLink> </Reference> <Reference refNo="3"> <RefAuthor>Russotto V</RefAuthor> <RefAuthor>Cortegiani A</RefAuthor> <RefAuthor>Graziano G</RefAuthor> <RefAuthor>Saporito L</RefAuthor> <RefAuthor>Raineri SM</RefAuthor> <RefAuthor>Mammina C</RefAuthor> <RefAuthor>Giarratano A</RefAuthor> <RefTitle>Bloodstream infections in intensive care unit patients: distribution and antibiotic resistance of bacteria</RefTitle> <RefYear>2015</RefYear> <RefJournal>Infect Drug Resist</RefJournal> <RefPage>287-96</RefPage> <RefTotal>Russotto V, Cortegiani A, Graziano G, Saporito L, Raineri SM, Mammina C, Giarratano A. Bloodstream infections in intensive care unit patients: distribution and antibiotic resistance of bacteria. Infect Drug Resist. 2015;8:287-96. DOI: 10.2147/IDR.S48810</RefTotal> <RefLink>http://dx.doi.org/10.2147/IDR.S48810</RefLink> </Reference> <Reference refNo="4"> <RefAuthor>Scholte JB</RefAuthor> <RefAuthor>Duong HL</RefAuthor> <RefAuthor>Linssen C</RefAuthor> <RefAuthor>Van Dessel H</RefAuthor> <RefAuthor>Bergmans D</RefAuthor> <RefAuthor>van der Horst R</RefAuthor> <RefAuthor>Savelkoul P</RefAuthor> <RefAuthor>Roekaerts P</RefAuthor> <RefAuthor>van Mook W</RefAuthor> <RefTitle>Empirical antibiotic therapy for pneumonia in intensive care units: a multicentre, retrospective analysis of potentially pathogenic microorganisms identified by endotracheal aspirates cultures</RefTitle> <RefYear>2015</RefYear> <RefJournal>Eur J Clin Microbiol Infect Dis</RefJournal> <RefPage>2295-305</RefPage> <RefTotal>Scholte JB, Duong HL, Linssen C, Van Dessel H, Bergmans D, van der Horst R, Savelkoul P, Roekaerts P, van Mook W. Empirical antibiotic therapy for pneumonia in intensive care units: a multicentre, retrospective analysis of potentially pathogenic microorganisms identified by endotracheal aspirates cultures. Eur J Clin Microbiol Infect Dis. 2015 Nov;34(11):2295-305. DOI: 10.1007/s10096-015-2482-y</RefTotal> <RefLink>http://dx.doi.org/10.1007/s10096-015-2482-y</RefLink> </Reference> <Reference refNo="5"> <RefAuthor>Pendleton JN</RefAuthor> <RefAuthor>Gorman SP</RefAuthor> <RefAuthor>Gilmore BF</RefAuthor> <RefTitle>Clinical relevance of the ESKAPE pathogens</RefTitle> <RefYear>2013</RefYear> <RefJournal>Expert Rev Anti Infect Ther</RefJournal> <RefPage>297-308</RefPage> <RefTotal>Pendleton JN, Gorman SP, Gilmore BF. Clinical relevance of the ESKAPE pathogens. Expert Rev Anti Infect Ther. 2013 Mar;11(3):297-308. DOI: 10.1586/eri.13.12</RefTotal> <RefLink>http://dx.doi.org/10.1586/eri.13.12</RefLink> </Reference> <Reference refNo="6"> <RefAuthor>Stein GE</RefAuthor> <RefAuthor>Babinchak T</RefAuthor> <RefTitle>Tigecycline: an update</RefTitle> <RefYear>2013</RefYear> <RefJournal>Diagn Microbiol Infect Dis</RefJournal> <RefPage>331-6</RefPage> <RefTotal>Stein GE, Babinchak T. Tigecycline: an update. Diagn Microbiol Infect Dis. 2013 Apr;75(4):331-6. DOI: 10.1016/j.diagmicrobio.2012.12.004</RefTotal> <RefLink>http://dx.doi.org/10.1016/j.diagmicrobio.2012.12.004</RefLink> </Reference> <Reference refNo="7"> <RefAuthor>Peterson LR</RefAuthor> <RefTitle>Bad bugs, no drugs: no ESCAPE revisited</RefTitle> <RefYear>2009</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>992-3</RefPage> <RefTotal>Peterson LR. Bad bugs, no drugs: no ESCAPE revisited. Clin Infect Dis. 2009 Sep;49(6):992-3. DOI: 10.1086/605539</RefTotal> <RefLink>http://dx.doi.org/10.1086/605539</RefLink> </Reference> <Reference refNo="8"> <RefAuthor>European Medicines Agency</RefAuthor> <RefTitle></RefTitle> <RefYear>2009</RefYear> <RefBookTitle>Tigecycline (Tygacil®). Product information. Annex I - Summary of product characteristics</RefBookTitle> <RefPage></RefPage> <RefTotal>European Medicines Agency. Tigecycline (Tygacil®). Product information. Annex I - Summary of product characteristics. EMA; 2009 [last updated 21/06/2016]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000644/human_med_001118.jsp&mid=WC0b01ac058001d124</RefTotal> <RefLink>http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000644/WC500044508.pdf</RefLink> </Reference> <Reference refNo="9"> <RefAuthor>Visalli MA</RefAuthor> <RefAuthor>Murphy E</RefAuthor> <RefAuthor>Projan SJ</RefAuthor> <RefAuthor>Bradford PA</RefAuthor> <RefTitle>AcrAB multidrug efflux pump is associated with reduced levels of susceptibility to tigecycline (GAR-936) in Proteus mirabilis</RefTitle> <RefYear>2003</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>665-9</RefPage> <RefTotal>Visalli MA, Murphy E, Projan SJ, Bradford PA. AcrAB multidrug efflux pump is associated with reduced levels of susceptibility to tigecycline (GAR-936) in Proteus mirabilis. Antimicrob Agents Chemother. 2003 Feb;47(2):665-9. DOI: 10.1128/AAC.47.2.665-669.2003</RefTotal> <RefLink>http://dx.doi.org/10.1128/AAC.47.2.665-669.2003</RefLink> </Reference> <Reference refNo="10"> <RefAuthor>Dabul AN</RefAuthor> <RefAuthor>Camargo IL</RefAuthor> <RefTitle>Molecular characterization of methicillin-resistant Staphylococcus aureus resistant to tigecycline and daptomycin isolated in a hospital in Brazil</RefTitle> <RefYear>2014</RefYear> <RefJournal>Epidemiol Infect</RefJournal> <RefPage>479-83</RefPage> <RefTotal>Dabul AN, Camargo IL. Molecular characterization of methicillin-resistant Staphylococcus aureus resistant to tigecycline and daptomycin isolated in a hospital in Brazil. Epidemiol Infect. 2014 Mar;142(3):479-83. DOI: 10.1017/S0950268813001325</RefTotal> <RefLink>http://dx.doi.org/10.1017/S0950268813001325</RefLink> </Reference> <Reference refNo="11"> <RefAuthor>European Centre for Disease Prevention and Control (ECDC)</RefAuthor> <RefTitle></RefTitle> <RefYear></RefYear> <RefBookTitle>Antimicrobial Resistance Interactive Database (EARS-Net)</RefBookTitle> <RefPage></RefPage> <RefTotal>European Centre for Disease Prevention and Control (ECDC). Antimicrobial Resistance Interactive Database (EARS-Net). Available from: http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/database/Pages/database.aspx</RefTotal> <RefLink>http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/database/Pages/database.aspx</RefLink> </Reference> <Reference refNo="12"> <RefAuthor>Kresken M</RefAuthor> <RefAuthor>Leitner E</RefAuthor> <RefAuthor>Brauers J</RefAuthor> <RefAuthor>Geiss HK</RefAuthor> <RefAuthor>Halle E</RefAuthor> <RefAuthor>von Eiff C</RefAuthor> <RefAuthor>Peters G</RefAuthor> <RefAuthor>Seifert H</RefAuthor> <RefAuthor> German Tigecycline Evaluation Surveillance Trial Study Group</RefAuthor> <RefTitle>Susceptibility of common aerobic pathogens to tigecycline: results of a surveillance study in Germany</RefTitle> <RefYear>2009</RefYear> <RefJournal>Eur J Clin Microbiol Infect Dis</RefJournal> <RefPage>83-90</RefPage> <RefTotal>Kresken M, Leitner E, Brauers J, Geiss HK, Halle E, von Eiff C, Peters G, Seifert H; German Tigecycline Evaluation Surveillance Trial Study Group. Susceptibility of common aerobic pathogens to tigecycline: results of a surveillance study in Germany. Eur J Clin Microbiol Infect Dis. 2009 Jan;28(1):83-90. DOI: 10.1007/s10096-008-0589-0</RefTotal> <RefLink>http://dx.doi.org/10.1007/s10096-008-0589-0</RefLink> </Reference> <Reference refNo="13"> <RefAuthor>Kresken M</RefAuthor> <RefAuthor>Leitner E</RefAuthor> <RefAuthor>Seifert H</RefAuthor> <RefAuthor>Peters G</RefAuthor> <RefAuthor>von Eiff C</RefAuthor> <RefTitle>Susceptibility of clinical isolates of frequently encountered bacterial species to tigecycline one year after the introduction of this new class of antibiotics: results of the second multicentre surveillance trial in Germany (G-TEST II, 2007)</RefTitle> <RefYear>2009</RefYear> <RefJournal>Eur J Clin Microbiol Infect Dis</RefJournal> <RefPage>1007-11</RefPage> <RefTotal>Kresken M, Leitner E, Seifert H, Peters G, von Eiff C. Susceptibility of clinical isolates of frequently encountered bacterial species to tigecycline one year after the introduction of this new class of antibiotics: results of the second multicentre surveillance trial in Germany (G-TEST II, 2007). Eur J Clin Microbiol Infect Dis. 2009 Aug;28(8):1007-11. DOI: 10.1007/s10096-009-0725-5</RefTotal> <RefLink>http://dx.doi.org/10.1007/s10096-009-0725-5</RefLink> </Reference> <Reference refNo="14"> <RefAuthor>Kresken M</RefAuthor> <RefAuthor>Becker K</RefAuthor> <RefAuthor>Seifert H</RefAuthor> <RefAuthor>Leitner E</RefAuthor> <RefAuthor>Körber-Irrgang B</RefAuthor> <RefAuthor>von Eiff C</RefAuthor> <RefAuthor>Löschmann PA</RefAuthor> <RefAuthor> Study Group</RefAuthor> <RefTitle>Resistance trends and in vitro activity of tigecycline and 17 other antimicrobial agents against Gram-positive and Gram-negative organisms, including multidrug-resistant pathogens, in Germany</RefTitle> <RefYear>2011</RefYear> <RefJournal>Eur J Clin Microbiol Infect Dis</RefJournal> <RefPage>1095-103</RefPage> <RefTotal>Kresken M, Becker K, Seifert H, Leitner E, Körber-Irrgang B, von Eiff C, Löschmann PA; Study Group. Resistance trends and in vitro activity of tigecycline and 17 other antimicrobial agents against Gram-positive and Gram-negative organisms, including multidrug-resistant pathogens, in Germany. Eur J Clin Microbiol Infect Dis. 2011 Sep;30(9):1095-103. DOI: 10.1007/s10096-011-1197-y</RefTotal> <RefLink>http://dx.doi.org/10.1007/s10096-011-1197-y</RefLink> </Reference> <Reference refNo="15"> <RefAuthor>Cattoir V</RefAuthor> <RefAuthor>Dowzicky MJ</RefAuthor> <RefTitle>A longitudinal assessment of antimicrobial susceptibility among important pathogens collected as part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) in France between 2004 and 2012</RefTitle> <RefYear>2014</RefYear> <RefJournal>Antimicrob Resist Infect Control</RefJournal> <RefPage>36</RefPage> <RefTotal>Cattoir V, Dowzicky MJ. A longitudinal assessment of antimicrobial susceptibility among important pathogens collected as part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) in France between 2004 and 2012. Antimicrob Resist Infect Control. 2014;3(1):36. DOI: 10.1186/2047-2994-3-36</RefTotal> <RefLink>http://dx.doi.org/10.1186/2047-2994-3-36</RefLink> </Reference> <Reference refNo="16"> <RefAuthor>Stefani S</RefAuthor> <RefAuthor>Dowzicky MJ</RefAuthor> <RefTitle>Longitudinal Assessment of Antimicrobial Susceptibility among Gram-Negative and Gram-Positive Organisms Collected from Italy as Part of the Tigecycline Evaluation and Surveillance Trial between 2004 and 2011</RefTitle> <RefYear>2013</RefYear> <RefJournal>Pharmaceuticals (Basel)</RefJournal> <RefPage>1381-406</RefPage> <RefTotal>Stefani S, Dowzicky MJ. Longitudinal Assessment of Antimicrobial Susceptibility among Gram-Negative and Gram-Positive Organisms Collected from Italy as Part of the Tigecycline Evaluation and Surveillance Trial between 2004 and 2011. Pharmaceuticals (Basel). 2013;6(11):1381-406. DOI: 10.3390/ph6111381</RefTotal> <RefLink>http://dx.doi.org/10.3390/ph6111381</RefLink> </Reference> <Reference refNo="17"> <RefAuthor>Balode A</RefAuthor> <RefAuthor>Punda-Polic V</RefAuthor> <RefAuthor>Dowzicky MJ</RefAuthor> <RefTitle>Antimicrobial susceptibility of gram-negative and gram-positive bacteria collected from countries in Eastern Europe: results from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) 2004-2010</RefTitle> <RefYear>2013</RefYear> <RefJournal>Int J Antimicrob Agents</RefJournal> <RefPage>527-35</RefPage> <RefTotal>Balode A, Punda-Polic V, Dowzicky MJ. Antimicrobial susceptibility of gram-negative and gram-positive bacteria collected from countries in Eastern Europe: results from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) 2004-2010. Int J Antimicrob Agents. 2013 Jun;41(6):527-35. DOI: 10.1016/j.ijantimicag.2013.02.022</RefTotal> <RefLink>http://dx.doi.org/10.1016/j.ijantimicag.2013.02.022</RefLink> </Reference> <Reference refNo="18"> <RefAuthor>Morfin-Otero R</RefAuthor> <RefAuthor>Noriega ER</RefAuthor> <RefAuthor>Dowzicky MJ</RefAuthor> <RefTitle>Antimicrobial susceptibility trends among gram-positive and -negative clinical isolates collected between 2005 and 2012 in Mexico: results from the Tigecycline Evaluation and Surveillance Trial</RefTitle> <RefYear>2015</RefYear> <RefJournal>Ann Clin Microbiol Antimicrob</RefJournal> <RefPage>53</RefPage> <RefTotal>Morfin-Otero R, Noriega ER, Dowzicky MJ. Antimicrobial susceptibility trends among gram-positive and -negative clinical isolates collected between 2005 and 2012 in Mexico: results from the Tigecycline Evaluation and Surveillance Trial. Ann Clin Microbiol Antimicrob. 2015;14:53. DOI: 10.1186/s12941-015-0116-y</RefTotal> <RefLink>http://dx.doi.org/10.1186/s12941-015-0116-y</RefLink> </Reference> <Reference refNo="19"> <RefAuthor>Kanj SS</RefAuthor> <RefAuthor>Whitelaw A</RefAuthor> <RefAuthor>Dowzicky MJ</RefAuthor> <RefTitle>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</RefTitle> <RefYear>2014</RefYear> <RefJournal>Int J Antimicrob Agents</RefJournal> <RefPage>170-8</RefPage> <RefTotal>Kanj SS, Whitelaw A, Dowzicky MJ. 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. Int J Antimicrob Agents. 2014 Feb;43(2):170-8. DOI: 10.1016/j.ijantimicag.2013.10.011</RefTotal> <RefLink>http://dx.doi.org/10.1016/j.ijantimicag.2013.10.011</RefLink> </Reference> <Reference refNo="20"> <RefAuthor>Denys GA</RefAuthor> <RefAuthor>Callister SM</RefAuthor> <RefAuthor>Dowzicky MJ</RefAuthor> <RefTitle>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.)</RefTitle> <RefYear>2013</RefYear> <RefJournal>Ann Clin Microbiol Antimicrob</RefJournal> <RefPage>24</RefPage> <RefTotal>Denys GA, Callister SM, Dowzicky MJ. 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.). Ann Clin Microbiol Antimicrob. 2013;12:24. DOI: 10.1186/1476-0711-12-24</RefTotal> <RefLink>http://dx.doi.org/10.1186/1476-0711-12-24</RefLink> </Reference> <Reference refNo="21"> <RefAuthor>Hoban DJ</RefAuthor> <RefAuthor>Bouchillon SK</RefAuthor> <RefAuthor>Johnson BM</RefAuthor> <RefAuthor>Johnson JL</RefAuthor> <RefAuthor>Dowzicky MJ</RefAuthor> <RefAuthor> Tigecycline Evaluation and Surveillance Trial (TEST Program) Group</RefAuthor> <RefTitle>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)</RefTitle> <RefYear>2005</RefYear> <RefJournal>Diagn Microbiol Infect Dis</RefJournal> <RefPage>215-27</RefPage> <RefTotal>Hoban DJ, Bouchillon SK, Johnson BM, Johnson JL, Dowzicky MJ; Tigecycline Evaluation and Surveillance Trial (TEST Program) Group. 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). Diagn Microbiol Infect Dis. 2005 Jul;52(3):215-27. DOI: 10.1016/j.diagmicrobio.2005.06.001</RefTotal> <RefLink>http://dx.doi.org/10.1016/j.diagmicrobio.2005.06.001</RefLink> </Reference> <Reference refNo="22"> <RefAuthor>Kehl SC</RefAuthor> <RefAuthor>Dowzicky MJ</RefAuthor> <RefTitle>Global assessment of antimicrobial susceptibility among Gram-negative organisms collected from pediatric patients between 2004 and 2012: results from the Tigecycline Evaluation and Surveillance Trial</RefTitle> <RefYear>2015</RefYear> <RefJournal>J Clin Microbiol</RefJournal> <RefPage>1286-93</RefPage> <RefTotal>Kehl SC, Dowzicky MJ. Global assessment of antimicrobial susceptibility among Gram-negative organisms collected from pediatric patients between 2004 and 2012: results from the Tigecycline Evaluation and Surveillance Trial. J Clin Microbiol. 2015 Apr;53(4):1286-93. DOI: 10.1128/JCM.03184-14</RefTotal> <RefLink>http://dx.doi.org/10.1128/JCM.03184-14</RefLink> </Reference> <Reference refNo="24"> <RefAuthor>Seifert H</RefAuthor> <RefAuthor>Dowzicky MJ</RefAuthor> <RefTitle>A longitudinal analysis of antimicrobial susceptibility in clinical institutions in Germany as part of the Tigecycline Evaluation and Surveillance Trial (2004-2007)</RefTitle> <RefYear>2009</RefYear> <RefJournal>Chemotherapy</RefJournal> <RefPage>241-52</RefPage> <RefTotal>Seifert H, Dowzicky MJ. A longitudinal analysis of antimicrobial susceptibility in clinical institutions in Germany as part of the Tigecycline Evaluation and Surveillance Trial (2004-2007). Chemotherapy. 2009;55(4):241-52. DOI: 10.1159/000220245</RefTotal> <RefLink>http://dx.doi.org/10.1159/000220245</RefLink> </Reference> <Reference refNo="23"> <RefAuthor>Anonym</RefAuthor> <RefTitle></RefTitle> <RefYear></RefYear> <RefBookTitle>T.E.S.T. (Tigecycline Evaluation and Surveillance Trial)</RefBookTitle> <RefPage></RefPage> <RefTotal>T.E.S.T. (Tigecycline Evaluation and Surveillance Trial). Available from: http://www.testsurveillance.com/</RefTotal> <RefLink>http://www.testsurveillance.com/</RefLink> </Reference> <Reference refNo="25"> <RefAuthor>Peter S</RefAuthor> <RefAuthor>Wolz C</RefAuthor> <RefAuthor>Kaase M</RefAuthor> <RefAuthor>Marschal M</RefAuthor> <RefAuthor>Schulte B</RefAuthor> <RefAuthor>Vogel W</RefAuthor> <RefAuthor>Autenrieth I</RefAuthor> <RefAuthor>Willmann M</RefAuthor> <RefTitle>Emergence of Citrobacter freundii carrying IMP-8 metallo-beta-lactamase in Germany</RefTitle> <RefYear>2014</RefYear> <RefJournal>New Microbes New Infect</RefJournal> <RefPage>42-5</RefPage> <RefTotal>Peter S, Wolz C, Kaase M, Marschal M, Schulte B, Vogel W, Autenrieth I, Willmann M. Emergence of Citrobacter freundii carrying IMP-8 metallo-beta-lactamase in Germany. New Microbes New Infect. 2014 Mar;2(2):42-5. DOI: 10.1002/nmi2.36</RefTotal> <RefLink>http://dx.doi.org/10.1002/nmi2.36</RefLink> </Reference> <Reference refNo="26"> <RefAuthor>Clinical and Laboratory Standards Institute (CLSI)</RefAuthor> <RefTitle></RefTitle> <RefYear>2013</RefYear> <RefBookTitle>Performance standards for antimicrobial susceptibility testing: 23rd informational supplement. Document M100-S23</RefBookTitle> <RefPage></RefPage> <RefTotal>Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial susceptibility testing: 23rd informational supplement. Document M100-S23. Wayne, PA: CLSI; 2013.</RefTotal> </Reference> <Reference refNo="27"> <RefAuthor>European Committee on Antimicrobial Susceptibility Testing (EUCAST)</RefAuthor> <RefTitle></RefTitle> <RefYear>2015</RefYear> <RefBookTitle>Breakpoint tables for interpretation of MICs and zone diameters. Version 5.0</RefBookTitle> <RefPage></RefPage> <RefTotal>European Committee on Antimicrobial Susceptibility Testing (EUCAST). Breakpoint tables for interpretation of MICs and zone diameters. Version 5.0. 2015. Available from: http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_5.0_Breakpoint_Table_01.pdf</RefTotal> <RefLink>http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_5.0_Breakpoint_Table_01.pdf</RefLink> </Reference> <Reference refNo="28"> <RefAuthor>Jones RN</RefAuthor> <RefAuthor>Ferraro MJ</RefAuthor> <RefAuthor>Reller LB</RefAuthor> <RefAuthor>Schreckenberger PC</RefAuthor> <RefAuthor>Swenson JM</RefAuthor> <RefAuthor>Sader HS</RefAuthor> <RefTitle>Multicenter studies of tigecycline disk diffusion susceptibility results for Acinetobacter spp</RefTitle> <RefYear>2007</RefYear> <RefJournal>J Clin Microbiol</RefJournal> <RefPage>227-30</RefPage> <RefTotal>Jones RN, Ferraro MJ, Reller LB, Schreckenberger PC, Swenson JM, Sader HS. Multicenter studies of tigecycline disk diffusion susceptibility results for Acinetobacter spp. J Clin Microbiol. 2007 Jan;45(1):227-30. DOI: 10.1128/JCM.01588-06</RefTotal> <RefLink>http://dx.doi.org/10.1128/JCM.01588-06</RefLink> </Reference> <Reference refNo="29"> <RefAuthor>Schröppel K</RefAuthor> <RefAuthor>Riessen R</RefAuthor> <RefTitle>Multiresistente gramnegative Bakterien. Problemkeime des 21. Jahrhunderts</RefTitle> <RefYear>2013</RefYear> <RefJournal>Med Klin Intensivmed Notfmed</RefJournal> <RefPage>107-12</RefPage> <RefTotal>Schröppel K, Riessen R. Multiresistente gramnegative Bakterien. Problemkeime des 21. Jahrhunderts [Multiresistant gram-negative bacteria. A bacterial challenge of the twenty-first century]. Med Klin Intensivmed Notfmed. 2013 Mar;108(2):107-12. DOI: 10.1007/s00063-012-0160-8</RefTotal> <RefLink>http://dx.doi.org/10.1007/s00063-012-0160-8</RefLink> </Reference> <Reference refNo="30"> <RefAuthor>Meyer E</RefAuthor> <RefAuthor>Schröder C</RefAuthor> <RefAuthor>Gastmeier P</RefAuthor> <RefAuthor>Geffers C</RefAuthor> <RefTitle>The reduction of nosocomial MRSA infection in Germany: an analysis of data from the Hospital Infection Surveillance System (KISS) between 2007 and 2012</RefTitle> <RefYear>2014</RefYear> <RefJournal>Dtsch Arztebl Int</RefJournal> <RefPage>331-6</RefPage> <RefTotal>Meyer E, Schröder C, Gastmeier P, Geffers C. The reduction of nosocomial MRSA infection in Germany: an analysis of data from the Hospital Infection Surveillance System (KISS) between 2007 and 2012. Dtsch Arztebl Int. 2014 May;111(19):331-6. DOI: 10.3238/arztebl.2014.0331</RefTotal> <RefLink>http://dx.doi.org/10.3238/arztebl.2014.0331</RefLink> </Reference> <Reference refNo="31"> <RefAuthor>Kresken M</RefAuthor> <RefAuthor>Hafner D</RefAuthor> <RefAuthor>Körber-Irrgang B</RefAuthor> <RefAuthor> Studiengruppe</RefAuthor> <RefTitle></RefTitle> <RefYear>2016</RefYear> <RefBookTitle>Epidemiologie und Resistenzsituation bei klinisch wichtigen Infektionserregern aus dem Hospitalbereich gegenüber Antibiotika. Bericht über die Ergebnisse einer multizentrischen Studie der Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. aus dem Jahre 2013</RefBookTitle> <RefPage></RefPage> <RefTotal>Kresken M, Hafner D, Körber-Irrgang B; Studiengruppe. Epidemiologie und Resistenzsituation bei klinisch wichtigen Infektionserregern aus dem Hospitalbereich gegenüber Antibiotika. Bericht über die Ergebnisse einer multizentrischen Studie der Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. aus dem Jahre 2013. Rheinbach: PEG; 2016. Available from: http://media.econtext.de/v1/stream/16-421/638c0ce046b3397ec39a5ee76fc9d0c7/1469637032/16/421.econtext</RefTotal> <RefLink>http://media.econtext.de/v1/stream/16-421/638c0ce046b3397ec39a5ee76fc9d0c7/1469637032/16/421.econtext</RefLink> </Reference> <Reference refNo="32"> <RefAuthor>Robert Koch-Institute</RefAuthor> <RefTitle></RefTitle> <RefYear></RefYear> <RefBookTitle>ARS - Antibiotika-Resistenz-Surveillance. [Database as of 1st July 2015]</RefBookTitle> <RefPage></RefPage> <RefTotal>Robert Koch-Institute. ARS – Antibiotika-Resistenz-Surveillance. [Database as of 1st July 2015]. Available from: https://ars.rki.de</RefTotal> <RefLink>https://ars.rki.de</RefLink> </Reference> <Reference refNo="33"> <RefAuthor>Gastmeier P</RefAuthor> <RefAuthor>Schröder C</RefAuthor> <RefAuthor>Behnke M</RefAuthor> <RefAuthor>Meyer E</RefAuthor> <RefAuthor>Geffers C</RefAuthor> <RefTitle>Dramatic increase in vancomycin-resistant enterococci in Germany</RefTitle> <RefYear>2014</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>1660-4</RefPage> <RefTotal>Gastmeier P, Schröder C, Behnke M, Meyer E, Geffers C. Dramatic increase in vancomycin-resistant enterococci in Germany. J Antimicrob Chemother. 2014 Jun;69(6):1660-4. DOI: 10.1093/jac/dku035</RefTotal> <RefLink>http://dx.doi.org/10.1093/jac/dku035</RefLink> </Reference> <Reference refNo="34"> <RefAuthor>Gheorghiu R</RefAuthor> <RefAuthor>Yuan M</RefAuthor> <RefAuthor>Hall LM</RefAuthor> <RefAuthor>Livermore DM</RefAuthor> <RefTitle>Bases of variation in resistance to beta-lactams in Klebsiella oxytoca isolates hyperproducing K1 beta-lactamase</RefTitle> <RefYear>1997</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>533-41</RefPage> <RefTotal>Gheorghiu R, Yuan M, Hall LM, Livermore DM. Bases of variation in resistance to beta-lactams in Klebsiella oxytoca isolates hyperproducing K1 beta-lactamase. J Antimicrob Chemother. 1997 Oct;40(4):533-41. DOI: 10.1093/jac/40.4.533</RefTotal> <RefLink>http://dx.doi.org/10.1093/jac/40.4.533</RefLink> </Reference> <Reference refNo="35"> <RefAuthor>Schleicher X</RefAuthor> <RefAuthor>Higgins PG</RefAuthor> <RefAuthor>Wisplinghoff H</RefAuthor> <RefAuthor>Körber-Irrgang B</RefAuthor> <RefAuthor>Kresken M</RefAuthor> <RefAuthor>Seifert H</RefAuthor> <RefTitle>Molecular epidemiology of Acinetobacter baumannii and Acinetobacter nosocomialis in Germany over a 5-year period (2005-2009)</RefTitle> <RefYear>2013</RefYear> <RefJournal>Clin Microbiol Infect</RefJournal> <RefPage>737-42</RefPage> <RefTotal>Schleicher X, Higgins PG, Wisplinghoff H, Körber-Irrgang B, Kresken M, Seifert H. Molecular epidemiology of Acinetobacter baumannii and Acinetobacter nosocomialis in Germany over a 5-year period (2005-2009). Clin Microbiol Infect. 2013 Aug;19(8):737-42. DOI: 10.1111/1469-0691.12026</RefTotal> <RefLink>http://dx.doi.org/10.1111/1469-0691.12026</RefLink> </Reference> <Reference refNo="36"> <RefAuthor>Bodmann KF</RefAuthor> <RefAuthor>Heizmann WR</RefAuthor> <RefAuthor>von Eiff C</RefAuthor> <RefAuthor>Petrik C</RefAuthor> <RefAuthor>Löschmann PA</RefAuthor> <RefAuthor>Eckmann C</RefAuthor> <RefTitle>Therapy of 1,025 severely ill patients with complicated infections in a German multicenter study: safety profile and efficacy of tigecycline in different treatment modalities</RefTitle> <RefYear>2012</RefYear> <RefJournal>Chemotherapy</RefJournal> <RefPage>282-94</RefPage> <RefTotal>Bodmann KF, Heizmann WR, von Eiff C, Petrik C, Löschmann PA, Eckmann C. Therapy of 1,025 severely ill patients with complicated infections in a German multicenter study: safety profile and efficacy of tigecycline in different treatment modalities. Chemotherapy. 2012;58(4):282-94. DOI: 10.1159/000342451</RefTotal> <RefLink>http://dx.doi.org/10.1159/000342451</RefLink> </Reference> <Reference refNo="37"> <RefAuthor>Heizmann WR</RefAuthor> <RefAuthor>Löschmann PA</RefAuthor> <RefAuthor>Eckmann C</RefAuthor> <RefAuthor>von Eiff C</RefAuthor> <RefAuthor>Bodmann KF</RefAuthor> <RefAuthor>Petrik C</RefAuthor> <RefTitle>Clinical efficacy of tigecycline used as monotherapy or in combination regimens for complicated infections with documented involvement of multiresistant bacteria</RefTitle> <RefYear>2015</RefYear> <RefJournal>Infection</RefJournal> <RefPage>37-43</RefPage> <RefTotal>Heizmann WR, Löschmann PA, Eckmann C, von Eiff C, Bodmann KF, Petrik C. Clinical efficacy of tigecycline used as monotherapy or in combination regimens for complicated infections with documented involvement of multiresistant bacteria. Infection. 2015 Feb;43(1):37-43. DOI: 10.1007/s15010-014-0691-4</RefTotal> <RefLink>http://dx.doi.org/10.1007/s15010-014-0691-4</RefLink> </Reference> <Reference refNo="38"> <RefAuthor>Eckmann C</RefAuthor> <RefAuthor>Montravers P</RefAuthor> <RefAuthor>Bassetti M</RefAuthor> <RefAuthor>Bodmann KF</RefAuthor> <RefAuthor>Heizmann WR</RefAuthor> <RefAuthor>Sánchez García M</RefAuthor> <RefAuthor>Guirao X</RefAuthor> <RefAuthor>Capparella MR</RefAuthor> <RefAuthor>Simoneau D</RefAuthor> <RefAuthor>Dupont H</RefAuthor> <RefTitle>Efficacy of tigecycline for the treatment of complicated intra-abdominal infections in real-life clinical practice from five European observational studies</RefTitle> <RefYear>2013</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>ii25-35</RefPage> <RefTotal>Eckmann C, Montravers P, Bassetti M, Bodmann KF, Heizmann WR, Sánchez García M, Guirao X, Capparella MR, Simoneau D, Dupont H. Efficacy of tigecycline for the treatment of complicated intra-abdominal infections in real-life clinical practice from five European observational studies. J Antimicrob Chemother. 2013 Jul;68 Suppl 2:ii25-35. DOI: 10.1093/jac/dkt142</RefTotal> <RefLink>http://dx.doi.org/10.1093/jac/dkt142</RefLink> </Reference> <Reference refNo="39"> <RefAuthor>Rodloff AC</RefAuthor> <RefAuthor>Dowzicky MJ</RefAuthor> <RefTitle>Antimicrobial Susceptibility among European Gram-Negative and Gram-Positive Isolates Collected as Part of the Tigecycline Evaluation and Surveillance Trial (2004-2014)</RefTitle> <RefYear>2016</RefYear> <RefJournal>Chemotherapy</RefJournal> <RefPage>1-11</RefPage> <RefTotal>Rodloff AC, Dowzicky MJ. Antimicrobial Susceptibility among European Gram-Negative and Gram-Positive Isolates Collected as Part of the Tigecycline Evaluation and Surveillance Trial (2004-2014). Chemotherapy. 2016 May 24;62(1):1-11. DOI: 10.1159/000445022</RefTotal> <RefLink>http://dx.doi.org/10.1159/000445022</RefLink> </Reference> <Reference refNo="40"> <RefAuthor>Brooke JS</RefAuthor> <RefTitle>Stenotrophomonas maltophilia: an emerging global opportunistic pathogen</RefTitle> <RefYear>2012</RefYear> <RefJournal>Clin Microbiol Rev</RefJournal> <RefPage>2-41</RefPage> <RefTotal>Brooke JS. Stenotrophomonas maltophilia: an emerging global opportunistic pathogen. Clin Microbiol Rev. 2012 Jan;25(1):2-41. DOI: 10.1128/CMR.00019-11</RefTotal> <RefLink>http://dx.doi.org/10.1128/CMR.00019-11</RefLink> </Reference> <Reference refNo="41"> <RefAuthor>De Pascale G</RefAuthor> <RefAuthor>Montini L</RefAuthor> <RefAuthor>Pennisi M</RefAuthor> <RefAuthor>Bernini V</RefAuthor> <RefAuthor>Maviglia R</RefAuthor> <RefAuthor>Bello G</RefAuthor> <RefAuthor>Spanu T</RefAuthor> <RefAuthor>Tumbarello M</RefAuthor> <RefAuthor>Antonelli M</RefAuthor> <RefTitle>High dose tigecycline in critically ill patients with severe infections due to multidrug-resistant bacteria</RefTitle> <RefYear>2014</RefYear> <RefJournal>Crit Care</RefJournal> <RefPage>R90</RefPage> <RefTotal>De Pascale G, Montini L, Pennisi M, Bernini V, Maviglia R, Bello G, Spanu T, Tumbarello M, Antonelli M. High dose tigecycline in critically ill patients with severe infections due to multidrug-resistant bacteria. Crit Care. 2014;18(3):R90. DOI: 10.1186/cc13858</RefTotal> <RefLink>http://dx.doi.org/10.1186/cc13858</RefLink> </Reference> <Reference refNo="42"> <RefAuthor>Ramirez J</RefAuthor> <RefAuthor>Dartois N</RefAuthor> <RefAuthor>Gandjini H</RefAuthor> <RefAuthor>Yan JL</RefAuthor> <RefAuthor>Korth-Bradley J</RefAuthor> <RefAuthor>McGovern PC</RefAuthor> <RefTitle>Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia</RefTitle> <RefYear>2013</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>1756-62</RefPage> <RefTotal>Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, McGovern PC. Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia. Antimicrob Agents Chemother. 2013 Apr;57(4):1756-62. DOI: 10.1128/AAC.01232-12</RefTotal> <RefLink>http://dx.doi.org/10.1128/AAC.01232-12</RefLink> </Reference> </References> <Media> <Tables> <Table format="png"> <MediaNo>1</MediaNo> <MediaID>1</MediaID> <Caption><Pgraph><Mark1>Table 1: MIC</Mark1><Mark1><Subscript>50/90</Subscript></Mark1><Mark1> values (µg/ml) and resistance rates (%) of bacterial isolates by species and year of collection in German TEST centers</Mark1></Pgraph></Caption> </Table> <NoOfTables>1</NoOfTables> </Tables> <Figures> <Figure format="png" height="483" width="785"> <MediaNo>1</MediaNo> <MediaID>1</MediaID> <Caption><Pgraph><Mark1>Figure 1: Percentages (%) of multiresistant isolates per total number of isolates for major pathogen species by year of isolation. Annual rates (table) and 3-years moving averages (diagram) are shown.</Mark1></Pgraph></Caption> </Figure> <NoOfPictures>1</NoOfPictures> </Figures> <InlineFigures> <NoOfPictures>0</NoOfPictures> </InlineFigures> <Attachments> <NoOfAttachments>0</NoOfAttachments> </Attachments> </Media> </OrigData> </GmsArticle>