Purpose
Tigecycline is a glycylcycline antibiotic with a broad spectrum of antimicrobial activity covering bacteria with resistance against multiple antibiotics (MRB) such as vancomycin-resistant enterococci (VRE), methicillin-resistant
Staphylococcus aureus (MRSA), extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL) and strains of the
Acinetobacter baumannii group [
1‐
4].
In the US [
5] and Europe [
6], tigecycline is approved for the treatment of complicated intraabdominal infections (cIAI) and complicated skin and skin tissue infections (cSSTI). In the US, tigecycline is also indicated for community-acquired bacterial pneumonia.
The patient population in the two pivotal phase III studies on tigecycline in cIAI had a relatively low mean initial APACHE II score of 6.3, as patients with APACHE II scores >30 were excluded [
7]. The number of severely ill patients was limited in both phase III cSSTI trials as well [
8]. Thus, published data from prospective (comparative) trials on tigecycline used in higher risk patients with complicated, pre-treated infections and high risk of drug-resistant pathogens are limited.
Most data on tigecycline in severely ill patients are derived from retrospective analyses or studies focused on identified pathogens rather than clinical syndromes. Bassetti et al. [
9] reported on a single-center prospective observational study of tigecycline in severely ill patients with various complicated infections. The authors found high response rates for peritonitis, cSSTI and blood stream infections despite unfavorable patient risk profiles (mean APACHE II score 21; high prevalence of severe comorbidities).
In recent years, Enterobacteriaceae developed a range of antimicrobial resistances that reduce therapeutic choices to a very limited set of active antibiotics. The spread of ESBL-producers and bacterial strains expressing carbapenemases is causing much concern on the future options of effective antibacterial therapy in hospitals [
10]. In addition, in the Gram-positive spectrum of pathogens, MRSA remains a threat in cSSTI [
11], DFI [
12], and hospital-acquired pneumonia (HAP) [
13], while VRE are commonly implicated in severe cIAI and blood stream infections (BSI) [
14]. Because these pathogens are commonly found in infections taking a severe course, tigecycline becomes an increasingly important treatment option for a broad range of severe infections, particularly as empirical therapy in patients at risk for MRB.
Consequently, there is a need for additional clinical data to evaluate the usefulness of tigecycline, thereby providing additional evidence for the rational and safe use of this antibiotic.
This sub-analysis of a prospective, non-interventional study investigated the efficacy and safety of tigecycline used alone or in combination in the real-life hospital setting in Germany. Results obtained in the total patient population have been published before [
15]. Here, we present data on patients suffering from infections with documented involvement of bacteria exhibiting multidrug-resistant phenotypes. We characterized the subpopulation treated with tigecycline for these infections in various indications and determined treatment outcomes associated with tigecycline used alone or in combination with other antimicrobials.
Discussion
The patients analyzed in this subpopulation with MRB infections were treated with tigecycline in routine settings in German hospitals. They suffered from complicated IAI, SSTI, and/or other severe infections involving multiresistant bacteria.
Rates of clinical cure or improvement were high in this subpopulation. A total of 91.6 % of patients with MRB infections were successfully treated, 93.6 % with monotherapy and 88.0 % with tigecycline combinations.
Success rates for monotherapy were consistently higher than 90 % for all multiresistant pathogens and higher than 80 % for all disease types; rates were particularly high in BSI (100 %), CAP (100 %) and cSSTI (95 %).
The success rates tended to be somewhat lower in combination therapies (88.0 vs. 93.6 % with monotherapy), mostly due to the response rates in patients with MSI (71.4 %), or HAP (72.3 %). This divergence may have been caused (1) by a higher likelihood of combination therapies being used in patients with higher disease severity, (2) the choice of the combination drug, (3) random effects due to small patient numbers, and (4) the likelihood of higher morbidity in patients with infection at multiple sites of infection.
Conversely, the treatment success rate of MRB nosocomial pneumonia was 94.7 % in patients receiving tigecycline monotherapy at standard dosage. This is a reassuringly high rate in the light of data obtained in the phase III HAP study of tigecycline versus imipenem that failed to confirm the non-inferiority of tigecycline in the clinically evaluable patient subset. A subsequent phase II study with tigecycline used at higher dosages indicated increased efficacy with a clinical cure rate of 85 % [
16]. There are several, at least, theoretical reasons why non-bactericidal antimicrobial agents such as tigecycline are effective in severe infections [
17].
The limitations of this study include its non-controlled observational design that may be associated with several biases and uncertainties, and the lack of rigorous criteria of diagnosis and assessment of response. Despite these shortcomings, this analysis of a sizeable sample of patients with severe MRB infections provides evidence of the usefulness of tigecycline in this diverse and difficult-to-treat population.
Non-interventional studies provide insights into the real-life utility of antibiotics beyond the preselected cohorts treated in randomized trials. Despite that patients infected with multiresistant bacteria are not excluded from pivotal trials, they usually do not represent a large proportion of the whole patient population. Observational studies are particularly useful for the evaluation of substances that are used in indications and situations outside the scope covered by pivotal trials, e.g., in patients with high-risk profiles, multiple comorbidities, highly resistant pathogens, extensively pre-treated infections [
18].
Acknowledgments
The following investigators documented the patients in this study: P. Abel, Universitätsklinikum Greifswald; W. Albert, Kliniken des Main-Taunus-Kreises Hofheim; F. Bach, Evangelisches Krankenhaus Bielefeld; J. Bamberger, Klinikum Nürnberg-Süd, Nürnberg; A. Biedler, Katholische Kliniken Essen-Nord Essen; U. Bindernagel, Krankenhaus Strausberg; M. Birth, Hanse-Klinikum Stralsund; R. Borgstedt, Evangelisches Krankenhaus-Johannesstift Bielefeld; A. Brackertz, Katholisches Klinikum Mainz; T. Brenig, Neurologisches Rehabilitationszentrum Greifswald; F. Brettner, Krankenhaus Barmherzige Brüder München; H. Burkhard, KMG Klinikum Güstrow; M. De Gols, AK Nord Heidberg Asklepios Klinik Hamburg; T. Derpa, Dominikus-Krankenhaus Düsseldorf; M. Dietlein, Gemeinschaftspraxis Nagel/Dietlein/Hunstiger Augsburg; B. Dummer, Krankenhaus MOL Strausberg; R. Dummler, Krankenhaus Bad Oeynhausen; H. Dürk, Marien-Hospital Hamm; L. Eckholt, Vivantes Klinik am Urban Berlin; E. Egyed, Zentralklinikum Suhl; T. El Ansari, Evangelisches Jung-Stilling-Krankenhaus Siegen; J. Engel, Universitätsklinikum Giessen; D. Engemann, Oberlausitz-Kliniken gGmbH, Krankenhaus Bischofswerda; F. Ettrich, Klinikum Oberlausitzer Bergland Ebersbach; M. Foedisch, Evangelische Kliniken Bonn; D. Foltys, Johannes-Gutenberg-Universität Mainz; H.G. Fritz, Städtisches Krankenhaus Martha-Maria Halle/Saale; H.G. Gnauk, Klinikum Ernst von Bergmann Potsdam; J. Götz, Klinikum Lippe-Detmold; H. Gratzla, St. Elisabeth-Krankenhaus Gütersloh; M. Groppe, Marienhospital Osnabrück; J. Grosse, Evangelisches Krankenhaus Wesel; M. Hasan, Klinik Löwenstein; M. Haut, Ammerland-Klinik GmbH Westerstede; A. Heininger, Universitätsklinikum Tübingen; J. Henschel, Universitätsklinikum Rostock; C. Hering-Schubert, St. Georg Klinikum Eisenach; K.P. Hermes, Klinikum Bremen-Mitte; R. Hetzer, Deutsches Herzzentrum Berlin; L. Heuer, Klinikum Osnabrück; W. Hilpert, Klinikum Ansbach; O. Hinze, Ruppiner Kliniken Neuruppin; M. Hitz, Krankenhaus St. Joseph-Stift Bremen; R. Höhl, Klinikum Nürnberg- Nord Nürnberg; W. Höhn, Krankenhaus Königin Elisabeth Herzberge Berlin; C. Hönemann, St. Marienhospital Vechta; H.B. Hopf, Asklepios Klinik Langen; A. Höpken, Evangelisches Krankenhaus Oberhausen; P. Hügler, Knappschaftskrankenhaus Bottrop; P. Ihle, Südharz-Krankenhaus Nordhausen; A. Jörres, Charité Campus Virchow-Klinikum Berlin; E. Kammer, Klinikum Stuttgart; M.A. Katz, Evangelisches Krankenhaus Herne; M. Keilen, Klinikum Leverkusen; D. Keller, Borromäus-Hospital Leer; H. Kern, DRK Kliniken Berlin; M. Kiehl, Klinikum Frankfurt/Oder; V. Kimmel, Vivantes Klinikum Prenzlauer Berg Berlin; K. Kogelmann, Klinikum Emden; S. Kopp, Vivantes GmbH Klinikum im Friedrichshain Berlin; A. Kraft, Evangelisches Krankenhaus Oldenburg; O. Krull, Johanniter-Krankenhaus Stendal; M. Kuckhoff, Klinikum Barnim Eberswalde; B. Labinski, Städtische Klinken Mönchengladbach; A. Lange, Oberhavel Kliniken Hennigsdorf; M. Langer, Krankenhaus Köthen; G. Lätzsch, Luisenhospital Aachen; M. Lebender, Asklepios Klinik Harburg Hamburg; M. Leschke, Klinikum Esslingen; H. Liedtke, Krankenhaus St. Elisabeth & St. Barbara Halle; P. Mailänder, Universitätsklinikum Schleswig–Holstein Lübeck; I. Maiwald, Kreiskrankenhaus Waldbröl; S. Manz, Klinikum Sindelfingen; A. Matuschek, A. Meiser, St. Josef-Hospital Bochum; J. Müller, Marienhospital Stuttgart; T. Müller, Bonhoeffer-Klinikum Neubrandenburg; E. Münch, Fakultät Mannheim, Universität Heidelberg Mannheim; T. Nordmeyer, Sana Kliniken Ostholstein Eutin; M. Paland, Diakoniekrankenhaus Rotenburg; D. Pappert, Ernst von-Bergmann Klinikum Potsdam; D. Paravicini, Städtisches Klinikum Gütersloh; A. Patzelt, Marienhospital Dortmund; L. Pfeiffer, Hufeland Klinikum GmbH Mühlhausen; T. Rabas, KMG Klinikum Wittstock; A. Raible, Universitätsklinik Tübingen; H. Rath, Krankenhaus Werden Essen; G. Rehatschek Kreiskrankenhaus Mechernich; H. Rensing, Universitätsklinikum des Saarlandes Homburg/Saar; M. Reumkens, Katholisches Krankenhaus Süd Essen; V. Rickerts, Klinikum der Johann-Wolfgang-Goethe- Universität Frankfurt/Main; R. Riessen, Medizinische Klinik Tübingen; A. Röhrs, Evangelisches Waldkrankenhaus Spandau Berlin; W. Roth, Universitätsklinikum Mainz; F. Rothfritz-Deutsch, Caritas-Krankenhaus St. Josef Regensburg; K. Röttger, DRK Klinken Westend Berlin; R. Schäfer, Universitätsklinikum Münster; S. Schamrow, Elisabeth-Krankenhaus Essen; U. Schenk, Evangelisches Krankenhaus Unna; A. Scherber, Krankenhaus Püttlingen; S. Schering, Klinikum Fichtelgebirge Marktredwitz; T. Scherke, KMG Klinikum Kyritz; P. Schleufe, Klinikum Region Hannover; A. Schramm, Klinikum Darmstadt; A. Schröder, Medizinische Klinik I Lemgo; J. Schröder, Klinikum Reinkenheide Bremerhaven; H. Schulze-Steinen, Universitätsklinikum Aachen; T. Schumacher, Klinikum Kemperhof Koblenz; K. Schwabe, Gesundheitszentrum Bitterfeld/Wolfen; G. Seifert, Klinikum Kaufbeuren-Ostallgäu Kaufbeuren; J. Soukup, Martin-Luther-Universität Halle-Wittenberg; G. Spalding, Herzzentrum Brandenburg Bernau; T. Standl, Städtisches Klinikum Solingen; W. Steurer, Westpfalz-Klinikum Kaiserslautern; S. Suttner, Gesellschaft für Klinische Forschung Ludwigshafen; W. Szafarczyk-Kuhl, St. Hedwig Kliniken Berlin; H. Tiedau, Klinikum Bremen-Nord Bremen; K. Tischbirek, Asklepiosklinik Paulinenkrankenhaus Wiesbaden; C. Träder, Vivantes Auguste-Viktoria-Klinkum Berlin; T. Treu, Müritz-Klinikum Waren; S. Turinsky, Elisabeth-Krankenhaus Essen; T. Uhlig, Klinikum Lüdenscheid; S. Utzolino, Universitätsklinikum Freiburg; D. Volkert, Waldkrankenhaus Rudolf Elle Eisenberg; M. von der Brelie, Universitätsklinikum Schleswig–Holstein Campus Kiel; H. Weigt, Klinikum am Plattenwald Bad Friedrichshall; D. Weiland, Werner-Forssmann-Krankenhaus Eberswalde; G. Weiss, Städtisches Klinikum Magdeburg; K. Wendt, Evangelisch-Freikirchliches Krankenhaus Rüdersdorf; U. Werfel, Klinikum Mitte Essen; S. Wittmann, Klinikum der Universität Regensburg; F. Wolffgramm, Klinikum Mitte Bremen; F. Ziegler, Caritasklinik St. Theresia Saarbrücken; C. Zimmer, Marienhospital Bottrop; H. Zühlke, Evangelisches Krankenhaus Paul-Gerhardt-Stift Wittenberg; M. Zunner, Klinikum Neumarkt, G. Zuz, St. Elisabeth-Krankenhaus Leipzig.